David Stevenson

All Publications

• RASopathies influences on neuroanatomical variation in children. Biological psychiatry. Cognitive neuroscience and neuroimaging McGhee, C. A., Honari, H., Siqueiros-Sanchez, M., Serur, Y., van Staalduinen, E. K., Stevenson, D., Bruno, J. L., Raman, M. M., Green, T. 2024

  Abstract

  RASopathies are a group of disorders characterized by pathogenic mutations in the Ras-mitogen-activated protein kinase (Ras/MAPK) signaling pathway. Distinct pathogenic variants in genes encoding proteins in the Ras/MAPK pathway cause Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), which are associated with increased risk for autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD).This study examines the effect RASopathies (NS and NF1) has on human neuroanatomy, specifically on surface area (SA), cortical thickness (CT), and subcortical volumes. We compared structural T1-weighted images, using vertex-based analysis for cortical measures and Desikan ROI parcellation for subcortical volumes on children with RASopathies (n=91, mean age = 8.81, SD = 2.12) to sex- and age-matched TD (n=74, mean age=9.07, SD = 1.77).Compared to TD, RASopathies had convergent effects on SA and CT, exhibiting increased SA in the precentral gyrus, decreased SA in occipital regions, and thinner CT in the precentral gyrus. RASopathies exhibit divergent effects on subcortical volumes, with syndrome-specific influences from NS and NF1. Overall children with NS display decreased volumes in striatal and thalamic structures and children with NF1 display increased volumes in the hippocampus, amygdala, and thalamus.Our study reveals the converging and diverging neuroanatomical effects of RASopathies on human neurodevelopment. The convergence of cortical effects on SA and CT indicates a shared influence of Ras/MAPK hyperactivation on the human brain. Therefore, considering these measures as objective outcome indicators for targeted treatments is imperative.

  View details for DOI 10.1016/j.bpsc.2024.04.003

  View details for PubMedID 38621478

• Immunological and hematological findings as major features in a patient with a new germline pathogenic CBL variant. American journal of medical genetics. Part A Stellacci, E., Carter, J. N., Pannone, L., Stevenson, D., Moslehi, D., Venanzi, S., Bernstein, J. A., Tartaglia, M., Martinelli, S. 2024: e63627

  Abstract

  Casitas B-lineage lymphoma (CBL) encodes an adaptor protein with E3-ligase activity negatively controlling intracellular signaling downstream of receptor tyrosine kinases. Somatic CBL mutations play a driver role in a variety of cancers, particularly myeloid malignancies, whereas germline defects in the same gene underlie a RASopathy having clinical overlap with Noonan syndrome (NS) and predisposing to juvenile myelomonocytic leukemia and vasculitis. Other features of the disorder include cardiac defects, postnatal growth delay, cryptorchidism, facial dysmorphisms, and predisposition to develop autoimmune disorders. Here we report a novel CBL variant (c.1202G>T; p.Cys401Phe) occurring de novo in a subject with café-au-lait macules, feeding difficulties, mild dysmorphic features, psychomotor delay, autism spectrum disorder, thrombocytopenia, hepatosplenomegaly, and recurrent hypertransaminasemia. The identified variant affects an evolutionarily conserved residue located in the RING finger domain, a known mutational hot spot of both germline and somatic mutations. Functional studies documented enhanced EGF-induced ERK phosphorylation in transiently transfected COS1 cells. The present findings further support the association of pathogenic CBL variants with immunological and hematological manifestations in the context of a presentation with only minor findings reminiscent of NS or a clinically related RASopathy.

  View details for DOI 10.1002/ajmg.a.63627

  View details for PubMedID 38613168

• Osteogenesis imperfecta type XVII: expansion of the phenotype EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS Dunleavy, B. M., Schildt, A. J., Harrington, C., Stevenson, D. A. 2024; 25 (1)

  View details for DOI 10.1186/s43042-024-00475-9

  View details for Web of Science ID 001147766500002

• Time to diagnosis in rapid exome/genome sequencing in the clinical inpatient setting. American journal of medical genetics. Part A Schildt, A., Stevenson, D. A., Yu, L., Anguiano, B., Suarez, C. J. 2023

  Abstract

  Exome and genome sequencing are clinically available, with many laboratories offering expedited testing (e.g., "rapid" and "ultra-rapid"). With the increase in uptake of expedited testing, there is a need for the development of inpatient protocols for best practices based on real-life data. A retrospective 2-year review (October 2019-November 2021) of the utilization of rapid exome and genome sequencing for inpatient cases at a tertiary care center using a utilization management tracking database with subsequent chart review was performed. Thirty-three expedited "rapid/priority" exome/genome tests were performed clinically. The average total turnaround time (TAT) was 17.88 days (5-43 days) with an average TAT of 13.97 days (3-41 days) for the performing laboratory. There were 5 positive diagnostic results (15.2%), 3 likely positive diagnostic results (9%), 2 noncontributory results (6%), and 26 nondiagnostic results (69.7%). Real-life data suggest that there is an approximately 3.91-day lag in getting samples to the performing laboratory. Although laboratories may advertise their expected TAT, a number of factors can potentially impact the actual time from test order placement to communication of the results for clinical use. Understanding the points of delay will enable the development of internal protocols and policies to improve time to diagnosis.

  View details for DOI 10.1002/ajmg.a.63483

  View details for PubMedID 38017634

• Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study. Obesity (Silver Spring, Md.) Miller, J. L., Gevers, E., Bridges, N., Yanovski, J. A., Salehi, P., Obrynba, K. S., Felner, E. I., Bird, L. M., Shoemaker, A. H., Angulo, M., Butler, M. G., Stevenson, D., Goldstone, A. P., Wilding, J., Lah, M., Shaikh, M. G., Littlejohn, E., Abuzzahab, M. J., Fleischman, A., Hirano, P., Yen, K., Cowen, N. M., Bhatnagar, A., C601/C602 Investigators 2023

  Abstract

  OBJECTIVE: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS).METHODS: The authors studied 125 participants with PWS, age≥4years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety.RESULTS: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p<0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT>22). Improvements were seen in aggression, anxiety, and compulsivity (all p<0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p<0.004). Lean body mass was increased (p<0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p<0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%).CONCLUSIONS: DCCR administration to people with PWS was well-tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.

  View details for DOI 10.1002/oby.23928

  View details for PubMedID 37919617

• Two epilepsy-associated variants in KCNA2 (KV1.2) at position H310 oppositely affect channel functional expression. The Journal of physiology Minguez-Vinas, T., Prakash, V., Wang, K., Lindstrom, S. H., Pozzi, S., Scott, S. A., Spiteri, E., Stevenson, D. A., Ashley, E. A., Gunnarsson, C., Pantazis, A. 2023

  Abstract

  Two KCNA2 variants (p.H310Y and p.H310R) were discovered in paediatric patients with epilepsy and developmental delay. KCNA2 encodes KV 1.2-channel subunits, which regulate neuronal excitability. Both gain and loss of KV 1.2 function cause epilepsy, precluding the prediction of variant effects; and while H310 is conserved throughout the KV -channel superfamily, it is largely understudied. We investigated both variants in heterologously expressed, human KV 1.2 channels by immunocytochemistry, electrophysiology and voltage-clamp fluorometry. Despite affecting the same channel, at the same position, and being associated with severe neurological disease, the two variants had diametrically opposite effects on KV 1.2 functional expression. The p.H310Y variant produced 'dual gain of function', increasing both cell-surface trafficking and activity, delaying channel closure. We found that the latter is due to the formation of a hydrogen bond that stabilizes the active state of the voltage-sensor domain. Additionally, H310Y abolished 'ball and chain' inactivation of KV 1.2 by KV beta1 subunits, enhancing gain of function. In contrast, p.H310R caused 'dual loss of function', diminishing surface levels by multiple impediments to trafficking and inhibiting voltage-dependent channel opening. We discuss the implications for KV -channel biogenesis and function, an emergent hotspot for disease-associated variants, and mechanisms of epileptogenesis. KEY POINTS: KCNA2 encodes the subunits of KV 1.2 voltage-activated, K+ -selective ion channels, which regulate electrical signalling in neurons. We characterize two KCNA2 variants from patients with developmental delay and epilepsy. Both variants affect position H310, highly conserved in KV channels. The p.H310Y variant caused 'dual gain of function', increasing both KV 1.2-channel activity and the number of KV 1.2 subunits on the cell surface. H310Y abolished 'ball and chain' (N-type) inactivation of KV 1.2 by KV beta1 subunits, enhancing the gain-of-function phenotype. The p.H310R variant caused 'dual loss of function', diminishing the presence of KV 1.2 subunits on the cell surface and inhibiting voltage-dependent channel opening. As H310Y stabilizes the voltage-sensor active conformation and abolishes N-type inactivation, it can serve as an investigative tool for functional and pharmacological studies.

  View details for DOI 10.1113/JP285052

  View details for PubMedID 37883018

• A core outcome domain set to assess cutaneous neurofibromas related to neurofibromatosis type 1 in clinical trials. The British journal of dermatology Fertitta, L., Bergqvist, C., Sarin, K., Plotkin, S. R., Moertel, C., Petersen, A. J., Cannon, A., Berman, Y., Pichard, D. C., Röhl, C., Lessing, A., Brizion, B., Peiffer, B., Ravaud, P., Tran, V. T., Armand, M. L., Moryousef, S., Ferkal, S., Jannic, A., Ezzedine, K., Wolkenstein, P. 2023

  Abstract

  Cutaneous neurofibromas (cNF) are considered one of the highest burdens of neurofibromatosis type 1 (NF1). To date, no medical treatment can cure cNF or prevent their development. In that context, there is an urgent need to prepare and standardize the methodology of future trials targeting cNF.The objective was to develop a core outcome domain set suitable for all clinical trials targeting NF1-associated cNF.The validated approach of this work consisted of a three-phase methodology: i) generating the domains (systematic review of literature (SRL) and qualitative studies), ii) agreeing (three-round international e-Delphi consensus process, working groups), and iii) voting.i) The SLR and the qualitative studies (three types of focus groups and a French e-survey with 234 participants) resulted in a preliminary list of 31 candidate items and their corresponding definitions. ii) A total of 229 individuals from 29 countries participated in the first round of the e-Delphi: 71 patients, relatives or representatives (31.0%), 130 health-care professionals (HCP, 56.8%) and 28 researchers, representatives of a drug regulatory authority, industry or pharmaceutical company representatives or journal editors (12.2%). The overall participation rate was 74%. Between rounds 2 and 3, international workshops were held to better understand the disagreement amongst stakeholders. This phase led to the identification of 19 items as outcome sub-domains. iii) The items were fused to create 4 outcome domains ("clinical assessment", "daily life impact", "patient satisfaction" and "perception of health") and prioritized. The 7 items which did not reach consensus were decided to be marked for the research agenda. The final core outcome domain set reached 100% of the votes of the steering committee members.Although numerous outcomes can be explored in studies related to cNF in NF1, the present study offers 4 outcome domains that should be reported in all trial studies, agreed upon by international patients, relatives and representatives of patients, HCP, researchers, representatives of drug regulatory authorities or pharmaceutical companies, and journal editors. The next step will include the development of a set of core outcome measurement instruments to further standardize how these outcomes should be assessed.

  View details for DOI 10.1093/bjd/ljad397

  View details for PubMedID 37877514

• Potential endpoints for assessment of bone health in persons with neurofibromatosis type 1. Clinical trials (London, England) Gross, A. M., Plotkin, S. R., Watts, N. B., Fisher, M. J., Klesse, L. J., Lessing, A. J., McManus, M. L., Larson, A. N., Oberlander, B., Rios, J. J., Sarnoff, H., Simpson, B. N., Ullrich, N. J., Stevenson, D. A. 2023: 17407745231201338

  Abstract

  Neurofibromatosis type 1 is a genetic syndrome characterized by a wide variety of tumor and non-tumor manifestations. Bone-related issues, such as scoliosis, tibial dysplasia, and low bone mineral density, are a significant source of morbidity for this population with limited treatment options. Some of the challenges to developing such treatments include the lack of consensus regarding the optimal methods to assess bone health in neurofibromatosis type 1 and limited data regarding the natural history of these manifestations. In this review, the Functional Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration: (1) presents the available techniques for measuring overall bone health and metabolism in persons with neurofibromatosis type 1, (2) reviews data for use of each of these measures in the neurofibromatosis type 1 population, and (3) describes the strengths and limitations for each method as they might be used in clinical trials targeting neurofibromatosis type 1 bone manifestations. The Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration supports the development of a prospective, longitudinal natural history study focusing on the bone-related manifestations and relevant biomarkers of neurofibromatosis type 1. In addition, we suggest that the neurofibromatosis type 1 research community consider adding the less burdensome measurements of bone health as exploratory endpoints in ongoing or planned clinical trials for other neurofibromatosis type 1 manifestations to expand knowledge in the field.

  View details for DOI 10.1177/17407745231201338

  View details for PubMedID 37772407

• Monozygotic twins discordant for a congenital cranial dysinnervation disorder with features of Moebius syndrome. American journal of medical genetics. Part A Gates, R. W., Webb, B. D., Stevenson, D. A., Jabs, E. W., DeFilippo, C., Ruzhnikov, M. R., Tise, C. G. 2023

  Abstract

  Moebius syndrome is a congenital cranial dysinnervation disorder (CCDD) that presents with nonprogressive cranial nerve (CN) VI and VII palsies resulting in facial weakness and inability to abduct the eye(s). While many CCDDs have an underlying genetic cause, the etiology of Moebius syndrome remains unclear as most cases are sporadic. Here, we describe a pair of monochorionic, diamniotic twin girls; one with normal growth and development, and one with micrognathia, reduced facial expression, and poor feeding. Magnetic resonance imaging of the brain performed on the affected twin at 19 months of age showed severely hypoplastic or absent CN IV bilaterally, left CN VI smaller than right, and bilateral hypoplastic CN VII and IX, consistent with a diagnosis of a CCDD, most similar to that of Moebius syndrome. Genomic sequencing was performed on each twin and data was assessed for discordant variants, as well as variants in novel and CCDD-associated genes. No pathogenic, likely pathogenic, or variants of uncertain significance were identified in genes known to be associated with CCDDs or other congenital facial weakness conditions. This family provides further evidence in favor of a stochastic event as the etiology in Moebius syndrome, rather than a monogenic condition.

  View details for DOI 10.1002/ajmg.a.63389

  View details for PubMedID 37675855

• Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families. American journal of medical genetics. Part A Wojcik, M. H., Srivastava, S., Agrawal, P. B., Balci, T. B., Callewaert, B., Calvo, P. L., Carli, D., Caudle, M., Colaiacovo, S., Cross, L., Demetriou, K., Drazba, K., Dutra-Clarke, M., Edwards, M., Genetti, C. A., Grange, D. K., Hickey, S. E., Isidor, B., Kury, S., Lachman, H. M., Lavillaureix, A., Lyons, M. J., Marcelis, C., Marco, E. J., Martinez-Agosto, J. A., Nowak, C., Pizzol, A., Planes, M., Prijoles, E. J., Riberi, E., Rush, E. T., Russell, B. E., Sachdev, R., Schmalz, B., Shears, D., Stevenson, D. A., Wilson, K., Jansen, S., de Vries, B. B., Curry, C. J. 2023

  Abstract

  Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75years (range 8months to 62years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

  View details for DOI 10.1002/ajmg.a.63226

  View details for PubMedID 37183572

• Frequency of Epistaxis and Telangiectasia in patients with Hereditary Hemorrhagic Telangiectasia (HHT) in comparison with the General Population: Curaçao Diagnostic Criteria Revisited. Genetics in medicine : official journal of the American College of Medical Genetics McDonald, J., Kornish, J., Stevenson, D. A., Hanson-Kahn, A., Balch, H., James, J., Naik, H., Whitehead, K. J. 2023: 100865

  Abstract

  The Curaçao criteria are well-established diagnostic criteria for HHT but lack details regarding a predictive presentation of epistaxis and telangiectasias. This study collects and compares data in HHT and population cohorts to inform the application of these criteria.In-person interviews regarding epistaxis and targeted examination for telangiectases in a general population cohort (n=204) and an HHT cohort (n=432).Frequency of epistaxis, rather than intensity or duration, was the best discriminator of HHT. A cut-off of 4 or more nosebleeds per year, alone, yielded a diagnostic sensitivity of 97%, and specificity of 84%. The mean number of telangiectases at the sites investigated was 0.4 in the general population cohort and 26.5 in the HHT cohort. The most distinctive sites for telangiectases in HHT were lips and palmar fingers; whereas telangiectases of the face and dorsum of the hand were comparable in both cohorts.We propose that the Curaçao criteria be modified to include the following cutoffs: 1) epistaxis frequency of 4 or more nosebleeds per year, 2) telangiectasia count of at least 2 in characteristic locations (palmar aspect of fingers, lips and oral cavity); and that cutaneous telangiectases at other sites not be considered relevant for diagnostic purposes.

  View details for DOI 10.1016/j.gim.2023.100865

  View details for PubMedID 37125633

• Papillomas of Costello syndrome are not associated with human papillomavirus (HPV) infection in a small case series. Journal of the American Academy of Dermatology Olsen, G. M., Johnson, L., Castel, P., Stevenson, D. A., White, K., Chiu, Y. E., Krol, A., Siegel, D. H. 2023

  View details for DOI 10.1016/j.jaad.2023.03.043

  View details for PubMedID 37028601

• Single Versus Multigene Testing for Hereditary Hearing Loss: Use and Costs in a Commercially Insured Cohort. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Moon, P. K., Qian, Z. J., Stevenson, D. A., Chang, K. W. 2023

  Abstract

  The objectives of this study were to describe trends in single-gene GJB2/6 (connexin 26/30) and multigene hearing loss panel (HLP) testing for hereditary hearing loss using real-world evidence.Retrospective study using insurance claims data.Optum Data Mart database from 2015 to 2020.Rates of overall and hearing-specific genetic testing and costs to insurers and patients were reported. Linear regression models were used to assess the proportion of single-gene GJB2/6 testing over time. Additional linear regression models were used to assess changes in costs over time.From 2015 to 2020, 91,986 children received genetic testing for any indication, of which 601 (0.65%) received hearing-specific tests. The proportion of single-gene GJB2/6 testing remained similar over time (mean difference [MD]: -1.3% per year; 95% confidence interval [CI]: -4.3%, 1.7%), while multigene HLP use increased over time (MD: 4.0% per year; 95% CI: 0.4%, 7.5%). The median charge for single-gene GJB2/6 testing remained constant during the study period (MD: -$34; 95% CI: -$86, $18), while the median charge for multigene HLP decreased during the study period (MD: -$145 per year; 95% CI: -$278, -$12).Compared to molecular testing for GJB2/6, HLPs are becoming more common for hereditary hearing loss. The comprehensiveness of HLP and decreasing costs provide justification for its more widespread adoption moving forward.

  View details for DOI 10.1002/ohn.204

  View details for PubMedID 36939467

• Single Versus Multigene Testing for Hereditary Hearing Loss: Use and Costs in a Commercially Insured Cohort OTOLARYNGOLOGY-HEAD AND NECK SURGERY Moon, P. K., Qian, Z., Stevenson, D. A., Chang, K. W. 2023

  View details for DOI 10.1002/ohn.204

  View details for Web of Science ID 000919051300001

• Diazoxide Choline Extended-Release Tablet in People with Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial. The Journal of clinical endocrinology and metabolism Miller, J. L., Gevers, E., Bridges, N., Yanovski, J. A., Salehi, P., Obrynba, K. S., Felner, E. I., Bird, L. M., Shoemaker, A. H., Angulo, M., Butler, M. G., Stevenson, D., Abuzzahab, J., Barrett, T., Lah, M., Littlejohn, E., Mathew, V., Cowen, N. M., Bhatnagar, A. 2023

  Abstract

  INTRODUCTION: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled.MATERIALS AND METHODS: In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, Phase 3 trial, 127 participants with PWS age ≥4 years with hyperphagia were randomized 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. The primary endpoint was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other endpoints included Global Impression Scores, and changes in body composition, behaviors, and hormones.RESULTS: DCCR did not significantly improve hyperphagia (HQ-CT Least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145], p=0.198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896], p=0.012). Two of three secondary endpoints were improved (Clinical Global Impression of Improvement [CGI-I], p=0.029; fat mass, p=0.023). In an analysis of results generated Pre-COVID, the primary (HQ-CT, p=0.037) and secondary endpoints were all improved (CGI-I p=0.015, Caregiver Global Impression of Change p=0.031, fat mass p=0.003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment emergent adverse event and 73.8% in the placebo group (NS).DISCUSSION: DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the Pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician reported outcomes.

  View details for DOI 10.1210/clinem/dgad014

  View details for PubMedID 36639249

• Bone health in RASopathies. American journal of medical genetics. Part C, Seminars in medical genetics Stevenson, D. A., Viscogliosi, G., Leoni, C. 2022

  Abstract

  The RASopathies are a group of disorders due to pathogenic variants in genes involved in the Ras/MAPK pathway, many of which have overlapping clinical features (e.g., neurofibromatosis type 1, Costello syndrome, cardiofaciocutaneous syndrome and Noonan syndrome) including musculoskeletal manifestations. Osteopenia and osteoporosis are reported in many of the RASopathies suggesting a shared pathogenesis. Even though osteopenia and osteoporosis are often detected and fractures have been reported, the clinical impact of bone mineralization defects on the skeleton of the various syndromes is poorly understood. Further knowledge of the role of the Ras/MAPK pathway on the bone cellular function, and more detailed musculoskeletal phenotyping will be critical in helping to develop therapies to improve bone health in the RASopathies.

  View details for DOI 10.1002/ajmg.c.32020

  View details for PubMedID 36461161

• Factors associated with the time to complete clinical exome sequencing in a pediatric patient population. Genetics in medicine : official journal of the American College of Medical Genetics Lee, G., Yu, L., Suarez, C. J., Stevenson, D. A., Ling, A., Killer, L. 2022

  Abstract

  Exome sequencing (ES) is becoming increasingly important for diagnosing rare genetic disorders. Patients and clinicians face several barriers when attempting to obtain ES. This study is aimed to describe factors associated with a longer time interval between provider recommendation of testing and sample collection for ES.A retrospective chart review was conducted for insurance-authorized, completed pediatric ES in which initial requests were reviewed by Stanford's Genetic Testing Optimization Service between November 2018 and December 2019. Regression analysis was used to determine the association between the geocoded median household income and 3 different time point intervals defined as time to test, insurance decision, and scheduling/consent.Of the 281 charts reviewed, 115 cases were included in the final cohort. The average time from provider preauthorization request to sample collection took 104.4 days, and income was negatively correlated with the length of the insurance decision interval.Pediatric patients undergo a lengthy, uncertain process when attempting to obtain ES, some of which is associated with income. More research and clinician interventions are required to clarify specific socioeconomic factors that influence the ability to obtain timely ES and develop optimal protocols.

  View details for DOI 10.1016/j.gim.2022.06.006

  View details for PubMedID 35951015

• 50 Years Ago in TheJournalofPediatrics: Advances in the Understanding of Prader-Willi syndrome. The Journal of pediatrics Stafford, D. E., Stevenson, D. A. 2022; 247: 154

  View details for DOI 10.1016/j.jpeds.2022.05.054

  View details for PubMedID 36058596

• Advances in the Understanding of Prader-Willi syndrome JOURNAL OF PEDIATRICS Stafford, D. J., Stevenson, D. A. 2022; 247: 154

  View details for Web of Science ID 000854101300036

• MEK Inhibitors for Neurofibromatosis Type 1 Manifestations: Clinical Evidence and Consensus. Neuro-oncology de Blank, P. M., Gross, A. M., Akshintala, S., Blakeley, J. O., Bollag, G., Cannon, A., Dombi, E., Fangusaro, J., Gelb, B. D., Hargrave, D., Kim, A., Klesse, L. J., Loh, M., Martin, S., Moertel, C., Packer, R., Payne, J. M., Rauen, K. A., Rios, J. J., Robison, N., Schorry, E. K., Shannon, K., Stevenson, D. A., Stieglitz, E., Ullrich, N. J., Walsh, K. S., Weiss, B. D., Wolters, P. L., Yohay, K., Yohe, M. E., Widemann, B. C., Fisher, M. J. 2022

  Abstract

  The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 has made it the first medical therapy approved for this indication in the United States, the European Union and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefit for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.

  View details for DOI 10.1093/neuonc/noac165

  View details for PubMedID 35788692

• Evaluation of the impact of the 2021 revised Neurofibromatosis type 1 diagnostic criteria on time to diagnosis. American journal of medical genetics. Part A Ho, W. Y., Farrelly, E., Stevenson, D. A. 2022

  Abstract

  Neurofibromatosis type 1 (NF1) has historically been diagnosed clinically based on the NIH Consensus Conference diagnostic criteria. The molecular and clinical knowledge of NF1 has subsequently improved, and an international group of experts published revised diagnostic criteria in 2021, incorporating new diagnostic criteria such as pathogenic variants in NF1. This study aimed to investigate the impact of these new diagnostic criteria on time to diagnosis (TTD) of NF1. A retrospective chart review of individuals evaluated for a diagnosis of NF1 at the Medical Genetics Clinic at Stanford Children's Health was performed. The TTD was determined by calculating the days between their first visit with a medical geneticist for NF1 and the date they would have received a diagnosis based on the previous NF1 diagnostic criteria and the 2021 updated diagnostic criteria. The revised diagnostic criteria for NF1 decreased TTD. The mean difference in TTD was 113days shorter for the new criteria (p-value=1.306x-05 ). This study highlights that the revised 2021 NF1 diagnostic criteria can decrease the TTD. The addition of a heterozygous pathogenic variant in NF1 as a criterion was the change that decreased TTD.

  View details for DOI 10.1002/ajmg.a.62890

  View details for PubMedID 35779212

• Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation. Genetics in medicine : official journal of the American College of Medical Genetics Plotkin, S. R., Messiaen, L., Legius, E., Pancza, P., Avery, R. A., Blakeley, J. O., Babovic-Vuksanovic, D., Ferner, R., Fisher, M. J., Friedman, J. M., Giovannini, M., Gutmann, D. H., Hanemann, C. O., Kalamarides, M., Kehrer-Sawatzki, H., Korf, B. R., Mautner, V. F., MacCollin, M., Papi, L., Rauen, K. A., Riccardi, V., Schorry, E., Smith, M. J., Stemmer-Rachamimov, A., Stevenson, D. A., Ullrich, N. J., Viskochil, D., Wimmer, K., Yohay, K., Huson, S. M., Wolkenstein, P., Evans, D. G. 2022

  Abstract

  Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging.We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups.We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1.The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity.

  View details for DOI 10.1016/j.gim.2022.05.007

  View details for PubMedID 35674741

• A survey of program directors for combined pediatrics and medical genetics and genomics residency programs: Perspectives when evaluating applicants. American journal of medical genetics. Part A Niehaus, A. D., Rassbach, C. E., Stevenson, D. A. 2022

  Abstract

  While combined pediatrics and medical genetics and genomics residency programs are growing in number and applicants, there are still workforce shortages within the medical genetics field. Medical students would benefit from additional information on the training pathways and insight into the application process itself. Program Directors of combined pediatrics and medical genetics and genomics residency programs were surveyed to characterize factors that influence interview selection and rank list decisions, application logistics, recruitment, and training pathways. When evaluating applicants, representatives from both pediatrics and medical genetics are involved in the screening process. Additionally, both groups value prior research experience, but do not have a clear preference for a particular subcategory or domain of research. Most program directors think that all currently-available training pathways can provide optimal training. Further action is needed to provide medical students with the knowledge to make more informed decisions about their career and medical school advisors with objective data to counsel students. There was support among program directors to initiate consideration of creating a pathway for medical students to match directly into a medical genetics and genomics residency.

  View details for DOI 10.1002/ajmg.a.62846

  View details for PubMedID 35633299

• The seventh international RASopathies symposium: Pathways to a cure-expanding knowledge, enhancing research, and therapeutic discovery. American journal of medical genetics. Part A Kontaridis, M. I., Roberts, A. E., Schill, L., Schoyer, L., Stronach, B., Andelfinger, G., Aoki, Y., Axelrad, M. E., Bakker, A., Bennett, A. M., Broniscer, A., Castel, P., Chang, C. A., Cyganek, L., Das, T. K., den Hertog, J., Galperin, E., Garg, S., Gelb, B. D., Gordon, K., Green, T., Gripp, K. W., Itkin, M., Kiuru, M., Korf, B. R., Livingstone, J. R., Lopez-Juarez, A., Magoulas, P. L., Mansour, S., Milner, T., Parker, E., Pierpont, E. I., Plouffe, K., Rauen, K. A., Shankar, S. P., Smith, S. B., Stevenson, D. A., Tartaglia, M., Van, R., Wagner, M. E., Ware, S. M., Zenker, M. 2022

  Abstract

  RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.

  View details for DOI 10.1002/ajmg.a.62716

  View details for PubMedID 35266292

• A survey of program directors for combined pediatrics-medical genetics and genomics residency programs: Perspectives when evaluating applicants Niehaus, A., Rassbach, C., Stevenson, D. ELSEVIER SCIENCE INC. 2022: S369-S370

  View details for DOI 10.1016/j.gim.2022.01.591

  View details for Web of Science ID 000796586200334

• Factors associated with the time to complete clinical exome sequencing in a pediatric patient population Lee, G., Yu, L., Suarez, C., Stevenson, D., Ling, A., Derby, L. ELSEVIER SCIENCE INC. 2022: S268-S269

  View details for DOI 10.1016/j.gim.2022.01.463

  View details for Web of Science ID 000796586200202

• Natural history of NF1 c.2970_2972del p.(Met992del): confirmation of a low risk of complications in a longitudinal study. European journal of human genetics : EJHG Forde, C., Burkitt-Wright, E., Turnpenny, P. D., Haan, E., Ealing, J., Mansour, S., Holder, M., Lahiri, N., Dixit, A., Procter, A., Pacot, L., Vidaud, D., Capri, Y., Gerard, M., Dollfus, H., Schaefer, E., Quelin, C., Sigaudy, S., Busa, T., Vera, G., Damaj, L., Messiaen, L., Stevenson, D. A., Davies, P., Palmer-Smith, S., Callaway, A., Wolkenstein, P., Pasmant, E., Upadhyaya, M. 1800

  Abstract

  Individuals with the three base pair deletion NM_000267.3(NF1):c.2970_2972del p.(Met992del) have been recognised to present with a milder neurofibromatosis type 1 (NF1) phenotype characterised by cafe-au-lait macules (CALs) and intertriginous freckling, as well as a lack of cutaneous, subcutaneous and plexiform neurofibromas and other NF1-associated complications. Examining large cohorts of patients over time with this specific genotype is important to confirm the presentation and associated risks of this variant across the lifespan. Forty-one individuals with the in-frame NF1 deletion p.Met992del were identified from 31 families. Clinicians completed a standardised clinical questionnaire for each patient and the resulting data were collated and compared to published cohorts. Thirteen patients have been previously reported, and updated clinical information has been obtained for these individuals. Both CALs and intertriginous freckling were present in the majority of individuals (26/41, 63%) and the only confirmed features in 11 (27%). 34/41 (83%) of the cohort met NIH diagnostic criteria. There was a notable absence of all NF1-associated tumour types (neurofibroma and glioma). Neurofibroma were observed in only one individual-a subcutaneous lesion (confirmed histologically). Nineteen individuals were described as having a learning disability (46%). This study confirms that individuals with p.Met992del display a mild tumoural phenotype compared to those with 'classical', clinically diagnosed NF1, and this appears to be the case longitudinally through time as well as at presentation. Learning difficulties, however, appear to affect a significant proportion of NF1 subjects with this phenotype. Knowledge of this genotype-phenotype association is fundamental to accurate prognostication for families and caregivers.

  View details for DOI 10.1038/s41431-021-01015-4

  View details for PubMedID 34897289

• Response to Hamosh etal. American journal of human genetics Biesecker, L. G., Adam, M. P., Alkuraya, F. S., Amemiya, A. R., Bamshad, M. J., Beck, A. E., Bennett, J. T., Bird, L. M., Carey, J. C., Chung, B., Clark, R. D., Cox, T. C., Curry, C., Dinulos, M. B., Dobyns, W. B., Giampietro, P. F., Girisha, K. M., Glass, I. A., Graham, J. M., Gripp, K. W., Haldeman-Englert, C. R., Hall, B. D., Innes, A. M., Kalish, J. M., Keppler-Noreuil, K. M., Kosaki, K., Kozel, B. A., Mirzaa, G. M., Mulvihill, J. J., Nowaczyk, M. J., Pagon, R. A., Retterer, K., Rope, A. F., Sanchez-Lara, P. A., Seaver, L. H., Shieh, J. T., Slavotinek, A. M., Sobering, A. K., Stevens, C. A., Stevenson, D. A., Tan, T. Y., Tan, W., Tsai, A. C., Weaver, D. D., Williams, M. S., Zackai, E., Zarate, Y. A. 2021; 108 (9): 1809-1810

  View details for DOI 10.1016/j.ajhg.2021.07.006

  View details for PubMedID 34478656

• Arteriovenous Malformations-Current Understanding of the Pathogenesis with Implications for Treatment. International journal of molecular sciences Schimmel, K., Ali, M. K., Tan, S. Y., Teng, J., Do, H. M., Steinberg, G. K., Stevenson, D. A., Spiekerkoetter, E. 2021; 22 (16)

  Abstract

  Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. Therapeutic approaches are limited, and AVMs can cause significant morbidity and mortality. Here, we describe our current understanding of the pathogenesis of arteriovenous malformations based on preclinical and clinical findings. We discuss past and present accomplishments and challenges in the field and identify research gaps that need to be filled for the successful development of therapeutic strategies in the future.

  View details for DOI 10.3390/ijms22169037

  View details for PubMedID 34445743

• REiNS: Reliability of Handheld Dynamometry to Measure Focal Muscle Weakness in Neurofibromatosis Types 1 and 2. Neurology Akshintala, S., Khalil, N., Yohay, K., Muzikansky, A., Allen, J., Yaffe, A., Gross, A. M., Fisher, M. J., Blakeley, J. O., Oberlander, B., Pudel, M., Engelson, C., Obletz, J., Mitchell, C., Widemann, B. C., Stevenson, D. A., Plotkin, S. R. 2021

  Abstract

  OBJECTIVE: To determine a suitable outcome measure for assessing muscle strength in neurofibromatosis type 1 (NF1) and type 2 (NF2) clinical trials, we evaluated the intra-observer reliability of hand-held dynamometry (HHD) and developed consensus recommendations for its use in neurofibromatosis clinical trials.METHODS: Patients ≥5 years with weakness in at least 1 muscle group by manual muscle testing (MMT) were eligible. Maximal isometric muscle strength of a weak muscle group and the biceps of the dominant arm were measured by HHD. An average of 3 repetitions per session was used as an observation, and 3 sessions with rest period between each were performed on the same day by a single observer. Intra- and inter-session intraclass correlation (ICC) and coefficient of variation (CV) were calculated to assess reliability and measurement error.RESULTS: Twenty NF1 and 13 NF2 patients enrolled; median age was 12 years (interquartile range (IQR) 9-17) and 29 years (IQR 22-38) respectively. By MMT, weak muscle strength ranged from 2-/5 to 4+/5. Biceps strength was 5/5 in all patients. Inter-session ICC for the weak muscles were 0.98 and 0.99 in the NF1 and NF2 cohorts respectively and for biceps were 0.97 and 0.97 respectively. The median CV for average session strength were 5.4% (IQR 2.6%-7.3%) and 2.9% (IQR 2.0%-6.2%) for weak muscles and biceps respectively.CONCLUSION: HHD performed by a trained examiner with a well-defined protocol is a reliable technique to measure muscle strength in NF1 and NF2. Recommendations for strength testing in NF1 and NF2 trials are provided.

  View details for DOI 10.1212/WNL.0000000000012439

  View details for PubMedID 34230196

• Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genetics in medicine : official journal of the American College of Medical Genetics Legius, E., Messiaen, L., Wolkenstein, P., Pancza, P., Avery, R. A., Berman, Y., Blakeley, J., Babovic-Vuksanovic, D., Cunha, K. S., Ferner, R., Fisher, M. J., Friedman, J. M., Gutmann, D. H., Kehrer-Sawatzki, H., Korf, B. R., Mautner, V., Peltonen, S., Rauen, K. A., Riccardi, V., Schorry, E., Stemmer-Rachamimov, A., Stevenson, D. A., Tadini, G., Ullrich, N. J., Viskochil, D., Wimmer, K., Yohay, K., International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC), Huson, S. M., Evans, D. G., Plotkin, S. R., Gomes, A., Jordan, J. T., Mautner, V., Merker, V. L., Smith, M. J., Stevenson, D., Anten, M., Aylsworth, A., Baralle, D., Barbarot, S., Barker, F. 2., Ben-Shachar, S., Bergner, A., Bessis, D., Blanco, I., Cassiman, C., Ciavarelli, P., Clementi, M., Frebourg, T., Giovannini, M., Halliday, D., Hammond, C., Hanemann, C. O., Hanson, H., Heiberg, A., Joly, P., Kalamarides, M., Karajannis, M., Kroshinsky, D., Larralde, M., Lazaro, C., Le, L., Link, M., Listernick, R., MacCollin, M., Mallucci, C., Moertel, C., Mueller, A., Ngeow, J., Oostenbrink, R., Packer, R., Papi, L., Parry, A., Peltonen, J., Pichard, D., Poppe, B., Rezende, N., Rodrigues, L. O., Rosser, T., Ruggieri, M., Serra, E., Steinke-Lange, V., Stivaros, S. M., Taylor, A., Toelen, J., Tonsgard, J., Trevisson, E., Upadhyaya, M., Varan, A., Wilson, M., Wu, H., Zadeh, G. 2021

  Abstract

  PURPOSE: By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS).METHODS: We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups.RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended.CONCLUSION: The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

  View details for DOI 10.1038/s41436-021-01170-5

  View details for PubMedID 34012067

• Typical 22q11.2 deletion syndrome appears to confer a reduced risk of schwannoma. Genetics in medicine : official journal of the American College of Medical Genetics Evans, D. G., Messiaen, L. M., Foulkes, W. D., Irving, R. E., Murray, A. J., Perez-Becerril, C., Rivera, B., McDonald-McGinn, D. M., Stevenson, D. A., Smith, M. J. 2021

  Abstract

  PURPOSE: The LZTR1 gene has been associated with schwannomatosis tumor predisposition and is located in a region that is deleted in the great majority (89%) of patients with 22q11.2 deletion syndrome (22q11.2DS). Since it is known that approximately 1 in 500 people in the general population will develop a sporadic schwannoma and there are no reports of the occurrence of schwannoma in 22q11.2DS, we investigated whether whole-gene deletion of LZTR1 occurs in schwannomatosis and assessed the risk of schwannoma in 22q11.2DS.METHODS: We assessed the genetic testing results for LZTR1-associated schwannomatosis and the clinical phenotypes of patients with 22q11.2DS.RESULTS: There were no reports of schwannoma in over 1,500 patients with 22q11.2DS. In addition, no patients meeting clinical diagnostic criteria for schwannomatosis had a whole-gene deletion in LZTR1. Only 1 patient in 110 with an apparently sporadic vestibular schwannoma had a constitutional whole-gene deletion of LZTR1.CONCLUSION: People with a large 22q11.2 deletion may have a reduced risk of developing a schwannoma compared to the general population.

  View details for DOI 10.1038/s41436-021-01175-0

  View details for PubMedID 33879870

• Congenital polyvalvular disease expands the cardiac phenotype of the RASopathies. American journal of medical genetics. Part A Matalon, D. R., Stevenson, D. A., Bhoj, E. J., Santani, A. B., Keena, B. n., Cohen, M. S., Lin, A. E., Sheppard, S. E., Zackai, E. H. 2021

  Abstract

  The RASopathies are a group of similar genetic syndromes with cardiovascular abnormalities, characteristic facial features, short stature, abnormalities of the skin and musculoskeletal system, and variable neurodevelopmental challenges. The most common cardiovascular abnormalities include pulmonary valvular stenosis and hypertrophic cardiomyopathy. Congenital polyvalvular disease (CPVD) refers to congenital dysplasia of two or more cardiac valves. We diagnosed a RASopathy in two individuals with CPVD and noted that CPVD in RASopathies has rarely been reported in the literature. Thus, we performed a retrospective chart review and literature review to investigate the association and characterize the phenotype of CPVD in the RASopathies. CPVD was present in 2.5% (n = 6/243) of individuals in our RASopathy cohort. Involvement of two cardiac valves, commonly the aortic and pulmonic valves, was seen in the majority of individuals (6/8; 75%) in our cohort, but only 27% (3/11) of reported CPVD and RASopathy cases in the literature. CPVD should be considered an associated cardiovascular phenotype of the RASopathies, which has implications for diagnosis and management.

  View details for DOI 10.1002/ajmg.a.62146

  View details for PubMedID 33683002

• Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome. HGG advances Wakeling, E. n., McEntagart, M. n., Bruccoleri, M. n., Shaw-Smith, C. n., Stals, K. L., Wakeling, M. n., Barnicoat, A. n., Beesley, C. n., Hanson-Kahn, A. K., Kukolich, M. n., Stevenson, D. A., Campeau, P. M., Ellard, S. n., Elsea, S. H., Yang, X. J., Caswell, R. C. 2021; 2 (1): 100015

  Abstract

  Histone deacetylases play crucial roles in the regulation of chromatin structure and gene expression in the eukaryotic cell, and disruption of their activity causes a wide range of developmental disorders in humans. Loss-of-function alleles of HDAC4, a founding member of the class IIa deacetylases, have been reported in brachydactyly-mental retardation syndrome (BDMR). However, while disruption of HDAC4 activity and deregulation of its downstream targets may contribute to the BDMR phenotype, loss of HDAC4 function usually occurs as part of larger deletions of chromosome 2q37; BDMR is also known as chromosome 2q37 deletion syndrome, and the precise role of HDAC4 within the phenotype remains uncertain. Thus, identification of missense variants should shed new light on the role of HDAC4 in normal development. Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR, all of whom have heterozygous de novo missense variants that affect a major regulatory site of HDAC4, required for signal-dependent 14-3-3 binding and nucleocytoplasmic shuttling. Two individuals possess variants altering Thr244 or Glu247, whereas the remaining five all carry variants altering Pro248, a key residue for 14-3-3 binding. We propose that the variants in all seven individuals impair 14-3-3 binding (as confirmed for the first two variants by immunoprecipitation assays), thereby identifying deregulation of HDAC4 as a pathological mechanism in a previously uncharacterized developmental disorder.

  View details for DOI 10.1016/j.xhgg.2020.100015

  View details for PubMedID 33537682

  View details for PubMedCentralID PMC7841527

• A dyadic approach to the delineation of diagnostic entities in clinical genomics. American journal of human genetics Biesecker, L. G., Adam, M. P., Alkuraya, F. S., Amemiya, A. R., Bamshad, M. J., Beck, A. E., Bennett, J. T., Bird, L. M., Carey, J. C., Chung, B. n., Clark, R. D., Cox, T. C., Curry, C. n., Dinulos, M. B., Dobyns, W. B., Giampietro, P. F., Girisha, K. M., Glass, I. A., Graham, J. M., Gripp, K. W., Haldeman-Englert, C. R., Hall, B. D., Innes, A. M., Kalish, J. M., Keppler-Noreuil, K. M., Kosaki, K. n., Kozel, B. A., Mirzaa, G. M., Mulvihill, J. J., Nowaczyk, M. J., Pagon, R. A., Retterer, K. n., Rope, A. F., Sanchez-Lara, P. A., Seaver, L. H., Shieh, J. T., Slavotinek, A. M., Sobering, A. K., Stevens, C. A., Stevenson, D. A., Tan, T. Y., Tan, W. H., Tsai, A. C., Weaver, D. D., Williams, M. S., Zackai, E. n., Zarate, Y. A. 2021; 108 (1): 8–15

  Abstract

  The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.

  View details for DOI 10.1016/j.ajhg.2020.11.013

  View details for PubMedID 33417889

• Missense variants in CTNNB1 can be associated with vitreoretinopathy-Seven new cases of CTNNB1-associated neurodevelopmental disorder including a previously unreported retinal phenotype. Molecular genetics & genomic medicine Rossetti, L. Z., Bekheirnia, M. R., Lewis, A. M., Mefford, H. C., Golden-Grant, K., Tarczy-Hornoch, K., Briere, L. C., Sweetser, D. A., Walker, M. A., Kravets, E., Stevenson, D. A., Bruenner, G., Sebastian, J., Knapo, J., Rosenfeld, J. A., Marcogliese, P. C., Undiagnosed Diseases Network, Wangler, M. F. 2020: e1542

  Abstract

  BACKGROUND: CTNNB1 (MIM 116806) encodes beta-catenin, an adherens junction protein that supports the integrity between layers of epithelial tissue and mediates intercellular signaling. Recently, various heterozygous germline variants in CTNNB1 have been associated with human disease, including neurodevelopmental disorder with spastic diplegia and visual defects (MIM 615075) as well as isolated familial exudative vitreoretinopathy without developmental delays or other organ system involvement (MIM 617572). From over 40 previously reported patients with CTNNB1-related neurodevelopmental disorder, many have had ocular anomalies including strabismus, hyperopia, and astigmatism. More recently, multiple reports indicate that these abnormalities are associated with the presence of vitreoretinopathy.METHODS: We gathered a cohort of three patients with CTNNB1-related neurodevelopmental disorder, recruited from both our own clinic and referred from outside providers. We then searched for a clinical database comprised of over 12,000 exome sequencing studies to identify and recruit four additional patients.RESULTS: Here, we report seven new cases of CTNNB1-related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy.CONCLUSIONS: Our findings suggest ophthalmologic screening should be performed in all patients with CTNNB1 variants.

  View details for DOI 10.1002/mgg3.1542

  View details for PubMedID 33350591

• Are Some Randomized Clinical Trials Impossible? Journal of pediatric orthopedics Rios, J. J., Richards, B. S., Stevenson, D. A., Oberlander, B., Viskochil, D., Gross, A. M., Dombi, E., Widemann, B. C., Plotkin, S. R., May, C. J., Ullrich, N. J., Goldstein, R. Y., Jain, V., Schorry, E. K., NFCTC Consortium 2020

  Abstract

  Congenital tibial pseudarthrosis is a rare condition seen in neurofibromatosis type 1 (NF1), and treatment is complex. A randomized, placebo-controlled trial of bone morphogenetic protein (rhBMP-2; INFUSE bone graft) at time of tibial surgery was developed by the Neurofibromatosis Clinical Trials Consortium. Patients were randomized to receive rhBMP-2 that would, or would not, be added to the standard surgical procedure consisting of resection of pseudarthrosis tissue, insertion of a rigid intramedullary rod, and placement of autogenous iliac crest bone graft. Despite involvement of 16 centers with wide experience with NF1 orthopaedic management, only 5 patients (of 54 required) were able to be enrolled in the study during a 3-year time period. Because of the inability to recruit sufficient patients, this study was closed in June 2019, with plans to terminate. The obstacles that were encountered during the study are summarized. The authors question whether a randomized, placebo-controlled trial of a rare pediatric orthopaedic condition is possible to accomplish. Recommendations are provided to guide future studies of orthopaedic manifestations of NF1.Level of Evidence: Level V.

  View details for DOI 10.1097/BPO.0000000000001650

  View details for PubMedID 32852366

• KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation. Brain : a journal of neurology Cif, L. n., Demailly, D. n., Lin, J. P., Barwick, K. E., Sa, M. n., Abela, L. n., Malhotra, S. n., Chong, W. K., Steel, D. n., Sanchis-Juan, A. n., Ngoh, A. n., Trump, N. n., Meyer, E. n., Vasques, X. n., Rankin, J. n., Allain, M. W., Applegate, C. D., Attaripour Isfahani, S. n., Baleine, J. n., Balint, B. n., Bassetti, J. A., Baple, E. L., Bhatia, K. P., Blanchet, C. n., Burglen, L. n., Cambonie, G. n., Seng, E. C., Bastaraud, S. C., Cyprien, F. n., Coubes, C. n., d'Hardemare, V. n., Doja, A. n., Dorison, N. n., Doummar, D. n., Dy-Hollins, M. E., Farrelly, E. n., Fitzpatrick, D. R., Fearon, C. n., Fieg, E. L., Fogel, B. L., Forman, E. B., Fox, R. G., Gahl, W. A., Galosi, S. n., Gonzalez, V. n., Graves, T. D., Gregory, A. n., Hallett, M. n., Hasegawa, H. n., Hayflick, S. J., Hamosh, A. n., Hully, M. n., Jansen, S. n., Jeong, S. Y., Krier, J. B., Krystal, S. n., Kumar, K. R., Laurencin, C. n., Lee, H. n., Lesca, G. n., François, L. L., Lynch, T. n., Mahant, N. n., Martinez-Agosto, J. A., Milesi, C. n., Mills, K. A., Mondain, M. n., Morales-Briceno, H. n., Ostergaard, J. R., Pal, S. n., Pallais, J. C., Pavillard, F. n., Perrigault, P. F., Petersen, A. K., Polo, G. n., Poulen, G. n., Rinne, T. n., Roujeau, T. n., Rogers, C. n., Roubertie, A. n., Sahagian, M. n., Schaefer, E. n., Selim, L. n., Selway, R. n., Sharma, N. n., Signer, R. n., Soldatos, A. G., Stevenson, D. A., Stewart, F. n., Tchan, M. n., Verma, I. C., de Vries, B. B., Wilson, J. L., Wong, D. A., Zaitoun, R. n., Zhen, D. n., Znaczko, A. n., Dale, R. C., de Gusmão, C. M., Friedman, J. n., Fung, V. S., King, M. D., Mohammad, S. S., Rohena, L. n., Waugh, J. L., Toro, C. n., Raymond, F. L., Topf, M. n., Coubes, P. n., Gorman, K. M., Kurian, M. A. 2020

  Abstract

  Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

  View details for DOI 10.1093/brain/awaa304

  View details for PubMedID 33150406

• Stress and Coping in Caregivers of Children with RASopathies: Assessment of the Impact of Caregiver Conferences. Journal of pediatric genetics Ganetsos, A. n., Farrelly, E. n., Magoulas, P. n., Stevenson, D. A. 2020; 9 (4): 235–42

  Abstract

  The study aimed to assess baseline stress and coping mechanisms among caregivers of children with RASopathies (i.e., cardiofaciocutaneous and Costello's syndrome) and the impact of attending biennial caregiver conferences. Caregivers completed the Perceived Stress Scale, Coping Health Inventory for Parents, and demographic surveys prior to family conferences, and 1- and 6-month postconferences. Baseline stress was increased and associated with child age, parental age, and number of conferences attended. After 1 month, caregiver stress was lowered among men and caregivers attending ≥2 support conferences.

  View details for DOI 10.1055/s-0040-1712178

  View details for PubMedID 32765926

  View details for PubMedCentralID PMC7396473

• Localization and age distribution of telangiectases in children and adolescents with hereditary hemorrhagic telangiectasia: A retrospective cohort study JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Gonzalez, C. D., Cipriano, S. D., Topham, C. A., Stevenson, D. A., Whitehead, K. J., Vanderhooft, S., Presson, A. P., McDonald, J. 2019; 81 (4): 950–55

  View details for DOI 10.1016/j.jaad.2018.11.014

  View details for Web of Science ID 000485261000025

• Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)? GENETICS IN MEDICINE Wooderchak-Donahue, W. L., Akay, G., Whitehead, K., Briggs, E., Stevenson, D. A., O'Fallon, B., Velinder, M., Farrell, A., Shen, W., Bedoukian, E., Skrabann, C. M., Antaya, R. J., Henderson, K., Pollak, J., Treat, J., Day, R., Jacher, J. E., Hannibal, M., Bontempo, K., Marth, G., Bayrak-Toydemir, P., McDonald, J. 2019; 21 (9): 2007–14

  View details for DOI 10.1038/s41436-019-0443-z

  View details for Web of Science ID 000484400800012

• Cardiac transplantation in children with Noonan syndrome. Pediatric transplantation McCallen, L. M., Ameduri, R. K., Denfield, S. W., Dodd, D. A., Everitt, M. D., Johnson, J. N., Lee, T. M., Lin, A. E., Lohr, J. L., May, L. J., Pierpont, M. E., Stevenson, D. A., Chatfield, K. C. 2019: e13535

  Abstract

  NS and related RAS/MAPK pathway (RASopathy) disorders are the leading genetic cause of HCM presenting in infancy. HCM is a major cause of morbidity and mortality in children with Noonan spectrum disorders, especially in the first year of life. Previously, there have been only isolated reports of heart transplantation as a treatment for heart failure in NS. We report on 18 patients with NS disorders who underwent heart transplantation at seven US pediatric heart transplant centers. All patients carried a NS diagnosis: 15 were diagnosed with NS and three with NSML. Sixteen of eighteen patients had comprehensive molecular genetic testing for RAS pathway mutations, with 15 having confirmed pathogenic mutations in PTPN11, RAF1, and RIT1 genes. Medical aspects of transplantation are reported as well as NS-specific medical issues. Twelve of eighteen patients described in this series were surviving at the time of data collection. Three patients died following transplantation prior to discharge from the hospital, and another three died post-discharge. Heart transplantation in NS may be a more frequent occurrence than is evident from the literature or registry data. A mortality rate of 33% is consistent with previous reports of patients with HCM transplanted in infancy and early childhood. Specific considerations may be important in evaluation of this population for heart transplant, including a potentially increased risk for malignancies as well as lymphatic, bleeding, and coagulopathy complications.

  View details for DOI 10.1111/petr.13535

  View details for PubMedID 31259454

• PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention CEREBRAL CORTEX Johnson, E. M., Ishak, A. D., Naylor, P. E., Stevenson, D. A., Reiss, A. L., Green, T. 2019; 29 (7): 2915–23

  View details for DOI 10.1093/cercor/bhy158

  View details for Web of Science ID 000477708300011

• Costello syndrome: Clinical phenotype, genotype, and management guidelines. American journal of medical genetics. Part A Gripp, K. W., Morse, L. A., Axelrad, M., Chatfield, K. C., Chidekel, A., Dobyns, W., Doyle, D., Kerr, B., Lin, A. E., Schwartz, D. D., Sibbles, B. J., Siegel, D., Shankar, S. P., Stevenson, D. A., Thacker, M. M., Weaver, K. N., White, S. M., Rauen, K. A. 2019

  Abstract

  Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence-based guidelines due to the lack of data for this rare condition.

  View details for DOI 10.1002/ajmg.a.61270

  View details for PubMedID 31222966

• Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review AMERICAN JOURNAL OF MEDICAL GENETICS PART A Kumar, A., Zastrow, D. B., Kravets, E. J., Beleford, D., Ruzhnikov, M. Z., Grove, M. E., Dries, A. M., Kohler, J. N., Waggott, D. M., Yang, Y., Huang, Y., Mackenzie, K. M., Eng, C. M., Fisher, P. G., Ashley, E. A., Teng, J. M., Stevenson, D. A., Shieh, J. T., Wheeler, M. T., Bernstein, J. A., Adams, D. R., Aday, A., Alejandro, M. E., Allard, P., Azamian, M. S., Bacino, C. A., Baker, E., Balasubramanyam, A., Barseghyan, H., Batzli, G. F., Beggs, A. H., Behnam, B., Bellen, H. J., Bican, A., Bick, D. P., Birch, C. L., Bonner, D., Boone, B. E., Bostwick, B. L., Briere, L. C., Brokamp, E., Brown, D. M., Brush, M., Burke, E. A., Burrage, L. C., Butte, M. J., Chen, S., Clark, G. D., Coakley, T. R., Cogan, J. D., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., D'Souza, P., Davids, M., Davidson, J. M., Dayal, J. G., Dell'Angelica, E. C., Dhar, S. U., Dipple, K. M., Donnell-Fink, L. A., Dorrani, N., Dorset, D. C., Douine, E. D., Draper, D. D., Eckstein, D. J., Emrick, L. T., Enns, G. M., Eskin, A., Esteves, C., Estwick, T., Fairbrother, L., Fernandez, L., Ferreira, C., Fieg, E. L., Fogel, B. L., Friedman, N. D., Gahl, W. A., Glanton, E., Godfrey, R. A., Goldman, A. M., Goldstein, D. B., Gould, S. E., Gourdine, J. F., Groden, C. A., Gropman, A. L., Haendel, M., Hamid, R., Hanchard, N. A., High, F., Holm, I. A., Hom, J., Howerton, E. M., Jamal, F., Jiang, Y., Johnston, J. M., Jones, A. L., Karaviti, L., Koeller, D. M., Kohane, I. S., Krasnewich, D. M., Korrick, S., Koziura, M., Krier, J. B., Kyle, J. E., Lalani, S. R., Lau, C., Lazar, J., LeBlanc, K., Lee, B. H., Lee, H., Levy, S. E., Lewis, R. A., Lincoln, S. A., Loo, S. K., Loscalzo, J., Maas, R. L., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Majcherska, M. M., Malicdan, M., Mamounas, L. A., Manolio, T. A., Markello, T. C., Marom, R., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., May, T., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., Merker, J. D., Metz, T. O., Might, M., Moretti, P. M., Morimoto, M., Mulvihill, J. J., Murdock, D. R., Murphy, J. L., Muzny, D. M., Nehrebecky, M. E., Nelson, S. F., Newberry, J., Newman, J. H., Nicholas, S. K., Novacic, D., Orange, J. S., Orengo, J. P., Pallais, J., Palmer, C. S., Papp, J. C., Parker, N. H., Pena, L. M., Phillips, J. A., Posey, J. E., Postlethwait, J. H., Potocki, L., Pusey, B. N., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Sampson, J. B., Samson, S. L., Schoch, K., Scott, D. A., Shakachite, L., Sharma, P., Shashi, V., Signer, R., Silverman, E. K., Sinsheimer, J. S., Smith, K. S., Spillmann, R. C., Staler, J. M., Stong, N., Sullivan, J. A., Sweetser, D. A., Tan, Q., Tifft, C. J., Toro, C., Tran, A. A., Urv, T. K., Vilain, E., Vogel, T. P., Wahl, C. E., Walley, N. M., Walsh, C. A., Walker, M., Wan, J., Wangler, M. F., Ward, P. A., Waters, K. M., Webb-Robertson, B. M., Westerfield, M., Wise, A. L., Wolfe, L. A., Worthey, E. A., Yamamoto, S., Yang, J., Yoon, A. J., Yu, G., Zhao, C., Zheng, A., Undiagnosed Dis Network 2019; 179 (6): 966–77

  View details for DOI 10.1002/ajmg.a.61134

  View details for Web of Science ID 000468322800015

• NF1 Somatic Mutation in Dystrophic Scoliosis JOURNAL OF MOLECULAR NEUROSCIENCE Margraf, R. L., VanSant-Webb, C., Mao, R., Viskochil, D. H., Carey, J., Hanson, H., D'Astous, J., Grossmann, A., Stevenson, D. A. 2019; 68 (1): 11–18

  View details for DOI 10.1007/s12031-019-01277-0

  View details for Web of Science ID 000464208600002

• Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review. American journal of medical genetics. Part A Kumar, A., Zastrow, D. B., Kravets, E. J., Beleford, D., Ruzhnikov, M. R., Grove, M. E., Dries, A. M., Kohler, J. N., Waggott, D. M., Yang, Y., Huang, Y., Undiagnosed Diseases Network, Mackenzie, K. M., Eng, C. M., Fisher, P. G., Ashley, E. A., Teng, J. M., Stevenson, D. A., Shieh, J. T., Wheeler, M. T., Bernstein, J. A. 2019

  Abstract

  Phacomatosis pigmentovascularis (PPV) comprises a family of rare conditions that feature vascular abnormalities and melanocytic lesions that can be solely cutaneous or multisystem in nature. Recently published work has demonstrated that both vascular and melanocytic abnormalities in PPV of the cesioflammea and cesiomarmorata subtypes can result from identical somatic mosaic activating mutations in the genes GNAQ and GNA11. Here, we present three new cases of PPV with features of the cesioflammea and/or cesiomarmorata subtypes and mosaic mutations in GNAQ or GNA11. To better understand the risk of potentially occult complications faced by such patients we additionally reviewed 176 cases published in the literature. We report the frequency of clinical findings, their patterns of co-occurrence as well as published recommendations for surveillance after diagnosis. Features assessed include: capillary malformation; dermal and ocular melanocytosis; glaucoma; limb asymmetry; venous malformations; and central nervous system (CNS) anomalies, such as ventriculomegaly and calcifications. We found that ocular findings are common in patients with phacomatosis cesioflammea and cesiomarmorata. Facial vascular involvement correlates with a higher risk of seizures (p=.0066). Our genetic results confirm the role of mosaic somatic mutations in GNAQ and GNA11 in phacomatosis cesioflammea and cesiomarmorata. Their clinical and molecular findings place these conditions on a clinical spectrum encompassing other GNAQ and GNA11 related disorders and inform recommendations for their management.

  View details for PubMedID 30920161

• Localization and age distribution of telangiectases in children and adolescents with hereditary hemorrhagic telangiectasia: A retrospective cohort study. Journal of the American Academy of Dermatology Gonzalez, C. D., Cipriano, S. D., Topham, C. A., Stevenson, D. A., Whitehead, K. J., Vanderhooft, S., Presson, A. P., McDonald, J. 2019

  Abstract

  BACKGROUND: The location of telangiectases in hereditary hemorrhagic telangiectasia (HHT), as set forth in the consensus diagnostic (Curacao) criteria, is based primarily on adults.OBJECTIVE: Document the locations and numbers of telangiectases in a cohort of pediatric patients with HHT.METHODS: A retrospective chart review using a standardized data collection form for site and number of telangiectases was performed for pediatric patients with HHT (age, 0-18years) from 2005 to 2016.RESULTS: Of 90 pediatric patients with HHT, 71% had one or more telangiectases. Of all the telangiectases counted (N=319), cutaneous telangiectases were more common (73%) than oral telangiectases (27%). The hands were the most frequent site, accounting for 33% of all telangiectases. Adolescents were more likely than children to have cutaneous telangiectases (85% vs 50% [Q=0.005]). The most frequent sites in children younger than 10years were the hands excluding the fingers (27%), fingers (25%), and face (23%). Only 23% of subjects (21 of 90) presented with multiple (≥3) telangiectases at locations considered characteristic for the current consensus diagnosis guidelines (lips, oral cavity, and fingers).LIMITATIONS: Ascertainment bias based on recruitment.CONCLUSIONS: In this pediatric population, telangiectases at sites not included as "characteristic" by the Curacao diagnostic criteria were common. The Curacao criteria in regard to both number and location of telangiectases may be inadequate in the pediatric HHT population.

  View details for PubMedID 30819528

• NF1 Somatic Mutation in Dystrophic Scoliosis. Journal of molecular neuroscience : MN Margraf, R. L., VanSant-Webb, C., Mao, R., Viskochil, D. H., Carey, J., Hanson, H., D'Astous, J., Grossmann, A., Stevenson, D. A. 2019

  Abstract

  Scoliosis is a common manifestation of neurofibromatosis type 1, causing significant morbidity. The etiology of dystrophic scoliosis in neurofibromatosis type 1 is not fully understood and therapies are lacking. Somatic mutations in NF1 have been shown in tibial pseudarthrosis providing rationale for similar processes in neurofibromatosis type 1-associated dystrophic scoliosis. Spinal samples from surgical procedures with matched peripheral blood of two individuals with neurofibromatosis type 1 and dystrophic scoliosis were obtained and DNA extracted. Next generation sequencing of various spinal sections as well as the germline/blood sample were performed using a RASopathy gene panel (includes the NF1 gene). Variants were compared between the spinal tissue samples and the germline data. In addition, the next generation sequencing allele frequency data were used to detect somatic loss of heterozygosity. All samples had a detected potentially inactivating NF1 germline mutation. Both individuals demonstrated an allelic imbalance inclusive of NF1 in the next generation sequencing data. In addition, for the same two individuals, there was an increase in the % variant reads for the germline mutation in some of the surgical spinal samples corresponding to the allelic imbalance. Contra analysis did not show any deletion in Chromosome 17 next generation sequencing data. Microarray analysis verified somatic copy neutral loss of heterozygosity for these two individuals for the majority of the chromosome 17 q-arm, inclusive of the NF1 gene. These results suggest that the cause of dystrophic scoliosis is multifactorial and that a somatic NF1 mutation contributes to the etiology.

  View details for PubMedID 30778836

• Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)? Genetics in medicine : official journal of the American College of Medical Genetics Wooderchak-Donahue, W. L., Akay, G., Whitehead, K., Briggs, E., Stevenson, D. A., O'Fallon, B., Velinder, M., Farrell, A., Shen, W., Bedoukian, E., Skrabann, C. M., Antaya, R. J., Henderson, K., Pollak, J., Treat, J., Day, R., Jacher, J. E., Hannibal, M., Bontempo, K., Marth, G., Bayrak-Toydemir, P., McDonald, J. 2019

  Abstract

  PURPOSE: EPHB4 variants were recently reported to cause capillary malformation-arteriovenous malformation 2 (CM-AVM2). CM-AVM2 mimics RASA1-related CM-AVM1 and hereditary hemorrhagic telangiectasia (HHT), as clinical features include capillary malformations (CMs), telangiectasia, and arteriovenous malformations (AVMs). Epistaxis, another clinical feature that overlaps with HHT, was reported in several cases. Based on the clinical overlap of CM-AVM2 and HHT, we hypothesized that patients considered clinically suspicious for HHT with no variant detected in an HHT gene (ENG, ACVRL1, or SMAD4) may have an EPHB4 variant.METHODS: Exome sequencing or a next-generation sequencing panel including EPHB4 was performed on individuals with previously negative molecular genetic testing for the HHT genes and/or RASA1.RESULTS: An EPHB4 variant was identified in ten unrelated cases. Seven cases had a pathogenic EPHB4 variant, including one with mosaicism. Three cases had an EPHB4 variant of uncertain significance. The majority had epistaxis (6/10 cases) and telangiectasia (8/10 cases), as well as CMs. Two of ten cases had a central nervous system AVM.CONCLUSIONS: Our results emphasize the importance of considering CM-AVM2 as part of the clinical differential for HHT and other vascular malformation syndromes. Yet, these cases highlight significant differences in the cutaneous presentations of CM-AVM2 versus HHT.

  View details for PubMedID 30760892

• Contributing factors of mortality in Prader-Willi syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Proffitt, J., Osann, K., McManus, B., Kimonis, V. E., Heinemann, J., Butler, M. G., Stevenson, D. A., Gold, J. 2019; 179 (2): 196–205

  View details for DOI 10.1002/ajmg.a.60688

  View details for Web of Science ID 000459032300009

• “Following Through”: Addressing the Racial Inequality for Preterm Infants and Their Families Pediatric Research Stevenson, D. K., Wong, R. J., Profit, J. J., Shaw, G. M., Wang, C. J., Lee, H. C. 2019

  View details for DOI 10.1038/s41390-019-0602-6

• Contributing factors of mortality in Prader-Willi syndrome. American journal of medical genetics. Part A Proffitt, J., Osann, K., McManus, B., Kimonis, V. E., Heinemann, J., Butler, M. G., Stevenson, D. A., Gold, J. 2018

  Abstract

  Prader-Willi syndrome (PWS) is a multi-system disorder resulting from a lack of paternal gene expression in the 15q11.2-q13 region. Using databases compiled through response questionnaires completed by families known to the Prader-Willi Syndrome Association (USA), this study tested the hypothesis that PWS genetic subtype, BMI, age of diagnosis, clinical symptoms, and growth hormone treatment differ among deceased and living individuals with PWS. Categorical and continuous variables were compared using chi-square and two-group t tests, respectively. Deceased individuals had higher rates of clinical features, including increased weight concerns, heart problems, sleep apnea, other respiratory complications, diabetes, osteoporosis, high pain tolerance, and severe skin picking, when compared to living individuals. Meanwhile, living individuals had higher rates of growth hormone use and early puberty. Obesity and subsequent consequences are the primary contributors to increased mortality in PWS. Additional emphasis on areas to decrease mortality is needed.

  View details for PubMedID 30569567

• Proceedings of the fifth international RASopathies symposium: When development and cancer intersect AMERICAN JOURNAL OF MEDICAL GENETICS PART A Rauen, K. A., Schoyer, L., Schill, L., Stronach, B., Albeck, J., Andresen, B. S., Cave, H., Ellis, M., Fruchtman, S. M., Gelb, B. D., Gibson, C. C., Gripp, K., Hefner, E., Huang, W. C., Itkin, M., Kerr, B., Linardic, C. M., McMahon, M., Oberlander, B., Perlstein, E., Ratner, N., Rogers, L., Schenck, A., Shankar, S., Shvartsman, S., Stevenson, D. A., Stites, E. C., Stork, P. S., Sun, C., Therrien, M., Ullian, E. M., Widemann, B. C., Yeh, E., Zampino, G., Zenker, M., Timmer, W., McCormick, F. 2018; 176 (12): 2924–29

  View details for DOI 10.1002/ajmg.a.40632

  View details for Web of Science ID 000454612700060

• Proceedings of the fifth international RASopathies symposium: When development and cancer intersect. American journal of medical genetics. Part A Rauen, K. A., Schoyer, L., Schill, L., Stronach, B., Albeck, J., Andresen, B. S., Cave, H., Ellis, M., Fruchtman, S. M., Gelb, B. D., Gibson, C. C., Gripp, K., Hefner, E., Huang, W. Y., Itkin, M., Kerr, B., Linardic, C. M., McMahon, M., Oberlander, B., Perlstein, E., Ratner, N., Rogers, L., Schenck, A., Shankar, S., Shvartsman, S., Stevenson, D. A., Stites, E. C., Stork, P. J., Sun, C., Therrien, M., Ullian, E. M., Widemann, B. C., Yeh, E., Zampino, G., Zenker, M., Timmer, W., McCormick, F. 2018: e40632

  Abstract

  This report summarizes and highlights the fifth International RASopathies Symposium: When Development and Cancer Intersect, held in Orlando, Florida in July 2017. The RASopathies comprise a recognizable pattern of malformation syndromes that are caused by germ line mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. Because of their common underlying pathogenetic etiology, there is significant overlap in their phenotypic features, which includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, gastrointestinal and ocular abnormalities, neurological and neurocognitive issues, and a predisposition to cancer. The RAS pathway is a well-known oncogenic pathway that is commonly found to be activated in somatic malignancies. As in somatic cancers, the RASopathies can be caused by various pathogenetic mechanisms that ultimately impact or alter the normal function and regulation of the MAPK pathway. As such, the RASopathies represent an excellent model of study to explore the intersection of the effects of dysregulation and its consequence in both development and oncogenesis.

  View details for PubMedID 30302932

• Response to Hannah-Shmouni and Stratakis. Genetics in medicine : official journal of the American College of Medical Genetics Stewart, D. R., Korf, B. R., Nathanson, K. L., Stevenson, D. A., Yohay, K. 2018

  View details for PubMedID 30283095

• Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation EUROPEAN JOURNAL OF HUMAN GENETICS Wooderchak-Donahue, W. L., Johnson, P., McDonald, J., Blei, F., Berenstein, A., Sorscher, M., Mayer, J., Scheuerle, A. E., Lewis, T., Grimmer, J., Richter, G. T., Steeves, M. A., Lin, A. E., Stevenson, D. A., Bayrak-Toydemir, P. 2018; 26 (10): 1521–36

  Abstract

  RASA1-related disorders are vascular malformation syndromes characterized by hereditary capillary malformations (CM) with or without arteriovenous malformations (AVM), arteriovenous fistulas (AVF), or Parkes Weber syndrome. The number of cases reported is relatively small; and while the main clinical features are CMs and AVMs/AVFs, the broader phenotypic spectrum caused by variants in the RASA1 gene is still being defined. Here, we report the clinical and molecular findings in 69 unrelated cases with a RASA1 variant identified at ARUP Laboratories. Sanger sequencing and multiplex ligation-dependent probe amplification were primarily used to evaluate RASA1. Several atypical cases were evaluated using next-generation sequencing (NGS) and array-comparative genomic hybridization (aCGH). Sixty individuals had a deleterious RASA1 variant of which 29 were novel. Nine individuals had a variant of uncertain significance. Five large RASA1 deletions were detected, giving an overall deletion/duplication rate of 8.3% (5/60) among positive cases. Most (75.4%) individuals with a RASA1 variant had CMs, and 44.9% had an AVM/AVF. Clinical findings in several cases expand the RASA1 phenotype. Our data suggest that screening for large RASA1 deletions and duplications in this disorder is important and suggest that NGS multi-gene panel testing is beneficial for the molecular diagnosis of cases with complex vascular phenotypes.

  View details for PubMedID 29891884

• A case report of a suspected dual diagnosis: 22q11.2 deletion syndrome and X-linked chondrodysplasia punctata CLINICAL DYSMORPHOLOGY Brimble, E., Pacione, M., Farrelly, E., Stevenson, D. A., Ruzhnikov, M. Z. 2018; 27 (4): 151–53

  View details for DOI 10.1097/MCD.0000000000000231

  View details for Web of Science ID 000445749500011

  View details for PubMedID 29912012

• Predictive Value and Interrater Reliability of Radiographic Factors in Neurofibromatosis Patients With Dystrophic Scoliosis. Spine deformity Larson, A. N., Ledonio, C. G., Brearley, A. M., Sucato, D. J., Carreon, L. Y., Crawford, A. H., Stevenson, D. A., Vitale, M. G., Moertel, C. L., Polly, D. W. 2018; 6 (5): 560–67

  Abstract

  BACKGROUND: Scoliosis in patients with neurofibromatosis type I (NF1) can manifest as dystrophic or nondystrophic curves. Dystrophic scoliosis is rapidly progressive, rendering treatment challenging. Radiographic characteristics have been reported to predict dystrophic scoliosis, but their reliability and predictive value have not been well described. The purpose of this study is to assess the interobserver reliability for eight radiographic characteristics of dystrophic scoliosis and to evaluate the sensitivity and specificity of these characteristics relative to the gold standard of a definitive clinical diagnosis.METHODS: Spine radiographs of 122 NF1 patients from multiple institutions were graded by five spine surgeons as dystrophic or nondystrophic, based on eight radiographic characteristics of dystrophic modulation: rib penciling, vertebral rotation, scalloping, wedging, spindling of transverse processes, short sharp angular curve, widened interpedicular distance, and atypical location. The curves were classified by each submitting institution as dystrophic or nondystrophic based on clinical outcome. Interobserver reliability analysis was performed using Fleiss kappa.RESULTS: For the 122 cases, the interrater agreement among the five readers for the diagnosis of dystrophic scoliosis was good at 0.61. The agreement for individual radiographic characteristic ranged from 0.62 for wedging to 0.14 (poor) for scalloping. Surgeons underestimated the number of dystrophic curves, rating from 45% to 67% of the curve patterns as dystrophic, compared to the gold standard, which revealed 68% of the curves to be dystrophic. On multivariate analysis, rib penciling, vertebral rotation, vertebral wedging, and atypical location were significantly associated with true dystrophic status (odds ratios of 2.4, 3.0, 2.4, and 3.0, respectively).CONCLUSION: Overall dystrophic diagnosis can be assessed by radiographic characteristics. Better understanding of the predictive value of specific radiographic features may assist in early diagnosis of patients with dystrophic NF and assist surgeons in identifying dystrophic curve patterns and instituting prompt, appropriate treatment.LEVEL OF EVIDENCE: Level III.

  View details for PubMedID 30122392

• Racial/ethnic disparities and incidence of malignant peripheral nerve sheath tumors: results from the Surveillance, Epidemiology, and End Results Program, 2000-2014 JOURNAL OF NEURO-ONCOLOGY Peckham-Gregory, E. C., Montenegro, R. E., Stevenson, D. A., Viskochil, D. H., Scheurer, M. E., Lupo, P. J., Schiffman, J. D. 2018; 139 (1): 69–75

  Abstract

  Malignant peripheral nerve sheath tumors (MPNSTs) are rare tumors, generally high-grade, and comprise ~ 5-10% of soft tissue sarcomas. Over two-thirds of MPNSTs metastasize, and upwards of 40% clinically recur. Etiologic risk factors for MPNSTs are historically understudied. There is evidence to suggest MPNST incidence differs across racial/ethnic groups in pediatric populations. Therefore, we sought to estimate differences in MPNST incidence by race/ethnicity among all ages in the United States.Incidence data were obtained from the Surveillance, Epidemiology, and End Results (SEER-18) Program, 2000-2014. Race/ethnicity was categorized as: White; Black; Asian; Other; and Latino/a ("Spanish-Hispanic-Latino"). Latino/a included all races, while all other categories excluded those identified as Latino/a. Age-adjusted incidence rate ratios (IRR) and 95% confidence intervals (CIs) were generated in SEER-STAT (v8.3.4). We estimated incidence rates among all ages, and among those diagnosed < 25 and ≥ 25 years.MPNST cases were abstracted from SEER-18 (n = 1047). Among all age groups, Blacks experienced an elevated incidence of MPNSTs compared to Whites (IRRBlacks = 1.26, 95% CI 1.04-1.50). Asian and Latinos/as experienced lower incidences compared to Whites (IRRAsians = 0.78, 95% CI 0.61-0.99; IRRLatinos/as = 0.84, 95% CI 0.69-1.02). In subgroup analyses, no statistically significant associations with MPNSTs were identified among cases diagnosed < 25 years of age, whereas the associations observed among all age groups were prominent among those diagnosed ≥ 25 years of age.Incidence rates of MPNSTs were highest in Blacks compared to Whites and other minority groups. This study suggests specific patterns exist in terms of race/ethnicity and age at diagnosis of MPNSTs.

  View details for PubMedID 29663170

• Use of Flow Cytometry for Diagnosis of Epilepsy Associated With Homozygous PIGW Variants PEDIATRIC NEUROLOGY Foskett, G., Engleman, E., Klotz, J., Choi, O., Tolentino, L., Kochhar, A., Yang, Q., Stevenson, D. A. 2018; 85: 67–70

  View details for DOI 10.1016/j.pediatrneurol.2018.05.010

  View details for Web of Science ID 000449449600010

• PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention. Cerebral cortex (New York, N.Y. : 1991) Johnson, E. M., Ishak, A. D., Naylor, P. E., Stevenson, D. A., Reiss, A. L., Green, T. 2018

  Abstract

  The Ras-MAPK pathway has an established role in neural development and synaptic signaling. Mutations in this pathway are associated with a collection of neurodevelopmental syndromes, Rasopathies; among these, Noonan syndrome (NS) is the most common (1:2000). Prior research has focused on identifying genetic mutations and cellular mechanisms of the disorder, however, effects of NS on the human brain remain unknown. Here, imaging and cognitive data were collected from 12 children with PTPN11-related NS, ages 4.0-11.0 years (8.98 ± 2.33) and 12 age- and sex-matched typically developing controls (8.79 ± 2.17). We observe reduced gray matter volume in bilateral corpus striatum (Cohen's d = -1.0:-1.3), reduced surface area in temporal regions (d = -1.8:-2.2), increased cortical thickness in frontal regions (d = 1.2-1.3), and reduced cortical thickness in limbic regions (d = -1.6), including limbic structures integral to the circuitry of the hippocampus. Further, we find high levels of inattention, hyperactivity, and memory deficits in children with NS. Taken together, these results identify effects of NS on specific brain regions associated with ADHD and learning in children. While our research lays the groundwork for elucidating the neural and behavioral mechanisms of NS, it also adds an essential tier to understanding the Ras-MAPK pathway's role in human brain development.

  View details for PubMedID 30059958

• Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG) GENETICS IN MEDICINE Stewart, D. R., Korf, B. R., Nathanson, K. L., Stevenson, D. A., Yohay, K. 2018; 20 (7): 671–82

  Abstract

  This practice resource is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this practice resource is completely voluntary and does not necessarily assure a successful medical outcome. This practice resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this practice resource. Clinicians also are advised to take notice of the date this practice resource was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that is caused by a heterozygous loss-of-function variant in the tumor suppressor gene NF1; it affects ~1/1,900-1/3,500 people worldwide. The disorder is associated with an 8-15-year reduction in average life expectancy in both men and women, primarily due to malignant neoplasms and cardiovascular causes.A work group of experts sought to determine the prevalence, morbidity and mortality, and available treatments of common and emerging NF1-related clinical problems in adults. Work-group members identified peer-reviewed publications from PubMed. Publications derived from populations and multi-institution cohorts were prioritized. Recommendations for management arose by consensus from this literature and the collective expertise of the authors.Malignant peripheral nerve sheath tumor (MPNST), breast cancer, cutaneous neurofibromas, and significant psychiatric and neurologic diagnoses are common problems in patients with NF1.Patient education and sensitization to worrisome signs and symptoms such as progressive severe pain (MPNST), changes in tumor volume (MPNST), new, unexplained neurologic symptoms (MPNST, brain tumors), and diaphoresis/palpitations (pheochromocytoma) are important. Although many issues in adults with NF1 can be managed by an internist or family physician, we strongly encourage evaluation by, and care coordination with, a specialized NF1 clinic.

  View details for PubMedID 30006586

• Epistaxis in children and adolescents with hereditary hemorrhagic telangiectasia. The Laryngoscope Gonzalez, C. D., Mcdonald, J., Stevenson, D. A., Whitehead, K. J., Petersen, M. G., Presson, A. P., Ding, Q., Wilson, K. F. 2018; 128 (7): 1714-1719

  Abstract

  Our objective was to describe epistaxis onset and severity in pediatric hereditary hemorrhagic telangiectasia (HHT) patients and study the cumulative incidence of epistaxis by age of onset within each genetic subtype.Retrospective cohort chart review.Charts were reviewed of patients age 0 to 18 years with a clinical or genetic diagnosis of HHT who were evaluated at a tertiary multidisciplinary HHT clinic from January 2010 to June 2016. The epistaxis severity score (ESS), a validated tool for assessing epistaxis severity, was used to assess epistaxis. Statistical analyses were conducted on the full HHT cohort as well as subgroups stratified by the HHT causative gene (HHT1 = ENG and HHT2 = ACVRL1).Sixty-nine pediatric subjects were identified; 60 had HHT confirmed by genetic testing, and nine (from families with known mutations) met published clinical diagnostic criteria alone. Fifty-nine (85%) had onset of epistaxis. The median age of onset of epistaxis was 5 years (interquartile range [IQR]: 2-9 years). The median ESS for the entire cohort was 1.6 (IQR: 0-2.6). The median ESS was higher in HHT1 versus HHT2 (2.3 vs. 1.1, P = .002), and age of epistaxis onset was earlier in HHT1 (3 vs. 5 years, P = .03). Sex and age were not associated with ESS.Epistaxis may present early in HHT, but is typically mild in the pediatric period. Severity in the pediatric population is worse in patients with HHT1. By recognizing the significance of even mild, infrequent epistaxis in a child with a family history of HHT, and understanding that not all HHT patients have epistaxis during childhood, community providers and otolaryngologist can assist in the early detection of HHT.4 Laryngoscope, 128:1714-1719, 2018.

  View details for DOI 10.1002/lary.27015

  View details for PubMedID 29171658

• Epistaxis in Children and Adolescents With Hereditary Hemorrhagic Telangiectasia Gonzalez, C. D., Mcdonald, J., Stevenson, D. A., Whitehead, K. J., Petersen, M. G., Presson, A. P., Ding, Q., Wilson, K. F. WILEY. 2018: 1714–19

  View details for DOI 10.1002/lary.27015

  View details for Web of Science ID 000440007000050

• Use of Flow Cytometry for Diagnosis of Epilepsy Associated With Homozygous PIGW Variants. Pediatric neurology Foskett, G. K., Engleman, E., Klotz, J., Choi, O., Tolentino, L., Kochhar, A., Yang, Q. Z., Stevenson, D. A. 2018

  Abstract

  BACKGROUND: Biallelic variants in PIGW have been suggested to cause infantile spasms and hyperphosphatasia. PIGW encodes for a protein involved in the third step of glycosylphosphatidylinositol (GPI) synthesis. GPI anchored proteins are increasingly recognized as important structures for cellular interactions and neuronal development.METHODS: Molecular testing of PIGW was performed followed by fluorescence activating cell sorting analysis of granulocytes, lymphocytes, and monocytes, and compared to controls.FINDINGS: An infant was homozygous for variants in PIGW (c.199C>G; p.Pro67Ala) with an associated phenotype of infantile spasms, myoclonic seizures, cortical visual impairment, developmental delay, and minor dysmorphic features. Alkaline phosphatase levels ranged from normal to mildly elevated. Flow cytometric studies showed significantly decreased expression of important GPIs, providing functional evidence of pathogenicity.CONCLUSION: Our data provide further evidence of a novel autosomal recessive PIGW-related epilepsy disorder. Flow cytometry provided functional evidence of the pathogenicity of homozygous variants of uncertain significance in PIGW, and supports the use of flow cytometry as a functional tool to demonstrate decreased surface expression of GPI anchored proteins in cases where there are variants of unknown significance.

  View details for PubMedID 30078644

• Evaluation of racial disparities in pediatric optic pathway glioma incidence: Results from the Surveillance, Epidemiology, and End Results Program, 2000-2014 CANCER EPIDEMIOLOGY Peckham-Gregory, E. C., Montenegro, R. E., Stevenson, D. A., Viskochil, D. H., Scheurer, M. E., Lupo, P. J., Schiffman, J. D. 2018; 54: 90–94

  Abstract

  Racial predilection to pediatric cancer exists; however optic pathway glioma (OPG) risk differences by race/ethnicity are undefined. We estimated differences in OPG incidence across racial/ethnic groups in a multi-state cancer surveillance registry in the United States.OPG data were obtained from the Surveillance, Epidemiology, and End Results (SEER-18) Program, 2000-2014. Race/ethnicity was categorized as: White; Black; Asian; Other; and Latino/a ("Spanish-Hispanic-Latino"). Latino/a included all races, while all other categories excluded those identified as Latino/a. Age-adjusted incidence rates and rate ratios (IRR) with 95% confidence intervals (CIs) were generated in SEER-STAT (v8.3.4).Data on 709 OPG cases ages 0-19 were abstracted from SEER-18. Minority children experienced lower age-adjusted OPG incidence rates compared to White children (IRRBlack = 0.38, 95% CI: 0.28-0.50; IRRAsian = 0.41, 95% CI: 0.29-0.58; and IRRLatino/a = 0.39, 95% CI: 0.32-0.48). In subgroup analyses among the highest risk age categories (0-4, 5-9), minority children experienced lower incidence rates compared to White children. Specific patterns for Latinos/as also emerged. Latino/a children ages 0-4 experienced the lowest incidence rates of all racial/ethnic groups compared to Whites (0.24 per 100,000 person-years versus 0.66 per 100,000 person-years, respectively), whereas among those ages 5-9, Black and Asian children experienced the lowest incidence rates (0.08 per 100,000 person-years each).Incidence of OPGs was highest among White children. This study represents one of the largest to assess differences in OPG susceptibility by race/ethnicity. These findings may inform future studies that seek to evaluate modifying factors for this pediatric tumor including tumorigenesis, treatment, outcome, and long-term late effects.

  View details for PubMedID 29684801

• Quantitative Ultrasound and Tibial Dysplasia in Neurofibromatosis Type 1 JOURNAL OF CLINICAL DENSITOMETRY Stevenson, D. A., Hanson, H., Stevens, A., Carey, J., Viskochil, D., Sheng, X., Wheeler, K., Slater, H. 2018; 21 (2): 179–84

  Abstract

  Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder associated with unilateral anterolateral bowing with subsequent fracture and nonunion. In infancy, physiologic bowing of the lower leg can be confused with pathologic tibial dysplasia in NF1. Little is known about the bone physiology of the tibiae prior to fracture or predictors of fracture. The aim of this study was to characterize bone quality of bowed tibiae prior to fracture in NF1 using quantitative ultrasound (QUS). Bone quality was assessed on both tibiae (the non-bowed and bowed tibiae) using QUS to measure speed of sound (SOS) at the mid-shaft in 23 individuals with NF1. SOS (m/s) was determined and Z-scores generated using cross-sectional reference data of the same sex and age. The mean difference in SOS Z-scores when comparing the bowed tibia vs the individual's contralateral unaffected tibia was statistically significant with lower mean Z-scores in the bowed tibia (p = 0.001). Radiographs of all individuals with a clinical diagnosis of anterolateral bowing were reviewed, and in 2 individuals the radiographs showed minimal bowing with absence of characteristic cortical thickening and medullary canal narrowing in NF1-related tibial dysplasia, suggesting physiologic bowing. In both individuals, the Z-scores of the bowed leg were not lower than the unaffected leg supporting the suggestion of physiologic bowing rather than pathologic tibial dysplasia. These data show that dysplastic tibiae in NF1 prior to fracture and nonunion have abnormal bone quality with significant decreases in SOS even though radiographically the tibiae show a thickened cortex. These data also suggest that QUS can help distinguish dysplastic bowing vs physiologic bowing in infancy in NF1. QUS is an effective quantitative outcome measure for trials aimed at improving tibial bowing to prevent fracture, and it is a potential aid in diagnosis and clinical management in NF1.

  View details for PubMedID 28438404

• Dietary intervention rescues myopathy associated with neurofibromatosis type 1 HUMAN MOLECULAR GENETICS Summers, M. A., Rupasinghe, T., Vasiljevski, E. R., Evesson, F. J., Mikulec, K., Peacock, L., Quinlan, K. R., Cooper, S. T., Roessner, U., Stevenson, D. A., Little, D. G., Schindeler, A. 2018; 27 (4): 577–88

  Abstract

  Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with complex symptomology. In addition to a predisposition to tumors, children with NF1 can present with reduced muscle mass, global muscle weakness, and impaired motor skills, which can have a significant impact on quality of life. Genetic mouse models have shown a lipid storage disease phenotype may underlie muscle weakness in NF1. Herein we confirm that biopsy specimens from six individuals with NF1 similarly manifest features of a lipid storage myopathy, with marked accumulation of intramyocellular lipid, fibrosis, and mononuclear cell infiltrates. Intramyocellular lipid was also correlated with reductions in neurofibromin protein expression by western analysis. An RNASeq profile of Nf1null muscle from a muscle-specific Nf1 knockout mouse (Nf1MyoD-/-) revealed alterations in genes associated with glucose regulation and cell signaling. Comparison by lipid mass spectrometry demonstrated that Nf1null muscle specimens were enriched for long chain fatty acid (LCFA) containing neutral lipids, such as cholesterol esters and triacylglycerides, suggesting fundamentally impaired LCFA metabolism. The subsequent generation of a limb-specific Nf1 knockout mouse (Nf1Prx1-/-) recapitulated all observed features of human NF1 myopathy, including lipid storage, fibrosis, and muscle weakness. Collectively, these insights led to the evaluation of a dietary intervention of reduced LCFAs, and enrichment of medium-chain fatty acids (MCFAs) with L-carnitine. Following 8-weeks of dietary treatment, Nf1Prx1-/- mice showed a 45% increase in maximal grip strength, and a 71% reduction in intramyocellular lipid staining compared with littermates fed standard chow. These data link NF1 deficiency to fundamental shifts in muscle metabolism, and provide strong proof of principal that a dietary intervention can ameliorate symptoms.

  View details for PubMedID 29228356

• Bilirubin Production Is Increased in Newborn Mice Exposed to Isoflurane. Neonatology Iwatani, S., Burgess, J., Kalish, F., Wong, R. J., Stevenson, D. K. 2018; 115 (1): 21-27

  Abstract

  Increased bilirubin production due to hemolysis can lead to severe neonatal hyperbilirubinemia and, if left untreated, to bilirubin neurotoxicity. Post-cardiac surgery newborns have been shown to be at an increased risk for developing hyperbilirubinemia and also hemolysis. Isoflurane (ISO), a volatile anesthetic agent routinely used in newborn surgery, has been reported to upregulate heme oxygenase 1 (HO-1) expression. HO is the rate-limiting enzyme in the bilirubin production pathway.Here, we evaluated whether ISO exposure induces HO-1 and further increases bilirubin production in a hemolytic newborn mouse model.Three-day-old newborn mice were exposed to 2% ISO for 18 min or air. Liver HO activity and HO-1 protein were measured after exposure to ISO. Next, we evaluated the effect of ISO exposure on bilirubin production as indexed by the total body excretion rate of carbon monoxide following heme loading.ISO significantly increased liver HO activity 120% and 116% at 24 and 48 h, respectively, after exposure. HO-1 protein levels also similarly increased after ISO exposure, but the increases were not statistically significant compared with controls. After heme loading, ISO-exposed pups had significantly higher bilirubin production rates (1.24-fold), and also peaked earlier, than age-matched nonexposed pups.ISO exposure can induce HO-1 expression in the liver and may explain the development of severe hyperbilirubinemia in postsurgical infants, especially in those undergoing hemolysis.

  View details for DOI 10.1159/000492421

• Variable clinical course of identical twin neonates with Alström syndrome presenting coincidentally with dilated cardiomyopathy. American journal of medical genetics. Part A Hollander, S. A., Alsaleh, N., Ruzhnikov, M., Jensen, K., Rosenthal, D. N., Stevenson, D. A., Manning, M. 2017; 173 (6): 1687-1689

  Abstract

  Alström Syndrome (AS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report monozygotic twin infants who presented concurrently with symptoms of congestive heart failure (CHF) due to dilated cardiomyopathy (DCM). Following their initial presentation, one twin improved both echocardiographically and functionally while the other twin showed a progressive decline in ventricular function and worsening CHF symptoms requiring multiple hospitalizations and augmentation of heart failure therapy. Concordant findings of nystagmus, vision loss, and developmental delay were noted in both twins. Additional discordant findings included obesity and signs of insulin resistance in one twin. Genetic testing on one sibling confirmed AS. These twins underscore the importance of considering AS in any child presenting with DCM, particularly in infancy, and highlights that, even in monozygotic twins, the clinical course of AS is variable with regard to both the cardiac and non-cardiac manifestations of the disease.

  View details for DOI 10.1002/ajmg.a.38200

  View details for PubMedID 28407410

• The path forward: 2015 International Children's Tumor Foundation conference on neurofibromatosis type 1, type 2, and schwannomatosis. American journal of medical genetics. Part A Blakeley, J. O., Bakker, A., Barker, A., Clapp, W., Ferner, R., Fisher, M. J., Giovannini, M., Gutmann, D. H., Karajannis, M. A., Kissil, J. L., Legius, E., Lloyd, A. C., Packer, R. J., Ramesh, V., Riccardi, V. M., Stevenson, D. A., Ullrich, N. J., Upadhyaya, M., Stemmer-Rachamimov, A. 2017; 173 (6): 1714-1721

  Abstract

  The Annual Children's Tumor Foundation International Neurofibromatosis Meeting is the premier venue for connecting discovery, translational and clinical scientists who are focused on neurofibromatosis types 1 and 2 (NF1 and NF2) and schwannomatosis (SWN). The meeting also features rare tumors such as glioma, meningioma, sarcoma, and neuroblastoma that occur both within these syndromes and spontaneously; associated with somatic mutations in NF1, NF2, and SWN. The meeting addresses both state of the field for current clinical care as well as emerging preclinical models fueling discovery of new therapeutic targets and discovery science initiatives investigating mechanisms of tumorigenesis. Importantly, this conference is a forum for presenting work in progress and bringing together all stakeholders in the scientific community. A highlight of the conference was the involvement of scientists from the pharmaceutical industry who presented growing efforts for rare disease therapeutic development in general and specifically, in pediatric patients with rare tumor syndromes. Another highlight was the focus on new investigators who presented new data about biomarker discovery, tumor pathogenesis, and diagnostic tools for NF1, NF2, and SWN. This report summarizes the themes of the meeting and a synthesis of the scientific discoveries presented at the conference in order to make the larger research community aware of progress in the neurofibromatoses.

  View details for DOI 10.1002/ajmg.a.38239

  View details for PubMedID 28436162

• Utilization of Whole-Exome Next-Generation Sequencing Variant Read Frequency for Detection of Lesion-Specific, Somatic Loss of Heterozygosity in a Neurofibromatosis Type 1 Cohort with Tibial Pseudarthrosis JOURNAL OF MOLECULAR DIAGNOSTICS Margraf, R. L., VanSant-Webb, C., Sant, D., Carey, J., Hanson, H., D'Astous, J., Viskochil, D., Stevenson, D. A., Mao, R. 2017; 19 (3): 468-474

  Abstract

  A subset of neurofibromatosis type 1 patients develop tibial dysplasia, which can lead to pseudarthrosis. The tissue from the tibial pseudarthrosis region commonly has a somatic second hit in NF1: single-nucleotide variants, small deletions, or loss of heterozygosity (LOH). We used exome next-generation sequencing (NGS) variant frequency data (allelic imbalance analysis) to detect somatic LOH in pseudarthrosis tissue from three individuals with clinically and diagnostically confirmed neurofibromatosis type 1, and verified the results with microarray. The variant files were parsed and plotted using python scripts, and the NGS variant frequencies between the affected tissue and blood sample were compared. Individuals without somatic single-nucleotide variants or small insertions/deletions were tested for somatic LOH using the NGS variant allele frequencies. One individual's NGS data indicated no LOH in chromosome 17. The other two individuals demonstrated somatic LOH inclusive of NF1: one had an LOH region of approximately one million bases and Contra (NGS copy number program) indicated a somatic deletion and the other individual had LOH for most of chromosome 17q and Contra indicated no copy number change (microarray data verified this sample as copy neutral somatic LOH). Both LOH and copy number variation detected by NGS data correlated with microarray data, demonstrating the somatic LOH second hit can be detected directly from the NGS data.

  View details for DOI 10.1016/j.jmoldx.2017.01.008

  View details for PubMedID 28433079

• Analysis of Copy Number Variants in 11 Pairs of Monozygotic Twins with Neurofibromatosis Type AMERICAN JOURNAL OF MEDICAL GENETICS PART A Sites, E. R., Smolarek, T. A., Martin, L. J., Viskochil, D. H., Stevenson, D. A., Ullrich, N. J., Messiaen, L. M., Schorry, E. K. 2017; 173 (3): 647-653

  Abstract

  Phenotypic variability among individuals with neurofibromatosis type 1 (NF1) has long been a challenge for clinicians and an enigma for researchers. Members of the same family and even identical twins with NF1 often demonstrate variable disease expression. Many mechanisms for this variability have been proposed. We have performed an exploratory study of copy number variants (CNVs) as a possible source of phenotypic variability in NF1. We enrolled 11 pairs of monozygotic (MZ) twins with NF1 and their parents, catalogued their clinical characteristics, and utilized a single nucleotide polymorphism (SNP) microarray to identify CNVs in blood and saliva. The 11 twin pairs showed high concordance for presence and number of café-au-lait spots, cutaneous neurofibromas, IQ, and ADHD. They were more likely to be discordant for optic pathway glioma, plexiform neurofibromas, skeletal manifestations, and malignancy. Microarray analysis identified a total of 81 CNVs meeting our conservative criteria, 37 of which overlap known genes. Of interest, three CNVs were previously unreported. Microarray analysis failed to ascertain any CNV differences within twin pairs, between twins and parents, or between tissues in any one individual. Results of this small pilot study did not demonstrate any de novo CNV events in our MZ twin pairs, nor were de novo CNVs overrepresented in these individuals with NF1. A much larger sample size would be needed to form any conclusions about the role of CNVs in NF1 variable expressivity. Alternative explanations for discordant phenotypes include epigenetic changes, smaller genetic alterations, or environmental factors. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.38058

  View details for PubMedID 27862945

• Promoting appropriate genetic testing: the impact of a combined test review and consultative service. Genetics in medicine Suarez, C. J., Yu, L., Downs, N., Costa, H. A., Stevenson, D. A. 2017

  Abstract

  Genetic test misorders can adversely affect patient care. However, little is known about the types of misorders and the overall impact of a utilization management (UM) program on curbing misorders. This study aimed to identify different types of misorders and analyze the impact of a combined test review and consultative service on reducing misorders over time.Selected genetic tests were systematically reviewed between January and December 2015 at Stanford Health Care. Misorders were categorized into five types: clerical errors, redundant testing, better alternatives, controversial, and uncategorized. Moreover, consultations were offered to help clinicians with test selection.Of the 629 molecular test orders reviewed, 13% were classified as misorders, and 7% were modified or canceled. Controversial misorders constitute the most common type (42%); however, unlike the other misorder types, they were negligibly affected by test review. Simultaneously, 71 consults were received. With the introduction of the UM program, genetic test misorders went from 22% at baseline to 3% at the end of the year.Our results show that the combined approach of test review and consultative service effectively reduced misorders over time and suggest that a UM program focused on eliminating misorders can positively influence health-care providers' behaviors.Genet Med advance online publication 26 January 2017Genetics in Medicine (2017); doi:10.1038/gim.2016.219.

  View details for DOI 10.1038/gim.2016.219

  View details for PubMedID 28125079

• Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders. Genome medicine Bostwick, B. L., McLean, S. n., Posey, J. E., Streff, H. E., Gripp, K. W., Blesson, A. n., Powell-Hamilton, N. n., Tusi, J. n., Stevenson, D. A., Farrelly, E. n., Hudgins, L. n., Yang, Y. n., Xia, F. n., Wang, X. n., Liu, P. n., Walkiewicz, M. n., McGuire, M. n., Grange, D. K., Andrews, M. V., Hummel, M. n., Madan-Khetarpal, S. n., Infante, E. n., Coban-Akdemir, Z. n., Miszalski-Jamka, K. n., Jefferies, J. L., Rosenfeld, J. A., Emrick, L. n., Nugent, K. M., Lupski, J. R., Belmont, J. W., Lee, B. n., Lalani, S. R. 2017; 9 (1): 73

  Abstract

  De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder.To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review.We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites.Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.

  View details for PubMedID 28807008

• Molecular and clinical spectra of FBXL4 deficiency. Human mutation El-Hattab, A. W., Dai, H. n., Almannai, M. n., Wang, J. n., Faqeih, E. A., Al Asmari, A. n., Saleh, M. A., Elamin, M. A., Alfadhel, M. n., Alkuraya, F. S., Hashem, M. n., Aldosary, M. S., Almass, R. n., Almutairi, F. B., Alsagob, M. n., Al-Owain, M. n., Al-Sharfa, S. n., Al-Hassnan, Z. N., Al Rahbeeni, Z. n., Al-Muhaizea, M. A., Makhseed, N. n., Foskett, G. K., Stevenson, D. A., Gomez-Ospina, N. n., Lee, C. n., Boles, R. G., Schrier Vergano, S. A., Wortmann, S. B., Sperl, W. n., Opladen, T. n., Hoffmann, G. F., Hempel, M. n., Prokisch, H. n., Alhaddad, B. n., Mayr, J. A., Chan, W. n., Kaya, N. n., Wong, L. C. 2017

  Abstract

  F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype-phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies. This article is protected by copyright. All rights reserved.

  View details for PubMedID 28940506

• Brief Report: The Prevalence of Neurofibromatosis Type 1 among Children with Autism Spectrum Disorder Identified by the Autism and Developmental Disabilities Monitoring Network JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Bilder, D. A., Bakian, A. V., Stevenson, D. A., Carbone, P. S., Cunniff, C., Goodman, A. B., McMahon, W. M., Fisher, N. P., Viskochil, D. 2016; 46 (10): 3369-3376

  Abstract

  Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous disorder associated with neurodevelopmental disorders including autism spectrum disorder (ASD). The frequency of ASD/NF1 co-occurrence has been subject to debate since the 1980s. This relationship was investigated in a large population-based sample of 8-year-old children identified with ASD (N = 12,271) by the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring (ADDM) Network. Twenty-two (1-in-558) children with ASD had diagnosed NF1, exceeding NF1 general population estimates by four to five fold. Children with ASD/NF1 versus ASD without NF1 were significantly less likely to receive a community-based ASD diagnosis (p = 0.04) and understand non-verbal communication (p = 0.001). These findings underscore the importance of including social-communication ability among relevant developmental concerns in children with NF1.

  View details for DOI 10.1007/s10803-016-2877-3

  View details for PubMedID 27465244

• NALCN channelopathies: Distinguishing gain-of-function and loss-of-function mutations NEUROLOGY Bend, E. G., Si, Y., Stevenson, D. A., Bayrak-Toydemir, P., Newcomb, T. M., Jorgensen, E. M., Swoboda, K. J. 2016; 87 (11): 1131-1139

  Abstract

  To perform genotype-phenotype analysis in an infant with congenital arthrogryposis due to a de novo missense mutation in the NALCN ion channel and explore the mechanism of pathogenicity using a Caenorhabditis elegans model.We performed whole-exome sequencing in a preterm neonate with congenital arthrogryposis and a severe life-threatening clinical course. We examined the mechanism of pathogenicity of the associated NALCN mutation by engineering the orthologous mutation into the nematode C elegans using CRISPR-Cas9.We identified a de novo missense mutation in NALCN, c.1768C>T, in an infant with a severe neonatal lethal form of the recently characterized CLIFAHDD syndrome (congenital contractures of the limbs and face with hypotonia and developmental delay). We report novel phenotypic features including prolonged episodes of stimulus-sensitive sustained muscular contraction associated with life-threatening episodes of desaturation and autonomic instability, extending the severity of previously described phenotypes associated with mutations in NALCN. When engineered into the C elegans ortholog, this mutation results in a severe gain-of-function phenotype, with hypercontraction and uncoordinated movement. We engineered 6 additional CLIFAHDD syndrome mutations into C elegans and the mechanism of action could be divided into 2 categories: half phenocopied gain-of-function mutants and half phenocopied loss-of-function mutants.The clinical phenotype of our patient and electrophysiologic studies show sustained muscular contraction in response to transient sensory stimuli. In C elegans, this mutation causes neuronal hyperactivity via a gain-of-function NALCN ion channel. Testing human variants of NALCN in C elegans demonstrates that CLIFAHDD can be caused by dominant loss- or gain-of-function mutations in ion channel function.

  View details for DOI 10.1212/WNL.0000000000003095

  View details for PubMedID 27558372

• DNA Methylation Profiling of Uniparental Disomy Subjects Provides a Map of Parental Epigenetic Bias in the Human Genome. American journal of human genetics Joshi, R. S., Garg, P., Zaitlen, N., Lappalainen, T., Watson, C. T., Azam, N., Ho, D., Li, X., Antonarakis, S. E., Brunner, H. G., Buiting, K., Cheung, S. W., Coffee, B., Eggermann, T., Francis, D., Geraedts, J. P., Gimelli, G., Jacobson, S. G., Le Caignec, C., de Leeuw, N., Liehr, T., Mackay, D. J., Montgomery, S. B., Pagnamenta, A. T., Papenhausen, P., Robinson, D. O., Ruivenkamp, C., Schwartz, C., Steiner, B., Stevenson, D. A., Surti, U., Wassink, T., Sharp, A. J. 2016; 99 (3): 555-566

  Abstract

  Genomic imprinting is a mechanism in which gene expression varies depending on parental origin. Imprinting occurs through differential epigenetic marks on the two parental alleles, with most imprinted loci marked by the presence of differentially methylated regions (DMRs). To identify sites of parental epigenetic bias, here we have profiled DNA methylation patterns in a cohort of 57 individuals with uniparental disomy (UPD) for 19 different chromosomes, defining imprinted DMRs as sites where the maternal and paternal methylation levels diverge significantly from the biparental mean. Using this approach we identified 77 DMRs, including nearly all those described in previous studies, in addition to 34 DMRs not previously reported. These include a DMR at TUBGCP5 within the recurrent 15q11.2 microdeletion region, suggesting potential parent-of-origin effects associated with this genomic disorder. We also observed a modest parental bias in DNA methylation levels at every CpG analyzed across ∼1.9 Mb of the 15q11-q13 Prader-Willi/Angelman syndrome region, demonstrating that the influence of imprinting is not limited to individual regulatory elements such as CpG islands, but can extend across entire chromosomal domains. Using RNA-seq data, we detected signatures consistent with imprinted expression associated with nine novel DMRs. Finally, using a population sample of 4,004 blood methylomes, we define patterns of epigenetic variation at DMRs, identifying rare individuals with global gain or loss of methylation across multiple imprinted loci. Our data provide a detailed map of parental epigenetic bias in the human genome, providing insights into potential parent-of-origin effects.

  View details for DOI 10.1016/j.ajhg.2016.06.032

  View details for PubMedID 27569549

• The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Schill, L., Schoyer, L., Andresen, B. S., Bakker, A., Bayrak-Toydemir, P., Burkitt-Wright, E., Chatfield, K., Elefteriou, F., Elgersma, Y., Fisher, M. J., Franz, D., Gelb, B. D., Goriely, A., Gripp, K. W., Hardan, A. Y., Keppler-Noreuil, K. M., Kerr, B., Korf, B., Leoni, C., McCormick, F., Plotkin, S. R., Rauen, K. A., Reilly, K., Roberts, A., Sandler, A., Siegel, D., Walsh, K., Widemann, B. C. 2016; 170 (8): 1959-1966

  Abstract

  The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37723

  View details for PubMedID 27155140

• Respiratory System Involvement in Costello Syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Gomez-Ospina, N., Kuo, C., Ananth, A. L., Myers, A., Brennan, M., Stevenson, D. A., Bernstein, J. A., Hudgins, L. 2016; 170 (7): 1849-1857

  Abstract

  Costello syndrome (CS) is a multisystem disorder caused by heterozygous germline mutations in the HRAS proto-oncogene. Respiratory system complications have been reported in individuals with CS, but a comprehensive description of the full spectrum and incidence of respiratory symptoms in these patients is not available. Here, we report the clinical course of four CS patients with respiratory complications as a major cause of morbidity. Review of the literature identified 56 CS patients with descriptions of their neonatal course and 17 patients in childhood/adulthood. We found that in the neonatal period, respiratory complications are seen in approximately 78% of patients with transient respiratory distress reported in 45% of neonates. Other more specific respiratory diagnoses were reported in 62% of patients, the majority of which comprised disorders of the upper and lower respiratory tract. Symptoms of upper airway obstruction were reported in CS neonates but were more commonly diagnosed in childhood/adulthood (71%). Analysis of HRAS mutations and their respiratory phenotype revealed that the common p.Gly12Ser mutation is more often associated with transient respiratory distress and other respiratory diagnoses. Respiratory failure and dependence on mechanical ventilation occurs almost exclusively with rare mutations. In cases of prenatally diagnosed CS, the high incidence of respiratory complications in the neonatal period should prompt anticipatory guidance and development of a postnatal management plan. This may be important in cases involving rarer mutations. Furthermore, the high frequency of airway obstruction in CS patients suggests that otorhinolaryngological evaluation and sleep studies should be considered. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37655

  View details for PubMedID 27102959

• RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome. American journal of medical genetics. Part A Macmurdo, C. F., Wooderchak-Donahue, W., Bayrak-Toydemir, P., Le, J., Wallenstein, M. B., Milla, C., Teng, J. M., Bernstein, J. A., Stevenson, D. A. 2016; 170 (6): 1450-1454

  Abstract

  Germline mutations in RASA1 are associated with capillary malformation-arteriovenous malformation (CM-AVM) syndrome. CM-AVM syndrome is characterized by multi-focal capillary malformations and arteriovenous malformations. Lymphatic anomalies have been proposed as part of the phenotype. Intrafamilial variability has been reported, suggesting modifiers and somatic events. The objective of the study was to identify somatic RASA1 "second hits" from vascular malformations associated with CM-AVM syndrome, and describe phenotypic variability. Participants were examined and phenotyped. Genomic DNA was extracted from peripheral blood on all participants. Whole-exome sequencing was performed on the proband. Using Sanger sequencing, RASA1 exon 8 was PCR-amplified to track the c.1248T>G, p.Tyr416X germline variant through the family. A skin biopsy of a capillary malformation from the proband's mother was also obtained, and next-generation sequencing was performed on DNA from the affected tissue. A familial germline heterozygous novel pathogenic RASA1 variant, c.1248T>G (p.Tyr416X), was identified in the proband and her mother. The proband had capillary malformations, chylothorax, lymphedema, and overgrowth, while her affected mother had only isolated capillary malformations. Sequence analysis of DNA extracted from a skin biopsy of a capillary malformation of the affected mother showed a second RASA1 somatic mutation (c.2245C>T, p.Arg749X). These results and the extreme variable expressivity support the hypothesis that somatic "second hits" are required for the development of vascular anomalies associated with CM-AVM syndrome. In addition, the phenotypes of the affected individuals further clarify that lymphatic manifestations are also part of the phenotypic spectrum of RASA1-related disorders. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37613

  View details for PubMedID 26969842

• The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer PLOS GENETICS Hartung, A., Swensen, J., Uriz, I. E., Lapin, M., Kristjansdottir, K., Petersen, U. S., Bang, J. M., Guerra, B., Andersen, H. S., Dobrowolski, S. F., Carey, J. C., Yu, P., Vaughn, C., Calhoun, A., Larsen, M. R., Dyrskjot, L., Stevenson, D. A., Andresen, B. S. 2016; 12 (5)

  Abstract

  Costello syndrome (CS) may be caused by activating mutations in codon 12/13 of the HRAS proto-oncogene. HRAS p.Gly12Val mutations have the highest transforming activity, are very frequent in cancers, but very rare in CS, where they are reported to cause a severe, early lethal, phenotype. We identified an unusual, new germline p.Gly12Val mutation, c.35_36GC>TG, in a 12-year-old boy with attenuated CS. Analysis of his HRAS cDNA showed high levels of exon 2 skipping. Using wild type and mutant HRAS minigenes, we confirmed that c.35_36GC>TG results in exon 2 skipping by simultaneously disrupting the function of a critical Exonic Splicing Enhancer (ESE) and creation of an Exonic Splicing Silencer (ESS). We show that this vulnerability of HRAS exon 2 is caused by a weak 3' splice site, which makes exon 2 inclusion dependent on binding of splicing stimulatory proteins, like SRSF2, to the critical ESE. Because the majority of cancer- and CS- causing mutations are located here, they affect splicing differently. Therefore, our results also demonstrate that the phenotype in CS and somatic cancers is not only determined by the different transforming potentials of mutant HRAS proteins, but also by the efficiency of exon 2 inclusion resulting from the different HRAS mutations. Finally, we show that a splice switching oligonucleotide (SSO) that blocks access to the critical ESE causes exon 2 skipping and halts proliferation of cancer cells. This unravels a potential for development of new anti-cancer therapies based on SSO-mediated HRAS exon 2 skipping.

  View details for DOI 10.1371/journal.pgen.1006039

  View details for PubMedID 27195699

• Maternal uniparental disomy of chromosome 20: a novel imprinting disorder of growth failure GENETICS IN MEDICINE Mulchandani, S., Bhoj, E. J., Luo, M., Powell-Hamilton, N., Jenny, K., Gripp, K. W., Elbracht, M., Eggermann, T., Turner, C. L., Temple, I. K., Mackay, D. J., Dubbs, H., Stevenson, D. A., Slattery, L., Zackai, E. H., Spinner, N. B., Krantz, I. D., Conlin, L. K. 2016; 18 (4): 309-315

  Abstract

  Maternal uniparental disomy of chromosome 20 (UPD(20)mat) has been reported in only four patients, three of whom also had mosaicism for complete or partial trisomy of chromosome 20. We sought to evaluate the clinical significance of isolated UPD(20)mat in eight individuals.We evaluated phenotypic and genomic findings of a series of eight new patients with UPD(20)mat.All eight individuals with UPD(20)mat had intrauterine growth restriction, short stature, and prominent feeding difficulties with failure to thrive. As a common feature, they often required gastric tube feeds. Genomic data in most patients are indicative of UPD as a result of trisomy rescue after meiosis II nondisjunction.We describe the first natural history of the disorder and the results of therapeutic interventions, including the frequent requirement of direct gastric feedings only during the first few years of life, and propose that growth hormone supplementation is probably safe and effective for this condition. We suggest that UPD(20)mat can be regarded as a new imprinting disorder and its identification requires specialized molecular testing, which should be performed in patients with early-onset idiopathic isolated growth failure.Genet Med 18 4, 309-315.

  View details for DOI 10.1038/gim.2015.103

  View details for PubMedID 26248010

• The Occurrence of Occult Acetabular Dysplasia in Relatives of Individuals With Developmental Dysplasia of the Hip. Journal of pediatric orthopedics Carroll, K. L., Schiffern, A. N., Murray, K. A., Stevenson, D. A., Viskochil, D. H., Toydemir, R., MacWilliams, B. A., Roach, J. W. 2016; 36 (1): 96-100

  Abstract

  This study sought to determine the hip pathology of family members of patients with developmental dysplasia of the hip (DDH). The authors evaluated 120 people from 19 families known to have at least 1 member with surgically treated DDH. Each individual's functional outcome scores and pelvic radiographs were assessed for hip symptoms or pathology.Using a genetic population database and a pediatric hospital patient population, 19 families with high rates of DDH were identified. All family members (n=120) underwent physical examination, radiographic assessment, and completion of outcome instruments [American Academy of Orthopedics (AAOS) Hip and Knee; Harris Hip Score (HHS); and Western Ontario and McMaster Universities Arthritis Index (WOMAC)].The 120 subjects ranged from 1 to 84 years, 34 had orthopaedically treated DDH. Of the remaining 86 supposedly normal subjects, 23 (27%) had occult acetabular dysplasia (OAD) as defined by center edge angle (CEA) <20 and/or a Severin score of III or greater. Sixty percent of the 86 individuals were less than 30 years old, 74% of the OAD group were less than 30. Outcome scores of the treated DDH patients (AAOS, HHS, and WOMAC) were worse on the involved side regardless of age. Over age 30 individuals with OAD had statistically significant decreases in their AAOS Hip and Knee and WOMAC scores on the dysplastic side, but their HHS scores were not significantly different.Twenty-seven percent of first-degree and second-degree relatives of patients with DDH had unsuspected radiographic acetabular dysplasia in our study. Most of the subjects with OAD were younger than 30. After age 30, many of these patients developed symptoms.In families with a significant history of DDH, radiographic screening of siblings of patients with DDH to define OAD may be prudent.Level I—diagnostic study.

  View details for DOI 10.1097/BPO.0000000000000403

  View details for PubMedID 25705807

• Molecular diagnostics in the new era: clinical utility of a next generation sequencing panel in the diagnosis of HHT Wooderchak-Donahue, W. L., McDonald, J., VanSant-Webb, C., Lewis, T., Stevenson, D. A., Bayrak-Toydemir, P. SPRINGER. 2015: 533

  View details for Web of Science ID 000362683200031

• An Attenuated Phenotype of Costello Syndrome in Three Unrelated Individuals with a HRAS c.179G>A (p.Gly60Asp) Mutation Correlates with Uncommon Functional Consequences AMERICAN JOURNAL OF MEDICAL GENETICS PART A Gripp, K. W., Sol-Church, K., Smpokou, P., Graham, G. E., Stevenson, D. A., Hanson, H., Viskochil, D. H., Baker, L. C., Russo, B., Gardner, N., Stabley, D. L., Kolbe, V., Rosenberger, G. 2015; 167 (9): 2085-2097

  Abstract

  Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome (CS), an intellectual disability condition with severe failure to thrive, cardiac abnormalities, predisposition to tumors, and neurologic abnormalities. More than 80% of patients share the HRAS mutation c.34G>A (p.Gly12Ser) associated with the typical, relatively homogeneous phenotype. Rarer mutations occurred in individuals with an attenuated phenotype and less characteristic facial features. Most pathogenic HRAS alterations affect hydrolytic HRAS activity resulting in constitutive activation. "Gain-of-function" and "hyperactivation" concerning downstream pathways are widely used to explain the molecular basis and dysregulation of the RAS-MAPK pathway is the biologic mechanism shared amongst rasopathies. Panel testing for rasopathies identified a novel HRAS mutation (c.179G>A; p.Gly60Asp) in three individuals with attenuated features of Costello syndrome. De novo paternal origin occurred in two, transmission from a heterozygous mother in the third. Individuals showed subtle facial features; curly hair and relative macrocephaly were seen in three; atrial tachycardia and learning difficulties in two, and pulmonic valve dysplasia and mildly thickened left ventricle in one. None had severe failure to thrive, intellectual disability or cancer, underscoring the need to consider HRAS mutations in individuals with an unspecific rasopathy phenotype. Functional studies revealed strongly increased HRAS(Gly60Asp) binding to RAF1, but not to other signaling effectors. Hyperactivation of the MAPK downstream signaling pathways was absent. Our results indicate that an increase in the proportion of activated RAS downstream signaling components does not entirely explain the molecular basis of CS. We conclude that the phenotypic variability in CS recapitulates variable qualities of molecular dysfunction.

  View details for DOI 10.1002/ajmg.a.37128

  View details for Web of Science ID 000360056700017

  View details for PubMedCentralID PMC4830354

• An attenuated phenotype of Costello syndrome in three unrelated individuals with a HRAS c.179G>A (p.Gly60Asp) mutation correlates with uncommon functional consequences. American journal of medical genetics. Part A Gripp, K. W., Sol-Church, K., Smpokou, P., Graham, G. E., Stevenson, D. A., Hanson, H., Viskochil, D. H., Baker, L. C., Russo, B., Gardner, N., Stabley, D. L., Kolbe, V., Rosenberger, G. 2015; 167A (9): 2085-2097

  Abstract

  Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome (CS), an intellectual disability condition with severe failure to thrive, cardiac abnormalities, predisposition to tumors, and neurologic abnormalities. More than 80% of patients share the HRAS mutation c.34G>A (p.Gly12Ser) associated with the typical, relatively homogeneous phenotype. Rarer mutations occurred in individuals with an attenuated phenotype and less characteristic facial features. Most pathogenic HRAS alterations affect hydrolytic HRAS activity resulting in constitutive activation. "Gain-of-function" and "hyperactivation" concerning downstream pathways are widely used to explain the molecular basis and dysregulation of the RAS-MAPK pathway is the biologic mechanism shared amongst rasopathies. Panel testing for rasopathies identified a novel HRAS mutation (c.179G>A; p.Gly60Asp) in three individuals with attenuated features of Costello syndrome. De novo paternal origin occurred in two, transmission from a heterozygous mother in the third. Individuals showed subtle facial features; curly hair and relative macrocephaly were seen in three; atrial tachycardia and learning difficulties in two, and pulmonic valve dysplasia and mildly thickened left ventricle in one. None had severe failure to thrive, intellectual disability or cancer, underscoring the need to consider HRAS mutations in individuals with an unspecific rasopathy phenotype. Functional studies revealed strongly increased HRAS(Gly60Asp) binding to RAF1, but not to other signaling effectors. Hyperactivation of the MAPK downstream signaling pathways was absent. Our results indicate that an increase in the proportion of activated RAS downstream signaling components does not entirely explain the molecular basis of CS. We conclude that the phenotypic variability in CS recapitulates variable qualities of molecular dysfunction.

  View details for DOI 10.1002/ajmg.a.37128

  View details for PubMedID 25914166

• Stress and Coping in Parents of Children with Prader-Willi Syndrome: Assessment of the Impact of a Structured Plan of Care AMERICAN JOURNAL OF MEDICAL GENETICS PART A Tvrdik, T., Mason, D., Dent, K. M., Thornton, L., Hornton, S. N., Viskochil, D. H., Stevenson, D. A. 2015; 167A (5): 974-982

  Abstract

  Hyperphagia, developmental delays, and maladaptive behaviors are common in Prader-Willi syndrome (PWS) likely resulting in heightened parental stress. Objectives were to evaluate stress, describe usefulness of coping behaviors, and assess the impact of a structured Plan of Care (PC) on parents with children with PWS. Parents answered Perceived Stress Scale (PSS-14), Coping Health Inventory for Parents (CHIP), and narrative/demographic surveys. The PC was introduced to a cohort of parents after completion of the PSS-14 and CHIP and re-administered 4-6 month after the introduction of the PC. Higher parental stress (n = 57) was observed compared to the general population, and associated with parent's age, number of children living at home, and child's age and residential setting. "Maintaining family integration, cooperation, and an optimistic definition of the situation" was the most useful coping pattern. Thirty-eight parents answered the PSS-14 and CHIP after the PC. Parental stress decreased after the PC (P = 0.035). Coping behaviors related to "maintaining family integration" increased after the PC (P = 0.042). Women and men preferred different coping patterns before and after the PC. In conclusion, parental stress is increased in PWS, and a PC decreased stress and increased coping behaviors related to family stability for parents with children with PWS. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.36971

  View details for Web of Science ID 000353171900002

  View details for PubMedID 25755074

• Corrigendum: Asfotase-a improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1. Nature medicine de la Croix Ndong, J., Makowski, A. J., Uppuganti, S., Vignaux, G., Ono, K., Perrien, D. S., Joubert, S., Baglio, S. R., Granchi, D., Stevenson, D. A., Rios, J. J., Nyman, J. S., Elefteriou, F. 2015; 21 (4): 414-?

  View details for DOI 10.1038/nm0415-414c

  View details for PubMedID 25849275

• Evaluation of somatic mutations in tibial pseudarthrosis samples in neurofibromatosis type 1 JOURNAL OF MEDICAL GENETICS Sant, D. W., Margraf, R. L., Stevenson, D. A., Grossmann, A. H., Viskochil, D. H., Hanson, H., Everitt, M. D., Rios, J. J., Elefteriou, F., Hennessey, T., Mao, R. 2015; 52 (4): 256-261

  Abstract

  Tibial pseudarthrosis is associated with neurofibromatosis type 1 (NF1) and there is wide clinical variability of the tibial dysplasia in NF1, suggesting the possibility of genetic modifiers. Double inactivation of NF1 is postulated to be necessary for the development of tibial pseudarthrosis, but tissue or cell of origin of the 'second hit' mutation remains unclear.Exome sequencing of different sections of surgically resected NF1 tibial pseudarthrosis tissue was performed and compared to germline (peripheral blood).A germline NF1 splice site mutation (c.61-2A>T, p.L21 M68del) was identified from DNA extracted from peripheral blood. Exome sequencing of DNA extracted from tissue removed during surgery of the tibial pseudarthrosis showed a somatic mutation of NF1 (c.3574G>T, p.E1192*) in the normal germline allele. Further analysis of different regions of the tibial pseudarthrosis sample showed enrichment of the somatic mutation in the soft tissue within the pseudarthrosis site and absence of the somatic mutation in cortical bone. In addition, a germline variant in PTPN11 (c.1658C>T, p.T553M), a gene involved in the RAS signal transduction pathway was identified, although the clinical significance is unknown.Given that the NF1 somatic mutation was primarily detected in the proliferative soft tissue at the pseudarthrosis site, it is likely that the second hit occurred in mesenchymal progenitors from the periosteum. These results are consistent with a defect of differentiation, which may explain why the mutation is found in proliferative cells and not within cortical bone tissue, as the latter by definition contains mostly mature differentiated osteoblasts and osteocytes.

  View details for DOI 10.1136/jmedgenet-2014-102815

  View details for PubMedID 25612910

• Dystrophic Spinal Deformities in a Neurofibromatosis Type 1 Murine Model PLOS ONE Rhodes, S. D., Zhang, W., Yang, D., Yang, H., Chen, S., Wu, X., Li, X., Yang, X., Mohammad, K. S., Guise, T. A., Bergner, A. L., Stevenson, D. A., Yang, F. 2015; 10 (3)

  Abstract

  Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown. Here, we present two murine models: Nf1flox/-;PeriCre and Nf1flox/-;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease. Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis. Intriguingly, 36-60% of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice exhibit segmental vertebral fusion anomalies with boney obliteration of the intervertebral disc (IVD). While analogous findings have not yet been reported in the NF1 patient population, we herein present two case reports of IVD defects and interarticular vertebral fusion in patients with NF1. Collectively, these data provide novel insights regarding the pathophysiology of dystrophic spinal anomalies in NF1, and provide impetus for future radiographic analyses of larger patient cohorts to determine whether IVD and vertebral fusion defects may have been previously overlooked or underreported in the NF1 patient population.

  View details for DOI 10.1371/journal.pone.0119093

  View details for Web of Science ID 000352138500072

  View details for PubMedID 25786243

  View details for PubMedCentralID PMC4364663

• Function and disability in children with Costello syndrome and Cardiofaciocutaneous syndrome. American journal of medical genetics. Part A Johnson, B., Goldberg-Strassler, D., Gripp, K., Thacker, M., Leoni, C., Stevenson, D. 2015; 167 (1): 40-44

  Abstract

  There is limited research on function in individuals with RASopathies. Our hypothesis was that there was function and disability differences between Costello syndrome (CS) and Cardiofaciocutaneous syndrome (CFCS). The purpose of this study was to describe and compare the functional performance and level of disability of children with CS and CFCS using the Pediatric Outcomes Data Collection Instrument (PODCI) and Pediatric Evaluation of Disability Index (PEDI). Parents of individuals with a medical diagnosis of CS and CFCS completed the computer or paper version of the questionnaires. Comparisons of response data were made between the two syndromes and published normative data. Fifty-two parents participated in the study, 38 in the CS group and 14 in the CFCS group. There were no significant differences in PODCI or PEDI scores between the CS and CFCS groups. There were statistically significant differences from normative values for all PODCI domains (P ≤ 0.012). The PEDI T-scores of both groups were greater than two standard deviations below normative scores in mobility (CS = 12.37, CFCS = 2.37), social (CS = 24.01, CFCS = 20.08), and activity (CS = 15.88, CFCS = 14.32). Responsibility T scores were in the normal range (30-70) for the CS group (31.38), but not for the CFCS group (28.40). The CS and CFCS groups had activity limitations in the PODCI domains of upper extremity function, transfers, and mobility, sport and physical function. These functional limitations cause significant disability in the PEDI domains of daily activity, mobility, and socialization and cognition. CS and CFCS are similar conditions in respect to functional limitations and severity of disability. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.36828

  View details for PubMedID 25346259

• Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia. Nature communications Lukacs, V., Mathur, J., Mao, R., Bayrak-Toydemir, P., Procter, M., Cahalan, S. M., Kim, H. J., Bandell, M., Longo, N., Day, R. W., Stevenson, D. A., Patapoutian, A., Krock, B. L. 2015; 6: 8329-?

  Abstract

  Piezo1 ion channels are mediators of mechanotransduction in several cell types including the vascular endothelium, renal tubular cells and erythrocytes. Gain-of-function mutations in PIEZO1 cause an autosomal dominant haemolytic anaemia in humans called dehydrated hereditary stomatocytosis. However, the phenotypic consequence of PIEZO1 loss of function in humans has not previously been documented. Here we discover a novel role of this channel in the lymphatic system. Through whole-exome sequencing, we identify biallelic mutations in PIEZO1 (a splicing variant leading to early truncation and a non-synonymous missense variant) in a pair of siblings affected with persistent lymphoedema caused by congenital lymphatic dysplasia. Analysis of patients' erythrocytes as well as studies in a heterologous system reveal greatly attenuated PIEZO1 function in affected alleles. Our results delineate a novel clinical category of PIEZO1-associated hereditary lymphoedema.

  View details for DOI 10.1038/ncomms9329

  View details for PubMedID 26387913

  View details for PubMedCentralID PMC4578306

• Genetic Variants Associated with Port-Wine Stains. PloS one Frigerio, A., Wright, K., Wooderchak-Donahue, W., Tan, O. T., Margraf, R., Stevenson, D. A., Grimmer, J. F., Bayrak-Toydemir, P. 2015; 10 (7): e0133158

  Abstract

  Port-wine stains (PWS) are capillary malformations, typically located in the dermis of the head and neck, affecting 0.3% of the population. Current theories suggest that port-wine stains are caused by somatic mutations that disrupt vascular development.Understanding PWS genetic determinants could provide insight into new treatments.Our study used a custom next generation sequencing (NGS) panel and digital polymerase chain reaction to investigate genetic variants in 12 individuals with isolated port-wine stains. Importantly, affected and healthy skin tissue from the same individual were compared. A subtractive correction method was developed to eliminate background noise from NGS data. This allowed the detection of a very low level of mosaicism.A novel somatic variant GNAQ, c.547C>G, p.Arg183Gly was found in one case with 4% allele frequency. The previously reported GNAQ c.548G>A, p.Arg183Gln was confirmed in 9 of 12 cases with an allele frequency ranging from 1.73 to 7.42%. Digital polymerase chain reaction confirmed novel variants detected by next generation sequencing. Two novel somatic variants were also found in RASA1, although neither was predicted to be deleterious.This is the second largest study on isolated, non-syndromic PWS. Our data suggest that GNAQ is the main genetic determinant in this condition. Moreover, isolated port-wine stains are distinct from capillary malformations seen in RASA1 disorders, which will be helpful in clinical evaluation.

  View details for DOI 10.1371/journal.pone.0133158

  View details for PubMedID 26192947

  View details for PubMedCentralID PMC4508108

• Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia. Nature communications Lukacs, V., Mathur, J., Mao, R., Bayrak-Toydemir, P., Procter, M., Cahalan, S. M., Kim, H. J., Bandell, M., Longo, N., Day, R. W., Stevenson, D. A., Patapoutian, A., Krock, B. L. 2015; 6: 8329-?

  Abstract

  Piezo1 ion channels are mediators of mechanotransduction in several cell types including the vascular endothelium, renal tubular cells and erythrocytes. Gain-of-function mutations in PIEZO1 cause an autosomal dominant haemolytic anaemia in humans called dehydrated hereditary stomatocytosis. However, the phenotypic consequence of PIEZO1 loss of function in humans has not previously been documented. Here we discover a novel role of this channel in the lymphatic system. Through whole-exome sequencing, we identify biallelic mutations in PIEZO1 (a splicing variant leading to early truncation and a non-synonymous missense variant) in a pair of siblings affected with persistent lymphoedema caused by congenital lymphatic dysplasia. Analysis of patients' erythrocytes as well as studies in a heterologous system reveal greatly attenuated PIEZO1 function in affected alleles. Our results delineate a novel clinical category of PIEZO1-associated hereditary lymphoedema.

  View details for DOI 10.1038/ncomms9329

  View details for PubMedID 26387913

• Genetic Variants Associated with Port-Wine Stains. PloS one Frigerio, A., Wright, K., Wooderchak-Donahue, W., Tan, O. T., Margraf, R., Stevenson, D. A., Grimmer, J. F., Bayrak-Toydemir, P. 2015; 10 (7)

  Abstract

  Port-wine stains (PWS) are capillary malformations, typically located in the dermis of the head and neck, affecting 0.3% of the population. Current theories suggest that port-wine stains are caused by somatic mutations that disrupt vascular development.Understanding PWS genetic determinants could provide insight into new treatments.Our study used a custom next generation sequencing (NGS) panel and digital polymerase chain reaction to investigate genetic variants in 12 individuals with isolated port-wine stains. Importantly, affected and healthy skin tissue from the same individual were compared. A subtractive correction method was developed to eliminate background noise from NGS data. This allowed the detection of a very low level of mosaicism.A novel somatic variant GNAQ, c.547C>G, p.Arg183Gly was found in one case with 4% allele frequency. The previously reported GNAQ c.548G>A, p.Arg183Gln was confirmed in 9 of 12 cases with an allele frequency ranging from 1.73 to 7.42%. Digital polymerase chain reaction confirmed novel variants detected by next generation sequencing. Two novel somatic variants were also found in RASA1, although neither was predicted to be deleterious.This is the second largest study on isolated, non-syndromic PWS. Our data suggest that GNAQ is the main genetic determinant in this condition. Moreover, isolated port-wine stains are distinct from capillary malformations seen in RASA1 disorders, which will be helpful in clinical evaluation.

  View details for DOI 10.1371/journal.pone.0133158

  View details for PubMedID 26192947

  View details for PubMedCentralID PMC4508108

• Activity and participation in children with neurofibromatosis type 1 RESEARCH IN DEVELOPMENTAL DISABILITIES Johnson, B. A., Sheng, X., Perry, A. S., Stevenson, D. A. 2015; 36: 213-221

  View details for DOI 10.1016/j.ridd.2014.10.004

  View details for Web of Science ID 000346689400023

• Dystrophic spinal deformities in a neurofibromatosis type 1 murine model. PloS one Rhodes, S. D., Zhang, W., Yang, D., Yang, H., Chen, S., Wu, X., Li, X., Yang, X., Mohammad, K. S., Guise, T. A., Bergner, A. L., Stevenson, D. A., Yang, F. 2015; 10 (3)

  Abstract

  Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1), the pathogenesis of these defects remains largely unknown. Here, we present two murine models: Nf1flox/-;PeriCre and Nf1flox/-;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease. Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis. Intriguingly, 36-60% of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice exhibit segmental vertebral fusion anomalies with boney obliteration of the intervertebral disc (IVD). While analogous findings have not yet been reported in the NF1 patient population, we herein present two case reports of IVD defects and interarticular vertebral fusion in patients with NF1. Collectively, these data provide novel insights regarding the pathophysiology of dystrophic spinal anomalies in NF1, and provide impetus for future radiographic analyses of larger patient cohorts to determine whether IVD and vertebral fusion defects may have been previously overlooked or underreported in the NF1 patient population.

  View details for DOI 10.1371/journal.pone.0119093

  View details for PubMedID 25786243

• The Cyclic AMP Pathway Is a Sex-Specific Modifier of Glioma Risk in Type I Neurofibromatosis Patients. Cancer research Warrington, N. M., Sun, T., Luo, J., McKinstry, R. C., Parkin, P. C., Ganzhorn, S., Spoljaric, D., Albers, A. C., Merkelson, A., Stewart, D. R., Stevenson, D. A., Viskochil, D., Druley, T. E., Forys, J. T., Reilly, K. M., Fisher, M. J., Tabori, U., Allen, J. C., Schiffman, J. D., Gutmann, D. H., Rubin, J. B. 2015; 75 (1): 16-21

  Abstract

  Identifying modifiers of glioma risk in patients with type I neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis, and potentially identify novel therapeutic targets. Here, we report genetic polymorphisms in the human adenylate cyclase gene adenylate cyclase 8 (ADCY8) that correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth-promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1. Cancer Res; 75(1); 16-21. ©2014 AACR.

  View details for DOI 10.1158/0008-5472.CAN-14-1891

  View details for PubMedID 25381154

• Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Frontiers in genetics McDonald, J., Wooderchak-Donahue, W., VanSant Webb, C., Whitehead, K., Stevenson, D. A., Bayrak-Toydemir, P. 2015; 6: 1-?

  Abstract

  Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by telangiectases and arteriovenous malformations (AVMs) in particular locations described in consensus clinical diagnostic criteria published in 2000. Two genes in the transforming growth factor-beta (TGF-β) signaling pathway, ENG and ACVRL1, were discovered almost two decades ago, and mutations in these genes have been reported to cause up to 85% of HHT. In our experience, approximately 96% of individuals with HHT have a mutation in these two genes, when published (Curaçao) diagnostic criteria for HHT are strictly applied. More recently, two additional genes in the same pathway, SMAD4 and GDF2, have been identified in a much smaller number of patients with a similar or overlapping phenotype to HHT. Yet families still exist with compelling evidence of a hereditary telangiectasia disorder, but no identifiable mutation in a known gene. Recent availability of whole exome and genome testing has created new opportunities to facilitate gene discovery, identify genetic modifiers to explain clinical variability, and potentially define an increased spectrum of hereditary telangiectasia disorders. An expanded approach to molecular diagnostics for inherited telangiectasia disorders that incorporates a multi-gene next generation sequencing (NGS) HHT panel is proposed.

  View details for DOI 10.3389/fgene.2015.00001

  View details for PubMedID 25674101

• Update from the 2013 International Neurofibromatosis Conference AMERICAN JOURNAL OF MEDICAL GENETICS PART A Plotkin, S. R., Albers, A. C., Babovic-Vuksanovic, D., Blakeley, J. O., Breakefield, X. O., Dunn, C. M., Evans, D. G., Fisher, M. J., Friedman, J. M., Giovannini, M., Gutmann, D. H., Kalamarides, M., McClatchey, A. I., Messiaen, L., Morrison, H., Parkinson, D. B., Stemmer-Rachamimov, A. O., Van Raamsdonk, C. D., Riccardi, V. M., Rosser, T., Schindeler, A., Smith, M. J., Stevenson, D. A., Ullrich, N. J., van der Vaart, T., Weiss, B., Widemann, B. C., Zhu, Y., Bakker, A. C., Lloyd, A. C. 2014; 164A (12): 2969-2978

  View details for DOI 10.1002/ajmg.a.36754

  View details for Web of Science ID 000345293300003

  View details for PubMedID 25255738

  View details for PubMedCentralID PMC4236251

• Neurofibromin Deficiency-Associated Transcriptional Dysregulation Suggests a Novel Therapy for Tibial Pseudoarthrosis in NF1 JOURNAL OF BONE AND MINERAL RESEARCH Paria, N., Cho, T., Choi, I. H., Kamiya, N., Kayembe, K., Mao, R., Margraf, R. L., Obermosser, G., Oxendine, I., Sant, D. W., Song, M. H., Stevenson, D. A., Viskochil, D. H., Wise, C. A., Kim, H. K., Rios, J. J. 2014; 29 (12): 2636-2642

  Abstract

  Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in NF1. Among the earliest manifestations is tibial pseudoarthrosis and persistent nonunion after fracture. To further understand the pathogenesis of pseudoarthrosis and the underlying bone remodeling defect, pseudoarthrosis tissue and cells cultured from surgically resected pseudoarthrosis tissue from NF1 individuals were analyzed using whole-exome and whole-transcriptome sequencing as well as genomewide microarray analysis. Genomewide analysis identified multiple genetic mechanisms resulting in somatic biallelic NF1 inactivation; no other genes with recurring somatic mutations were identified. Gene expression profiling identified dysregulated pathways associated with neurofibromin deficiency, including phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways. Unlike aggressive NF1-associated malignancies, tibial pseudoarthrosis tissue does not harbor a high frequency of somatic mutations in oncogenes or other tumor-suppressor genes, such as p53. However, gene expression profiling indicates that pseudoarthrosis tissue has a tumor-promoting transcriptional pattern, despite lacking tumorigenic somatic mutations. Significant overexpression of specific cancer-associated genes in pseudoarthrosis highlights a potential for receptor tyrosine kinase inhibitors to target neurofibromin-deficient pseudoarthrosis and promote proper bone remodeling and fracture healing.

  View details for DOI 10.1002/jbmr.2298

  View details for Web of Science ID 000346274700015

  View details for PubMedID 24932921

• Goltz syndrome and PORCN mosaicism INTERNATIONAL JOURNAL OF DERMATOLOGY Stevenson, D. A., Chirpich, M., Contreras, Y., Hanson, H., Dent, K. 2014; 53 (12): 1481-1484

  Abstract

  Goltz syndrome, also known as focal dermal hypoplasia, is characterized primarily by ectodermal and mesodermal defects. Manifestations include cutis aplasia, dermal hypoplasia, papillomas, chorioretinal colobomas, absent/dysplastic teeth, and skeletal anomalies. Goltz syndrome is an X-linked disorder due to mutations in PORCN, with a predominance of females affected. Germline mutations in PORCN are thought to result in embryonically lethality in males. We present a boy with a phenotype consistent with Goltz syndrome with low-level mosaicism for a novel mutation in PORCN from peripheral blood (c.956dupA; p.Asn320GlufsX99).

  View details for DOI 10.1111/ijd.12605

  View details for Web of Science ID 000345595800029

  View details for PubMedID 25040319

• Neural Tube Defects and Atypical Deletion on 22q11.2 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Leoni, C., Stevenson, D. A., Geiersbach, K. B., Paxton, C. N., Krock, B. L., Mao, R., Rope, A. F. 2014; 164A (11): 2701-2706

  Abstract

  The 22q11.2 deletion syndrome (22q11.2DS) is a common microdeletion disorder. Most of the patients show the common 3 Mb deletion but proximal 1.5 Mb deletion and unusual deletions located outside the common deleted region, have been detected particularly with the advance of comparative cytogenomic microarray technologies. The individuals reported in the literature with unusual deletions involving the 22q11 region, showed milder facial phenotypes, decreased incidence of cardiac anomalies, and intellectual disability. We describe two sibs with an atypical 0.8 Mb microdeletion of chromosome 22q11 who both showed myelomeningocele and mild facial dysmorphisms. The association between neural tube defect and the clinical diagnosis of Di George anomaly/velocardiofacial syndrome is well documented in the literature, but not all cases had molecular studies to determine breakpoint regions. This report helps to narrow a potential critical region for neural tube defects associated with 22q11 deletions.

  View details for DOI 10.1002/ajmg.a.36701

  View details for Web of Science ID 000344187200006

  View details for PubMedID 25123577

• Activity and participation in children with neurofibromatosis type 1. Research in developmental disabilities Johnson, B. A., Sheng, X., Perry, A. S., Stevenson, D. A. 2014; 36C: 213-221

  Abstract

  We describe activity and participation in children and youth with neurofibromatosis type 1 (NF1), and compared an intervention and control group after a strengthening program using the Pediatric Outcomes Data Collection Instrument (PODCI) and the Children's Assessment of Participation and Enjoyment (CAPE). Questionnaires were filled out by parents at baseline, 12-weeks, and 1-year. The intervention group performed a strengthening program twice a week for ten weeks, followed by a 9-month independent program. Thirty-six participants (18 control, 18 intervention) between the ages of 5- and 18-years (mean 10.6 years, SD 4.6 years) were enrolled, and 34 completed the 1-year assessment. There were significant differences between formal and informal participation (p<0.0001) in baseline CAPE scores for the entire cohort. At 12 weeks, PODCI upper extremity function improved in intervention and decreased in controls (p=0.040), while happiness declined in intervention and increased in control (p=0.003). There were no significant differences between control and intervention groups in any of the CAPE or PODCI change scores from baseline to 1-year. Upper extremity function, sport and physical function, comfort/pain and happiness PODCI scores were lower than normative values. The NF1 cohort had low participation in formal active physical and skill-based activities. The companionship and location dimensions suggest participation occurs with family and other relatives in the home or a relative's home and reflects a pattern of social isolation from peers.

  View details for DOI 10.1016/j.ridd.2014.10.004

  View details for PubMedID 25462482

• Asfotase-alpha improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1 NATURE MEDICINE Ndong, J. d., Makowski, A. J., Uppuganti, S., Vignaux, G., Ono, K., Perrien, D. S., Joubert, S., Baglio, S. R., Granchi, D., Stevenson, D. A., Rios, J. J., Nyman, J. S., Elefteriou, F. 2014; 20 (8): 904-910

  Abstract

  Individuals with neurofibromatosis type-1 (NF1) can manifest focal skeletal dysplasias that remain extremely difficult to treat. NF1 is caused by mutations in the NF1 gene, which encodes the RAS GTPase-activating protein neurofibromin. We report here that ablation of Nf1 in bone-forming cells leads to supraphysiologic accumulation of pyrophosphate (PPi), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PPi synthesis and extracellular transport, namely Enpp1 and Ank, causes this phenotype. Nf1 ablation also prevents bone morphogenic protein-2-induced osteoprogenitor differentiation and, consequently, expression of alkaline phosphatase and PPi breakdown, further contributing to PPi accumulation. The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase-α enzyme therapy aimed at reducing PPi concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PPi homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically.

  View details for DOI 10.1038/nm.3583

  View details for Web of Science ID 000340074600022

• Screening children with neurofibromatosis type 1 for autism spectrum disorder AMERICAN JOURNAL OF MEDICAL GENETICS PART A Tinker, J., Carbone, P. S., Viskochil, D., Mathiesen, A., Ma, K., Stevenson, D. A. 2014; 164 (7): 1706-1712

  Abstract

  Autism spectrum disorder (ASD) is reported to be increased in neurofibromatosis type 1 (NF1), but it's unknown if ASD screening tools are sensitive and specific for NF1. This study compared the rate at which children with NF1 screen-positive for two ASD screening tools [Modified Checklist for Autism in Toddlers (M-CHAT) and Childhood Autism Spectrum Test (CAST)] to the screen-positive rate of the general population. A retrospective cross-sectional observational design to investigate the association between children with NF1 and at risk status for ASD was used. Medical records of children between 16 months and 11 years of age seen in an NF Clinic were reviewed for an ASD screening questionnaire. There were no statistically significant differences in the screen-positive rate for ASD in NF1 compared to published controls, but mean CAST scores were higher in NF1.

  View details for DOI 10.1002/ajmg.a.36549

  View details for Web of Science ID 000337633300016

• L1CAM whole gene deletion in a child with L1 syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Chidsey, B. A., Baldwin, E. E., Toydemir, R., Ahles, L., Hanson, H., Stevenson, D. A. 2014; 164 (6): 1555-1558

  Abstract

  L1 syndrome is a group of overlapping, X-linked disorders caused by mutations in L1CAM. Clinical phenotypes within L1 syndrome include X-linked hydrocephalus with stenosis of the aqueduct of sylvius (HSAS); mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome; spastic paraplegia type 1; and agenesis of the corpus callosum. Over 200 mutations in L1CAM have been reported; however, only a few large gene deletions have been observed. We report on a 4-month-old male with a de novo whole gene deletion of L1CAM presenting with congenital hydrocephalus, aqueductal stenosis, and adducted thumbs. Initial failure of L1CAM gene sequencing suggested the possibility of a whole gene deletion of L1CAM. Further investigation through chromosome microarray analysis showed a 62Kb deletion encompassing the first exon of the PDZD4 gene and the entire L1CAM gene. Investigations into genotype-phenotype correlations have suggested that mutations leading to truncated or absent L1 protein cause more severe forms of L1 syndrome. Based on the presentation of the proband and other reported patients with whole gene deletions, we provide further evidence that L1CAM whole gene deletions result in L1 syndrome with a severe phenotype, deletions of PDZD4 do not cause additional manifestations, and that X-linked nephrogenic diabetes insipidus reported in a subset of patients with large L1CAM deletions results from the loss of AVPR2.

  View details for DOI 10.1002/ajmg.a.36474

  View details for Web of Science ID 000335926600027

• Postural control in children with and without neurofibromatosis type 1 HUMAN MOVEMENT SCIENCE Johnson, B. A., MacWilliams, B. A., Stevenson, D. A. 2014; 34: 157-163

  Abstract

  Previous research has evaluated the motor proficiency of children with neurofibromatosis type 1 (NF1) and found delays on the balance subtest. However the balance subtest was found to have low sensitivity for identifying balance impairments. This study examines the differences in postural control between children with NF1 and peers with typical development using a force plate. A single limb stance test on a force plate was completed for all participants. The force plate variables, center of pressure maximum distance in the anterior/posterior direction (COPmax A/P) and center of pressure velocity (COPvel A/P) were compared between groups. The NF1 group's performance was significantly poorer than the control group in both COPmax A/P (p=.01) and COPvel A/P (p=.01). When separated into specific age ranges, only the children in the NF1 group between 5 and 12years of age demonstrated statistically significant differences in the COP variables. The COP variables for the 13- to 18-year-old group were not significantly different. These results indicate that young children with NF1 have poor postural control. However, postural control appears to improve with maturation.

  View details for DOI 10.1016/j.humov.2014.01.008

  View details for Web of Science ID 000337009900014

  View details for PubMedID 24630611

• CTF Meeting 2012: Translation of the Basic Understanding of the Biology and Genetics of NF1, NF2, and Schwannomatosis Toward the Development of Effective Therapies AMERICAN JOURNAL OF MEDICAL GENETICS PART A Widemann, B. C., Acosta, M. T., Ammoun, S., Belzberg, A. J., Bernards, A., Blakeley, J., Bretscher, A., Cichowski, K., Clapp, D. W., Dombi, E., Evans, G. D., Ferner, R., Fernandez-Valle, C., Fisher, M. J., Giovannini, M., Gutmann, D. H., Hanemann, C. O., Hennigan, R., Huson, S., Ingram, D., Kissil, J., Korf, B. R., Legius, E., Packer, R. J., McClatchey, A. I., McCormick, F., North, K., Pehrsson, M., Plotkin, S. R., Ramesh, V., Ratner, N., Schirmer, S., Sherman, L., Schorry, E., Stevenson, D., Stewart, D. R., Ullrich, N., Bakker, A. C., Morrison, H. 2014; 164 (3): 563-578

  Abstract

  The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a "state-of-the-field" for NF research in 2012.

  View details for DOI 10.1002/ajmg.a.36312

  View details for Web of Science ID 000331978700001

• Multiscale, Converging Defects of Macro-Porosity, Microstructure and Matrix Mineralization Impact Long Bone Fragility in NF1 PLOS ONE Kuehnisch, J., Seto, J., Lange, C., Schrof, S., Stumpp, S., Kobus, K., Grohmann, J., Kossler, N., Varga, P., Osswald, M., Emmerich, D., Tinschert, S., Thielemann, F., Duda, G., Seifert, W., El Khassawna, T., Stevenson, D. A., Elefteriou, F., Kornak, U., Raum, K., Fratzl, P., Mundlos, S., Kolanczyk, M. 2014; 9 (1)

  Abstract

  Bone fragility due to osteopenia, osteoporosis or debilitating focal skeletal dysplasias is a frequent observation in the Mendelian disease Neurofibromatosis type 1 (NF1). To determine the mechanisms underlying bone fragility in NF1 we analyzed two conditional mouse models, Nf1Prx1 (limb knock-out) and Nf1Col1 (osteoblast specific knock-out), as well as cortical bone samples from individuals with NF1. We examined mouse bone tissue with micro-computed tomography, qualitative and quantitative histology, mechanical tensile analysis, small-angle X-ray scattering (SAXS), energy dispersive X-ray spectroscopy (EDX), and scanning acoustic microscopy (SAM). In cortical bone of Nf1Prx1 mice we detected ectopic blood vessels that were associated with diaphyseal mineralization defects. Defective mineral binding in the proximity of blood vessels was most likely due to impaired bone collagen formation, as these areas were completely devoid of acidic matrix proteins and contained thin collagen fibers. Additionally, we found significantly reduced mechanical strength of the bone material, which was partially caused by increased osteocyte volume. Consistent with these observations, bone samples from individuals with NF1 and tibial dysplasia showed increased osteocyte lacuna volume. Reduced mechanical properties were associated with diminished matrix stiffness, as determined by SAM. In line with these observations, bone tissue from individuals with NF1 and tibial dysplasia showed heterogeneous mineralization and reduced collagen fiber thickness and packaging. Collectively, the data indicate that bone fragility in NF1 tibial dysplasia is partly due to an increased osteocyte-related micro-porosity, hypomineralization, a generalized defect of organic matrix formation, exacerbated in the regions of tensional and bending force integration, and finally persistence of ectopic blood vessels associated with localized macro-porotic bone lesions.

  View details for DOI 10.1371/journal.pone.0086115

  View details for Web of Science ID 000330244500186

  View details for PubMedID 24465906

• An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge GENOME BIOLOGY Brownstein, C. A., Beggs, A. H., Homer, N., Merriman, B., Yu, T. W., Flannery, K. C., DeChene, E. T., Towne, M. C., Savage, S. K., Price, E. N., Holm, I. A., Luquette, L. J., Lyon, E., Majzoub, J., Neupert, P., McCallie, D., Szolovits, P., Willard, H. F., Mendelsohn, N. J., Temme, R., Finkel, R. S., Yum, S. W., Medne, L., Sunyaev, S. R., Adzhubey, I., Cassa, C. A., de Bakker, P. I., Duzkale, H., Dworzynski, P., Fairbrother, W., Francioli, L., Funke, B. H., Giovanni, M. A., Handsaker, R. E., Lage, K., Lebo, M. S., Lek, M., Leshchiner, I., MacArthur, D. G., McLaughlin, H. M., Murray, M. F., Pers, T. H., Polak, P. P., Raychaudhuri, S., Rehm, H. L., Soemedi, R., Stitziel, N. O., Vestecka, S., Supper, J., Gugenmus, C., Klocke, B., Hahn, A., Schubach, M., Menzel, M., Biskup, S., Freisinger, P., Deng, M., Braun, M., Perner, S., Smith, R. J., Andorf, J. L., Huang, J., Ryckman, K., Sheffield, V. C., Stone, E. M., Bair, T., Black-Ziegelbein, E. A., Braun, T. A., Darbro, B., DeLuca, A. P., Kolbe, D. L., Scheetz, T. E., Shearer, A. E., Sompallae, R., Wang, K., Bassuk, A. G., Edens, E., Mathews, K., Moore, S. A., Shchelochkov, O. A., Trapane, P., Bossler, A., Campbell, C. A., Heusel, J. W., Kwitek, A., Maga, T., Panzer, K., Wassink, T., Van Daele, D., Azaiez, H., Booth, K., Meyer, N., Segal, M. M., Williams, M. S., Tromp, G., White, P., Corsmeier, D., Fitzgerald-Butt, S., Herman, G., Lamb-Thrush, D., McBride, K. L., Newsom, D., Pierson, C. R., Rakowsky, A. T., Maver, A., Lovrecic, L., Palandacic, A., Peterlin, B., Torkamani, A., Wedell, A., Huss, M., Alexeyenko, A., Lindvall, J. M., Magnusson, M., Nilsson, D., Stranneheim, H., Taylan, F., Gilissen, C., Hoischen, A., van Bon, B., Yntema, H., Nelen, M., Zhang, W., Sager, J., Zhang, L., Blair, K., Kural, D., Cariaso, M., Lennon, G. G., Javed, A., Agrawal, S., Ng, P. C., Sandhu, K. S., Krishna, S., Veeramachaneni, V., Isakov, O., Halperin, E., friedman, e., Shomron, N., Glusman, G., Roach, J. C., Caballero, J., Cox, H. C., Mauldin, D., Ament, S. A., Rowen, L., Richards, D. R., San Lucas, F. A., Gonzalez-Garay, M. L., Caskey, C. T., Bai, Y., Huang, Y., Fang, F., Zhang, Y., Wang, Z., Barrera, J., Garcia-Lobo, J. M., Gonzalez-Lamuno, D., Llorca, J., Rodriguez, M. C., Varela, I., Reese, M. G., De La Vega, F. M., Kiruluta, E., Cargill, M., Hart, R. K., Sorenson, J. M., Lyon, G. J., Stevenson, D. A., Bray, B. E., Moore, B. M., Eilbeck, K., Yandell, M., Zhao, H., Hou, L., Chen, X., Yan, X., Chen, M., Li, C., Yang, C., Gunel, M., Li, P., Kong, Y., Alexander, A. C., Albertyn, Z. I., Boycott, K. M., Bulman, D. E., Gordon, P. M., Innes, A. M., Knoppers, B. M., Majewski, J., Marshall, C. R., Parboosingh, J. S., Sawyer, S. L., Samuels, M. E., Schwartzentruber, J., Kohane, I. S., Margulies, D. M. 2014; 15 (3)

  Abstract

  There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance.A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization.The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.

  View details for DOI 10.1186/gb-2014-15-3-r53

  View details for Web of Science ID 000338981300014

  View details for PubMedCentralID PMC4073084

• Biomarkers of bone remodeling in children with mucopolysaccharidosis types I, II, and VI. Journal of pediatric rehabilitation medicine Stevenson, D. A., Rudser, K., Kunin-Batson, A., Fung, E. B., Viskochil, D., Shapiro, E., Orchard, P. J., Whitley, C. B., Polgreen, L. E. 2014; 7 (2): 159-165

  Abstract

  Skeletal disease causes significant morbidity in mucopolysaccharidoses (MPS), and bone remodeling processes in MPS have not been well characterized. The objective of this study was to determine if biomarkers of bone turnover are abnormal in children with specific MPS disorders (i.e. MSP-I, MPS-II, and MPS-VI) compared to healthy children.A cross-sectional study was performed of serum biomarkers of bone formation (bone-specific alkaline phosphatase [BSAP], osteocalcin) and urine biomarkers of bone resorption (pyridinoline, deoxypyridinoline) in MPS and healthy controls. Measures of physical function and pain were obtained using the Children's Health Questionnaire (CHQ).The cohort consisted of 39 children with MPS (MPS-I=26; MPS-II=11; MPS-VI=4) and 51 healthy children. Adjusting for sex and Tanner stage group, MPS individuals had statistically significant increases for osteocalcin (p< 0.001), with trends toward higher BSAP (p=0.054) and urinary pyridinoline (p=0.084). These biomarkers were not significantly associated with CHQ bodily pain and physical-function scores.Osteocalcin was increased in children with MPS disorders, with trends for increases in BSAP and urinary pyridinoline, suggesting that bone remodeling is altered in children with MPS. Future studies to assess the ability of these biomarkers to quantify and monitor MPS skeletal disease in response to therapy are needed.

  View details for DOI 10.3233/PRM-140285

  View details for PubMedID 25096868

• Low Bone Mineral Content and Challenges in Interpretation of Dual-Energy X-Ray Absorptiometry in Children With Mucopolysaccharidosis Types I, II, and VI JOURNAL OF CLINICAL DENSITOMETRY Polgreen, L. E., Thomas, W., Fung, E., Viskochil, D., Stevenson, D. A., Steinberger, J., Orchard, P., Whitley, C. B., Ensrud, K. E. 2014; 17 (1): 200-206

  Abstract

  Osteoporosis has been described in animal models of mucopolysaccharidosis (MPS). Whether clinically significant osteoporosis is common among children with MPS is unknown. Therefore, cross-sectional data from whole body (WB; excluding head) and lumbar spine (LS) bone mineral density (BMD) compared with sex-, chronologic age-, and ethnicity-matched healthy individuals (Zage), height-for-age (HAZ) Z-score (ZHAZ) and bone mineral content (BMC) measured by dual-energy X-ray absorptiometry (DXA) in 40 children with MPS were analyzed. A subset of these children (n=24) was matched 1:3 by age and sex to a group of healthy children (n=72) for comparison of BMC adjusted for Tanner stage, race, lean body mass, height, and bone area. Low BMD Z-score was defined as Z-score of -2 or less. In children with MPS, 15% had low WB Zage and 48% had low LS Zage; 0% and 6% had low WB ZHAZ and low LS ZHAZ, respectively. Adjusted WB BMC was lower in MPS participants (p=0.009). In conclusion, children with MPS had deficits in WB BMC after adjustments for stature and bone area. HAZ adjustment underestimated bone deficits (i.e., overestimated WB BMD Z-scores) in children with MPS likely owing to their abnormal bone shape. The influence of severe short stature and bone geometry on DXA measurements must be considered in children with MPS to avoid unnecessary exposure to antiresorptive treatments.

  View details for DOI 10.1016/j.jocd.2013.03.004

  View details for Web of Science ID 000331598300033

  View details for PubMedID 23562131

• Decreased bone mineral density in Costello syndrome MOLECULAR GENETICS AND METABOLISM Leoni, C., Stevenson, D. A., Martini, L., De Sanctis, R., Mascolo, G., Pantaleoni, F., De Santis, S., La Torraca, I., Persichilli, S., Caradonna, P., Tartaglia, M., Zampino, G. 2014; 111 (1): 41-45

  Abstract

  Costello syndrome (CS) is a multisystemic disorder characterized by postnatal reduced growth, facial dysmorphism, cardiac defects, cognitive impairment, skin and musculo-skeletal anomalies, and predisposition to certain cancers. CS is caused by activating germline mutations in the HRAS proto-oncogene. Similar to what is observed in other RASopathies, CS causative HRAS mutations promote enhanced signal flow through the RAF-MEK-ERK and PI3K-AKT signaling cascades. While decreased bone mineralization has been documented in other RASopathies, such as neurofibromatosis type 1 and Noonan syndrome, systematic studies investigating bone mineral density (BMD) are lacking in CS.Dual-energy X-ray absorptiometry (DXA) was utilized to assess BMD and body composition (fat and fat-free mass) in a cohort of subjects with molecularly confirmed diagnosis of CS (n = 9) and age-matched control individuals (n = 29). Using general linear regression, subtotal body (total body less head), lumbar, femoral neck and femur BMD parameters were compared considering age, sex, body mass index (BMI) and Tanner stage. Blood and urine biomarkers of bone metabolism were also assessed.All individuals with CS showed significantly lower mean values of subtotal, lumbar and femoral neck BMD compared to the control group (p ≤ 0.01). Similarly, mean total body mass and fat-free mass parameters were lower among the CS patients than in controls (p < 0.01). Low 25-OH vitamin D concentration was documented in all individuals with CS, with values below the reference range in two patients. No significant correlation between vitamin D levels and BMD parameters was observed.CS belongs to a family of developmental disorders, the RASopathies, that share skeletal defects as a common feature. The present data provide evidence that, similar to what is recently seen in NF1 and NS, bone homeostasis is impaired in CS. The significant decrease in BMD and low levels of vitamin D documented in the present cohort, along with the risk for pathologic fractures reported in adult individuals with CS, testifies the requirement for a preventive treatment to alleviate evolutive complications resulting from dysregulated bone metabolism.

  View details for DOI 10.1016/j.ymgme.2013.08.007

  View details for Web of Science ID 000330158100006

  View details for PubMedID 24246682

• Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurofibromin-deficient mice HUMAN MOLECULAR GENETICS Sharma, R., Wu, X., Rhodes, S. D., Chen, S., He, Y., Yuan, J., Li, J., Yang, X., Li, X., Jiang, L., Kim, E. T., Stevenson, D. A., Viskochil, D., Xu, M., Yang, F. 2013; 22 (23): 4818-4828

  Abstract

  Neurofibromatosis type 1 (NF1) is a common genetic disorder affecting 1 in 3500 individuals. Patients with NF1 are predisposed to debilitating skeletal manifestations, including osteopenia/osteoporosis and long bone pseudarthrosis (nonunion fracture). Hyperactivation of the Ras/mitogen-activated protein kinase (MAPK) pathway in NF1 is known to underlie aberrant proliferation and differentiation in cell lineages, including osteoclast progenitors and mesenchymal stem cells (MSCs) also known as osteoblast progenitors (pro-OBLs). Our current study demonstrates the hyper Ras/MAPK as a critical pathway underlying the pathogenesis of NF1-associated fracture repair deficits. Nf1-deficient pro-OBLs exhibit Ras/MAPK hyperactivation. Introduction of the NF1 GTPase activating-related domain (NF1 GAP-related domain) in vitro is sufficient to rescue hyper Ras activity and enhance osteoblast (OBL) differentiation in Nf1(-/-) pro-OBLs and NF1 human (h) MSCs cultured from NF1 patients with skeletal abnormalities, including pseudarthrosis or scoliosis. Pharmacologic inhibition of mitogen-activated protein kinase kinase (MEK) signaling with PD98059 partially rescues aberrant Erk activation while enhancing OBL differentiation and expression of OBL markers, osterix and osteocalcin, in Nf1-deficient murine pro-OBLs. Similarly, MEK inhibition enhances OBL differentiation of hMSCs. In addition, PD98059 rescues aberrant osteoclast maturation in Nf1 haploinsufficient bone marrow mononuclear cells (BMMNCs). Importantly, MEK inhibitor significantly improves fracture healing in an NF1 murine model, Col2.3Cre;Nf1(flox/-). Collectively, these data indicate the Ras/MAPK cascade as a critical pathway in the pathogenesis of bone loss and pseudarthrosis related to NF1 mutations. These studies provide evidence for targeting the MAPK pathway to improve bone mass and treat pseudarthrosis in NF1.

  View details for DOI 10.1093/hmg/ddt333

  View details for Web of Science ID 000326973000014

  View details for PubMedID 23863460

• BMP9 Mutations Cause a Vascular-Anomaly Syndrome with Phenotypic Overlap with Hereditary Hemorrhagic Telangiectasia AMERICAN JOURNAL OF HUMAN GENETICS Wooderchak-Donahue, W. L., McDonald, J., O'Fallon, B., Upton, P. D., Li, W., Roman, B. L., Young, S., Plant, P., Fueloep, G. T., Langa, C., Morrell, N. W., Botella, L. M., Bernabeu, C., Stevenson, D. A., Runo, J. R., Bayrak-Toydemir, P. 2013; 93 (3): 530-537

  Abstract

  Hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is caused by mutations in genes involved in the transforming growth factor beta (TGF-β) signaling pathway (ENG, ACVRL1, and SMAD4). Yet, approximately 15% of individuals with clinical features of HHT do not have mutations in these genes, suggesting that there are undiscovered mutations in other genes for HHT and possibly vascular disorders with overlapping phenotypes. The genetic etiology for 191 unrelated individuals clinically suspected to have HHT was investigated with the use of exome and Sanger sequencing; these individuals had no mutations in ENG, ACVRL1, and SMAD4. Mutations in BMP9 (also known as GDF2) were identified in three unrelated probands. These three individuals had epistaxis and dermal lesions that were described as telangiectases but whose location and appearance resembled lesions described in some individuals with RASA1-related disorders (capillary malformation-arteriovenous malformation syndrome). Analyses of the variant proteins suggested that mutations negatively affect protein processing and/or function, and a bmp9-deficient zebrafish model demonstrated that BMP9 is involved in angiogenesis. These data confirm a genetic cause of a vascular-anomaly syndrome that has phenotypic overlap with HHT.

  View details for DOI 10.1016/j.ajhg.2013.07.004

  View details for Web of Science ID 000330268900012

  View details for PubMedID 23972370

• Association of Twinning and Maternal Age with Major Structural Birth Defects in Utah, 1999 to 2008 BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Rider, R. A., Stevenson, D. A., Rinsky, J. E., Feldkamp, M. L. 2013; 97 (8): 554-563

  Abstract

  Twinning is a risk factor for birth defects. Using population-based data from the Utah Birth Defect Network and the Utah Department of Health Vital Records, we investigated whether twinning increases the risk of major structural birth defects in live-born opposite-sex (OS) and same-sex (SS) twins as proxies for monozygotic and dizygotic twins, respectively. We also assessed whether maternal age modified the association between twinning and birth defects.All resident live-born singleton (n = 492,143) and twin (n = 13,596) infants issued a Utah birth certificate and delivered from 1999 through 2008 were included. Unadjusted and adjusted odds ratios (aORs) with 95% confidence intervals were calculated for each birth defect using unconditional logistic regression.Birth defects were slightly more likely to occur in SS (aOR = 1.94; 95% confidence interval, 1.70-2.21) than OS (aOR = 1.55; 95% confidence interval, 1.27-1.90) twins. The aORs stratified by maternal age did not show a trend for any twin type when calculated for all birth defects combined. However, trends were observed for coarctation, pyloric stenosis, and shaft or penoscrotal hypospadias in OS twins; microcephaly, anotia/microtia, conotruncal defects, membranous ventricular septal defects, pyloric stenosis, all hypospadias, and craniosynostosis in SS twins; and tetralogy of Fallot, right ventricular outflow tract obstructions, renal agenesis/hypoplasia, and craniosynostosis in all twins.All twin types have an increased risk for birth defects compared with singletons. SS twins have the highest risk, presumably due to the influence of monozygotic twins. The risk for birth defects in twins was not significantly modified by the mother's age.

  View details for DOI 10.1002/bdra.23156

  View details for Web of Science ID 000326398800006

  View details for PubMedID 23913417

• The generalized bone phenotype in children with neurofibromatosis 1: A sibling matched case-control study AMERICAN JOURNAL OF MEDICAL GENETICS PART A Armstrong, L., Jett, K., Birch, P., Kendler, D. L., McKay, H., Tsang, E., Stevenson, D. A., Hanley, D. A., Egeli, D., Burrows, M., Friedman, J. M. 2013; 161A (7): 1654-1661

  Abstract

  People with neurofibromatosis 1 (NF1) have low bone mineralization, but the natural history and pathogenesis are poorly understood. We performed a sibling-matched case-control study of bone mineral status, morphology, and metabolism. Eighteen children with NF1 without focal bony lesions were compared to unaffected siblings and local population controls. Bone mineral content at the lumbar spine and proximal femur (dual energy X-ray absorptiometry (DXA)) was lower in children with NF1; this difference persisted after adjusting for height and weight. Peripheral quantitative computed tomography (pQCT) of the distal tibia showed that trabecular density was more severely compromised than cortical. Peripheral QCT-derived estimates of bone strength and resistance to bending and stress were poorer among children with NF1 although there was no difference in fracture frequencies. There were no differences in the size or shape of bones after adjusting for height. Differences in markers of bone turnover between cases and controls were in the directions predicted by animal studies, but did not reach statistical significance. Average serum calcium concentration was higher (although within the normal range) in children with NF1; serum 25-OH vitamin D, and PTH levels did not differ significantly between cases and controls. Children with NF1 were less mature (assessed by pubertal stage) than unaffected siblings or population controls. Children with NF1 have a generalized difference of bone metabolism that predominantly affects trabecular bone. Effects of decreased neurofibromin on bone turnover, calcium homeostasis, and pubertal development may contribute to the differences in bone mineral content observed among people with NF1.

  View details for DOI 10.1002/ajmg.a.36001

  View details for Web of Science ID 000320650100017

  View details for PubMedID 23713011

• Skeletal abnormalities in lysosomal storage diseases. Pediatric endocrinology reviews : PER Stevenson, D. A., Steiner, R. D. 2013; 10: 406-416

  Abstract

  Many of the lysosomal storage diseases (LSDs) have skeletal abnormalities causing significant morbidity. Dysostosis multiplex describes a constellation of radiographic skeletal findings that are helpful in diagnosing many of the LSDs, particularly the mucopolysaccharidoses (MPS). This review discusses the clinical and radiographic skeletal manifestations of various LSDs with an emphasis on disorders that have significant skeletal involvement (eg, MPS disorders, mucolipidosis type II and Iil, Gaucher). Enzyme replacement therapy (ERT) for several of the LSDs has been beneficial for many of the clinical manifestations, but efficacy with regard to the skeletal abnormalities is not as obvious. As the pathophysiology of the skeletal abnormalities associated with LSDs becomes better elucidated, investigators will likely develop improved therapies to specifically target bone and alleviate the skeletal problems.

  View details for PubMedID 23858624

• Fractures in Children With Neurofibromatosis Type 1 From Two NF Clinics AMERICAN JOURNAL OF MEDICAL GENETICS PART A George-Abraham, J. K., Martin, L. J., Kalkwarf, H. J., Rieley, M. B., Stevenson, D. A., Viskochil, D. H., Hopkin, R. J., Stevens, A. M., Hanson, H., Schorry, E. K. 2013; 161A (5): 921-926

  Abstract

  Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with osseous abnormalities occurring in up to one-third of patients. Several studies have documented osteopenia in both children and adults with NF1; however, the significance of lower bone mineral density (BMD) in relationship to fracture incidence is not well elucidated in NF1, particularly in children. We undertook a retrospective study to determine prevalence and location of fractures in children and adolescents with NF1, ages 5-20 years, using a standardized questionnaire. We surveyed 256 individuals with NF1 from two multidisciplinary NF centers and 178 controls without NF1 of similar ages and sex. Participants with known long bone dysplasia (LBD) were analyzed separately. Data collected included numbers and location of fractures, dietary calcium intake, and physical activity levels. There was no difference in prevalence of ever having a fracture between the NF1 group without LBD (22%) and the control group (25%); median number of fractures also did not differ. There were significant differences in fracture location with a higher frequency of fractures of the lower extremities in NF1 individuals without LBD compared to controls. Both NF1 cohorts had lower rates of physical activity than controls (P < 0.0001). Our data demonstrate that the likelihood of having had a fracture is not higher in young NF1 individuals without LBD in comparison to healthy controls. The lower physical activity level may have a "protective effect" for those with NF1, thus keeping their fracture incidence lower than expected for their relative degree of osteopenia.

  View details for DOI 10.1002/ajmg.a.35541

  View details for Web of Science ID 000320648800001

  View details for PubMedID 23529831

• Approaches to Treating NF1 Tibial Pseudarthrosis: Consensus From the Children's Tumor Foundation NF1 Bone Abnormalities Consortium JOURNAL OF PEDIATRIC ORTHOPAEDICS Stevenson, D. A., Little, D., Armstrong, L., Crawford, A. H., Eastwood, D., Friedman, J. M., Greggi, T., Gutierrez, G., Hunter-Schaedle, K., Kendler, D. L., Kolanczyk, M., Monsell, F., Oetgen, M., Richards, B. S., Schindeler, A., Schorry, E. K., Wilkes, D., Viskochil, D. H., Yang, F., Elefteriou, F. 2013; 33 (3): 269-275

  Abstract

  Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with various skeletal abnormalities occurring as part of a complex phenotype. Tibial dysplasia, which typically presents as anterolateral bowing of the leg with subsequent fracture and nonunion (pseudarthrosis), is a serious but infrequent osseous manifestation of NF1. Over the past several years, results from clinical and experimental studies have advanced our knowledge of the role of NF1 in bone. On the basis of current knowledge, we propose a number of concepts to consider as a theoretical approach to the optimal management of tibial pseudarthrosis.A literature review for both clinical treatment and preclinical models for tibial dysplasia in NF1 was performed. Concepts were discussed and developed by experts who participated in the Children's Tumor Foundation sponsored International Bone Abnormalities Consortium meeting in 2011.Concepts for a theoretical approach to treating tibial pseudarthrosis include: bone fixation appropriate to achieve stability in any given case; debridement of the "fibrous pseudarthrosis tissue" between the bone segments associated with the pseudarthrosis; creating a healthy vascular bed for bone repair; promoting osteogenesis; controlling overactive bone resorption (catabolism); prevention of recurrence of the "fibrous pseudarthrosis tissue"; and achievement of long-term bone health to prevent recurrence.Clinical trials are needed to assess effectiveness of the wide variation of surgical and pharmacologic approaches currently in practice for the treatment of tibial pseudarthrosis in NF1.Level V, expert opinion.

  View details for DOI 10.1097/BPO.0b013e31828121b8

  View details for Web of Science ID 000316196400013

  View details for PubMedID 23482262

• Copy Number Variation Analysis in 98 Individuals with PHACE Syndrome JOURNAL OF INVESTIGATIVE DERMATOLOGY Siegel, D. H., Shieh, J. T., Kwon, E., Baselga, E., Blei, F., Cordisco, M., Dobyns, W. B., Duffy, K. J., Garzon, M. C., Gibbs, D. L., Grimmer, J. F., Hayflick, S. J., Krol, A. L., Kwok, P., Lorier, R., Matter, A., McWeeney, S., Metry, D., Mitchell, S., Pope, E., Santoro, J. L., Stevenson, D. A., Bayrak-Toydemir, P., Wilmot, B., Worthey, E. A., Frieden, I. J., Drolet, B. A., Broeckel, U. 2013; 133 (3): 677-684

  Abstract

  PHACE syndrome is the association of large segmental facial hemangiomas and congenital anomalies, such as posterior fossa malformations, cerebral arterial anomalies, coarctation of the aorta, eye anomalies, and sternal defects. To date, the reported cases of PHACE syndrome have been sporadic, suggesting that PHACE may have a complex pathogenesis. We report here genomic copy number variation (CNV) analysis of 98 individuals with PHACE syndrome as a first step in deciphering a potential genetic basis of PHACE syndrome. A total of 3,772 CNVs (2,507 duplications and 1,265 deletions) were detected in 98 individuals with PHACE syndrome. CNVs were then eliminated if they failed to meet established criteria for quality, spanned centromeres, or did not contain genes. CNVs were defined as "rare" if not documented in the database of genomic variants. Ten rare CNVs were discovered (size range: 134-406  kb), located at 1q32.1, 1q43, 3q26.32-3q26.33, 3p11.1, 7q33, 10q24.32, 12q24.13, 17q11.2, 18p11.31, and Xq28. There were no rare CNV events that occurred in more than one subject. Therefore, further study is needed to determine the significance of these CNVs in the pathogenesis of PHACE syndrome.

  View details for DOI 10.1038/jid.2012.367

  View details for Web of Science ID 000315008500015

  View details for PubMedID 23096700

  View details for PubMedCentralID PMC3971866

• A cost savings approach to SPRED1 mutational analysis in individuals at risk for neurofibromatosis type 1 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Muram, T. M., Stevenson, D. A., Watts-Justice, S., Viskochil, D. H., Carey, J. C., Mao, R., Jackson, B. 2013; 161A (3): 467-472

  Abstract

  Neurofibromatosis type 1 (NF1) is a clinically diagnosed autosomal dominant disorder requiring routine clinical management, particularly during the pediatric years. An overlapping disorder, Legius syndrome, at times is clinically indistinguishable from NF1 and results in a small percentage of individuals being mischaracterized. Distinguishing these two entities is increasingly important for prognosis, reproductive planning, and clinical management. The goal of our study was to evaluate the cost impact of genetic testing for patients with solely pigmentary findings. The costs of genetic testing in patients aged 1.5-18 years were modeled using a simulated population, assuming the clinical management approach of a single NF1 clinic. Two genetic testing algorithms (SPRED1 testing alone, and NF1 mutation analysis with reflex to SPRED1) were compared against a baseline of no genetic testing. The cost for SPRED1 mutation analysis for each individual meeting NF1 diagnostic criteria without neoplastic or boney manifestation, when compared to the no-testing approach with routine follow-up mutations between the ages of 10 and 14 years, was minimal (range of $4-$16). Based on the clinical practice of one NF1 clinic, we found that the cost difference to perform SPRED1 mutation analysis on individuals who meet diagnostic criteria for NF1 without neoplastic or boney manifestation were minimal. Therefore it is important that "when to test decisions" remain a physician/patient discussion, as individual benefits may be greatest at a different age than when it is most cost efficient.

  View details for DOI 10.1002/ajmg.a.35718

  View details for Web of Science ID 000315341700009

  View details for PubMedID 23401230

• The genetics of vascular anomalies CURRENT OPINION IN OTOLARYNGOLOGY & HEAD AND NECK SURGERY Frigerio, A., Stevenson, D. A., Grimmer, J. F. 2012; 20 (6): 527-532

  Abstract

  To summarize clinically relevant findings in the genetic cause and gene expression of vascular anomalies.Infantile hemangioma demonstrates familial clustering and is associated with atopic disease. Variable gene expression is seen in infantile hemangioma during proliferation and involution. Capillary malformation may be sporadic or inherited in an autosomal dominant pattern. Capillary malformation-arteriovenous malformation is caused by mutation in RASA1. Some inherited forms of lymphedema are due to mutation in VEGFR3. Venous malformation may be sporadic, paradominant, or autosomal dominant inheritance. Autosomal dominantly inherited forms of venous malformation are due to mutations in TIE2/TEK. Additionally, TIE2 somatic mutations have been identified in about half of sporadic venous malformations.Multiple genes have been identified causing inherited forms of vascular anomalies including capillary malformations, venous malformations and lymphedema. Variable gene expression of infantile hemangioma during proliferation and involution may offer new therapeutic targets for treatment.

  View details for DOI 10.1097/MOO.0b013e3283587415

  View details for Web of Science ID 000311106500017

  View details for PubMedID 22913934

• Peripheral muscle weakness in RASopathies MUSCLE & NERVE Stevenson, D. A., Allen, S., Tidyman, W. E., Carey, J. C., Viskochil, D. H., Stevens, A., Hanson, H., Sheng, X., Thompson, B. A., Okumura, M. J., Reinker, K., Johnson, B., Rauen, K. A. 2012; 46 (3): 394-399

  Abstract

  RASopathies are a group of genetic conditions due to alterations of the Ras/MAPK pathway. Neurocutaneous findings are hallmark features of the RASopathies, but musculoskeletal abnormalities are also frequent. The objective was to evaluate handgrip strength in the RASopathies.Individuals with RASopathies (e.g., Noonan syndrome, Costello syndrome, cardio-facio-cutaneous [CFC] syndrome, and neurofibromatosis type 1 [NF1]) and healthy controls were evaluated. Two methods of handgrip strength were tested: GRIP-D Takei Hand Grip Dynamometer and the Martin vigorimeter. A general linear model was fitted to compare average strength among the groups, controlling for confounders such as age, gender, height, and weight.Takei dynamometer: handgrip strength was decreased in each of the syndromes compared with controls. Decreased handgrip strength compared with sibling controls was also seen with the Martin vigorimeter (P < 0.0001).Handgrip strength is decreased in the RASopathies. The etiology of the reduced muscle force is unknown, but likely multifactorial.

  View details for DOI 10.1002/mus.23324

  View details for Web of Science ID 000308084500011

  View details for PubMedID 22907230

• Total Hip Arthroplasty, Hip Osteoarthritis, Total Knee Arthroplasty, and Knee Osteoarthritis in Patients With Developmental Dysplasia of the Hip and Their Family Members: A Kinship Analysis Report JOURNAL OF PEDIATRIC ORTHOPAEDICS Schiffern, A. N., Stevenson, D. A., Carroll, K. L., Pimentel, R., Mineau, G., Viskochil, D. H., Roach, J. W. 2012; 32 (6): 609-612

  Abstract

  Developmental dysplasia of the hip (DDH) is a familial condition with a wide phenotypic expression. Families with high rates of DDH may have individuals with subtle phenotypic expression that can progress to osteoarthritis and require total hip arthroplasty (THA). This study compares the rates of THA in relatives of individuals with DDH with individuals in control families.Probands with a diagnosis of DDH were identified using medical records linked to the Utah Population Database. Ten age-matched and sex-matched controls were randomly selected from a pool of unaffected individuals within the Utah Population Database. Diagnostic and procedural codes were used to determine the incidence of hip and knee osteoarthritis (HOA and KOA) and of THA and total knee arthroplasty (TKA) among the cases and controls and their relatives. Relative risks (RR) for HOA and KOA and for THA and TKA were calculated for the probands/controls and their family members.The RR of HOA was significantly increased in probands (RR=82.4; P<2e-16), their parents (R=2.22; P=0.0003), and in their grandparents (RR=1.33; P=0.011). The RR of THA was also significantly increased in probands (RR=1168; P <3e-08) and in their grandparents (RR=2.06; P=0.01). The RR of KOA was significantly increased in probands with a diagnosis of DDH (RR=20.96; P=2.2e-8) but not in their parents or grandparents. The RR of TKA was also increased in probands alone (RR=57.47; P=1.7e-05).Parents and grandparents of individuals with diagnosed DDH are significantly more likely to be diagnosed with HOA and undergo THA than members of the general population. These first-degree and second-degree relatives were not at higher risk for KOA or TKA. Given the known familial association of DDH, this association with osteoarthritis of the hip suggests a risk of undiagnosed hip dysplasia in individuals whose families have a high rate of DDH.Level III.

  View details for DOI 10.1097/BPO.0b013e31825fa7f2

  View details for Web of Science ID 000307868400013

  View details for PubMedID 22892624

• Effects of a Plyometric Training Program for 3 Children With Neurofibromatosis Type 1 PEDIATRIC PHYSICAL THERAPY Johnson, B. A., Salzberg, C. L., Stevenson, D. A. 2012; 24 (2): 199-208

  Abstract

  To evaluate the feasibility and safety of plyometric training and to determine the effects on motor proficiency.Three children with neurofibromatosis type 1, aged 5, 7, and 10 years, selected for representative ages, sexes, abilities, and outcomes participated in a 10-week plyometric training program. Outcome measures included throwing and jumping distance, performance on a self-selected goal, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, and the Children's Assessment of Participation and Enjoyment.All participants safely completed the program. Improvements were seen in distance and consistency of throwing and jumping, performance on the self-selected goal, and bilateral coordination composite scores. Increased diversity, but not intensity of physical activity, was observed.A safe plyometric training program was implemented, resulting in gains in motor performance. It may be important to address personal and environmental barriers to physical activity participation to improve intensity of physical activity.

  View details for DOI 10.1097/PEP.0b013e31824d30ee

  View details for Web of Science ID 000302263600017

  View details for PubMedID 22466394

• Mosaicism in Stickler syndrome EUROPEAN JOURNAL OF MEDICAL GENETICS Stevenson, D. A., Vanzo, R., Damjanovich, K., Hanson, H., Muntz, H., Hoffman, R. O., Bayrak-Toydemir, P. 2012; 55 (6-7): 418-422

  Abstract

  Stickler syndrome is a heterogeneous condition due to mutations in COL2A1, COL11A1, COL11A2, and COL9A1. To our knowledge, neither non-penetrance nor mosaicism for COL2A1 mutations has been reported for Stickler syndrome. We report on a family with two clinically affected sibs with Stickler syndrome who have clinically unaffected parents. Both sibs have a novel heterozygous mutation in exon 26 of COL2A1 (c.1525delT); this results in a premature termination codon downstream of the mutation site. One parent was found to have low level mosaicism in DNA extracted from whole blood. This scenario encourages consideration of molecular testing in seemingly unaffected parents for recurrence risks and potential screening for mild age-related manifestations.

  View details for DOI 10.1016/j.ejmg.2012.03.006

  View details for Web of Science ID 000307540300006

  View details for PubMedID 22522174

• Candidate locus analysis for PHACE syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Mitchell, S., Siegel, D. H., Shieh, J. T., Stevenson, D. A., Grimmer, J. F., Lewis, T., Metry, D., Frieden, I., Blei, F., Kayserili, H., Drolet, B. A., Bayrak-Toydemir, P. 2012; 158A (6): 1363-1367

  Abstract

  PHACE syndrome (OMIM #606519) is a neurocutaneous syndrome of unknown etiology and pathogenesis. We report on an individual with PHACE syndrome with a complete deletion of SLC35B4 on 7q33. In order to further analyze this region, SLC35B4 was sequenced for 33 individuals with PHACE syndrome and one parental set. Common polymorphisms with a possible haplotype but no disease causing mutation were identified. Sixteen of 33 samples of the PHACE syndrome patients were also analyzed for copy number variations using high-resolution oligo-comparative genomic hybridization (CGH) microarray. A second individual in this cohort had a 26.5 kb deletion approximately 80 kb upstream of SLC35B4 with partial deletion of the AKR1B1 on 7q33. The deletions observed on 7q33 are not likely the singular cause of PHACE syndrome; however, it is possible that this region provides a genetic susceptibility to phenotypic expression with other confounding genetic or environmental factors.

  View details for DOI 10.1002/ajmg.a.35341

  View details for Web of Science ID 000304133700017

  View details for PubMedID 22544659

• Spinal arteriovenous fistulas in children with hereditary hemorrhagic telangiectasia JOURNAL OF NEUROSURGERY-PEDIATRICS Calhoun, A. R., Bollo, R. J., Garber, S. T., McDonald, J., Stevenson, D. A., Hung, I. H., Brockmeyer, D. L., Walker, M. L. 2012; 9 (6): 654-659

  Abstract

  Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant angiodysplasia with high penetrance and variable expression. The manifestations of HHT are often age related, and spinal arteriovenous fistula (AVF) may be the initial presentation of HHT in young children. Because spinal AVFs are rarely reported, however, screening is not incorporated into current clinical recommendations for the treatment of patients with HHT. The authors describe 2 cases of children younger than 2 years of age with acute neurological deterioration in the context of a spinal AVF and in whom HHT was subsequently diagnosed. One patient presented with intraventricular and subarachnoid hemorrhage and the other with acute thrombosis of an intramedullary varix. These cases highlight the potential for significant neurological morbidity from a symptomatic AVF in very young children with HHT. Given the lack of data regarding the true incidence and natural history of these lesions, these cases raise the question of whether spinal cord imaging should be incorporated into screening recommendations for patients with HHT.

  View details for DOI 10.3171/2012.2.PEDS11446

  View details for Web of Science ID 000304294700014

  View details for PubMedID 22656258

• Gastrointestinal Bleeding in Infantile Hemangioma: A Complication of Segmental, Rather than Multifocal, Infantile Hemangiomas JOURNAL OF PEDIATRICS Drolet, B. A., Pope, E., Juern, A. M., Sato, T., Howell, B., Puttgen, K. B., Lara-Corrales, I., Gilliam, A., Mancini, A., Powell, J., Siegel, D., Metry, D., Stevenson, D. A., Grimmer, J. F., Frieden, I. J. 2012; 160 (6): 1021-?

  Abstract

  To highlight an association of facial segmental hemangiomas with gastrointestinal bleeding in infants with infantile hemangiomas.We conducted a multicenter retrospective case series study.Ten female patients met study inclusion criteria; 8 were Caucasian, 9 had a facial segmental hemangioma, and 9 cases met the diagnostic criteria for definitive posterior fossa malformations, hemangioma, arterial lesions, cardiac anomalies/coarctation of the aorta and eye abnormalities syndrome with abnormalities of the aorta and cerebral arteriopathy. Severe gastrointestinal bleeding requiring blood transfusion occurred in 9 cases, with age at presentation of gastrointestinal bleeding ranging from 8 days to 6 months. When detected, the location of the hemangioma in the small intestine was in the distribution of the superior mesenteric artery. More than one agent was required to control the gastrointestinal bleeding, including oral or intravenous steroids, vincristine, oral propranolol, interferon, and resection of the small intestine. All cases needed ongoing support care with red blood cell transfusions.Gastrointestinal bleeding is a rare complication of true infantile hemangioma. The segmental pattern of the cutaneous hemangioma associated with gastrointestinal bleeding should suggest a segmental infantile hemangioma of the lower gastrointestinal tract.

  View details for DOI 10.1016/j.jpeds.2011.12.026

  View details for Web of Science ID 000304377300027

  View details for PubMedID 22240112

• Analysis of skeletal dysplasias in the Utah population AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Carey, J. C., Byrne, J. L., Srisukhumbowornchai, S., Feldkamp, M. L. 2012; 158A (5): 1046-1054

  Abstract

  The Utah Birth Defect Network (UBDN) collects population-based data for Utah on births from all resident women. The prevalence of skeletal dysplasias and epidemiologic characteristics/outcomes were evaluated. Cases categorized as a skeletal dysplasia from all live births, stillbirths, and pregnancy terminations (TAB) between 1999 and 2008 were reviewed by three clinical geneticists. After case review, 153 were included for analysis (88% live births, 3% stillborn, 9% TAB), and categorized by groupings defined by molecular, biochemical, and/or radiographic criteria as outlined in the 2010 Nosology and Classification of Genetic Skeletal Disorders. The overall prevalence for skeletal dysplasias was 3.0 per 10,000 births, and 20.0 per 10,000 stillbirths. The most common diagnostic groups were osteogenesis imperfecta (OI; n = 40; 0.79 per 10,000), thanatophoric dysplasia (n = 22; 0.43 per 10,000), achondroplasia (n = 18; 0.35 per 10,000), and cleidocranial dysplasia (n = 6; 0.12 per 10,000). The most common groups based on the 2010 Nosology and Classification of Genetic Skeletal Disorders were the FGFR3 chondrodysplasia group (n = 41; 0.81 per 10,000), the OI/decreased bone density group (n = 40; 0.79 per 10,000), and the type 2 collagen group (n = 10; 0.2 per 10,000). Median age of postnatal diagnosis was 30 days (range 1-2,162). Of those deceased, 88% were prenatally suspected; of those alive 29% prenatally suspected. Median age of death for live born individuals was 1 day (range 1-1,450 days). Previously reported prevalence rates vary, but our data provide a population-based approach not limited to the perinatal/neonatal period. Understanding the range for survival within each group/diagnosis is beneficial for health care providers when counseling families.

  View details for DOI 10.1002/ajmg.a.35327

  View details for Web of Science ID 000303000200011

  View details for PubMedID 22461456

• Letter to the Editor: Long-Term Experience with Duodenal Switch in Adolescents OBESITY SURGERY Scheimann, A. O., Butler, M. G., Miller, J. L., Lee, P. D., Stevenson, D. A., Heinemann, J., Driscoll, D. J. 2012; 22 (3): 517-518

  View details for DOI 10.1007/s11695-011-0502-2

  View details for Web of Science ID 000300251900027

  View details for PubMedID 21874367

• Microdeletion 9q22.3 syndrome includes metopic craniosynostosis, hydrocephalus, macrosomia, and developmental delay AMERICAN JOURNAL OF MEDICAL GENETICS PART A Muller, E. A., Aradhya, S., Atkin, J. F., Carmany, E. P., Elliott, A. M., Chudley, A. E., Clark, R. D., Everman, D. B., Garner, S., Hall, B. D., Herman, G. E., Kivuva, E., Ramanathan, S., Stevenson, D. A., Stockton, D. W., Hudgins, L. 2012; 158A (2): 391-399

  Abstract

  Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome (OMIM #109400) is a well-described rare autosomal dominant condition due to haploinsufficiency of PTCH1. With the availability of comparative genomic hybridization arrays, increasing numbers of individuals with microdeletions involving this locus are being identified. We present 10 previously unreported individuals with 9q22.3 deletions that include PTCH1. While 7 of the 10 patients (7 females, 3 males) did not meet strict clinical criteria for BCNS at the time of molecular diagnosis, almost all of the patients were too young to exhibit many of the diagnostic features. A number of the patients exhibited metopic craniosynostosis, severe obstructive hydrocephalus, and macrosomia, which are not typically observed in BCNS. All individuals older than a few months of age also had developmental delays and/or intellectual disability. Only facial features typical of BCNS, except in those with prominent midforeheads secondary to metopic craniosynostosis, were shared among the 10 patients. The deletions in these individuals ranged from 352  kb to 20.5  Mb in size, the largest spanning 9q21.33 through 9q31.2. There was significant overlap of the deleted segments among most of the patients. The smallest common regions shared among the deletions were identified in order to localize putative candidate genes that are potentially responsible for each of the non-BCNS features. These were a 929  kb region for metopic craniosynostosis, a 1.08  Mb region for obstructive hydrocephalus, and a 1.84  Mb region for macrosomia. Additional studies are needed to further characterize the candidate genes within these regions.

  View details for DOI 10.1002/ajmg.a.34216

  View details for PubMedID 22190277

• Hemangioma Is Associated with Atopic Disease OTOLARYNGOLOGY-HEAD AND NECK SURGERY Grimmer, J. F., Williams, M. S., Pimentel, R., Mineau, G., Wood, G. M., Bayrak-Toydemir, P., Stevenson, D. A. 2012; 146 (2): 206-209

  Abstract

  To determine if atopic disease is associated with infantile hemangioma.Case control study.State of Utah inpatient and outpatient records obtained from the Department of Health, Intermountain Healthcare medical records, and the University of Utah Health Care medical records using the Utah Population Database.Patients given an International Classification of Diseases, Ninth Revision diagnosis of hemangioma prior to age 5 years, from 1991 to 2009.Allergy, asthma, and eczema rates in the hemangioma cohort compared to randomly matched controls using logistic regression analysis.The authors identified 2063 patients in the hemangioma group. The overall odds ratio of atopic disease in patients diagnosed with hemangioma was 1.67 compared to the control group (P < .0001). In the hemangioma cohort, the authors found a 36% increased risk of allergies (P < .0001), 67% increased risk of asthma (P < 4e-12), and 82% increased risk of eczema (P < 2e-16).This study indicates that allergy, asthma, and eczema are positively associated with hemangioma. Eczema was most strongly associated with hemangioma, with a nearly 2-fold increased risk. Understanding the relationship between atopic disease and infantile hemangioma may elucidate the pathophysiology of each and ultimately lead to better treatment options.

  View details for DOI 10.1177/0194599811427242

  View details for Web of Science ID 000303541300006

  View details for PubMedID 22031593

• RASA1 analysis: Clinical and molecular findings in a series of consecutive cases EUROPEAN JOURNAL OF MEDICAL GENETICS Wooderchak-Donahue, W., Stevenson, D. A., McDonald, J., Grimmer, J. F., Gedge, F., Bayrak-Toydemir, P. 2012; 55 (2): 91-95

  Abstract

  RASA1 mutations have been reported to be associated with hereditary capillary malformations (CM) with or without arteriovenous malformations (AVM), arteriovenous fistulas (AVF), or Parkes Weber syndrome. But the number of cases with RASA1 mutations reported to date is relatively small and the spectrum of phenotypes caused by mutations in this gene is not well defined. Mutation results and clinical findings in thirty-five unrelated consecutive cases sent for RASA1 molecular sequencing testing at ARUP Laboratories within the last two years were evaluated. Eight individuals had a pathogenic RASA1 mutation of which six were novel. These eight individuals all had CMs (seven had multifocal CMs; one had multiple CMs), and six also had a brain or facial AVM. Two individuals with multifocal CMs including one with a fast flow lesion had a variant of uncertain significance. All other individuals, including sixteen with CMs and one with a vein of Galen aneurysm, tested negative for a RASA1 mutation. Our data suggest that multifocal CM is the key clinical finding to suggest a RASA1 mutation. The clinical diagnostic mutation detection rate among all samples sent for RASA1 testing was 29% (10/35) which increases to approximately 39% (10/26) if patients without CMs are excluded.

  View details for DOI 10.1016/j.ejmg.2011.11.008

  View details for Web of Science ID 000307539200002

  View details for PubMedID 22200646

• Lower extremity strength and hopping and jumping ground reaction forces in children with neurofibromatosis type 1 HUMAN MOVEMENT SCIENCE Johnson, B. A., MacWilliams, B., Carey, J. C., Viskochil, D. H., D'Astous, J. L., Stevenson, D. A. 2012; 31 (1): 247-254

  Abstract

  The purpose of this study was to (1) extend the research findings of decreased muscular force production in grip strength to the lower extremity strength of children with NF1 and (2) to determine if there was a relationship between isometric strength and functional activities in children with NF1. Force production was assessed using a hand held dynamometer (HHD) and a functional task (hopping and jumping) on a force plate. Data from twenty-six children with NF1 were compared to data from 48 typically developing children of similar sex, weight and height. Children with NF1 demonstrated statistically significant lower force production with HHD (p<0.01) during hip extension, but similar force production for knee extension and ankle plantar flexion compared to the control group. A relationship existed between the ground reaction forces at take-off from both hopping and jumping and the force generated from knee extensor strength in the NF1 group. The addition of a functional task to hand held dynamometry is useful for determining a relationship between common clinical measures and functional activities.

  View details for DOI 10.1016/j.humov.2011.05.004

  View details for Web of Science ID 000301220000019

  View details for PubMedID 21906829

• 5 ' UTR mutations of ENG cause hereditary hemorrhagic telangiectasia ORPHANET JOURNAL OF RARE DISEASES Damjanovich, K., Langa, C., Blanco, F. J., McDonald, J., Botella, L. M., Bernabeu, C., Wooderchak-Donahue, W., Stevenson, D. A., Bayrak-Toydemir, P. 2011; 6

  Abstract

  Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by epistaxis, arteriovenous malformations, and telangiectases. The majority of the patients have a mutation in the coding region of the activin A receptor type II-like 1 (ACVRL1) or Endoglin (ENG) gene. However, in approximately 15% of cases, sequencing analysis and deletion/duplication testing fail to identify mutations in the coding regions of these genes. Knowing its vital role in transcription and translation control, we were prompted to investigate the 5'untranslated region (UTR) of ENG.We sequenced the 5'UTR of ENG for 154 HHT patients without mutations in ENG or ACVRL1 coding regions. We found a mutation (c.-127C > T), which is predicted to affect translation initiation and alter the reading frame of endoglin. This mutation was found in a family with linkage to the ENG, as well as in three other patients, one of which had an affected sibling with the same mutation. In vitro expression studies showed that a construct with the c.-127C > T mutation alters the translation and decreases the level of the endoglin protein. In addition, a c.-9G > A mutation was found in three patients, one of whom was homozygous for this mutation. Expression studies showed decreased protein levels suggesting that the c.-9G > A is a hypomorphic mutation.Our results emphasize the need for the inclusion of the 5'UTR region of ENG in clinical testing for HHT.

  View details for DOI 10.1186/1750-1172-6-85

  View details for Web of Science ID 000300370300001

  View details for PubMedID 22192717

• Bone resorption in syndromes of the Ras/MAPK pathway CLINICAL GENETICS Stevenson, D. A., Schwarz, E. L., Carey, J. C., Viskochil, D. H., Hanson, H., Bauer, S., Weng, H. C., Greene, T., Reinker, K., Swensen, J., Chan, R. J., Yang, F., Senbanjo, L., Yang, Z., Mao, R., Pasquali, M. 2011; 80 (6): 566-573

  Abstract

  Disorders of the Ras/mitogen-activated protein kinase (MAPK) pathway have an overlapping skeletal phenotype (e.g. scoliosis, osteopenia). The Ras proteins regulate cell proliferation and differentiation and neurofibromatosis type 1 (NF1) individuals have osteoclast hyperactivity and increased bone resorption as measured by urine pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Pyd and Dpd are hydroxylysine-derived crosslinks of collagen found in bone and cartilage and excreted in the urine. Dpd is most abundant in bone. The aim of this study was to evaluate if other syndromes of the Ras/MAPK pathway have increased bone resorption, which may impact the skeletal phenotype. Participants were individuals with Noonan syndrome (n = 14), Costello syndrome (n = 21), and cardiofaciocutaneous (CFC) syndrome (n = 14). Pyridinium crosslinks from two consecutive first morning urines were extracted after acid hydrolysis and analyzed by high performance liquid chromatography. Three separate analyses of covariance were performed to compare Pyd, Dpd, and Dpd/Pyd ratio of each group to controls after controlling for age. Data were compared to 99 healthy controls. The Dpd and the Dpd/Pyd ratio were elevated (p < 0.0001) in all three conditions compared to controls suggesting that collagen degradation was predominantly from bone. The data suggest that the Ras/MAPK signal transduction pathway is important in bone homeostasis.

  View details for DOI 10.1111/j.1399-0004.2010.01619.x

  View details for Web of Science ID 000296915000010

  View details for PubMedID 21204800

• Mice lacking Nf1 in osteochondroprogenitor cells display skeletal dysplasia similar to patients with neurofibromatosis type I HUMAN MOLECULAR GENETICS Wang, W., Nyman, J. S., Ono, K., Stevenson, D. A., Yang, X., Elefteriou, F. 2011; 20 (20): 3910-3924

  Abstract

  Mutations in NF1 cause neurofibromatosis type I (NF1), a disorder characterized, among other clinical manifestations, by generalized and focal bony lesions. Dystrophic scoliosis and tibial pseudoarthrosis are the most severe skeletal manifestations for which treatment is not satisfactory, emphasizing the dearth of knowledge related to the biology of NF1 in bone cells. Using reporter mice, we report here that the mouse Col2α1-Cre promoter (collagen, type II, alpha 1) is active not only in chondrocytes but also in adult bone marrow osteoprogenitors giving rise to osteoblasts. Based on this finding, we crossed the Col2α1-Cre transgenic and Nf1(flox/flox) mice to determine whether loss of Nf1 in axial and appendicular osteochondroprogenitors recapitulates the skeletal abnormalities of NF1 patients. By microtomographic and X-rays studies, we show that Nf1(Col2)(-/-) mice display progressive scoliosis and kyphosis, tibial bowing and abnormalities in skull and anterior chest wall formation. These defects were accompanied by a low bone mass phenotype, high bone cortical porosity, osteoidosis, increased osteoclastogenesis and decreased osteoblast number, as quantified by histomorphometry and 3D-microtomography. Loss of Nf1 in osteochondroprogenitors also caused severe short stature and intervertebral disc defects. Blockade of the RAS/ERK activation characteristic of Nf1(-/-) osteoprogenitors by lovastatin during embryonic development could attenuate the increased cortical porosity observed in mutant pups. These data and the skeletal similarities between this mouse model and NF1 patients thus suggest that activation of the RAS/ERK pathway by Nf1 loss-of-function in osteochondroprogenitors is responsible for the vertebral and tibia lesions in NF1 patients, and that this molecular signature may represent a good therapeutic target.

  View details for DOI 10.1093/hmg/ddr310

  View details for Web of Science ID 000295171200002

  View details for PubMedID 21757497

• Molecular Confirmation of HRAS p.G12S in Siblings With Costello Syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Gripp, K. W., Stabley, D. L., Geller, P. L., Hopkins, E., Stevenson, D. A., Carey, J. C., Sol-Church, K. 2011; 155A (9): 2263-2268

  Abstract

  Costello syndrome was first reported based on its characteristic phenotype. Its presentation affects multiple organ systems, including severe failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. Heterozygous germline mutations in the proto-oncogene HRAS have been recognized to cause Costello syndrome, and its inheritance pattern would thus be autosomal dominant. Here, we report on the identification of an HRAS mutation c.34G>A, predicting a p.G12S amino acid substitution, in the surviving brother of a previously reported sibling pair, and documentation of the same change in autopsy material from his deceased sister. This represents, to our knowledge, the first molecularly confirmed Costello syndrome in siblings. We did not detect the mutation in a heterozygous state or mosaicism in peripheral white blood cell or cheek swab-derived DNA samples from either parent. Using single nucleotide polymorphic markers and allele-specific amplification, we clearly identified the mutation in the surviving sibling to be of maternal origin. While we cannot exclude two independently occurring de novo mutations, the complete sharing of polymorphic markers around the mutation site in both siblings supports maternal germ cell mosaicism. Recurrence risk counseling for families with apparently de novo occurring autosomal dominant conditions includes discussion of germ cell mosaicism, and this report underscores the applicability of this concern to Costello syndrome.

  View details for DOI 10.1002/ajmg.a.34150

  View details for Web of Science ID 000294182500036

  View details for PubMedID 21834037

• A SYSTEMATIC REVIEW: PLYOMETRIC TRAINING PROGRAMS FOR YOUNG CHILDREN JOURNAL OF STRENGTH AND CONDITIONING RESEARCH Johnson, B. A., Salzberg, C. L., Stevenson, D. A. 2011; 25 (9): 2623-2633

  Abstract

  The purpose of this systematic review was to evaluate the efficacy and safety of plyometric training for improving motor performance in young children; to determine if this type of training could be used to improve the strength, running speed, agility, and jumping ability of children with low motor competence; and to examine the extent and quality of the current research literature. Primary research articles were selected if they (a) described the outcomes of a plyometric exercise intervention; (b) included measures of strength, balance, running speed, jumping ability, or agility; (c) included prepubertal children 5-14 years of age; and (d) used a randomized control trial or quasiexperimental design. Seven articles met the inclusion criteria for the final review. The 7 studies were judged to be of low quality (values of 4-6). Plyometric training had a large effect on improving the ability to run and jump. Preliminary evidence suggests plyometric training also had a large effect on increasing kicking distance, balance, and agility. The current evidence suggests that a twice a week program for 8-10 weeks beginning at 50-60 jumps a session and increasing exercise load weekly results in the largest changes in running and jumping performance. An alternative program for children who do not have the capability or tolerance for a twice a week program would be a low-intensity program for a longer duration. The research suggests that plyometric training is safe for children when parents provide consent, children agree to participate, and safety guidelines are built into the intervention.

  View details for DOI 10.1519/JSC.0b013e318204caa0

  View details for Web of Science ID 000294280200035

  View details for PubMedID 21849911

• Familial Clustering of Hemangiomas ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Grimmer, J. F., Williams, M. S., Pimentel, R., Mineau, G., Wood, G. M., Bayrak-Toydemir, P., Stevenson, D. A. 2011; 137 (8): 757-760

  Abstract

  To assess the degree of relationship among individuals with hemangiomas and to evaluate the relative risk (RR) for family members of individuals with hemangiomas.Retrospective case-control study.Utah Population Database.Data sets of individuals of different ages with International Classification of Diseases, Ninth Revision (ICD-9) codes for hemangiomas were created from sources having medical records linked to the Utah Population Database. Controls were selected who matched cases for sex, birth year, and birthplace inside vs outside of Utah. Ten controls were selected per case, and sampling was performed without replacement. Kinship analysis tools were used to identify pedigrees having excess individuals with hemangiomas.Using conditional logistic regression analysis, RR for hemangiomas among several kinship classes was determined.Identified were 2514 distinct cases 12 years or younger with ICD-9 code 228.01, and the RR for sibs in this group was significantly increased (RR, 2.52; P < .001). Seventy-three founder families had 5 or more affected descendants with cluster P values ≤ .01; familial standardized incidence ratios ranged from 1.64 to 9.50. Family sizes ranged from 546 to 22 291 descendants.Sibs have increased RR for infantile hemangiomas, suggesting a potential genetic contribution to this likely multifactorial disease. Identification of large families with distantly related individuals will be helpful for future shared segment identification analyses.

  View details for Web of Science ID 000293857000003

  View details for PubMedID 21844408

• Neurofibromin (Nf1) is required for skeletal muscle development HUMAN MOLECULAR GENETICS Kossler, N., Stricker, S., Roedelsperger, C., Robinson, P. N., Kim, J., Dietrich, C., Osswald, M., Kuehnisch, J., Stevenson, D. A., Braun, T., Mundlos, S., Kolanczyk, M. 2011; 20 (14): 2697-2709

  Abstract

  Neurofibromatosis type 1 (NF1) is a multi-system disease caused by mutations in the NF1 gene encoding a Ras-GAP protein, neurofibromin, which negatively regulates Ras signaling. Besides neuroectodermal malformations and tumors, the skeletal system is often affected (e.g. scoliosis and long bone dysplasia) demonstrating the importance of neurofibromin for development and maintenance of the musculoskeletal system. Here, we focus on the role of neurofibromin in skeletal muscle development. Nf1 gene inactivation in the early limb bud mesenchyme using Prx1-cre (Nf1(Prx1)) resulted in muscle dystrophy characterized by fibrosis, reduced number of muscle fibers and reduced muscle force. This was caused by an early defect in myogenesis affecting the terminal differentiation of myoblasts between E12.5 and E14.5. In parallel, the muscle connective tissue cells exhibited increased proliferation at E14.5 and an increase in the amount of connective tissue as early as E16.5. These changes were accompanied by excessive mitogen-activated protein kinase pathway activation. Satellite cells isolated from Nf1(Prx1) mice showed normal self-renewal, but their differentiation was impaired as indicated by diminished myotube formation. Our results demonstrate a requirement of neurofibromin for muscle formation and maintenance. This previously unrecognized function of neurofibromin may contribute to the musculoskeletal problems in NF1 patients.

  View details for DOI 10.1093/hmg/ddr149

  View details for Web of Science ID 000292560300001

  View details for PubMedID 21478499

• Orthopaedic Conditions in Ras/MAPK Related Disorders JOURNAL OF PEDIATRIC ORTHOPAEDICS Reinker, K. A., Stevenson, D. A., Tsung, A. 2011; 31 (5): 599-605

  Abstract

  The RAS/MAPK disorders [Noonan syndrome, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, and Leopard syndrome] are heterogenous conditions with phenotypic overlap. Their orthopaedic manifestations are not well defined, and their phenotypic similarity makes differentiating them difficult.We prospectively evaluated 60 individuals: 26 with Noonan syndrome, 32 with CFC syndrome, and 2 with Costello syndrome. Each individual underwent a structured orthopaedic history and physical evaluation by an orthopaedic surgeon, and a syndromic evaluation by a geneticist.All groups had a high prevalence of scoliosis (8/26 Noonan syndrome, 8/32 CFC syndrome, and 1/2 Costello). Those with Noonan syndrome or CFC syndrome had a high instance of serious cervical spine disorders, including cervical stenosis, Arnold-Chiari malformation, and syringomyelia in the Noonan syndrome individuals and hydrocephalus, cervical stenosis, torticollis, and Arnold-Chiari in the CFC syndrome individuals. Noonan syndrome manifestations included chronic pain (n=21), pes planus (n=11), pes cavus (n=5), hip contractures (n=5), hand dysfunction (n=3), and hip dysplasia (n=2). Manifestations of CFC syndrome included pes planovalgus (n=20), knee flexion contractures (n=7), hip dysplasia (n=5), elbow flexion contractures (n=4), pedal calluses (n=4), toe crowding (n=4), and hip contractures (n=4). Individuals with Costello syndrome had shorter stature than the other groups and were prone to have hand contractures.Orthopaedic manifestations are frequent and diverse in Ras/MAPK disorders and can be used in phenotypic differentiation between these disorders.II.

  View details for DOI 10.1097/BPO.0b013e318220396e

  View details for Web of Science ID 000291427700027

  View details for PubMedID 21654472

• The Musculoskeletal Phenotype of the RASopathies AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS Stevenson, D. A., Yang, F. 2011; 157C (2): 90-103

  Abstract

  The Ras/MAPK signal transduction pathway is critical for the regulation of proliferation and differentiation of multiple cell types. Neurofibromatosis type 1 (NF1) is caused by inactivating mutations in the NF1 gene resulting in an increased Ras signaling cascade. Subsequently, additional syndromes with some overlapping physical manifestations such as Noonan syndrome, Costello syndrome, and cardiofaciocutaneous (CFC) syndrome were also shown to be due in many cases to mutations in genes encoding for proteins interacting with the Ras/MAPK pathway. Although neurocutaneous manifestations have been considered hallmark features for these disorders, multiple organ systems including the musculoskeletal system are affected. Some of the overlapping musculoskeletal phenotypes include scoliosis, kyphosis, anterior chest wall anomalies, pes planus, osteopenia, and hand anomalies. However, there are also discordant skeletal phenotypes such as sphenoid wing dysplasia and tibial pseudarthrosis seen only in NF1. We provide an overview of the concordant and discordant musculoskeletal manifestations in the RASopathies.

  View details for DOI 10.1002/ajmg.c.30296

  View details for Web of Science ID 000290717500003

  View details for PubMedID 21495174

• Multiple Increased Osteoclast Functions in Individuals with Neurofibromatosis Type 1 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Yan, J., He, Y., Li, H., Liu, Y., Zhang, Q., Jing, Y., Guo, Z., Zhang, W., Yang, D., Wu, X., Hanson, H., Li, X., Staser, K., Viskochil, D. H., Carey, J. C., Chen, S., Miller, L., Roberson, K., Moyer-Mileur, L., Yu, M., Schwarz, E. L., Pasquali, M., Yang, F. 2011; 155A (5): 1050-1059

  Abstract

  Skeletal abnormalities including scoliosis, tibial dysplasia, sphenoid wing dysplasia, and decreased bone mineral density (BMD) are associated with neurofibromatosis type 1 (NF1). We report the cellular phenotype of NF1 human-derived osteoclasts and compare the in vitro findings with the clinical phenotype. Functional characteristics (e.g., osteoclast formation, migration, adhesion, resorptive capacity) and cellular mechanistic alterations (e.g., F-actin polymerization, MAPK phosphorylation, RhoGTPase activity) from osteoclasts cultured from peripheral blood of individuals with NF1 (N = 75) were assessed. Osteoclast formation was compared to phenotypic, radiologic, and biochemical data. NF1 osteoprogenitor cells demonstrated increased osteoclast forming capacity. Human NF1-derived osteoclasts demonstrated increased migration, adhesion, and in vitro bone resorption. These activities coincided with increased actin belt formation and hyperactivity in MAPK and RhoGTPase pathways. Although osteoclast formation was increased, no direct correlation of osteoclast formation with BMD, markers of bone resorption, or the clinical skeletal phenotype was observed suggesting that osteoclast formation in vitro cannot directly predict NF1 skeletal phenotypes. While NF1 haploinsufficiency produces a generalized osteoclast gain-in-function and may contribute to increased bone resorption, reduced BMD, and focal skeletal defects associated with NF1, additional and perhaps local modifiers are likely required for the development of skeletal abnormalities in NF1.

  View details for DOI 10.1002/ajmg.a.33965

  View details for Web of Science ID 000290716700015

  View details for PubMedID 21465658

• Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis CLINICAL GENETICS McDonald, J., Damjanovich, K., Millson, A., Wooderchak, W., Chibuk, J. M., Stevenson, D. A., Gedge, F., Bayrak-Toydemir, P. 2011; 79 (4): 335-344

  Abstract

  Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by a unique pattern of telangiectasia and arteriovenous malformations (AVMs). Mutations in one of two genes (ENG and ACVRL1) cause approximately 85% of cases. Genetic testing impacts clinical management because genotype/phenotype correlations exist, and early preventive screening for internal AVMs is recommended in affected individuals prior to the age at which a diagnosis can typically be made based on clinical criteria. We report 383 consecutive cases in which sequencing and large deletion/duplication analysis were performed simultaneously for endoglin (ENG) and activin-like receptor kinase 1 (ACVRL1). We report the first case of mosaicism in an affected individual and 61 novel mutations. We discuss the potential benefits of a diagnostic testing approach for HHT whereby ENG and ACVRL1 are analyzed simultaneously by sequencing and a method which detects large deletion/duplications, rather than by a sequential or reflex testing protocol. We report a case in which a deletion would probably have been missed if large deletion/duplication analysis was performed only if a suspected pathogenic mutation was not first identified by sequencing.

  View details for DOI 10.1111/j.1399-0004.2010.01596.x

  View details for Web of Science ID 000288018700006

  View details for PubMedID 21158752

• Pediatric 25-hydroxyvitamin D concentrations in neurofibromatosis type 1 JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM Stevenson, D. A., Viskochil, D. H., Carey, J. C., Sheng, X., Murray, M., Moyer-Mileur, L., Shelton, J., Roberts, W. L., Bunker, A. M., Hanson, H., Bauer, S., D'Astous, J. L. 2011; 24 (3-4): 169-174

  Abstract

  Low 25-hydroxyvitamin D (25OHD) concentrations have been associated with tumors and osteopenia or fractures in adults with neurofibromatosis type 1 (NF1). We report 25OHD concentrations in 109 children with NF1 and 218 controls matched for age, sex, geographic location, and time of year.Children with NF1 were recruited (n=109; 2-17 years), and clinical data and dual-energy X-ray absorptiometry measurements were obtained. 25OHD concentrations were measured in subjects and controls.More NF1 individuals (50%) were in the 25OHD insufficient or deficient range (<30 ng/mL) (1 ng/mL = 2.496 nmol/L) compared to controls (36%) (p = 0.0129). 25OHD concentrations were higher in individuals with neurofibromas after controlling for age (p = 0.0393), and were negatively associated with whole-body subtotal bone mineral density (BMD) z-scores (p = 0.0385).More children with NF1 had 25OHD concentrations <30 ng/mL, potentially because of increased pigmentation and/or decreased sunlight exposure. In contrast to adults, decreased 25OHD concentrations were not associated with neurofibromas, and there was no positive association between 25OHD and BMD.

  View details for DOI 10.1515/JPEM.2011.092

  View details for Web of Science ID 000297466600011

  View details for PubMedID 21648285

• Variable Expression of Neurofibromatosis 1 in Monozygotic Twins AMERICAN JOURNAL OF MEDICAL GENETICS PART A Rieley, M. B., Stevenson, D. A., Viskochil, D. H., Tinkle, B. T., Martin, L. J., Schorry, E. K. 2011; 155A (3): 478-485

  Abstract

  Neurofibromatosis 1 (NF1) is a common autosomal dominant disorder with high penetrance but extreme variability of expression. Monozygotic (MZ) twins with NF1 who have phenotypic discordances are a useful tool in evaluating which traits are influenced by non-hereditary influences such as second hit somatic events, environmental agents, epigenetic modification, or post-zygotic mutations. We evaluated nine sets of MZ twins and one set of MZ triplets, ages 4-18 years, for NF1 features and calculated probandwise concordance (P(C)) for each feature. MZ twins were highly concordant in numbers of café-au-lait spots (P(C) = 0.89) and cutaneous neurofibromas. IQ scores were within 10 points for all twin pairs tested, and similar patterns of learning disabilities and speech disorders were observed. Twin pairs showed significant discordance for tumors, particularly plexiform neurofibromas (P(C) = 0.40) and malignant peripheral nerves sheath tumors (MPNST), as expected if post-natal second-hit events were contributing to these features. One set of twins was concordant for multiple, large paraspinal neurofibromas, suggesting that there may be more hereditary factors involved in production of paraspinal neurofibromas. Four sets were concordant for pectus deformities of the chest (P(C) = 0.80). Three sets of twins were discordant for scoliosis (P(C) = 0.40); an additional set was concordant for scoliosis but differed in presence of dystrophic features and need for surgery. Our data suggest there are additional non-hereditary factors modifying the NF1 phenotype and causing discordancies between MZ twins. Future studies may focus on differences in epigenetic changes or somatic mosaicism which have been documented for other disease genes in MZ twins.

  View details for DOI 10.1002/ajmg.a.33851

  View details for Web of Science ID 000288033300007

  View details for PubMedID 21337692

• The role of motor proficiency in bone health in genetic syndromes DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Stevenson, D. A. 2011; 53 (2): 103-104

  View details for DOI 10.1111/j.1469-8749.2010.03799.x

  View details for Web of Science ID 000286329200005

  View details for PubMedID 21244408

• SPRED1 Mutations in a Neurofibromatosis Clinic JOURNAL OF CHILD NEUROLOGY Muram-Zborovski, T. M., Stevenson, D. A., Viskochil, D. H., Dries, D. C., Wilson, A. R., Mao, R. 2010; 25 (10): 1203-1209

  Abstract

  Legius syndrome, caused by SPRED1 mutations, has phenotypic overlap with neurofibromatosis type 1 (NF1) without tumorigenic manifestations. Patients fulfilling the National Institutes of Health (NIH) diagnostic criteria for NF1 were enrolled at the University of Utah NF Clinic, and SPRED1 mutation analysis was performed to identify the frequency of Legius syndrome within an NF1 clinic population. SPRED1 sequencing was performed on 151 individuals with the clinical diagnosis of NF1, and 2 individuals (1.3%) were found to have novel SPRED1 mutations, p.R18X and p.Q194X. The phenotypes for the 2 individuals with SPRED1 mutations included altered pigmentation without tumorigenesis. A specific SPRED1 haplotype allele was identified in 27 individuals. The frequency of SPRED1 mutations in patients meeting diagnostic criteria for NF1 in a hospital-based clinic is 1% to 2%. The likelihood an individual is harboring a SPRED1 mutation increases with age if multiple, nonpigmentary NF1 findings are absent. Legius syndrome patients may benefit from altered medical surveillance.

  View details for DOI 10.1177/0883073809359540

  View details for Web of Science ID 000282814800004

  View details for PubMedID 20179001

• NF1 Exon 22 Analysis of Individuals With the Clinical Diagnosis of Neurofibromatosis Type 1 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Muram-Zborovski, T. M., Vaughn, C. P., Viskochil, D. H., Hanson, H., Mao, R., Stevenson, D. A. 2010; 152A (8): 1973-1978

  Abstract

  Café-au-lait macules are frequently seen in Ras-MAPK pathway disorders and are a cardinal feature of neurofibromatosis type 1 (NF1). Most NF1 individuals develop age-related tumorigenic manifestations (e.g., neurofibromas), although individuals with a specific 3-bp deletion in exon 22 of NF1 (c.2970_2972delAAT) have an attenuated phenotype with primarily pigmentary manifestations. Previous reports identify this deletion c.2970_2972delAAT in exon 17 of NF1 using NF Consortium nomenclature. For this report, we elected to use standard NCBI nomenclature, which places this identical deletion within exon 22. SPRED1 mutations cause Legius syndrome, which clinically overlaps with this attenuated NF1 phenotype. In an unselected cohort of 50 individuals who fulfilled NIH clinical diagnostic criteria from an NF Clinic and did not have SPRED1 mutations, we sequenced NF1 exon 22 in order to identify children and adolescents with multiple café-au-lait spots who could be projected to have lower likelihood to develop tumors. Two individuals with NF1 exon 22 mutations were identified: an 11-year-old boy with the c.2970_2972delAAT in-frame deletion and a 4-year-old boy with c.2866dupA. The father of the second patient had an attenuated form of NF1 and showed 24% germline mosaicism of the c.2866dupA mutation in whole blood. These individuals emphasize the need for mutation analysis in some individuals with the clinical diagnosis of NF1 who lack the tumorigenic or classic skeletal abnormalities of NF1. Specifically, with the identification of Legius syndrome, the need to recognize the attenuated phenotype of NF1 mosaicism and confirmation by mutation analysis is increasingly important for appropriate medical management and family counseling.

  View details for DOI 10.1002/ajmg.a.33525

  View details for Web of Science ID 000280925800012

  View details for PubMedID 20602485

• Parental Attitudes, Beliefs, and Perceptions about Genetic Testing for FAP and Colorectal Cancer Surveillance in Minors JOURNAL OF GENETIC COUNSELING Levine, F. R., Coxworth, J. E., Stevenson, D. A., Tuohy, T., Burt, R. W., Kinney, A. Y. 2010; 19 (3): 269-279

  Abstract

  Familial adenomatous polyposis (FAP) is the second most common hereditary colorectal cancer syndrome and confers a nearly 100% lifetime risk of developing colorectal cancer. Understanding factors that facilitate and inhibit genetic testing and cancer surveillance in children who are members of families affected by FAP will better equip clinicians to clarify misunderstandings and facilitate appropriate care. The aims of this study were to examine parental attitudes and beliefs regarding endoscopic surveillance and genetic testing in minors at risk for developing FAP. This cross-sectional study includes analyses of qualitative and quantitative interview data collected from parents of children with or at risk for FAP. This report includes data from 28 parents with a total of 51 biological children between 10-17 years of age. The parents had a clinical and/or genetic diagnosis of FAP. Most commonly reported facilitators included provider recommendation (surveillance) and personalized medical management (genetic testing). Most commonly reported barriers included lack of provider recommendation (surveillance) and cost (genetic testing).

  View details for DOI 10.1007/s10897-010-9285-1

  View details for Web of Science ID 000277958500008

  View details for PubMedID 20195720

• Speech-Language Characteristics of Children With Neurofibromatosis Type 1 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Thompson, H. L., Viskochil, D. H., Stevenson, D. A., Chapman, K. L. 2010; 152A (2): 284-290

  Abstract

  Delays in speech and articulation development have been found in school-aged children and adolescents with neurofibromatosis type 1 (NF1). This report examines speech and language skills of preschool children with NF1. Nineteen 3- to 5-year-old children diagnosed with NF1 were assessed using measures of articulation (GFTA-2), and receptive and expressive language (CELF-P2). Significant differences were observed between mean scores obtained by the group of children with NF1 compared to the validated controls from the speech and language instruments (P < or = 0.009). Sixty-eight percent of the children exhibited delays in speech and/or language. Thirty-two percent demonstrated delays in articulation, 37% percent demonstrated delays in receptive language, and 37% exhibited delays in expressive language. Sixteen percent of the children exhibited a voice disorder and 42% were judged to have a resonance problem. No significant differences were observed on any of the measures of speech and language for children with non-familial versus familial NF1. Results of this study support the need for early assessment of speech and language problems for children diagnosed with NF1 and implementation of appropriate timely intervention as needed.

  View details for DOI 10.1002/ajmg.a.33235

  View details for Web of Science ID 000274508300003

  View details for PubMedID 20101681

• What's new in neurofibromatosis? Proceedings from the 2009 NF Conference: new frontiers. American journal of medical genetics. Part A Kissil, J. L., Blakeley, J. O., Ferner, R. E., Huson, S. M., Kalamarides, M., Mautner, V., McCormick, F., Morrison, H., Packer, R., Ramesh, V., Ratner, N., Rauen, K. A., Stevenson, D. A., Hunter-Schaedle, K., North, K. 2010; 152A (2): 269-283

  Abstract

  The NF Conference is the largest annual gathering of researchers and clinicians focused on neurofibromatosis and has been convened by the Children's Tumor Foundation for over 20 years. The 2009 NF Conference was held in Portland, Oregon from June 13 to June 16, 2009 and co-chaired by Kathryn North from the University of Sydney and The Children's Hospital at Westmead, Sydney, Australia; and Joseph Kissil from the Wistar Institute, Philadelphia. The Conference included 80 platform presentations in 9 sessions over 4 days; over 100 abstracts presented as posters; and three Keynote presentations. To date, there have been tremendous advances in basic research in the pathogenesis of neurofibromatosis, and more recently in progress toward identifying effective drug therapies and the commencement of neurofibromatosis clinical trials. The NF Conference attendees have significantly increased (doubling from 140 in 2005 to 280 attending in 2009) with a significant increase in attendance of physicians and clinical researchers. Correspondingly the NF Conference scope has expanded to include translational research, clinical trials and clinical management issues while retaining a core of basic research. These themes are reflected in the highlights from the 2009 NF Conference presented here.

  View details for DOI 10.1002/ajmg.a.33189

  View details for PubMedID 20082461

• Motor Proficiency in Children With Neurofibromatosis Type 1 PEDIATRIC PHYSICAL THERAPY Johnson, B. A., MacWilliams, B. A., Carey, J. C., Viskochil, D. H., D'Astous, J. L., Stevenson, D. A. 2010; 22 (4): 344-348

  Abstract

  Neurofibromatosis type 1 (NF1) is a genetic disorder with associated musculoskeletal abnormalities, tumors, and developmental delays. The purpose of this study was to investigate and characterize the motor proficiency of children with NF1.Children with NF1 were assessed using the Bruininks-Oseretsky Test (BOT 2) instrument. The NF1 group scores were compared with age and sex-matched test norms.Twenty-six children participated in the study. The NF1 group had statistically significant lower scores (P < .05) for the total motor composite (Z = -1.62) and 7 of the 8 subtests. Nineteen percent (n = 5) scored in the average category, 54% (n = 14) scored in the below-average category, and 27% (n = 7) scored in the well-below-average category.Children with NF1 have significantly lower motor proficiency than the BOT 2 normative scores. The results indicate the BOT 2 is useful in identifying and characterizing delays in motor proficiency for children with NF1.

  View details for DOI 10.1097/PEP.0b013e3181f9dbc8

  View details for Web of Science ID 000208226600002

  View details for PubMedID 21068634

• Proceedings from the 2009 genetic syndromes of the Ras/MAPK pathway: From bedside to bench and back. American journal of medical genetics. Part A Rauen, K. A., Schoyer, L., McCormick, F., Lin, A. E., Allanson, J. E., Stevenson, D. A., Gripp, K. W., Neri, G., Carey, J. C., Legius, E., Tartaglia, M., Schubbert, S., Roberts, A. E., Gelb, B. D., Shannon, K., Gutmann, D. H., McMahon, M., Guerra, C., Fagin, J. A., Yu, B., Aoki, Y., Neel, B. G., Balmain, A., Drake, R. R., Nolan, G. P., Zenker, M., Bollag, G., Sebolt-leopold, J., Gibbs, J. B., Silva, A. J., Patton, E. E., Viskochil, D. H., Kieran, M. W., Korf, B. R., Hagerman, R. J., Packer, R. J., Melese, T. 2010; 152A (1): 4-24

  Abstract

  The RASopathies are a group of genetic syndromes caused by germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Some of these syndromes are neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, LEOPARD syndrome and Legius syndrome. Their common underlying pathogenetic mechanism brings about significant overlap in phenotypic features and includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, GI and ocular abnormalities, and a predisposition to cancer. The proceedings from the symposium "Genetic Syndromes of the Ras/MAPK Pathway: From Bedside to Bench and Back" chronicle the timely and typical research symposium which brought together clinicians, basic scientists, physician-scientists, advocate leaders, trainees, students and individuals with Ras syndromes and their families. The goals, to discuss basic science and clinical issues, to set forth a solid framework for future research, to direct translational applications towards therapy and to set forth best practices for individuals with RASopathies were successfully meet with a commitment to begin to move towards clinical trials.

  View details for DOI 10.1002/ajmg.a.33183

  View details for PubMedID 20014119

• Pigmentary Findings in Neurofibromatosis Type 1-like Syndrome (Legius Syndrome) Potential Diagnostic Dilemmas JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Stevenson, D., Viskochil, D. 2009; 302 (19): 2150-2151

  View details for Web of Science ID 000271873900027

  View details for PubMedID 19920242

• Skeletal Abnormalities in Neurofibromatosis Type 1: Approaches to Therapeutic Options AMERICAN JOURNAL OF MEDICAL GENETICS PART A Elefteriou, F., Kolanczyk, M., Schindeler, A., Viskochil, D. H., Hock, J. M., Schorry, E. K., Crawford, A. H., Friedman, J. M., Little, D., Peltonen, J., Carey, J. C., Feldman, D., Yu, X., Armstrong, L., Birch, P., Kendler, D. L., Mundlos, S., Yang, F., Agiostratidou, G., Hunter-Schaedle, K., Stevenson, D. A. 2009; 149A (10): 2327-2338

  Abstract

  The skeleton is frequently affected in individuals with neurofibromatosis type 1, and some of these bone manifestations can result in significant morbidity. The natural history and pathogenesis of the skeletal abnormalities of this disorder are poorly understood and consequently therapeutic options for these manifestations are currently limited. The Children's Tumor Foundation convened an International Neurofibromatosis Type 1 Bone Abnormalities Consortium to address future directions for clinical trials in skeletal abnormalities associated with this disorder. This report reviews the clinical skeletal manifestations and available preclinical mouse models and summarizes key issues that present barriers to optimal clinical management of skeletal abnormalities in neurofibromatosis type 1. These concepts should help advance optimal clinical management of the skeletal abnormalities in this disease and address major difficulties encountered for the design of clinical trials.

  View details for DOI 10.1002/ajmg.a.33045

  View details for Web of Science ID 000270745000046

  View details for PubMedID 19764036

• Health-Related Quality of Life Measures in Genetic Disorders: An Outcome Variable for Consideration in Clinical Trials AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS Stevenson, D. A., Carey, J. C. 2009; 151C (3): 255-260

  Abstract

  The field of medical genetics is rapidly advancing, and therapeutic options to treat genetic syndromes are becoming increasingly available. An understanding of the pathophysiology of various genetic disorders has provided researchers the opportunity to propose and test pharmacologic agents in preclinical murine models with hopes of translation to human trials. The development of clinical trials can be costly and time consuming, particularly for rare conditions. Pilot feasibility studies should be performed when designing clinical trials for genetic disorders. The development and selection of appropriate outcome measures are particularly paramount in the implementation of clinical trials. The selection of inappropriate outcome measures can lead to non-measurable differences or clinically insignificant findings. In addition, just as age appropriate measures are needed, some instruments may not apply to populations with specific genetic disorders that have significant cognitive and physical impairment, as the measures may not be sensitive enough to identify clinically significant changes. In the last decade, health-related quality of life measures (HRQOL) have been increasingly included as an outcome measure in clinical trials. While traditional clinical outcomes are important, these newly developed instruments should be considered along with clinical indicators as measures of effect in clinical trials of interventions in genetic disorders.

  View details for DOI 10.1002/ajmg.c.30217

  View details for Web of Science ID 000268847500010

  View details for PubMedID 19621444

• Familial Predisposition to Developmental Dysplasia of the Hip JOURNAL OF PEDIATRIC ORTHOPAEDICS Stevenson, D. A., Mineau, G., Kerber, R. A., Viskochil, D. H., Schaefer, C., Roach, J. W. 2009; 29 (5): 463-466

  Abstract

  Developmental dysplasia of the hip (DDH) is a common birth defect and is thought to have genetic contributions to the phenotype. It is likely that DDH is genetically heterogeneous with environmental modifiers. The Utah Population Database (UPDB) is a computerized integration of pedigrees, vital statistics, and medical records representing over 6 million individuals, and is a unique resource providing the ability to search for familial factors beyond the nuclear family, decreasing the effect of a shared environment. The purpose of this study is to assess the degree of relationship between individuals with DDH.Datasets were created from UPDB statewide birth certificates and from the University of Utah Health Sciences Center enterprise data warehouse using records for DDH and linked to the UPDB. Controls for the dataset were selected that matched cases on birth year and sex and 10 controls were selected per case. Statistics computed for each family were the number of descendants, the observed number of affected, the expected number of affected, P value, familial standardize incidence ratio, relative risks (RRs), and standard error. A kinship analysis tool was used to find pedigrees with excess DDH.The combined data resulted in 1649 distinct individuals with DDH. RR was significantly increased in first-degree relatives (RR=12.1; P<0.000001), siblings (RR=11.9; P<0.000001) and first cousins (RR=1.7; P=0.04). A total of 468 families were identified with at least 5 affected individuals in a family. These results were then filtered to only contain families that had a P value of less than 0.01. This resulted in 141 founders with anywhere between 4 and 30 affected living descendants with a P value of less than 0.01 with family sizes ranging from 594 to 44,819 descendants. A total of 28 founders had a familial standardize incidence ratio of greater than 5.0.These data suggest a genetic contribution to DDH with a 12-fold increase in risk for first-degree relatives. Better phenotypic characterization and classification will be critical for future genetic analyses.

  View details for DOI 10.1097/BPO.0b013e3181aa586b

  View details for Web of Science ID 000267789000009

  View details for PubMedID 19568018

• Analysis of Radiographic Characteristics of Anterolateral Bowing of the Leg Before Fracture in Neurofibromatosis Type 1 JOURNAL OF PEDIATRIC ORTHOPAEDICS Stevenson, D. A., Carey, J. C., Viskochil, D. H., Moyer-Mileur, L. J., Slater, H., Murray, M. A., D'Astous, J. L., Murray, K. A. 2009; 29 (4): 385-392

  Abstract

  Anterolateral leg bowing is associated with neurofibromatosis type 1 (NF1) frequently leading to fracture and nonunion of the tibia. The objective of the study was to characterize the radiographic findings of tibial dysplasia in NF1.This study is a retrospective review of radiographs of tibial dysplasia obtained within 52 years, between 1950 and 2002, from the Shriners Hospitals for Children, Salt Lake City, and of peripheral quantitative computed tomographic images of 3 individuals with anterolateral bowing of the leg without fracture compared with age- and sex-matched controls.Individuals with NF1 with bowing of the leg have the appearance of thicker cortices with medullary narrowing on plain film radiographs. The peripheral quantitative computed tomographic images of individuals with NF1 with anterolateral bowing show an unusual configuration of the tibia.Anterolateral bowing of the leg in NF1 is associated with the appearance of thicker cortices with medullary narrowing rather than thinning of the long bone cortex on plain film radiographs as currently used as a qualifier in the sixth diagnostic criterion for the clinical diagnosis of NF1. Individuals with NF1 who have anterolateral bowing of the leg have differences in tibial geometry compared with age- and sex-matched controls.The characterization of the radiographic findings of long bone bowing in NF1 helps clarify the NF1 clinical diagnostic criteria.

  View details for DOI 10.1097/BPO.0b013e3181a567e3

  View details for Web of Science ID 000267788800013

  View details for PubMedID 19461382

• Tibial geometry in individuals with neurofibromatosis type 1 without anterolateral bowing of the lower leg using peripheral quantitative computed tomography BONE Stevenson, D. A., Viskochil, D. H., Carey, J. C., Slater, H., Murray, M., Sheng, X., D'Astous, J., Hanson, H., Schorry, E., Moyer-Mileur, L. J. 2009; 44 (4): 585-589

  Abstract

  Lower leg bowing with tibial pseudarthrosis is associated with neurofibromatosis type 1 (NF1). The objective of the study is to determine if the geometry of the lower limb in individuals with neurofibromatosis type 1 (NF1) differs from controls, and to characterize the osseous components of the tibia in NF1.Peripheral quantitative computed tomography (pQCT) of the lower limb was performed (90 individuals with NF1 without tibial and/or fibular dysplasia: 474 healthy individuals without NF1). Subjects were 4-18 years of age. Individuals with NF1 were compared to controls using an analysis-of-covariance with a fixed set of covariates (age, weight, height, Tanner stage, and gender).Using pQCT, NF1 individuals without bowing of the lower leg have smaller periosteal circumferences (p<0.0001), smaller cortical area (p<0.0001), and decreased tibial cortical and trabecular bone mineral content (BMC) (p<0.0001) compared to controls.Individuals with NF1 have a different geometry of the lower leg compared to healthy controls suggesting that NF1 haploinsufficiency impacts bone homeostasis although not resulting in overt anterolateral bowing of the lower leg.

  View details for DOI 10.1016/j.bone.2008.12.002

  View details for Web of Science ID 000264614400010

  View details for PubMedID 19118659

• Bone Mineral Density in Children With Neurofibromatosis Type 1 JOURNAL OF PEDIATRIC ORTHOPAEDICS Stevenson, D. A., Murray, M., Viskochil, D. H., Carey, J. C., Moyer-Mileur, L. J. 2008; 28 (7): 791-791

  View details for Web of Science ID 000262286400017

  View details for PubMedID 18812910

• Autosomal recessive hypophosphatasia manifesting in utero with long bone deformity but showing spontaneous postnatal improvement JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Stevenson, D. A., Carey, J. C., Coburn, S. P., Ericson, K. L., Byrne, J. L., Mumm, S., Whyte, M. P. 2008; 93 (9): 3443-3448

  Abstract

  Hypophosphatasia (HPP) is a heritable metabolic disorder of the skeleton that includes variable expressivity conditioned by gene dosage effect and the variety of mutations in the tissue nonspecific alkaline phosphatase (TNSALP) gene. Patient age when skeletal problems first manifest generally predicts the clinical course, with perinatal HPP causing bone disease in utero with postnatal lethality.Our objective was to identify TNSALP mutations and characterize the inheritance pattern of a family with clinically variable HPP with one child manifesting in utero with long bone deformity but showing spontaneous prenatal and postnatal improvement.TNSALP enzyme and substrate analysis and TNSALP mutation analysis were performed on all family members.A boy with HPP showing long bone deformity that spontaneously improved in utero and after birth is described. His older brother has the childhood form of HPP without findings until after infancy. His parents and twin sister are clinically unaffected.Both boys are compound heterozygotes for the same missense mutations in TNSALP, documenting autosomal recessive inheritance for their HPP. The parents each carry one defective allele.The patient is an autosomal recessive case of HPP with prenatal long bone deformity but with spontaneous prenatal and postnatal improvement. Thus, prenatal detection by sonography of bowing of long bones from HPP, even with autosomal recessive inheritance, does not necessarily predict lethality but can represent variable expressivity or the effects of modifiers on the TNSALP defect(s).

  View details for DOI 10.1210/jc.2008-0318

  View details for Web of Science ID 000258951100029

  View details for PubMedID 18559907

• Evidence of increased bone resorption in neurofibromatosis type 1 using urinary pyridinium crosslink analysis PEDIATRIC RESEARCH Stevenson, D. A., Schwarz, E. L., Viskochil, D. H., Moyer-Mileur, L. J., Murray, M., Firth, S. D., D'Astous, J. L., Carey, J. C., Pasquali, M. 2008; 63 (6): 697-701

  Abstract

  Although neurofibromatosis type 1 (NF1) is a neurocutaneous disorder, skeletal abnormalities such as long-bone dysplasia, scoliosis, sphenoid wing dysplasia, and osteopenia are observed. To investigate the role of bone resorption as a mechanism for the bony abnormalities, we selected urinary pyridinium crosslinks (collagen degradation products excreted in urine) as a measure of bone resorption in NF1. Bone resorption was evaluated by quantitative assessment of the urinary excretion of pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Total (free plus peptide-bound) pyridinium crosslinks from the first morning urines from 59 NF1 children (ages 5-19) were extracted and analyzed (17 children with a localized skeletal dysplasia, and 42 without). The data were compared with a healthy reference population without NF1 (n = 99). Multivariate analyses, controlling for age showed statistically significant increases for Dpd (p < 0.001) and the Dpd/Pyd ratio (p < 0.001) in NF1 individuals with and without a skeletal dysplasia. NF1 children have an increase in the urinary excretion of pyridinium crosslinks, reflecting increased bone resorption. The effects of NF1 haploinsufficiency likely contribute to abnormal bone remodeling, either directly or indirectly by aberrant Ras signaling, potentially predisposing NF1 individuals to localized skeletal defects.

  View details for Web of Science ID 000256130500019

  View details for PubMedID 18317233

• Brachymesomelic dysplasia with Peters anomaly of the eye results from disruptions of the X chromosome near the SHOX and SOX3 genes AMERICAN JOURNAL OF MEDICAL GENETICS PART A Bleyl, S. B., Byrne, J. L., South, S. T., Dries, D. C., Stevenson, D. A., Rope, A. F., Vianna-Morgante, A. M., Schoenwolf, G. C., Kivlin, J. D., Brothman, A., Carey, J. C. 2007; 143A (23): 2785-2795

  Abstract

  We report on a mother and son affected with an unusual skeletal dysplasia and anterior segment eye abnormalities. Their skeletal phenotype overlaps with the SHOX-related skeletal dysplasias and is intermediate between Leri-Weill dyschondrosteosis (LWD) and Langer Mesomelic dysplasia (LMD). The mother has bilateral Peters anomaly of the eye and was reported as having a new syndrome; the son had severe bilateral sclerocornea. Chromosome analysis showed that the mother has a pericentric inversion of the X chromosome [46,X,inv(X)(p22.3q27)] and the son, a resultant recombinant X chromosome [46,Y,rec(X)dup(Xq)inv(X)(p22.3q27)]. The observed skeletal and ophthalmologic abnormalities in both patients were similar in severity. The additional features of developmental delay, growth retardation, agenesis of the corpus callosum, cryptorchidism and hypoplastic scrotum in the son are consistent with Xq28 duplication. Analysis of the son's recombinant X chromosome showed that the Xp22.33 breakpoint lies 30-68 kb 5' of the SHOX gene. This finding suggests that the skeletal dysplasia in both mother and son is allelic with LWD and LMD and results from a novel misexpression of SHOX. Analysis of the Xq27.1 breakpoint localized it to a 90 kb interval 3' of the SOX3 gene, supporting a novel role of SOX3 misexpression in the development of Peters anomaly of the eye.

  View details for DOI 10.1002/ajmg.a.32036

  View details for Web of Science ID 000251353800005

  View details for PubMedID 17994562

• A novel multiple congenital anomaly-mental retardation syndrome with Pierre Robin sequence and cerebellar hypoplasia in two sisters AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Carey, J. C. 2007; 143A (19): 2221-2226

  Abstract

  We report on the similar phenotypes and clinical course of two sisters. Both patients had an enlarged cisterna magna suggestive of cerebellar hypoplasia, agenesis/hypoplasia of the corpus callosum, Pierre Robin sequence requiring tracheostomy, camptodactyly, microphthalmia, colobomas, seizures, a distinctive facial appearance, global developmental delay, and mental retardation. We propose that the distinct pattern in these sisters constitutes a previously undescribed syndrome of likely autosomal recessive inheritance.

  View details for DOI 10.1002/ajmg.a.31945

  View details for Web of Science ID 000249829900001

  View details for PubMedID 17764080

• Neurofibromatosis type 1 is a genetic skeletal disorder AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Viskochil, D. H., Carey, J. C. 2007; 143A (17): 2082-2083

  View details for DOI 10.1002/ajmg.a.31758

  View details for Web of Science ID 000249173900024

  View details for PubMedID 17702004

• Gastric rupture and necrosis in Prader-Willi syndrome JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Stevenson, D. A., Heinemann, J., Angulo, M., Butler, M. G., Loker, J., Rupe, N., Kendell, P., Cassidy, S. B., Scheimann, A. 2007; 45 (2): 272-274

  Abstract

  Hyperphagia and obesity are common features in individuals with Prader-Willi syndrome (PWS). Demographic and cause-of-death data from individuals with PWS were obtained through a national support organization. Four reports of unexpected mortality due to gastric rupture and necrosis were found in 152 reported deaths, accounting for 3% of the causes of mortality. Four additional individuals were suspected to have gastric rupture. Vomiting and abdominal pain, although rare in PWS, were frequent findings in this cohort. The physician should consider an emergent evaluation for gastric rupture and necrosis in individuals with PWS who present with vomiting and abdominal pain.

  View details for Web of Science ID 000248318400026

  View details for PubMedID 17667731

• The use of anterolateral bowing of the lower leg in the diagnostic criteria for neurofibromatosis type 1 GENETICS IN MEDICINE Stevenson, D. A., Viskochil, D. H., Schorry, E. K., Crawford, A. H., D'Astous, J., Murray, K. A., Friedman, J. M., Armstrong, L., Carey, J. C. 2007; 9 (7): 409-412

  Abstract

  Neurofibromatosis type 1 is diagnosed clinically based on the presence of two of seven criteria developed by a panel of experts in 1987. The sixth criterion focuses on skeletal findings and is as follows: "A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis." The wording for this criterion is misleading. In particular, "thinning of long bone cortex" is not the characteristic radiographic presentation, and no mention of long bone bowing is included. The distinctive clinical feature of long bone dysplasia in neurofibromatosis type 1 is anterolateral bowing of the lower leg (portion of the body delimited by the knee and ankle). The usual radiographic findings of long bone dysplasia in neurofibromatosis type 1 at first presentation, prior to fracture, are anterolateral bowing with medullary canal narrowing and cortical thickening at the apex of the bowing. We suggest that anterolateral bowing of the lower leg, with or without fracture or pseudarthrosis, is a more appropriate description of the primary finding that a clinician will use to fulfill the sixth diagnostic criterion for neurofibromatosis type 1. Clarification of this diagnostic criterion is important for the clinician and for research protocols. Appropriate interpretation will improve understanding of the natural history and pathophysiology of neurofibromatosis type 1.

  View details for DOI 10.1097/GIM.0b013e3180986e05

  View details for Web of Science ID 000248370700002

  View details for PubMedID 17666887

• Mandibulofacial dysostosis in a patient with a de novo 2;17 translocation that disrupts the HOXD gene cluster AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Bleyl, S. B., Maxwell, T., Brothman, A. R., South, S. T. 2007; 143A (10): 1053-1059

  Abstract

  Treacher Collins syndrome (TCS) is the prototypical mandibulofacial dysostosis syndrome, but other mandibulofacial dysostosis syndromes have been described. We report an infant with mandibulofacial dysostosis and an apparently balanced de novo 2;17 translocation. She presented with severe lower eyelid colobomas requiring skin grafting, malar and mandibular hypoplasia, bilateral microtia with external auditory canal atreasia, dysplastic ossicles, hearing loss, bilateral choanal stenosis, cleft palate without cleft lip, several oral frenula of the upper lip/gum, and micrognathia requiring tracheostomy. Her limbs were normal. Chromosome analysis at the 600-band level showed a 46,XX,t(2;17)(q24.3;q23) karyotype. Sequencing of the entire TCOF1 coding region did not show evidence of a sequence variation. High-resolution genomic microarray analysis did not identify a cryptic imbalance. FISH mapping refined the breakpoints to 2q31.1 and 17q24.3-25.1 and showed the 2q31.1 breakpoint likely affects the HOXD gene cluster. Several atypical findings and lack of an identifiable TCOF1 mutation suggest that this child has a provisionally unique mandibulofacial dysostosis syndrome. The apparently balanced de novo translocation provides candidate loci for atypical and TCOF1 mutation negative cases of TCS. Based on the agreement of our findings with one previous case of mandibulofacial dysostosis with a 2q31.1 transocation, we hypothesize that misexpression of genes in the HOXD gene cluster produced the described phenotype in this patient.

  View details for DOI 10.1002/ajmg.a.31715

  View details for Web of Science ID 000246237700006

  View details for PubMedID 17431905

• Deaths due to choking in Prader-Willi syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Heinemann, J., Angulo, M., Butler, M. G., Loker, J., Rupe, N., Kendell, P., Clericuzio, C. L., Scheimann, A. O. 2007; 143A (5): 484-487

  Abstract

  Prader-Willi syndrome (PWS) is the most common known syndromic cause of life-threatening obesity, yet few studies have examined the causes of death in PWS. The objective of this study was to examine the contribution of choking leading to mortality in PWS. In 1999, a brief survey was made available from the Prader-Willi Syndrome Association (USA) bereavement program, which documented demographic data and causes of death. Families were subsequently offered the opportunity to fill out a detailed questionnaire and additional forms to release medical records. Demographic information was available on 178 deceased individuals with PWS, and cause of death available on 152 individuals. Fifty-four families completed questionnaires. Of the deceased individuals with completed questionnaires, 34% reported a history of choking. Choking was listed by familial report as the cause of death in 12 (7.9%) of 152 subjects with an average age of 24 years (range 3-52 years; median 22.5 years) at death from choking. Only two of these individuals were less than 8 years of age. The data suggest that risks associated with choking are different in the PWS population compared with others. Potential causes of increased choking in PWS include poor oral/motor coordination, poor gag reflex, hypotonia, hyperphagia, decreased mastication, and voracious feeding habits. We recommend implementation of preventive measures and education for families and group home care providers for all individuals with PWS including the Heimlich maneuver, supervised meals, better food preparation, and diet modification to avoid high-risk choking items.

  View details for DOI 10.1002/ajmg.a.31502

  View details for Web of Science ID 000244661200010

  View details for PubMedID 17036318

• Bone mineral density in children and adolescents with neurofibromatosis type 1 JOURNAL OF PEDIATRICS Stevenson, D. A., Moyer-Mileur, L. J., Murray, M., Slater, H., Sheng, X., Carey, J. C., Dube, B., Viskochil, D. H. 2007; 150 (1): 83-88

  Abstract

  To assess whether children and adolescents with neurofibromatosis type 1 (NF1) have decreased bone mineral density (BMD).Bone densitometry of the whole body, hip, and lumbar spine was used in a case-to-control design (84 individuals with NF1: 293 healthy individuals without NF1). Subjects were 5 to 18 years old. Subjects with NF1 were compared with control subjects by using an analysis-of-covariance with a fixed set of covariates (age, weight, height, Tanner stage, and sex).Subjects with NF1 had decreased areal BMD (aBMD) of the hip (P <.0001), femoral neck (P <.0001), lumbar spine (P = .0025), and whole body subtotal (P <.0001). When subjects with NF1 were separated in groups with and without a skeletal abnormality, those who did not have a skeletal abnormality still had statistically significant decreases in aBMD compared with control subjects (P <.0001 for whole body subtotal aBMD), although they were less pronounced than in those with osseous abnormalities.These data suggest that individuals with NF1 have a unique generalized skeletal dysplasia, predisposing them to localized osseous defects. Dual energy x-ray absorptiometry may prove useful in identifying individuals with NF1 who are at risk for clinical osseous complications and monitoring therapeutic trials.

  View details for DOI 10.1016/j.jpeds.2006.10.048

  View details for Web of Science ID 000243450500019

  View details for PubMedID 17188620

• An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in Exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation AMERICAN JOURNAL OF HUMAN GENETICS Upadhyaya, M., Huson, S. M., Davies, M., Thomas, N., Chuzhanova, N., Giovannini, S., Evans, D. G., HOWARD, E., Kerr, B., Griffiths, S., Consoli, C., Side, L., Adams, D., Pierpont, M., Hachen, R., Barnicoat, A., Li, H., Wallace, P., Van Biervliet, J. P., Stevenson, D., Viskochil, D., Baralle, D., Haan, E., Riccardi, V., Turnpenny, P., Lazaro, C., Messiaen, L. 2007; 80 (1): 140-151

  Abstract

  Neurofibromatosis type 1 (NF1) is characterized by cafe-au-lait spots, skinfold freckling, and cutaneous neurofibromas. No obvious relationships between small mutations (<20 bp) of the NF1 gene and a specific phenotype have previously been demonstrated, which suggests that interaction with either unlinked modifying genes and/or the normal NF1 allele may be involved in the development of the particular clinical features associated with NF1. We identified 21 unrelated probands with NF1 (14 familial and 7 sporadic cases) who were all found to have the same c.2970-2972 delAAT (p.990delM) mutation but no cutaneous neurofibromas or clinically obvious plexiform neurofibromas. Molecular analysis identified the same 3-bp inframe deletion (c.2970-2972 delAAT) in exon 17 of the NF1 gene in all affected subjects. The Delta AAT mutation is predicted to result in the loss of one of two adjacent methionines (codon 991 or 992) ( Delta Met991), in conjunction with silent ACA-->ACG change of codon 990. These two methionine residues are located in a highly conserved region of neurofibromin and are expected, therefore, to have a functional role in the protein. Our data represent results from the first study to correlate a specific small mutation of the NF1 gene to the expression of a particular clinical phenotype. The biological mechanism that relates this specific mutation to the suppression of cutaneous neurofibroma development is unknown.

  View details for Web of Science ID 000243102500013

  View details for PubMedID 17160901

• A new distal arthrogryposis syndrome characterized by plantar flexion contractures AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Swoboda, K. J., Sanders, R. K., Bamshad, M. 2006; 140A (24): 2797-2801

  Abstract

  The distal arthrogryposis (DA) syndromes are a distinct group of disorders characterized by contractures of two or more different body areas. More than a decade ago, we revised the classification of DAs and distinguished several new syndromes. This revision has facilitated the identification of five genes (i.e., TNNI2, TNNT3, MYH3, MYH8, and TPM2) that encode components of the contractile apparatus of fast-twitch myofibers and cause DA syndromes. We now report on the phenotypic features of a novel DA disorder characterized primarily by plantar flexion contractures in a large five-generation Utah family. Contractures of hips, elbows, wrists, and fingers were much milder though they varied in severity among affected individuals. All affected individuals had normal neurological examinations; electromyography and creatinine kinase levels were normal on selected individuals. We have tentatively labeled this condition distal arthrogryposis type 10 (DA10).

  View details for DOI 10.1002/ajmg.a.31528

  View details for Web of Science ID 000242466200013

• Double inactivation of NF1 in tibial pseudarthrosis AMERICAN JOURNAL OF HUMAN GENETICS Stevenson, D. A., Zhou, H., Ashrafi, S., Messiaen, L. M., Carey, J. C., D'Astous, J. L., Santora, S. D., Viskochil, D. H. 2006; 79 (1): 143-148

  Abstract

  Osseous abnormalities, including long-bone dysplasia with pseudarthrosis (PA), are associated with neurofibromatosis type 1 (NF1). Prospectively acquired tissue from the PA site of two individuals with NF1 was used for immunohistochemical characterization and genotype analysis of the NF1 locus. Typical immunohistochemical features of neurofibroma were not observed. Genotype analysis of PA tissue with use of four genetic markers (D17S1863, GXALU, IN38, and 3NF1-1) spanning the NF1 locus demonstrated loss of heterozygosity. These results are the first to document double inactivation of NF1 in PA tissue and suggest that the neurofibromin-Ras signal transduction pathway is involved in this bone dysplasia in NF1.

  View details for Web of Science ID 000238341200015

  View details for PubMedID 16773574

• Clinical characteristics and natural history of Freeman-Sheldon syndrome PEDIATRICS Stevenson, D. A., Carey, J. C., Palumbos, J., Rutherford, A., Dolcourt, J., Bamshad, M. J. 2006; 117 (3): 754-762

  Abstract

  Freeman-Sheldon syndrome (FSS) is a rare, multiple congenital contracture syndrome that is nonetheless relatively well-known, because affected children have a striking appearance: it was historically called "whistling-face syndrome" because of involvement of the facial muscles. FSS is often confused with other congenital contracture syndromes and, as a result, the clinical characteristics and natural history are poorly understood. The objective of this study was to analyze the presentation, natural history, and outcome of a cohort of individuals ascertained using strict diagnostic criteria for FSS.Data from questionnaires, medical charts, examination, and photographs were analyzed to describe the physical features, therapeutic interventions, and functional outcomes in 73 individuals referred with the diagnosis of FSS.Only 32 referred cases (approximately 40%) met diagnostic criteria for FSS. In addition to contractures, common features in these cases included severe scoliosis (85%), strabismus (42%), and hearing loss (30%). Most infants required supplementary feedings via a nasogastric (45%) or gastrostomy tube (17%). Children walked by an average age of 19 months, but approximately 80% required ambulation-assist devices. An average of approximately 10 surgeries was performed on each child, and anesthetic and/or surgical complications were reported in 50% of individuals. All individuals were cognitively normal.The clinical characteristics and natural history of FSS distinguish it from other forms of arthrogryposis, yet FSS is frequently misdiagnosed. Children with FSS require considerable nutritional, surgical, and rehabilitative intervention. Such intensive therapeutic demands differ substantially from most other congenital contracture syndromes. These findings underscore the necessity of making an accurate diagnosis.

  View details for DOI 10.1542/peds.2005-1219

  View details for Web of Science ID 000235709000046

  View details for PubMedID 16510655

• Clinical and molecular aspects of an informative family with neurofibromatosis type 1 and Noonan phenotype CLINICAL GENETICS Stevenson, D. A., Viskochil, D. H., Rope, A. F., Carey, J. C. 2006; 69 (3): 246-253

  Abstract

  Neurofibromatosis-Noonan syndrome (NFNS) has been described as a unique phenotype, combining manifestations of neurofibromatosis type 1 (NF1) and Noonan syndrome, which are separate syndromes. Potential etiologies of NFNS include a discrete syndrome of distinct etiology, co-segregation of two mutated common genes, variable clinical expressivity of NF1, and/or allelic heterogeneity. We present an informative family with an unusual NF1 mutation with variable features of NF1 and Noonan syndrome. We hypothesize that an NF1 mutant allele can lead to diagnostic manifestations of Noonan syndrome, supporting the hypothesis that NF1 allelic heterogeneity causes NFNS.

  View details for DOI 10.1111/j.1399-0004.2006.00576.x

  View details for Web of Science ID 000235840300010

  View details for PubMedID 16542390

• Familial congenital non-immune hydrops, chylothorax, and pulmonary lymphangiectasia AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Pysher, T. J., Ward, R. M., Carey, J. C. 2006; 140A (4): 368-372

  Abstract

  Pulmonary lymphangiectasia is an uncommon congenital anomaly, and familial occurrence has rarely been reported. We report on two sibs with bilateral pleural effusion/chylothorax and hydrops who died neonatally. One sib required prenatal intrauterine hemithoracic drainage. Autopsy confirmed congenital pulmonary lymphangiectasia (CPL) histologically in the first case. Hydrops, characterized as subcutaneous edema and effusions in two or more body cavities, may be due to a variety of factors, but the co-occurrence of CPL in one of these sibs, although rare, supports the notion that chylothorax and hydrops may be caused by structural lesions of lymph channels. Although most cases of CPL are sporadic, the reported sibs support autosomal recessive inheritance, with intrafamilial variability of a lymphatic disorder on a genetic basis. Mutations in vascular endothelial growth factor receptor-3 (VEGFR3) in families with Milroy disease, mutations of FOXC2 in the lymphedema-distichiasis syndrome, and fatal chylothorax in alpha9-deficient mice are potential candidate genes.

  View details for DOI 10.1002/ajmg.a.31093

  View details for Web of Science ID 000235284000008

• Case-control study of the muscular compartments and osseous strength in neurofibromatosis type 1 using peripheral quantitative computed tomography. Journal of musculoskeletal & neuronal interactions Stevenson, D. A., Moyer-Mileur, L. J., Carey, J. C., Quick, J. L., Hoff, C. J., Viskochil, D. H. 2005; 5 (2): 145-149

  Abstract

  Skeletal anomalies are observed in neurofibromatosis type 1 (NF1), but the pathogenesis is unknown. Given that muscle mass is important in the development of the strength of bone, peripheral quantitative computed tomography (pQCT) was utilized to compare measurements of muscle compartments between NF1 individuals and controls. Forty individuals with NF1 (age 5-18 years) were evaluated. Cross-sectional measurements, at the 66% tibial site, were obtained using pQCT (XCT-2000, Stratec) and variables were compared to controls without NF1 ((age 5-18 years, N=380) using analysis-of-covariance controlling for age, height, Tanner stage, and gender. The NF1 cohort showed decreased total cross-sectional area [p<0.001], decreased muscle plus bone cross-sectional area [p<0.001], decreased muscle cross-sectional area [p<0.001], and decreased Stress Strain Index [p=0.010]. These data indicate that NF1 individuals have decreased muscle cross-sectional area and decreased bone strength than individuals without NF1.

  View details for PubMedID 15951630

• Calibration of 6q subtelomere deletions to define genotype/pheno type correlations CLINICAL GENETICS Eash, D., Waggoner, D., Chung, J., Stevenson, D., Martinc, C. L. 2005; 67 (5): 396-403

  Abstract

  Testing for subtelomere abnormalities in patients with idiopathic mental retardation has become a useful diagnostic tool. However, limited data exist regarding genotype/phenotype correlations for specific subtelomere imbalances. We have ascertained five patients with 6q subtelomere deletions either as a result of an isolated deletion or as a result of an unbalanced translocation, and developed a molecular ruler assay utilizing BAC or PAC clones and determined the size of the deleted regions to range from <0.5 to 8 Mb. To establish genotype/phenotype correlations for distal 6q, we compared the clinical features of these patients to previously reported cases of 6q subtelomere and cytogenetically visible deletions and found that they shared multiple abnormalities, suggesting that the causative genes may lie in the region of the smallest 6q subtelomeric deletion, approximately 400 kb from the telomere. However, multiple unique features were present only in patients with cytogenetically visible 6q deletions, indicative that genes involved in the development of these features may lie more proximally on 6q. These initial studies demonstrate the ability to develop genotype/phenotype correlations for subtelomere rearrangements, which will aid in the diagnosis and prognosis of these patients and may help narrow the search for relevant developmental genes.

  View details for DOI 10.1111/j.1399-0004.2005.00424.x

  View details for Web of Science ID 000228644600006

  View details for PubMedID 15811006

• 4p Terminal deletion and 11p subtelomeric duplication detected by genomic microarray in a patient with Wolf-Hirschhorn syndrome and an atypical phenotype JOURNAL OF PEDIATRICS Stevenson, D. A., Carey, J. C., Cowley, B. C., Bayrak-Toydemir, P., Mao, R., Brothman, A. R. 2004; 145 (6): 840-842

  Abstract

  We report a de novo cryptic 11p duplication found by genomic microarray with a cytogenetically detected 4p deletion. Terminal 4p deletions cause Wolf-Hirschhorn syndrome, but the phenotype probably was modified by the paternally derived 11p duplication. This emphasizes the clinical utility of genomic microarray.

  View details for DOI 10.1016/j.jpeds.2004.08.027

  View details for Web of Science ID 000225702300028

  View details for PubMedID 15580214

• Paternal uniparental disomy of chromosome 14: Confirmation of a clinically-recognizable phenotype AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Brothman, A. R., Chen, Z., Bayrak-Toydemir, P., Longo, N. 2004; 130A (1): 88-91

  Abstract

  We report on a girl with a dicentric chromosome 14 [45,XX,inv(9)(p11q13),dic(14;14)(p11.1;p11.1)] with paternal uniparental disomy (UPD) for chromosome 14. Clinical findings include severe hypotonia, thoracic dystrophy, diastasis recti, swallowing difficulties with aspiration, developmental delay, and multiple minor anomalies. UPD for chromosome 14 has been documented with paternal UPD much less commonly than with maternal UPD. There have been ten cases of paternal UPD for chromosome 14 and one case of segmental paternal isodisomy of chromosome 14. Many of the findings are nonspecific, but the radiographic rib findings (referred to as the "coat-hanger" sign) are characteristic for this condition. UPD 14 studies should be performed in children thought to have Jeune asphyxiating thoracic dystrophy or other related osteochondrodysplasias when the diagnosis is in question. Our patient and the previously reported cases support a discrete recognizable phenotype for paternal UPD for chromosome 14.

  View details for DOI 10.1002/ajmg.a.30200

  View details for Web of Science ID 000223610900017

  View details for PubMedID 15368501

• Pseudoaminopterin syndrome and trisomy 9 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Low, J., KING, J., Opitz, J. M., Miller, M. E. 2004; 128A (2): 217-218

  View details for DOI 10.1002/ajmg.a.30044

  View details for Web of Science ID 000222567900025

  View details for PubMedID 15214021

• Contribution of malformations and genetic disorders to mortality in a children's hospital AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Carey, J. C. 2004; 126A (4): 393-397

  Abstract

  Malformations and genetic disorders are the leading cause of infant mortality in the US. Many malformations have a genetic basis due to genic, chromosomal, or multifactorial causation. We have studied the proportion of pediatric cases in a university-affiliated children's hospital that died of malformations and genetic disorders. We reviewed, retrospectively, deaths over a 4 year period (1994-1998) at Primary Children's Medical Center (PCMC), a university-affiliated tertiary children's referral hospital in Utah. The age at death and the cause of death were recorded for each case. We analyzed 523 cases; 180 (34.4%) deaths were due to malformations and genetic disorders. Of those 180, 30 (16.7%) had chromosome anomalies, 21 (11.7%) had a recognizable malformation syndrome, 118 (65.6%) had a malformation of unknown cause, and 11 (6.1%) had some other genetic disorder. One hundred and twenty-two (23.3%) deaths were due to trauma (accidental and non-accidental). Seventy-nine (15.1%) deaths were due to short gestation or perinatal complications. Forty-five (8.6%) deaths were due to an infectious disease and 45 (8.6%) from neoplasms. Thirteen (2.5%) were diagnosed for sudden infant death "syndrome." Twelve (2.3%) patients with malformations and/or genetic disorders died of an acquired condition not clearly related to the underlying disorder. Seven (1.3%) patients died of an unknown cause and 20 (3.8%) patients died of other specified conditions. In addition, 51.0% patients (age <1 year) died of a malformation and/or genetic disorder. Genetic disorders and malformations are a substantial cause of mortality in a referral pediatric hospital. Knowledge of the impact of genetic diseases on mortality is important for the integration of preventive measures and health care strategies to care effectively for patients and their families. This information emphasizes the importance of further study of whether or not early recognition influences mortality rate and management.

  View details for DOI 10.1002/ajmg.a.20409

  View details for Web of Science ID 000221103100008

  View details for PubMedID 15098237

• 6q subtelomeric deletion: is there a recognizable syndrome? CLINICAL DYSMORPHOLOGY Stevenson, D. A., Brothman, A. R., Carey, J. C., Chen, Z., Dent, K. M., Bale, J. F., Longo, N. 2004; 13 (2): 103-106

  Abstract

  We report on a girl with an abnormal hybridization pattern for the subtelomeric fluorescence in-situ hybridization (FISH) probe panel showing deletion of the long arm telomeric region of chromosome 6. All other subtelomere DNA probes showed normal hybridization patterns. Metaphase cells analysed from cultures of peripheral blood revealed a normal female chromosome complement at the 650-band level. The deletion was further characterized using genomic microarray analysis. Clinical findings include: developmental delay, seizures, hypoplasia of the corpus callosum, dextrocardia, unusual dimpling of knees and elbows, and minor anomalies. We are aware of only two other reports of isolated cryptic 6q subtelomeric deletions not associated with other chromosomal abnormalities. The absence of retinal abnormalities in our case supports the theory that genes responsible for the retinal abnormalities in other terminal 6q deletions are proximal to 6q27. Subtelomeric FISH probes were useful in establishing a diagnosis in our patient. As more cases are reported, we may be able to establish discrete phenotypes and natural histories that can aid in counselling families.

  View details for DOI 10.1097/01.mcd.0000121523.42818.4b

  View details for Web of Science ID 000221146700010

  View details for PubMedID 15057127

• Unexpected death and critical illness in Prader-Willi syndrome: Report of ten individuals AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, D. A., Anaya, T. M., Clayton-Smith, J., Hall, B. D., Van Allen, M., Zori, R. T., Zackai, E. H., Frank, G., Clericuzio, C. L. 2004; 124A (2): 158-164

  Abstract

  Individuals with Prader-Willi syndrome (PWS) generally survive into adulthood. Common causes of death are obesity related cor pulmonale and respiratory failure. We report on a case series of eight children and two adults with unexpected death or critical illness. Our data show age-specific characteristics of PWS patients with fatal or life-threatening illnesses. Under the age of 2 years, childhood illnesses in general were associated with high fever and rapid demise or near-demise. Hypothalamic dysfunction likely plays a role in exaggerated fever response, but also perhaps in central regulation of adrenal function. Below average sized adrenal glands were found in three children, which raises the possibility of unrecognized adrenal insufficiency in a subset of individuals with PWS and emphasizes the vital role of autopsy. The tub drowning death of an adult patient could be related to central hypersomnia, which has been reported in PWS. We suggest that increased risk for critical illness be considered in the discussion of anticipatory guidance for the care of infants with PWS. Since a number of children died while hospitalized, particularly close observation of PWS children who are ill enough to warrant hospital admission is recommended.

  View details for DOI 10.1002/ajmg.a.20370

  View details for Web of Science ID 000187893100008

  View details for PubMedID 14699614

• Advise or consent? Issues in genetic testing of adolescents. Adolescent medicine (Philadelphia, Pa.) Stevenson, D. A., Strasburger, V. C. 2002; 13 (2): 213-?

  Abstract

  Medical genetics is a rapidly advancing field, and genetic testing is becoming readily accessible as well as more sophisticated. Genetic testing has the potential to be both harmful and beneficial in terms of physical, psychosocial, and reproductive health. Ethical and legal implications of genetic testing are profound and particularly confounding in children and adolescents. This chapter discusses points to consider in evaluating the potential benefit and harm of the decision to undergo testing in adolescence.

  View details for PubMedID 11986032

• Hydranencephaly in an infant with vascular malformations AMERICAN JOURNAL OF MEDICAL GENETICS Stevenson, D. A., Hart, B. L., Clericuzio, C. L. 2001; 104 (4): 295-298

  Abstract

  Hydranencephaly is a condition in which cerebral hemispheres are absent and reduced to fluid-filled sacs in a normal skull. Numerous causes have been proposed. We report a male infant with hydranencephaly and congenital vascular malformations (port wine stains, generalized nevus flammeus, anomalous retinal vessels, and absent internal carotid flow). Magnetic resonance imaging of the brain showed absence of most of the cerebrum except for small portions of the occipital cortex and thalami. Magnetic resonance angiography showed flow within the vertebral and basilar arteries without internal carotid intracranial flow above the internal carotid petrous and cavernous portion. This is a report of cutaneous and retinal malformations associated with hydranencephaly. Vascular malformations of larger vessels (e.g., webbing of the carotid arteries and an absent internal carotid arterial system) have been observed in other infants with hydranencephaly, and are proposed to lead to brain destruction. The case reported herein supports the role of primary vascular malformations in the development of some cases of hydranencephaly.

  View details for Web of Science ID 000172506600006

  View details for PubMedID 11754063

• Descriptive analysis of tibial pseudarthrosis in patients with neurofibromatosis 1 Western-Society-for-Pediatric-Research Meeting Stevenson, D. A., Birch, P. H., Friedman, J. M., Viskochil, D. H., Balestrazzi, P., Boni, S., Buske, A., Korf, B. R., Niimura, M., Pivnick, E. K., Schorry, E. K., Short, M. P., Tenconi, R., Tonsgard, J. H., Carey, J. C. WILEY-LISS. 1999: 413–19

  Abstract

  Five percent of individuals with neurofibromatosis type 1 (NF1) present with congenital long bone pseudarthrosis (PA). In large series, 50-80% of patients with congenital long bone PA also have NF1. Very little information exists on the natural history and pathogenesis of PA in NF1. This report is a descriptive analysis of a large series of patients with NF1 and tibial bowing or PA. Study A is a case-control study using the National Neurofibromatosis Foundation International Database (NNFFID). Eighty-five patients with PA were compared to a control group from the same database. There was a statistically significant male predominance of NF1 cases with PA (54 males to 31 females), compared to controls (85 males to 87 females) (chi2 = 4.0, P = 0.046, using a two-tailed test with Yates' correction). There was no significant difference in the clinical presentation of NF1 manifestations in NF1 patients with PA than in NF1 patients without PA. Of the affected individuals with PA, there were 24 de novo cases and 21 familial cases (9 through maternal and 12 through paternal inheritance). Questions that could not be answered by Study A were addressed by a partially overlapping case-series report, Study B, in which data on 75 cases ascertained through questionnaires completed by NF center directors were collected. From Study B we determined that half of the patients who had a fracture sustained it before age 2, and approximately 16% of the pseudarthrosis patients had an amputation. Our data indicate a male predominance and no parent-of-origin effect. Male gender may be a susceptibility factor for pseudarthrosis in NF1.

  View details for Web of Science ID 000080447800005

  View details for PubMedID 10360395