Clinical Focus


  • Medical Genetics
  • Anatomic and Clinical Pathology

Academic Appointments


Professional Education


  • Board Certification: American Board of Medical Genetics and Genomics, Clinical Cytogenetics (2005)
  • Board Certification: American Board of Pediatrics, Pediatrics (2000)
  • Board Certification: American Board of Medical Genetics and Genomics, Clinical Genetics and Genomics (2023)
  • Residency: Stanford University Division of Medical Genetics (2002) CA
  • Fellowship: Stanford University Pathology Fellowships (2003) CA
  • Residency: Phoenix Children's Hospital Pediatric Residency (2000) AZ
  • Medical Education: Eastern VA Medical School (1997) VA

2024-25 Courses


All Publications


  • Clinical Features of Typically Developing Children With and Without Prenatal Alcohol Exposure. The Journal of pediatrics May, P. A., Tabachnick, B., Hasken, J. M., Marais, A., de Vries, M. M., Kalberg, W. O., Buckley, D., Manning, M., Robinson, L. K., Parry, C. D., Seedat, S., Hoyme, H. E. 2024: 114327

    Abstract

    OBJECTIVE: To determine if prenatal alcohol exposure (PAE) affected physical and cognitive/behavioral outcomes in apparently typically developing, first-grade children.STUDY DESIGN: Three groups were compared: children with fetal alcohol spectrum disorders (FASD); children with PAE without FASD; and children without PAE.RESULTS: The three groups were significantly different on most physical traits and fewer neurodevelopmental traits. Two-group comparisons of exposed and unexposed, non-FASD groups were statistically different on: height, weight, head circumference (OFC), body mass index (BMI), and palpebral fissure length (PFL). Neurobehavioral outcomes were significant in three-group, but not two-group, comparisons. Few sex differences were observed; however, sex ratios indicated fewer male offspring in first grade among women who consumed 6+ drinks per occasion during pregnancy. For weight, OFC, BMI, age, rural residence, and drinking measures, mothers of exposed children without FASD were intermediaries between, and significantly different from, the other maternal groups. Adjusted for socioeconomic covariates, multivariate analysis of covariance (MANCOVA), three-group comparisons were significantly different for cognitive/behavioral variables (p<.001); however, two-group neurobehavior comparisons for children without FASD were not significant (p>.05). Physical trait MANCOVA comparisons of the non-FASD groups were significant only for weight (p<.004) when tested univariately and through stepdown analysis. Socioeconomic-adjusted trend plots were in the expected direction for nonverbal IQ, problem behaviors, attention, height, weight, OFC, vermilion, PFL, and total dysmorphology score.CONCLUSIONS: Even when meeting developmental norms, children with PAE exhibited trends of poorer growth and cognitive/behavioral traits than children without PAE. These findings support the notion that abstinence during pregnancy is best.

    View details for DOI 10.1016/j.jpeds.2024.114327

    View details for PubMedID 39357817

  • Neuroimaging abnormalities associated with immunotherapy responsiveness in Down syndrome regression disorder. Annals of clinical and translational neurology Santoro, J. D., Khoshnood, M. M., Jafarpour, S., Nguyen, L., Boyd, N. K., Vogel, B. N., Kammeyer, R., Patel, L., Manning, M. A., Rachubinski, A. L., Filipink, R. A., Baumer, N. T., Santoro, S. L., Franklin, C., Tamrazi, B., Yeom, K. W., Worley, G., Espinosa, J. M., Rafii, M. S. 2024

    Abstract

    To determine the prevalence of neuroimaging abnormalities in individuals with Down syndrome regression disorder (DSRD) and evaluate if neuroimaging abnormalities were predictive of therapeutic responses.A multicenter, retrospective, case-control study which reviewed neuroimaging studies of individuals with DSRD and compared them to a control cohort of individuals with Down syndrome (DS) alone was performed. Individuals aged 10-30 years and meeting international consensus criteria for DSRD were included. The presence of T1, T2/FLAIR, and SWI signal abnormalities was reviewed. Response rates to various therapies, including immunotherapy, were evaluated in the presence of neuroimaging abnormalities.In total, 74 individuals (35%) had either T2/FLAIR and/or SWI signal abnormality compared to 14 individuals (12%) without DSRD (p < 0.001, 95%CI: 2.18-7.63). T2/FLAIR signal abnormalities were not appreciated more frequently in individuals with DSRD (14%, 30/210) than in the control cohort (9%, 11/119) (p = 0.18, OR: 1.63, 95%CI: 0.79-3.40). SWI signal abnormalities were appreciated at a higher frequency in individuals with DSRD (24%, 51/210) compared to the control cohort (4%, 5/119) (p < 0.001, OR: 7.31, 95%CI: 2.83-18.90). T2/FLAIR signal abnormalities were localized to the frontal (40%, 12/30) and parietal lobes (37%, 11/30). SWI signal abnormalities were predominantly in the bilateral basal ganglia (94%, 49/52). Individuals with DSRD and the presence of T2/FLAIR and/or SWI signal abnormalities were much more likely to respond to immunotherapy (p < 0.001, OR: 8.42. 95%CI: 3.78-18.76) and less likely to respond to benzodiazepines (p = 0.01, OR: 0.45, 95%CI: 0.25-0.83), antipsychotics (p < 0.001, OR: 0.28, 95%CI: 0.11-0.55), or electroconvulsive therapy (p < 0.001, OR: 0.12; 95%CI: 0.02-0.78) compared to individuals without these neuroimaging abnormalities.This study indicates that in individuals diagnosed with DSRD, T2/FLAIR, and SWI signal abnormalities are more common than previously thought and predict response to immunotherapy.

    View details for DOI 10.1002/acn3.52023

    View details for PubMedID 38375538

  • Maternal risk factors for fetal alcohol spectrum disorders: Distal variables. Alcohol, clinical & experimental research May, P. A., Hasken, J. M., de Vries, M. M., Marais, A. S., Abdul-Rahman, O., Robinson, L. K., Adam, M. P., Manning, M. A., Kalberg, W. O., Buckley, D., Snell, C. L., Seedat, S., Parry, C. D., Hoyme, H. E. 2023

    Abstract

    The objective of this study was to conduct a multivariate analysis of distal influences on maternal risk for fetal alcohol spectrum disorders (FASD).Interviews were conducted with mothers of first grade students whose children were evaluated to assess risk for FASD. Topics included: physical/medical status, childbearing history, demographics, mental health, domestic violence, and trauma.Although there is some individual variation in distal maternal risk factors among and within the mothers of children with each of the common diagnoses of FASD, patterns emerged that differentiated risk among mothers of children with FASD from mothers whose children were developing typically. Case control comparisons indicate that mothers of children with FASD were significantly: smaller physically, had higher gravidity and parity, and experienced more miscarriages and stillbirths, were less likely to be married, reported later pregnancy recognition, more depression, and lower formal educational achievement. They were also less engaged with a formal religion, were less happy, suffered more childhood trauma and interpersonal violence, were more likely to drink alone or with her partner, and drank to deal with anxiety, tension, and to be part of a group. Regression modeling utilized usual level of alcohol consumption by trimester and six selected distal variables (maternal head circumference, body mass index, age at pregnancy, gravidity, marital status, and years of formal education) to conclude that these variables explain 57.7% of the variance in fetal alcohol syndrome (FAS) diagnoses, 30.1% of partial FAS (PFAS) diagnoses, and 46.4% of alcohol-related neurodevelopmental disorder (ARND) diagnoses in children with FASD when compared to controls. While the proximal variables explained most of the diagnostic variance, six distal variables explained 16.7% (1 /6 ) of the variance in FAS diagnoses, 13.9% (1 /7 ) of PFAS, and 12.1% (1 /8 ) of ARND.Differences of distal FASD risks were identified. Complex models to quantify risk for FASD hold promise for guiding prevention/intervention.

    View details for DOI 10.1111/acer.15246

    View details for PubMedID 38105110

  • Multifaceted case management during pregnancy is associated with better child outcomes and less fetal alcohol syndrome. Annals of medicine May, P. A., Marais, A., Kalberg, W. O., de Vries, M. M., Buckley, D., Hasken, J. M., Snell, C. L., Barnard Rohrs, R., Hedrick, D. M., Bezuidenhout, H., Anthonissen, L., Brocker, E., Robinson, L. K., Manning, M. A., Hoyme, H. E., Seedat, S., Parry, C. D. 2023; 55 (1): 926-945

    Abstract

    BACKGROUND: Pregnant women participated in multifaceted case management (MCM) to prevent Fetal Alcohol Spectrum Disorders (FASD).METHODS: Women recruited from antenatal clinics for a longitudinal child development study were screened for alcohol use. Forty-four pregnant women were defined as high-risk drinkers on the Alcohol Use Disorder Identification Test (AUDIT) by an AUDIT score ≥8 and participated in 18months of MCM to facilitate reduction or cessation of alcohol consumption. Forty-one women completed MCM. Fifty-five equally high-risk women who received standard antenatal care comprised the comparison/control group. Development in offspring was evaluated by a blinded interdisciplinary team of examiners through 5years of age.RESULTS: At five years of age, more children (34%) of MCM participating women did not meet the criteria for FASD vs. non-MCM offspring (22%). Furthermore, a statistically significant (p=.01) lower proportion of MCM offspring (24%) was diagnosed with fetal alcohol syndrome (FAS) compared to controls (49%). Children of MCM participants had significantly (p<.05) better physical outcomes: lower total dysmorphology scores, larger head circumferences, longer palpebral fissures, and higher midfacial measurements. Neurodevelopment results showed mixed outcomes. While Bayley developmental scores indicated that MCM offspring were performing significantly worse on most domains through 18months, group scores equalized and were not significantly different on Kaufman Assessment Battery neurobehavioral measures by five years. Regression analyses indicated that offspring of women who received standard antenatal care were associated with significantly more negative outcomes than MCM offspring: a diagnosis of FAS (OR = 3.2; 95% CI: 1.093-9.081), microcephaly (OR = 5.3; 95% CI: 2.1-13.5), head circumference ≤10th centile (OR = 4.3; 95%CI: 1.8-10.4), and short palpebral fissures (OR = 2.5; 95% CI: 1.0-5.8).CONCLUSION: At age five, proportionally fewer children of MCM participants qualified for a diagnosis of FAS, and proportionally more had physical outcomes indicating better prenatal brain development. Neurobehavioral indicators were not significantly different from controls by age five.KEY MESSAGESMultifaceted Case Management (MCM) was designed and employed for 18 months during the prenatal and immediate postpartum period to successfully meet multiple needs of women who had proven to be very high risk for birthing children with fetal alcohol spectrum disorders (FASD).Offspring of the women who participated in MCM were followed up through age five years and were found to have significantly better physical outcomes on multiple variables associated with fetal alcohol syndrome (FAS) and FASD, such as larger head circumferences and fewer minor anomalies, than those children born to equally at-risk women not receiving MCM.Fewer children of women receiving MCM were diagnosed with FASD than the offspring of equally-at-risk controls, and significantly (p=.01) fewer MCM offspring had FAS, the most severe FASD diagnosis.

    View details for DOI 10.1080/07853890.2023.2185808

    View details for PubMedID 36919586

  • Maternal and paternal risk factors for fetal alcohol spectrum disorders: Alcohol and other drug use as proximal influences. Alcohol, clinical & experimental research May, P. A., Hasken, J. M., de Vries, M. M., Marais, A. S., Abdul-Rahman, O., Robinson, L. K., Adam, M. P., Manning, M. A., Kalberg, W. O., Buckley, D., Seedat, S., Parry, C. D., Hoyme, H. E. 2023; 47 (11): 2090-2109

    Abstract

    To explore and analyze the significance of proximal influences of maternal and paternal traits associated with bearing a child with a fetal alcohol spectrum disorder (FASD).Aggregated, maternal interview-collected data (N = 2515) concerning alcohol, tobacco, and other drug use were examined to determine risk for FASD from seven cross-sectional samples of mothers of first-grade students who were evaluated for a possible diagnosis of FASD.Mothers of children with fetal alcohol syndrome (FAS) reported the highest alcohol use throughout pregnancy, proportion of binge drinking, drinks per drinking day (DDD), drinking days per week, and total drinks per week. Mothers of children with FAS also consumed significantly more alcohol than mothers of children with partial FAS (PFAS), alcohol-related neurodevelopmental disorder (ARND), or typically developing controls. Mothers of children with PFAS and ARND reported similar drinking patterns, which exposed fetuses to 3-4 times more alcohol than mothers of controls, but the PFAS group was more likely than the ARND group to abstain in latter trimesters. Fathers of all children were predominantly drinkers (70%-85%), but more fathers of children with FASD binged heavily on more days than fathers of controls. Compared to the few mothers of controls who used alcohol during pregnancy, the ARND group binge drank more (3+ DDD) throughout pregnancy and drank more DDD before pregnancy and first trimester. Regression analysis, controlling for tobacco use, indicated that mothers who reported drinking <1 DDD were significantly more likely than abstainers to bear a child with FASD (OR = 2.75) as were those reporting higher levels such as 5-5.9 DDD (OR = 32.99). Exclusive, first-trimester maternal drinking increased risk for FASD five times over that of abstinence (p < 0.001, OR = 5.05, 95% CI: 3.88-6.58), first- and second-trimester drinking by 12.4 times, and drinking all trimesters by 16 times (p < 0.001, OR = 15.69, 95% CI: 11.92-20.64). Paternal drinking during and prior to pregnancy, without adjustment, increased the likelihood of FASD significantly (OR = 1.06 and 1.11, respectively), but the significance of both relationships disappeared when maternal alcohol and tobacco use were controlled.Differences in FASD risk emerged from the examination of multiple proximal variables of maternal alcohol and tobacco use, reflecting increased FASD risk at greater levels of maternal alcohol consumption.

    View details for DOI 10.1111/acer.15193

    View details for PubMedID 38226752

    View details for PubMedCentralID PMC10792253

  • Hypovitaminosis D in persons with Down syndrome and autism spectrum disorder. Journal of neurodevelopmental disorders Boyd, N. K., Nguyen, J., Khoshnood, M. M., Jiang, T., Nguyen, L., Mendez, L., Spinazzi, N. A., Manning, M. A., Rafii, M. S., Santoro, J. D. 2023; 15 (1): 35

    Abstract

    Plasma levels of vitamin D have been reported to be low in persons with Down syndrome (DS) and existing data is limited to small and homogenous cohorts. This is of particular importance in persons with DS given the high rates of autoimmune disease in this population and the known relationship between vitamin D and immune function. This study sought to investigate vitamin D status in a multi-center cohort of individuals with DS and compare them to individuals with autism spectrum disorder (ASD) and neurotypical (NT) controls.A retrospective, multi-center review was performed. The three sites were located at latitudes of 42.361145, 37.44466, and 34.05349. Patients were identified by the International Classification of Diseases (ICD)-9 or ICD-10 codes for DS, ASD, or well-child check visits for NT individuals. The first vitamin D 25-OH level recorded in the electronic medical record (EMR) was used in this study as it was felt to be the most reflective of a natural and non-supplemented state. Vitamin D 25-OH levels below 30 ng/mL were considered deficient.In total, 1624 individuals with DS, 5208 with ASD, and 30,775 NT controls were identified. Individuals with DS had the lowest mean level of vitamin D 25-OH at 20.67 ng/mL, compared to those with ASD (23.48 ng/mL) and NT controls (29.20 ng/mL) (p < 0.001, 95% CI: -8.97 to -6.44). A total of 399 (24.6%) individuals with DS were considered vitamin D deficient compared to 1472 (28.3%) with ASD and 12,397 (40.3%) NT controls (p < 0.001, 95% CI: -5.43 to -2.36). Individuals with DS with higher body mass index (BMI) were found to be more likely to have lower levels of vitamin D (p < 0.001, 95% CI: -0.3849 to -0.1509). Additionally, having both DS and a neurologic diagnosis increased the likelihood of having lower vitamin D levels (p < 0.001, 95% CI: -5.02 to -1.28). Individuals with DS and autoimmune disease were much more likely to have lower vitamin D levels (p < 0.001, 95% CI: -6.22 to -1.55). Similarly, a history of autoimmunity in a first-degree relative also increased the likelihood of having lower levels of vitamin D in persons with DS (p = 0.01, 95% CI: -2.45 to -0.63).Individuals with DS were noted to have hypovitaminosis D in comparison to individuals with ASD and NT controls. Associations between vitamin D deficiency and high BMI, personal autoimmunity, and familial autoimmunity were present in individuals with DS.

    View details for DOI 10.1186/s11689-023-09503-y

    View details for PubMedID 37880588

    View details for PubMedCentralID 8060042

  • Maternal and paternal risk factors for fetal alcohol spectrum disorders: Alcohol and other drug use as proximal influences ALCOHOL-CLINICAL AND EXPERIMENTAL RESEARCH May, P. A., Hasken, J. M., de Vries, M. M., Marais, A., Abdul-Rahman, O., Robinson, L. K., Adam, M. P., Manning, M. A., Kalberg, W. O., Buckley, D., Seedat, S., Parry, C. H., Hoyme, H. 2023

    View details for DOI 10.1111/acer.15193

    View details for Web of Science ID 001077309500001

  • Generation of two induced pluripotent stem cell lines from patients with Down syndrome. Stem cell research Zhu, W., Liu, W., Yu, R., Manning, M., Waran Romfh, A., Wu, J. C. 2023; 72: 103204

    Abstract

    Down syndrome (DS) is caused by trisomy of Homo sapiens chromosome 21 (HSA21) and is by far the most common chromosomal disorder accompanied by neurodevelopmental disorders and congenital heart disease. Here, we generated two induced pluripotent stem cell (iPSC) lines from two patients with DS. These two lines exhibited normal morphology, trisomy 21 karyotype, pluripotency and differentiation capability into derivatives of three germ layers. The patient-specific iPSC lines arean invaluable resource in research to model DS-related cellular and molecular pathologies and test possible therapeutic strategies for DS.

    View details for DOI 10.1016/j.scr.2023.103204

    View details for PubMedID 37734318

  • Immunotherapy responsiveness and risk of relapse in Down syndrome regression disorder. Translational psychiatry Santoro, J. D., Spinazzi, N. A., Filipink, R. A., Hayati-Rezvan, P., Kammeyer, R., Patel, L., Sannar, E. A., Dwyer, L., Banerjee, A. K., Khoshnood, M., Jafarpour, S., Boyd, N. K., Partridge, R., Gombolay, G. Y., Christy, A. L., Real de Asua, D., Del Carmen Ortega, M., Manning, M. A., Van Mater, H., Worley, G., Franklin, C., Stanley, M. A., Brown, R., Capone, G. T., Quinn, E. A., Rafii, M. S. 2023; 13 (1): 276

    Abstract

    Down syndrome regression disorder (DSRD) is a clinical symptom cluster consisting of neuropsychiatric regression without an identifiable cause. This study evaluated the clinical effectiveness of IVIg and evaluated clinical characteristics associated with relapse after therapy discontinuation. A prospective, multi-center, non-randomized, observational study was performed. Patients met criteria for DSRD and were treated with IVIg. All patients underwent a standardized wean-off therapy after 9-12 months of treatment. Baseline, on-therapy, and relapse scores of the Neuropsychiatric Inventory Total Score (NPITS), Clinical Global Impression-Severity (CGI-S), and the Bush-Francis Catatonia Rating Scale (BFCRS) were used to track clinical symptoms. Eighty-two individuals were enrolled in this study. Patients had lower BFCRS (MD: -6.68; 95% CI: -8.23, -5.14), CGI-S (MD: -1.27; 95% CI: -1.73, -0.81), and NPITS scores (MD: -6.50; 95% CI: -7.53, -5.47) while they were on therapy compared to baseline. Approximately 46% of the patients (n = 38) experienced neurologic relapse with wean of IVIg. Patients with neurologic relapse were more likely to have any abnormal neurodiagnostic study (χ2 = 11.82, P = 0.001), abnormal MRI (χ2 = 7.78, P = 0.005), and abnormal LP (χ2 = 5.45, P = 0.02), and a personal history of autoimmunity (OR: 6.11, P < 0.001) compared to patients without relapse. IVIg was highly effective in the treatment of DSRD. Individuals with a history of personal autoimmunity or neurodiagnostic abnormalities were more likely to relapse following weaning of immunotherapy, indicating the potential for, a chronic autoimmune etiology in some cases of DSRD.

    View details for DOI 10.1038/s41398-023-02579-z

    View details for PubMedID 37553347

    View details for PubMedCentralID 9335003

  • Evidence of Neuroinflammation and Immunotherapy Responsiveness in Individuals with Down Syndrome Regression Disorder Santoro, J., Partridge, R., Tanna, R., Pagarkar, D., Khoshnood, M., Kammeyer, R., Gombolay, G., El-Dahr, J., Christy, A., Patel, L., Manning, M., Van Mater, H., Rafii, M., Quinn, E. LIPPINCOTT WILLIAMS & WILKINS. 2023
  • Neonatal lupus is a novel cause of positive newborn screening for X-linked adrenoleukodystrophy. American journal of medical genetics. Part A Niehaus, A. D., Mendelsohn, B. A., Zimmerman, B., Lee, C. U., Manning, M. A., Cusmano-Ozog, K. P., Tise, C. G. 2023

    Abstract

    We report three unrelated individuals, each exposed to maternal autoantibodies during gestation and found to have elevated very long-chain fatty acids (VLCFAs) in the newborn period after screening positive by California newborn screening (NBS) for X-linked adrenoleukodystrophy (ALD). Two probands presented with clinical and laboratory features of neonatal lupus erythematosus (NLE); the third had features suggestive of NLE and a known maternal history of Sjogren's syndrome and rheumatoid arthritis. In all three individuals, subsequent biochemical and molecular evaluation for primary and secondary peroxisomal disorders was nondiagnostic with normalization of VLCFAs by 15months of age. These cases add to the expanding differential diagnosis to consider in newborns who screen positive for ALD via elevated C26:0-lysophosphatidylcholine. Though the pathophysiology of how transplacental maternal anti-Ro antibodies damage fetal tissue is not well-understood, we postulate that the VLCFA elevations reflect a systemic inflammatory response and secondary peroxisomal dysfunction that improves once maternal autoantibodies wane after birth. Additional evaluation of this phenomenon is warranted to better understand the intricate biochemical, clinical, and possible therapeutic overlap between autoimmunity, inflammation, peroxisomal dysfunction, and human disease.

    View details for DOI 10.1002/ajmg.a.63144

    View details for PubMedID 36863699

  • Phenotypic variability in RERE-related disorders and the first report of an inherited variant. American journal of medical genetics. Part A Niehaus, A. D., Kim, J., Manning, M. A. 2022

    Abstract

    RERE-related disorders, also known as Neurodevelopmental Disorders with or without Anomalies of the Brain, Eye, or Heart (NEDBEH), are caused by heterozygous pathogenic variants in the arginine-glutamic acid dipeptide repeats gene (RERE). Up-to-date, 20 cases have been reported with the core characteristics of developmental delay, intellectual disability, and/or autism spectrum disorder. Here, we describe three additional cases. In the first case, the patient was found to have a previously reported de novo missense variant; her clinical findings of global developmental delay, intellectual disability, autism spectrum disorder, vision abnormalities, musculoskeletal anomalies, dysmorphic facial features, and a congenital heart defect strengthen existing genotype-phenotype correlations. We also describe the first inherited variant in RERE, found in a patient (case 2) with developmental delay, autism, and hyperopia and his mother (case 3) with ADHD, myopia, and history of mild speech delay. Lastly, by summarizing the clinical features presented in the 23 cases now reported, we provide an updated review of the literature.

    View details for DOI 10.1002/ajmg.a.62952

    View details for PubMedID 36053530

  • The prevalence of fetal alcohol spectrum disorders in rural communities in South Africa: A third regional sample of child characteristics and maternal risk factors. Alcoholism, clinical and experimental research May, P. A., de Vries, M. M., Marais, A., Kalberg, W. O., Buckley, D., Hasken, J. M., Abdul-Rahman, O., Robinson, L. K., Manning, M. A., Seedat, S., Parry, C. D., Hoyme, H. E. 2022

    Abstract

    BACKGROUND: A third comprehensive study of fetal alcohol spectrum disorders (FASD) in a rural, agricultural region of South Africa is described.METHODS: Population-based, active case ascertainment methods were employed among a school-based cohort to assess child physical and neurobehavioral traits, and maternal risk factor interviews conducted to identify all children with FASD to determine FASD prevalence.RESULTS: Consent was obtained for 76.7% of 1158 children attending first grade in the region's public schools. Case control results are presented for 95 with fetal alcohol syndrome (FAS), 64 with partial fetal alcohol syndrome (PFAS), 77 with alcohol-related neurodevelopmental disorder (ARND), 2 with alcohol-related birth defects (ARBD), and 213 randomly-selected controls. Four techniques estimating FASD prevalence from in-person examinations and testing yielded a range of total FASD prevalence of 206-366 per 1,000. Final weighted, estimated prevalence of FAS was 104.5 per 1,000, PFAS was 77.7 per 1,000, ARND was 125.2 per 1,000, and total FASD prevalence was 310 per 1,000 (95% CI=283.4 - 336.7). Expressed as a percentage, 31% had FASD. Although the rate of total FASD remained steady over nine years, the proportion of children within the FASD group has changed significantly: FAS trended downward, and ARND trended upward. A detailed evaluation is presented of the specific child physical and neurobehavioral traits integral to assessing the full continuum of FASD. The diagnosis of a child with FASD was significantly associated with maternal proximal risk factors such as: co-morbid prenatal use of alcohol and tobacco (OR=19.1); maternal drinking of two (OR=5.9), three (OR=5.9), four (OR=38.3), or more alcoholic drinks per drinking day; and drinking in the first trimester (OR=8.4), first and second trimesters (OR=17.7), or throughout pregnancy (OR=18.6). Distal maternal risk factors included: slight or small physical status (height, weight, and head circumference), lower BMI, less formal education, late recognition of pregnancy, and higher gravidity, parity, and older age during the index pregnancy.CONCLUSION: The prevalence of FASD remained a significant problem in this region, but the severity of physical traits and anomalies within the continuum of FASD is trending downwards.

    View details for DOI 10.1111/acer.14922

    View details for PubMedID 35971629

  • Evidence of neuroinflammation and immunotherapy responsiveness in individuals with down syndrome regression disorder. Journal of neurodevelopmental disorders Santoro, J. D., Partridge, R., Tanna, R., Pagarkar, D., Khoshnood, M., Rehmani, M., Kammeyer, R. M., Gombolay, G. Y., Fisher, K., Conravey, A., El-Dahr, J., Christy, A. L., Patel, L., Manning, M. A., Van Mater, H., Rafii, M. S., Quinn, E. A. 2022; 14 (1): 35

    Abstract

    BACKGROUND: Down syndrome regression disorder is a symptom cluster consisting of neuropsychiatric regression without cause. This study evaluated the incidence of neurodiagnostic abnormalities in individuals with Down syndrome regression disorder and determined if abnormalities are indicative of responses to therapeutic intervention.METHODS: A retrospective, multi-center, case-control study was performed. Patients were required to have subacute onset and the presence of four of five symptom groups present (cognitive decline, expressive language, sleep derangement, loss of ability to perform activities of daily living, and/or a new movement disorder) and no other explanation for symptoms.RESULTS: Individuals with Down syndrome regression disorder were comparable to a cohort of individuals with only Down syndrome although had higher rates of autoimmune disease (p = 0.02, 95%CI 1.04-1.75). Neurodiagnostic abnormalities were found on EEG (n = 19, 26%), neuroimaging (n = 16, 22%), and CSF (n = 9, 17%). Pleocytosis was appreciated in five cases, elevated total protein in nine, elevated IgG index in seven, and oligoclonal bands in two. Testing within 2 years of symptom onset was more likely to have neurodiagnostic abnormalities (p = 0.01, 95%CI 1.64-37.06). In individuals with neurodiagnostic abnormalities, immunotherapy was nearly four times more likely to have a therapeutic effect than in those without neurodiagnostic abnormalities (OR 4.11, 95%CI 1.88-9.02). In those with normal neurodiagnostic studies (n = 43), IVIg was effective in 14 of 17 (82%) patients as well although other immunotherapies were uniformly ineffective.CONCLUSIONS: This study reports the novel presence of neurodiagnostic testing abnormalities in individuals with Down syndrome regression disorder, providing credence to this symptom cluster potentially being of neurologic and/or neuroimmunologic etiology.

    View details for DOI 10.1186/s11689-022-09446-w

    View details for PubMedID 35659536

  • Short Bones, Renal Stones, and Diagnostic Moans: Hypercalcemia in a Girl Found to Have Coffin-Lowry Syndrome. Journal of investigative medicine high impact case reports Tise, C. G., Matalon, D. R., Manning, M. A., Byers, H. M., Grover, M. 2022; 10: 23247096221101844

    Abstract

    Pathogenic variants in RPS6KA3 are associated with Coffin-Lowry syndrome (CLS), an X-linked semidominant disorder characterized by intellectual disability, stimulus-induced drop attacks, distinctive facial features, progressive kyphoscoliosis, and digit anomalies in hemizygous males. Heterozygous females may also have features of CLS; however, there can be considerable phenotypic variation, often attributed to ratios of X-inactivation in various tissue types. Although skeletal anomalies and short stature are hallmarks of CLS, hypercalcemia has not been reported. Here we describe a 30-month-old girl with gross motor delays, short stature, dysmorphic features, bilateral duplicated renal collecting systems, and no family history of hypercalcemia who required multiple admissions for idiopathic hypercalcemia necessitating bisphosphonate infusions at 12.5 and 15 months of age. A maternally inherited likely-pathogenic variant in RPS6KA3 was identified by trio exome sequencing, consistent with the diagnosis of CLS in the proband and her mother. Maternal history was notable only for decreased height compared to first-degree relatives, bilateral genu valgum, and a bicornuate uterus; she was later found to also have a partially duplicated left renal collecting system. Subsequent X-inactivation studies in blood aligned with the phenotypic variation between mother and daughter. Although hypercalcemia is not a reported feature in CLS, there is evidence of interrupted osteoblast differentiation, providing a potential mechanism for hypercalcemia in this genetic condition. The hypercalcemia in this case may represent a severe presentation of an unrecognized clinical feature in CLS that resolves with age. This case further highlights the intrafamilial phenotypic variation of CLS among females, suggesting X-inactivation as the underlying mechanism, and demonstrates the value of exome sequencing in patients for whom a genetic disorder is highly suspected but not identified despite thorough evaluation.

    View details for DOI 10.1177/23247096221101844

    View details for PubMedID 35638718

  • Characteristic physical traits of first-grade children in the United States with fetal alcohol spectrum disorders (FASD) and associated alcohol and drug exposures. American journal of medical genetics. Part A May, P. A., Hasken, J. M., Manning, M. A., Robinson, L. K., Abdul-Rahman, O., Adam, M. P., Jewett, T., Elliott, A. J., Kalberg, W. O., Buckley, D., Hoyme, H. E. 2022

    Abstract

    We compared growth, physical features, and minor anomalies in 131 first-grade children with fetal alcohol spectrum disorders (FASD) to those of a representative comparison group of typically developing children from the same populations (n=1212). The data were collected from three regional sites in the NIAAA-funded Collaboration on FASD Prevalence (CoFASP). Dysmorphology examinations were performed by a team of expert clinical geneticists, and FASD diagnoses were assigned according to the Revised Institute of Medicine Guidelines, which include assessments of growth, dysmorphology, neurobehavior, and maternal risk interviews. We present detailed data on 32 physical traits, minor anomalies, and a summary dysmorphology score for children within each of the four diagnostic categories in the continuum of FASD. There were few differences in the frequency of FASD diagnoses by race or Hispanic ethnicity. Children with FASD were born to mothers who reported using alcohol, tobacco (28.3%), and other drugs (14.2%) during pregnancy. Controlling for tobacco and other drug use, risk analysis indicated that women with a drinking pattern of 3 drinks per drinking day prior to pregnancy were 10 times more likely (p<0.001, OR=9.92, 95% CI: 4.6-21.5) to bear a child with FASD than those who reported abstinence prior to pregnancy.

    View details for DOI 10.1002/ajmg.a.62738

    View details for PubMedID 35357075

  • The challenges and pitfalls of fetal alcohol spectrum disorders prevalence studies. Alcoholism, clinical and experimental research May, P. A., Hasken, J. M., Manning, M. A., Hoyme, H. E. 2021

    Abstract

    The experienced team of researchers, McCarthy, Mukerjee, Fleming, Green, Clayton-Smith, Price, Allely, and Cook describe a well-designed and thoughtful study of the "Prevalence of Fetal Alcohol Spectrum Disorders (FASD) in Greater Manchester, UK." This paper is a contribution to the field, for it represents one of a handful of active case ascertainment (ACA) studies of FASD carried out among school children in Europe. McCarthy et al. report a minimal prevalence of FASD of 1.8% and an estimated rate of 3.4% if probable cases are included.

    View details for DOI 10.1111/acer.14735

    View details for PubMedID 34726795

  • Increased Autoimmunity in Individuals With Down Syndrome and Moyamoya Disease FRONTIERS IN NEUROLOGY Santoro, J. D., Lee, S., Wang, A. C., Ho, E., Nagesh, D., Khoshnood, M., Tanna, R., Durazo-Arvizu, R. A., Manning, M. A., Skotko, B. G., Steinberg, G. K., Rafii, M. S. 2021; 12: 724969

    Abstract

    Objective: To determine if elevated rates of autoimmune disease are present in children with both Down syndrome and moyamoya disease given the high rates of autoimmune disease reported in both conditions and unknown etiology of angiopathy in this population. Methods: A multi-center retrospective case-control study of children with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome without cerebrovascular disease was performed. Outcome measures included presence of autoimmune disease, presence of autoantibodies and angiopathy severity data. Comparisons across groups was performed using the Kruskal-Wallis, χ2 and multivariate Poisson regression. Results: The prevalence of autoimmune disease were 57.7, 20.3, and 35.3% in persons with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome only groups, respectively (p < 0.001). The prevalence of autoimmune disease among children with Down syndrome and moyamoya syndrome is 3.2 times (p < 0.001, 95% CI: 1.82-5.58) higher than the idiopathic moyamoya group and 1.5 times (p = 0.002, 95% CI: 1.17-1.99) higher than the Down syndrome only group when adjusting for age and sex. The most common autoimmune diseases were thyroid disorders, type I diabetes and Celiac disease. No individuals with idiopathic moyamoya disease had more than one type of autoimmune disorder while 15.4% of individuals with Down syndrome and moyamoya syndrome and 4.8% of individuals with Down syndrome only had >1 disorder (p = 0.05, 95%CI: 1.08-6.08). Interpretation: This study reports elevated rates of autoimmune disease in persons with Down syndrome and moyamoya syndrome providing a nidus for study of the role of autoimmunity in angiopathy in this population.

    View details for DOI 10.3389/fneur.2021.724969

    View details for Web of Science ID 000697626100001

    View details for PubMedID 34566869

    View details for PubMedCentralID PMC8455812

  • Gestational age and birth growth parameters as early predictors of fetal alcohol spectrum disorders. Alcoholism, clinical and experimental research Hasken, J. M., Marais, A., de Vries, M., Joubert, B., Cloete, M., Botha, I., Symington, S. R., Kalberg, W. O., Buckley, D., Robinson, L. K., Manning, M. A., Parry, C. D., Seedat, S., Hoyme, H. E., May, P. A. 2021

    Abstract

    OBJECTIVE: To investigate gestational age and growth at birth as predictors of fetal alcohol spectrum disorders (FASD).METHODS: The sample analyzed here comprises 737 randomly selected children who were assessed for growth, dysmorphology, and neurobehavior at 7years of age. Maternal interviews were conducted to ascertain prenatal alcohol exposure and other maternal risk factors. Birth data originated from clinic records and the data at 7years of age originated from population-based, in-school studies. Binary linear regression assessed the relationship between preterm birth, small for gestational age (SGA), and their combination on the odds of a specific FASD diagnosis or any FASD.RESULTS: Among children diagnosed with FASD at 7years of age (n=255), a review of birth records indicated that 18.4% were born preterm, 51.4% were SGA, and 5.9% were both preterm and SGA. When compared to non-FASD controls (n=482), the birth percentages born preterm, SGA, and both preterm and SGA were respectively 12.0%, 27.7%, and 0.5%. Mothers of children with FASD reported more drinking during all trimesters, higher gravidity, lower educational attainment, and older age at pregnancy. After controlling for usual drinks per drinking day in the first trimester, number of trimesters of drinking, maternal education, tobacco use, and maternal age, the odds ratio of an FASD diagnosis by age 7 was significantly associated with SGA (OR=2.16, 95% CI: 1.35 to 3.45). SGA was also significantly associated with each of the 3most common specific diagnoses within the FASD continuum: fetal alcohol syndrome (FAS; OR=3.1), partial FAS (OR=2.1), and alcohol-related neurodevelopmental disorder (OR=2.0).CONCLUSION: SGA is a robust early indicator for FASD in this random sample of children assessed at 7years of age.

    View details for DOI 10.1111/acer.14656

    View details for PubMedID 34342019

  • Estimating the community prevalence, child traits, and maternal risk factors of fetal alcohol spectrum disorders (FASD) from a random sample of school children. Drug and alcohol dependence May, P. A., Hasken, J. M., Hooper, S. R., Hedrick, D. M., Jackson-Newsom, J., Mullis, C. E., Dobyns, E., Kalberg, W. O., Buckley, D., Robinson, L. K., Abdul-Rahman, O., Adam, M. P., Manning, M. A., Jewett, T., Hoyme, H. E. 2021; 227: 108918

    Abstract

    OBJECTIVE: Utilize a random sample to estimate the prevalence, child traits, and maternal risk for fetal alcohol spectrum disorders (FASD) in a Southeastern United States county.METHODS: From all first-grade students (n = 1073) a simple random sample was drawn, and 32 % (n = 231) were consented. All 231 children were examined for dysmorphology and growth, 84 were tested and rated on neurobehavior, and 72 mothers were interviewed for maternal risk.RESULTS: Significant differences (alpha = .05) between the physical traits of children diagnosed with FASD and the entire sample were height, weight, head circumference, body mass index, and total dysmorphology scores, and all three cardinal features of fetal alcohol syndrome: palpebral fissure length, smooth philtrum, and narrow vermilion. Intellectual function and inhibition were not significantly different between FASD and typically-functioning children, but two executive function measures and one visual/spatial measure approached significance (alpha = .10). Six behavioral measures were significantly worse for the FASD group: teacher-rated aggressive behavior, oppositional defiant problems, and conduct problems, and parent-rated problems of communication, daily living, and socialization. Significant maternal risk factors reported were postpartum depression, frequency of drinking, and recovery from problem drinking. The prevalence of FASD was 71.4 per 1,000 or 7.1 %. This rate falls clearly within the prevalence range identified in eight larger samples of other communities in the Collaboration on FASD Prevalence (CoFASP) study in four regions of the United States.CONCLUSION: Careful and detailed clinical evaluation of children from small random samples can be useful for estimating the prevalence and traits of FASD in a community.

    View details for DOI 10.1016/j.drugalcdep.2021.108918

    View details for PubMedID 34388579

  • Immunohistochemical ALK Expression in Granular Cell Atypical Fibroxanthoma: A Diagnostic Pitfall for ALK-Rearranged Non-neural Granular Cell Tumor. The American Journal of dermatopathology Brown, R. A., Cloutier, J. M., Bahrani, E. n., Liman, A. n., Tasso, D. n., Palmer, A. n., Manning, M. A., Galperin, I. n., Rieger, K. E., Novoa, R. A., Lau, H. n., Louie, C. Y. 2021

    Abstract

    Atypical fibroxanthoma (AFX) is a neoplasm that most commonly occurs on sun-damaged skin of the head and neck in elderly patients and that usually exhibits indolent clinical behavior with complete excision. The granular cell variant of AFX demonstrates overlapping histopathologic features with dermal non-neural granular cell tumor (NNGCT), which typically arises on the extremities of young to middle aged adults with rare reports of regional metastasis. A subset of NNGCT harbors ALK rearrangements and expresses ALK by immunohistochemistry. Here, we present 2 cases of granular cell AFX occurring on the scalp of males aged 73 and 87 with ALK expression by immunohistochemistry and no evidence of an ALK rearrangement on fluorescence in situ hybridization, representing a diagnostic pitfall for NNGCT.

    View details for DOI 10.1097/DAD.0000000000001931

    View details for PubMedID 33767072

  • Genotype-phenotype study and expansion of ARL6IP1-related complicated hereditary spastic paraplegia. Clinical genetics Cao, Y., Manning, M., Pope, K., He, W., Vetrini, F., Siskind, C., Rosenfeld, J. A., Yang, Y., Xiao, R. 2020

    View details for DOI 10.1111/cge.13870

    View details for PubMedID 33188530

  • The prevalence, child characteristics, and maternal risk factors for the continuum of fetal alcohol spectrum disorders: A sixth population-based study in the same South African community. Drug and alcohol dependence May, P. A., Marais, A., De Vries, M. M., Buckley, D., Kalberg, W. O., Hasken, J. M., Stegall, J. M., Hedrick, D. M., Robinson, L. K., Manning, M. A., Tabachnick, B. G., Seedat, S., Parry, C. D., Hoyme, H. E. 2020: 108408

    Abstract

    BACKGROUND: Prevalence and characteristics of fetal alcohol spectrum disorders (FASD) have been described previously in this community.METHODS: Active case ascertainment methods were employed in a new cross-sectional study with Revised Institute of Medicine criteria among first grade students (n = 735) via dysmorphology examinations and neurobehavioral assessments. Their mothers were interviewed regarding risk factors. Final diagnoses were assigned via structured case conferences.RESULTS: Children with fetal alcohol syndrome (FAS), partial FAS (PFAS), and alcohol related-neurodevelopmental disorder (ARND) were significantly different from controls on all cardinal variables, multiple dysmorphology traits and neurobehavioral performance. Mothers of children with FASD reported significantly more drinking before and during pregnancy (mothers of children with FAS reported 7.8 (±6.1) drinks per drinking day (DDD) prior to pregnancy and 5.1 (±5.9) after pregnancy recognition). Distal risk variables for a diagnosis on the continuum of FASD were: lower maternal height, weight, and body mass index; higher gravidity; lower education and household income; and later pregnancy recognition. Alcohol and tobacco remain the only commonly used drugs. Women reporting first trimester drinking of two DDD were 13 times more likely (95 % CI:1.3-133.4) to have a child with FASD than non-drinkers; and those who reported drinking throughout pregnancy were 19.4 times more likely (95 % CI:8.2-46.0) to have a child with FASD.CONCLUSION: Seventeen years after the first study in this community, FASD prevalence remains high at 16 %-31 %. The FAS rate may have declined somewhat, but rates of PFAS and ARND seemed to plateau, at a high rate.

    View details for DOI 10.1016/j.drugalcdep.2020.108408

    View details for PubMedID 33250379

  • Author Correction: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders. Nature communications Wang, T., Hoekzema, K., Vecchio, D., Wu, H., Sulovari, A., Coe, B. P., Gillentine, M. A., Wilfert, A. B., Perez-Jurado, L. A., Kvarnung, M., Sleyp, Y., Earl, R. K., Rosenfeld, J. A., Geisheker, M. R., Han, L., Du, B., Barnett, C., Thompson, E., Shaw, M., Carroll, R., Friend, K., Catford, R., Palmer, E. E., Zou, X., Ou, J., Li, H., Guo, H., Gerdts, J., Avola, E., Calabrese, G., Elia, M., Greco, D., Lindstrand, A., Nordgren, A., Anderlid, B., Vandeweyer, G., Van Dijck, A., Van der Aa, N., McKenna, B., Hancarova, M., Bendova, S., Havlovicova, M., Malerba, G., Bernardina, B. D., Muglia, P., van Haeringen, A., Hoffer, M. J., Franke, B., Cappuccio, G., Delatycki, M., Lockhart, P. J., Manning, M. A., Liu, P., Scheffer, I. E., Brunetti-Pierri, N., Rommelse, N., Amaral, D. G., Santen, G. W., Trabetti, E., Sedlacek, Z., Michaelson, J. J., Pierce, K., Courchesne, E., Kooy, R. F., SPARK Consortium, Nordenskjold, M., Romano, C., Peeters, H., Bernier, R. A., Gecz, J., Xia, K., Eichler, E. E., Acampado, J., Ace, A. J., Amatya, A., Astrovskaya, I., Bashar, A., Brooks, E., Butler, M. E., Cartner, L. A., Chin, W., Chung, W. K., Daniels, A. M., Feliciano, P., Fleisch, C., Ganesan, S., Jensen, W., Lash, A. E., Marini, R., Myers, V. J., O'Connor, E., Rigby, C., Robertson, B. E., Shah, N., Shah, S., Singer, E., Snyder, L. G., Stephens, A. N., Tjernagel, J., Vernoia, B. M., Volfovsky, N., White, L. C., Hsieh, A., Shen, Y., Zhou, X., Turner, T. N., Bahl, E., Thomas, T. R., Brueggeman, L., Koomar, T., Michaelson, J. J., O'Roak, B. J., Barnard, R. A., Gibbs, R. A., Muzny, D., Sabo, A., Ahmed, K. L., Eichler, E. E., Siegel, M., Abbeduto, L., Amaral, D. G., Hilscher, B. A., Li, D., Smith, K., Thompson, S., Albright, C., Butter, E. M., Eldred, S., Hanna, N., Jones, M., Coury, D. L., Scherr, J., Pifher, T., Roby, E., Dennis, B., Higgins, L., Brown, M., Alessandri, M., Gutierrez, A., Hale, M. N., Herbert, L. M., Schneider, H. L., David, G., Annett, R. D., Sarver, D. E., Arriaga, I., Camba, A., Gulsrud, A. C., Haley, M., McCracken, J. T., Sandhu, S., Tafolla, M., Yang, W. S., Carpenter, L. A., Bradley, C. C., Gwynette, F., Manning, P., Shaffer, R., Thomas, C., Bernier, R. A., Fox, E. A., Gerdts, J. A., Pepper, M., Ho, T., Cho, D., Piven, J., Lechniak, H., Soorya, L. V., Gordon, R., Wainer, A., Yeh, L., Ochoa-Lubinoff, C., Russo, N., Berry-Kravis, E., Booker, S., Erickson, C. A., Prock, L. M., Pawlowski, K. G., Matthews, E. T., Brewster, S. J., Hojlo, M. A., Abada, E., Lamarche, E., Wang, T., Murali, S. C., Harvey, W. T., Kaplan, H. E., Pierce, K. L., DeMarco, L., Horner, S., Pandey, J., Plate, S., Sahin, M., Riley, K. D., Carmody, E., Constantini, J., Esler, A., Fatemi, A., Hutter, H., Landa, R. J., McKenzie, A. P., Neely, J., Singh, V., Van Metre, B., Wodka, E. L., Fombonne, E. J., Huang-Storms, L. Y., Pacheco, L. D., Mastel, S. A., Coppola, L. A., Francis, S., Jarrett, A., Jacob, S., Lillie, N., Gunderson, J., Istephanous, D., Simon, L., Wasserberg, O., Rachubinski, A. L., Rosenberg, C. R., Kanne, S. M., Shocklee, A. D., Takahashi, N., Bridwell, S. L., Klimczac, R. L., Mahurin, M. A., Cotrell, H. E., Grant, C. A., Hunter, S. G., Martin, C. L., Taylor, C. M., Walsh, L. K., Dent, K. A., Mason, A., Sziklay, A., Smith, C. J. 2020; 11 (1): 5398

    Abstract

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    View details for DOI 10.1038/s41467-020-19289-5

    View details for PubMedID 33087701

  • Ocular measurements in fetal alcohol spectrum disorders. American journal of medical genetics. Part A Gomez, D. A., May, P. A., Tabachnick, B. G., Hasken, J. M., Lyden, E. R., Kalberg, W. O., Hoyme, H. E., Manning, M. A., Adam, M. P., Robinson, L. K., Jones, K. L., Buckley, D., Abdul-Rahman, O. A. 2020

    Abstract

    Fetal alcohol spectrum disorders (FASD) describe a range of physical, behavioral, and neurologic deficits in individuals exposed to alcohol prenatally. Reduced palpebral fissure length is one of the cardinal facial features of FASD. However, other ocular measurements have not been studied extensively in FASD. Using the Fetal Alcohol Syndrome Epidemiologic Research (FASER) database, we investigated how inner canthal distance (ICD), interpupillary distance (IPD), and outer canthal distance (OCD) centiles differed between FASD and non-FASD individuals. We compared ocular measurement centiles in children with FASD to non-FASD individuals and observed reductions in all three centiles for ICD, IPD, and OCD. However, when our non-FASD children who had various forms of growth deficiency (microcephaly, short-stature, or underweight) were compared to controls, we did not observe a similar reduction in ocular measurements. This suggests that reductions in ocular measurements are a direct effect of alcohol on ocular development independent of its effect on growth parameters, which is consistent with animal models showing a negative effect of alcohol on developing neural crest cells. Interpupillary distance centile appeared to be the most significantly reduced ocular measure we evaluated, suggesting it may be a useful measure to be considered in the diagnosis of FASD.

    View details for DOI 10.1002/ajmg.a.61759

    View details for PubMedID 32677343

  • Addendum: Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genetics in medicine : official journal of the American College of Medical Genetics Manning, M., Hudgins, L., American College of Medical Genetics and Genomics (ACMG) Professional Practice and Guidelines Committee 2020

    View details for DOI 10.1038/s41436-020-0848-8

    View details for PubMedID 32514088

  • Fetal Alcohol Spectrum Disorders in a Midwestern City: Child Characteristics, Maternal Risk Traits, and Prevalence. Alcoholism, clinical and experimental research May, P. A., Hasken, J. M., Baete, A., Russo, J., Elliott, A. J., Kalberg, W. O., Buckley, D., Brooks, M., Ortega, M. A., Hedrick, D. M., Tabachnick, B. G., Abdul-Rahman, O., Adam, M. P., Jewett, T., Robinson, L. K., Manning, M. A., Hoyme, H. E. 2020

    Abstract

    OBJECTIVE: To determine the characteristics of children with fetal alcohol spectrum disorders (FASD) and their mothers in a Midwestern city.METHODS: Case-control samples were drawn from 2 separate first-grade cohorts (combined N=4,047) in every city school using different methods. In Cohort Sample 1, all consented small children (≤25th centile on height, weight, and/or head circumference) entered the study along with a random sample from all enrolled students. Cohort Sample 2 was drawn totally at random. Child growth, dysmorphology, and neurobehavior were assessed using the Collaboration on FASD Prevalence (CoFASP) criteria, and mothers were interviewed.RESULTS: For the samples combined, 891 children received dysmorphology examinations, and 692 were case-conferenced for final diagnosis. Forty-four children met criteria for FASD. Total dysmorphology scores differentiated diagnostic groups: fetal alcohol syndrome (FAS), 16.7; partial FAS, 11.8; alcohol-related neurodevelopmental disorder (ARND), 6.1; and typically developing controls, 4.2. Neurobehavioral tests distinguished children with FASD from controls, more for behavioral problems than cognitive delay. Children with ARND demonstrated the poorest neurobehavioral indicators. An adjusted regression model of usual prepregnancy drinking indicated that maternal reports of 3 drinks per drinking day (DDD) weresignificantly associated with a FASD diagnosis (p=0.020, OR=10.1, 95% CI=1.44 to 70.54), as were 5 or more DDD (p<0.001, OR=26.47, 95% CI=4.65 to 150.62). Other significant maternal risk factors included the following: self-reported drinking in any trimester; smoking and cocaine use during pregnancy; later pregnancy recognition and later and less prenatal care; lower maternal weight, body mass index (BMI), and head circumference; and unmarried status. There was no significant difference in FASD prevalence by race, Hispanic ethnicity, or socioeconomic status at this site, where the prevalence of FASD was 14.4 to 41.2 per 1,000 (1.4 to 4.1%).CONCLUSION: This city displayed the lowest prevalence of FASD of the 4 CoFASP sites. Nevertheless, FASD were common, and affected children demonstrated a common, recognizable, and measurable array of traits.

    View details for DOI 10.1111/acer.14314

    View details for PubMedID 32293735

  • Fetal Alcohol Spectrum Disorders in a Southeastern County of the United States: Child Characteristics and Maternal Risk Traits. Alcoholism, clinical and experimental research May, P. A., Hasken, J. M., Stegall, J. M., Mastro, H. A., Kalberg, W. O., Buckley, D., Brooks, M., Hedrick, D. M., Ortega, M. A., Elliott, A. J., Tabachnick, B. G., Abdul-Rahman, O., Adam, M. P., Robinson, L. K., Manning, M. A., Jewett, T., Hoyme, H. E. 2020

    Abstract

    OBJECTIVE: To detail the characteristic traits of children with fetal alcohol spectrum disorders (FASDs) and maternal risk factors in a southeastern U.S. County.METHODS: Independent samples were drawn from 2 different cohorts of first-grade students. All consented children (49.8%) were measured for height, weight, and head circumference, and those≤25th centile entered the study along with a random sample drawn from all enrolled students. Study children were examined for physical growth, dysmorphology, and neurobehavior, and their mothers were interviewed.RESULTS: Total dysmorphology scores discriminated well the physical traits of children across the FASD continuum: fetal alcohol syndrome (FAS)=15.8, partial FAS (PFAS)=10.8, alcohol-related neurobehavioral disorder (ARND)=5.2, and typically developing controls=4.4. Additionally, a neurobehavioral battery distinguished children with each FASD diagnosis from controls. Behavioral problems qualified more children for FASD diagnoses than cognitive traits. Significant proximal maternal risk variables were as follows: reports of prepregnancy drinking, drinking in any trimester, and comorbid use of other drugs in lifetime and during pregnancy, especially alcohol and marijuana (14.9% among mothers of children with FASD vs. 0.4% for controls). Distal maternal risks included reports of other health problems (e.g., depression), living unmarried with a partner during pregnancy, and a lower level of spirituality. Controlling for other drug use during pregnancy, having a child diagnosed with a FASD was 17.5 times greater for women who reported usual consumption of 3 drinks per drinking day prior to pregnancy than for nondrinking mothers (p<0.001, 95% CI=5.1 to 59.9). There was no significant difference in the prevalence of FASD by race, Hispanic ethnicity, or socioeconomic status. The prevalence of FASD was not lower than 17.3 per 1,000, and weighted estimated prevalence was 49.0 per 1,000 or 4.9%.CONCLUSION: This site had the second lowest rate in the CoFASP study, yet children with FASD are prevalent.

    View details for DOI 10.1111/acer.14313

    View details for PubMedID 32293734

  • Fetal Alcohol Spectrum Disorders in a Rocky Mountain Region City: Child Characteristics, Maternal Risk Traits, and Prevalence. Alcoholism, clinical and experimental research May, P. A., Hasken, J. M., Bozeman, R., Jones, J., Burns, M. K., Goodover, J., Kalberg, W. O., Buckley, D., Brooks, M., Ortega, M. A., Elliott, A. J., Hedrick, D. M., Tabachnick, B. G., Abdul-Rahman, O., Adam, M. P., Jewett, T., Robinson, L. K., Manning, M. A., Hoyme, H. E. 2020

    Abstract

    OBJECTIVE: To document prevalence and traits of children with fetal alcohol spectrum disorders (FASD) and maternal risk factors in a Rocky Mountain city.METHODS: Variations on active case ascertainment methods were used in 2 first-grade cohorts in all city schools. The consent rate was 59.2%. Children were assessed for physical growth, dysmorphology, and neurobehavior and their mothers interviewed.RESULTS: Thirty-eight children were diagnosed with FASD and compared with 278 typically developing controls. Total dysmorphology scores summarized well the key physical indicators of FASD and defined specific diagnostic groups. On average, children with FASD performed significantly poorer than controls on intellectual, adaptive, learning, attention, and behavioral tasks. More mothers of children with FASD reported drinking prior to pregnancy and in the first and second trimesters, and had partners with drinking problems than mothers of controls; however, reports of comorbid alcohol use and 6 other drugs were similar for mothers of children with FASD and mothers of controls. Mothers of children with FASD were significantly younger at pregnancy, had lower average weight before pregnancy and less education, initiated prenatal clinic visits later, and reported more health problems (e.g., stomach ulcers and accidents). Children with FASD had significantly lower birth weight and more problems at birth, and were less likely to be living with biological mother and father. Controlling for other drug and tobacco use, a FASD diagnosis is 6.7 times (OR=6.720, 95% CI=1.6 to 28.0) more likely among children of women reporting prepregnancy drinking of 3 drinks per drinking day (DDD) and 7.6 times (OR=7.590, 95% CI=2.0 to 31.5) more likely at 5 DDD. Prevalence of FAS was 2.9-5.8 per 1,000 children, and total FASD was 34.9 to 82.5 per 1,000 children or 3.5 to 8.3% at this site.CONCLUSION: This site had the second highest prevalence of FASD of the 4 Collaboration on FASD Prevalence sites and clearly identifiable child and maternal risk traits.

    View details for DOI 10.1111/acer.14315

    View details for PubMedID 32293732

  • Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders. Nature communications Wang, T. n., Hoekzema, K. n., Vecchio, D. n., Wu, H. n., Sulovari, A. n., Coe, B. P., Gillentine, M. A., Wilfert, A. B., Perez-Jurado, L. A., Kvarnung, M. n., Sleyp, Y. n., Earl, R. K., Rosenfeld, J. A., Geisheker, M. R., Han, L. n., Du, B. n., Barnett, C. n., Thompson, E. n., Shaw, M. n., Carroll, R. n., Friend, K. n., Catford, R. n., Palmer, E. E., Zou, X. n., Ou, J. n., Li, H. n., Guo, H. n., Gerdts, J. n., Avola, E. n., Calabrese, G. n., Elia, M. n., Greco, D. n., Lindstrand, A. n., Nordgren, A. n., Anderlid, B. M., Vandeweyer, G. n., Van Dijck, A. n., Van der Aa, N. n., McKenna, B. n., Hancarova, M. n., Bendova, S. n., Havlovicova, M. n., Malerba, G. n., Bernardina, B. D., Muglia, P. n., van Haeringen, A. n., Hoffer, M. J., Franke, B. n., Cappuccio, G. n., Delatycki, M. n., Lockhart, P. J., Manning, M. A., Liu, P. n., Scheffer, I. E., Brunetti-Pierri, N. n., Rommelse, N. n., Amaral, D. G., Santen, G. W., Trabetti, E. n., Sedláček, Z. n., Michaelson, J. J., Pierce, K. n., Courchesne, E. n., Kooy, R. F., Nordenskjöld, M. n., Romano, C. n., Peeters, H. n., Bernier, R. A., Gecz, J. n., Xia, K. n., Eichler, E. E. 2020; 11 (1): 4932

    Abstract

    Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

    View details for DOI 10.1038/s41467-020-18723-y

    View details for PubMedID 33004838

  • Fetal Alcohol Spectrum Disorders in a Pacific Southwest City: Maternal and Child Characteristics. Alcoholism, clinical and experimental research Chambers, C. D., Coles, C., Kable, J., Akshoomoff, N., Xu, R., Zellner, J. A., Honerkamp-Smith, G., Manning, M. A., Adam, M. P., Jones, K. L. 2019

    Abstract

    BACKGROUND: There are limited data on the characteristics of children with fetal alcohol spectrum disorders (FASD) and their mothers from the general population in the United States.METHODS: During the 2012 and 2013 academic years, first-grade children in a large urban Pacific Southwest city were invited to participate in a study to estimate the prevalence of FASD. Children who screened positive on weight, height, or head circumference ≤25th centile or on parental report of developmental concerns were selected for evaluation, along with a random sample of those who screened negative. These children were examined for dysmorphology and neurobehavior and their mothers or collateral sources were interviewed. Children were classified as fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND), or No FASD.RESULTS: A total of 854 children were evaluated; 5 FAS, 44 pFAS, 44 ARND, and 761 No FASD. Children with FAS or pFAS were more likely to have dysmorphic features, and 32/49 (65.3%) of those met criteria for neurobehavioral impairment on cognitive measures with or without behavioral deficits. In contrast, 28/44 (63.6%) of children with ARND met criteria on behavioral measures alone. Mothers of FASD children were more likely to recognize pregnancy later, be unmarried, and report other substance use or psychiatric disorders, but did not differ on age, socioeconomic status, education, or parity. Mothers of FASD children reported more drinks/drinking day each trimester. The risk of FASD was elevated with increasing number of drinks/drinking day prior to pregnancy recognition, even at the level of 1 drink per day (adjusted odds ratio 3.802, 95% confidence interval 1.634, 8.374).CONCLUSIONS: Data from this general population sample in a large urban region in the United States demonstrate the variability of expression of FASD and point to risk and protective factors for mothers in this setting.

    View details for DOI 10.1111/acer.14213

    View details for PubMedID 31688971

  • Xq22 deletions and correlation with distinct neurological disease traits in females: further evidence for a contiguous gene syndrome. Human mutation Hijazi, H., Coelho, F. S., Gonzaga-Jauregui, C., Bernardini, L., Mar, S. S., Manning, M. A., Hanson-Kahn, A., Naidu, S., Srivastava, S., Lee, J. A., Jones, J. R., Friez, M. J., Alberico, T., Torres, B., Fang, P., Cheung, S. W., Song, X., Davis-Williams, A., Jornlin, C., Wight, P. A., Patyal, P., Taube, J., Poretti, A., Inoue, K., Zhang, F., Pehlivan, D., Carvalho, C. M., Hobson, G. M., Lupski, J. R. 2019

    Abstract

    Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of Spastic Paraplegia type 2 [MIM# 312920], sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array Comparative Genomic Hybridization (aCGH) and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (8 herein and 9 published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/humu.23902

    View details for PubMedID 31448840

  • Mutation update for the SATB2 gene HUMAN MUTATION Zarate, Y. A., Bosanko, K. A., Caffrey, A. R., Bernstein, J. A., Martin, D. M., Williams, M. S., Berry-Kravis, E. M., Mark, P. R., Manning, M. A., Bhambhani, V., Vargas, M., Seeley, A. H., Estrada-Veras, J., vanDooren, M. F., Schwab, M., Vanderver, A., Melis, D., Alsadah, A., Sadler, L., Van Esch, H., Callewaert, B., Oostra, A., Maclean, J., Dentici, M., Orlando, V., Lipson, M., Sparagana, S. P., Maarup, T. J., Alsters, S. M., Brautbar, A., Kovitch, E., Naidu, S., Lees, M., Smith, D. M., Turner, L., Raggio, V., Spangenberg, L., Garcia-Minaur, S., Roeder, E. R., Littlejohn, R. O., Grange, D., Pfotenhauer, J., Jones, M. C., Balasubramanian, M., Martinez-Monseny, A., Blok, L., Gavrilova, R., Fish, J. L. 2019; 40 (8): 1013–29

    View details for DOI 10.1002/humu.23771

    View details for Web of Science ID 000480595600003

  • Acute leukemia in a patient with 15q overgrowth syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Bodle, E. E., Gupta, R., Cherry, A. M., Muffly, L., Manning, M. A. 2019; 179 (6): 1025–29
  • Acute leukemia in a patient with 15q overgrowth syndrome. American journal of medical genetics. Part A Bodle, E. E., Gupta, R., Cherry, A. M., Muffly, L., Manning, M. A. 2019

    Abstract

    Overgrowth syndromes are rare genetic conditions which present as global or segmental hyperplasia and are sometimes associated with increased risk of malignancy. Trisomy of the terminal portion of 15q which includes the IGFR1 gene, produces a rare overgrowth phenotype that has been termed 15q overgrowth syndrome (15q OGS). Upregulation of IGF1R has long been implicated in oncogenesis of multiple cancer types, including acute leukemias, and has been shown to render cells more susceptible to other transforming events. To date, too few cases of 15q OGS have been reported to identify any cancer predisposition. We present a case of a 34-year-old female with intellectual disability, macrocephaly, and subtle dysmorphic features who was diagnosed with mixed phenotype acute leukemia (lymphoid and myeloid). Prior to initiation of therapy she was referred to medical genetics for further evaluation and was identified as having a chromosomal translocation resulting in a partial trisomy of chromosome 15q, consistent with 15q OGS. A review of the literature for cases of malignancy in individuals with increased copy number of 15q revealed only one other reported patient. Given the small number of reported individuals, we cannot rule out an increased risk of cancer associated with this chromosomal overgrowth syndrome. Although concerns have been raised regarding treatment feasibility in the setting of chromosomal disorders, the reported patient underwent successful treatment with allogeneic hematopoietic stem-cell transplant.

    View details for PubMedID 30861314

  • Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP BIOLOGICAL PSYCHIATRY Van Dijck, A., Vulto-van Silfhout, A. T., Cappuyns, E., van der Werf, I. M., Mancini, G. M., Tzschach, A., Bernier, R., Gozes, I., Eichler, E. E., Romano, C., Lindstrand, A., Nordgren, A., Kvarnung, M., Kleefstra, T., de Vries, B. A., Kury, S., Rosenfeld, J. A., Meuwissen, M. E., Vandeweyer, G., Kooy, R., Bakshi, M., Wilson, M., Berman, Y., Dickson, R., Fransen, E., Helsmoortel, C., Van den Ende, J., Van der Aa, N., van de Wijdeven, M. J., Rosenblum, J., Monteiro, F., Kok, F., Quercia, N., Bowdin, S., Dyment, D., Chitayat, D., Alkhunaizi, E., Boonen, S. E., Keren, B., Jacquette, A., Faivre, L., Bezieau, S., Isidor, B., Riess, A., Moog, U., Lynch, S., McVeigh, T., Elpeleg, O., Smeland, M., Fannemel, M., van Haeringen, A., Maas, S. M., Veenstra-Knol, H. E., Schouten, M., Willemsen, M. H., Marcelis, C. L., Ockeloen, C., van der Burgt, I., Feenstra, I., van der Smagt, J., Jezela-Stanek, A., Krajewska-Walasek, M., Gonzalez-Lamuno, D., Anderlid, B., Malmgren, H., Nordenskjold, M., Clement, E., Hurst, J., Metcalfe, K., Mansour, S., Lachlan, K., Clayton-Smith, J., Hendon, L. G., Abdulrahman, O. A., Morrow, E., McMillan, C., Gerdts, J., Peeden, J., Vergano, S., Valentino, C., Chung, W. K., Ozmore, J. R., Bedrosian-Sermone, S., Dennis, A., Treat, K., Hughes, S., Safina, N., Le Pichon, J., McGuire, M., Infante, E., Madan-Khetarpal, S., Desai, S., Benke, P., Krokosky, A., Cristian, I., Baker, L., Gripp, K., Stessman, H. A., Eichenberger, J., Jayakar, P., Pizzino, A., Manning, M., Slattery, L., ADNP Consortium 2019; 85 (4): 287–97

    Abstract

    In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking.We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires.We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected.This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.

    View details for PubMedID 29724491

  • Early-Life Predictors of Fetal Alcohol Spectrum Disorders. Pediatrics Kalberg, W. O., May, P. A., Buckley, D. n., Hasken, J. M., Marais, A. S., De Vries, M. M., Bezuidenhout, H. n., Manning, M. A., Robinson, L. K., Adam, M. P., Hoyme, D. B., Parry, C. D., Seedat, S. n., Elliott, A. J., Hoyme, H. E. 2019

    Abstract

    Fetal alcohol spectrum disorders (FASD) comprise the continuum of disabilities associated with prenatal alcohol exposure. Although infancy remains the most effective time for initiation of intervention services, current diagnostic schemes demonstrate the greatest confidence, accuracy, and reliability in school-aged children. Our aims for the current study were to identify growth, dysmorphology, and neurodevelopmental features in infants that were most predictive of FASD at age 5, thereby improving the timeliness of diagnoses.A cohort of pregnant South African women attending primary health care clinics or giving birth in provincial hospitals was enrolled in the project. Children were followed longitudinally from birth to 60 months to determine their physical and developmental trajectories (N = 155). Standardized protocols were used to assess growth, dysmorphology, and development at 6 weeks and at 9, 18, 42, and 60 months. A structured maternal interview, including estimation of prenatal alcohol intake, was administered at 42 or 60 months.Growth restriction and total dysmorphology scores differentiated among children with and without FASD as early as 9 months (area under the receiver operating characteristic curve = 0.777; P < .001; 95% confidence interval: 0.705-0.849), although children who were severely affected could be identified earlier. Assessment of developmental milestones revealed significant developmental differences emerging among children with and without FASD between 18 and 42 months. Mothers of children with FASD were significantly smaller, with lower BMIs and higher alcohol intake during pregnancy, than mothers of children without FASD.Assessment of a combination of growth, dysmorphology, and neurobehavioral characteristics allows for accurate identification of most children with FASD as early as 9 to 18 months.

    View details for DOI 10.1542/peds.2018-2141

    View details for PubMedID 31744890

  • Mutation update for the SATB2 gene. Human mutation Zarate, Y. A., Bosanko, K. A., Caffrey, A. R., Bernstein, J. A., Martin, D. M., Williams, M. S., Berry-Kravis, E. M., Mark, P. R., Manning, M. A., Bhambhani, V. n., Vargas, M. n., Seeley, A. H., Estrada-Veras, J. I., van Dooren, M. F., Schwab, M. n., Vanderver, A. n., Melis, D. n., Alsadah, A. n., Sadler, L. n., Van Esch, H. n., Callewaert, B. n., Oostra, A. n., Maclean, J. n., Dentici, M. L., Orlando, V. n., Lipson, M. n., Sparagana, S. P., Maarup, T. J., Alsters, S. I., Brautbar, A. n., Thropp, E. K., Naidu, S. n., Lees, M. n., Smith, D. M., Turner, L. n., Raggio, V. n., Spangenberg, L. n., Garcia-Miñaúr, S. n., Roeder, E. R., Littlejohn, R. O., Grange, D. n., Pfotenhauer, J. n., Jones, M. C., Balasubramanian, M. n., Martinez-Monseny, A. n., Blok, L. S., Gavrilova, R. n., Fish, J. L. 2019

    Abstract

    SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120=42.5%) followed by missense variants (31/120=25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge on animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS. This article is protected by copyright. All rights reserved.

    View details for PubMedID 31021519

  • Perinatal distress in 1p36 deletion syndrome can mimic hypoxic ischemic encephalopathy. American journal of medical genetics. Part A Carter, L. B., Battaglia, A. n., Cherry, A. n., Manning, M. A., Ruzhnikov, M. R., Bird, L. M., Dowsett, L. n., Graham, J. M., Alkuraya, F. S., Hashem, M. n., Dinulos, M. B., Vallee, S. n., Adam, M. P., Glass, I. n., Beck, A. E., Stevens, C. A., Zackai, E. n., McDougall, C. n., Keena, B. n., Peron, A. n., Vignoli, A. n., Seaver, L. H., Slavin, T. P., Hudgins, L. n. 2019

    Abstract

    1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.

    View details for DOI 10.1002/ajmg.a.61266

    View details for PubMedID 31207089

  • Heart transplantation in two adolescents with Danon disease. Pediatric transplantation Oren, D., Chau, P., Manning, M., Kwong, J., Kaufman, B. D., Maeda, K., Rosenthal, D. N., Hollander, S. A. 2018: e13335

    Abstract

    Danon disease (DD) is an X-linked dominant disorder caused by a mutation in the lysosomal-associated membrane protein-2 (LAMP-2) gene coding for the LAMP-2 protein. We report two cases of successful heart transplantation (HT) in adolescent brothers with DD, including one who was bridged to HT for 34days with a HeartWare left ventricular assist device. In both patients, the post-transplant course was complicated by profound skeletal muscle weakness that resolved with corticosteroid withdrawal. These cases highlight that both HT and ventricular assist device support are feasible in patients with DD. Corticosteroid use may exacerbate skeletal myopathy, and therefore, steroid minimization may be warranted whenever possible.

    View details for PubMedID 30536852

  • PRENATAL ULTRASOUND FINDINGS CONSISTENT WITH NAGER SYNDROME ALLOW FOR IMPROVED PREGNANCY MANAGEMENT Allain, M., Manning, M., Bernstein, J., Enns, G., Alsaleh, N., Derar, N., Hudgins, L. WILEY. 2018: 1488–89
  • Prevalence of Fetal Alcohol Spectrum Disorders in 4 US Communities JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION May, P. A., Chambers, C. D., Kalberg, W. O., Zellner, J., Feldman, H., Buckley, D., Kopald, D., Hasken, J. M., Xu, R., Honerkamp-Smith, G., Taras, H., Manning, M. A., Robinson, L. K., Adam, M. P., Abdul-Rahman, O., Vaux, K., Jewett, T., Elliott, A. J., Kable, J. A., Akshoomoff, N., Falk, D., Arroyo, J. A., Hereld, D., Riley, E. P., Charness, M. E., Coles, C. D., Warren, K. R., Jones, K., Hoyme, H. 2018; 319 (5): 474–82
  • Prevalence of Fetal Alcohol Spectrum Disorders in 4 US Communities. JAMA May, P. A., Chambers, C. D., Kalberg, W. O., Zellner, J., Feldman, H., Buckley, D., Kopald, D., Hasken, J. M., Xu, R., Honerkamp-Smith, G., Taras, H., Manning, M. A., Robinson, L. K., Adam, M. P., Abdul-Rahman, O., Vaux, K., Jewett, T., Elliott, A. J., Kable, J. A., Akshoomoff, N., Falk, D., Arroyo, J. A., Hereld, D., Riley, E. P., Charness, M. E., Coles, C. D., Warren, K. R., Jones, K. L., Hoyme, H. E. 2018; 319 (5): 474-482

    Abstract

    Fetal alcohol spectrum disorders are costly, life-long disabilities. Older data suggested the prevalence of the disorder in the United States was 10 per 1000 children; however, there are few current estimates based on larger, diverse US population samples.To estimate the prevalence of fetal alcohol spectrum disorders, including fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder, in 4 regions of the United States.Active case ascertainment methods using a cross-sectional design were used to assess children for fetal alcohol spectrum disorders between 2010 and 2016. Children were systematically assessed in the 4 domains that contribute to the fetal alcohol spectrum disorder continuum: dysmorphic features, physical growth, neurobehavioral development, and prenatal alcohol exposure. The settings were 4 communities in the Rocky Mountain, Midwestern, Southeastern, and Pacific Southwestern regions of the United States. First-grade children and their parents or guardians were enrolled.Alcohol consumption during pregnancy.Prevalence of fetal alcohol spectrum disorders in the 4 communities was the main outcome. Conservative estimates for the prevalence of the disorder and 95% CIs were calculated using the eligible first-grade population as the denominator. Weighted prevalences and 95% CIs were also estimated, accounting for the sampling schemes and using data restricted to children who received a full evaluation.A total of 6639 children were selected for participation from a population of 13 146 first-graders (boys, 51.9%; mean age, 6.7 years [SD, 0.41] and white maternal race, 79.3%). A total of 222 cases of fetal alcohol spectrum disorders were identified. The conservative prevalence estimates for fetal alcohol spectrum disorders ranged from 11.3 (95% CI, 7.8-15.8) to 50.0 (95% CI, 39.9-61.7) per 1000 children. The weighted prevalence estimates for fetal alcohol spectrum disorders ranged from 31.1 (95% CI, 16.1-54.0) to 98.5 (95% CI, 57.5-139.5) per 1000 children.Estimated prevalence of fetal alcohol spectrum disorders among first-graders in 4 US communities ranged from 1.1% to 5.0% using a conservative approach. These findings may represent more accurate US prevalence estimates than previous studies but may not be generalizable to all communities.

    View details for DOI 10.1001/jama.2017.21896

    View details for PubMedID 29411031

    View details for PubMedCentralID PMC5839298

  • Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy. American journal of human genetics Danhauser, K. n., Alhaddad, B. n., Makowski, C. n., Piekutowska-Abramczuk, D. n., Syrbe, S. n., Gomez-Ospina, N. n., Manning, M. A., Kostera-Pruszczyk, A. n., Krahn-Peper, C. n., Berutti, R. n., Kovács-Nagy, R. n., Gusic, M. n., Graf, E. n., Laugwitz, L. n., Röblitz, M. n., Wroblewski, A. n., Hartmann, H. n., Das, A. M., Bültmann, E. n., Fang, F. n., Xu, M. n., Schatz, U. A., Karall, D. n., Zellner, H. n., Haberlandt, E. n., Feichtinger, R. G., Mayr, J. A., Meitinger, T. n., Prokisch, H. n., Strom, T. M., Płoski, R. n., Hoffmann, G. F., Pronicki, M. n., Bonnen, P. E., Morlot, S. n., Haack, T. B. 2018; 103 (5): 817–25

    Abstract

    ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose from NAD+ to the target protein, and ADP-ribosylhydrolases, such as ADPRHL2, reverse the reaction. We used exome sequencing to identify five different bi-allelic pathogenic ADPRHL2 variants in 12 individuals from 8 families affected by a neurodegenerative disorder manifesting in childhood or adolescence with key clinical features including developmental delay or regression, seizures, ataxia, and axonal (sensori-)motor neuropathy. ADPRHL2 was virtually absent in available affected individuals' fibroblasts, and cell viability was reduced upon hydrogen peroxide exposure, although it was rescued by expression of wild-type ADPRHL2 mRNA as well as treatment with a PARP1 inhibitor. Our findings suggest impaired protein ribosylation as another pathway that, if disturbed, causes neurodegenerative diseases.

    View details for PubMedID 30401461

  • Who is most affected by prenatal alcohol exposure: Boys or girls? Drug and alcohol dependence May, P. A., Tabachnick, B., Hasken, J. M., Marais, A. S., de Vries, M. M., Barnard, R., Joubert, B., Cloete, M., Botha, I., Kalberg, W. O., Buckley, D., Burroughs, Z. R., Bezuidenhout, H., Robinson, L. K., Manning, M. A., Adnams, C. M., Seedat, S., Parry, C. D., Hoyme, H. E. 2017; 177: 258-267

    Abstract

    To examine outcomes among boys and girls that are associated with prenatal alcohol exposure.Boys and girls with fetal alcohol spectrum disorders (FASD) and randomly-selected controls were compared on a variety of physical and neurobehavioral traits.Sex ratios indicated that heavy maternal binge drinking may have significantly diminished viability to birth and survival of boys postpartum more than girls by age seven. Case control comparisons of a variety of physical and neurobehavioral traits at age seven indicate that both sexes were affected similarly for a majority of variables. However, alcohol-exposed girls had significantly more dysmorphology overall than boys and performed significantly worse on non-verbal IQ tests than males. A three-step sequential regression analysis, controlling for multiple covariates, further indicated that dysmorphology among girls was significantly more associated with five maternal drinking variables and three distal maternal risk factors. However, the overall model, which included five associated neurobehavioral measures at step three, was not significant (p=0.09, two-tailed test). A separate sequential logistic regression analysis of predictors of a FASD diagnosis, however, indicated significantly more negative outcomes overall for girls than boys (Nagelkerke R2=0.42 for boys and 0.54 for girls, z=-2.9, p=0.004).Boys and girls had mostly similar outcomes when prenatal alcohol exposure was linked to poor physical and neurocognitive development. Nevertheless, sex ratios implicate lower viability and survival of males by first grade, and girls have more dysmorphology and neurocognitive impairment than boys resulting in a higher probability of a FASD diagnosis.

    View details for DOI 10.1016/j.drugalcdep.2017.04.010

    View details for PubMedID 28624747

  • 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

  • Replication of High Fetal Alcohol Spectrum Disorders Prevalence Rates, Child Characteristics, and Maternal Risk Factors in a Second Sample of Rural Communities in South Africa. International journal of environmental research and public health May, P. A., de Vries, M. M., Marais, A., Kalberg, W. O., Buckley, D., Adnams, C. M., Hasken, J. M., Tabachnick, B., Robinson, L. K., Manning, M. A., Bezuidenhout, H., Adam, M. P., Jones, K. L., Seedat, S., Parry, C. D., Hoyme, H. E. 2017; 14 (5)

    Abstract

    Background: Prevalence and characteristics of fetal alcohol syndrome (FAS) and total fetal alcohol spectrum disorders (FASD) were studied in a second sample of three South African rural communities to assess change. Methods: Active case ascertainment focused on children with height, weight and/or head circumference ≤25th centile and randomly-selected children. Final diagnoses were based on dysmorphology, neurobehavioral scores, and maternal risk interviews. Results: Cardinal facial features, head circumference, and total dysmorphology scores differentiated specific FASD diagnostic categories in a somewhat linear fashion but all FASD traits were significantly worse than those of randomly-selected controls. Neurodevelopmental delays were significantly worse for children with FASD than controls. Binge alcohol use was clearly documented as the proximal maternal risk factor for FASD, and significant distal risk factors were: low body mass, education, and income; high gravidity, parity, and age at birth of the index child. FAS rates continue to extremely high in these communities at 9-129 per 1000 children. Total FASD affect 196-276 per 1000 or 20-28% of the children in these communities. Conclusions: Very high rates of FASD persist in these general populations where regular, heavy drinking, often in a binge fashion, co-occurs with low socioeconomic conditions.

    View details for DOI 10.3390/ijerph14050522

    View details for PubMedID 28498341

  • in a patient with a complex connective tissue phenotype. Cold Spring Harbor molecular case studies Zastrow, D. B., Zornio, P. A., Dries, A., Kohler, J., Fernandez, L., Waggott, D., Walkiewicz, M., Eng, C. M., Manning, M. A., Farrelly, E., Fisher, P. G., Ashley, E. A., Bernstein, J. A., Wheeler, M. T. 2017; 3 (1)

    Abstract

    Here we describe a patient who presented with a history of congenital diaphragmatic hernia, inguinal hernia, and recurrent umbilical hernia. She also has joint laxity, hypotonia, and dysmorphic features. A unifying diagnosis was not identified based on her clinical phenotype. As part of her evaluation through the Undiagnosed Diseases Network, trio whole-exome sequencing was performed. Pathogenic variants in FBN1 and TRPS1 were identified as causing two distinct autosomal dominant conditions, each with de novo inheritance. Fibrillin 1 (FBN1) mutations are associated with Marfan syndrome and a spectrum of similar phenotypes. TRPS1 mutations are associated with trichorhinophalangeal syndrome types I and III. Features of both conditions are evident in the patient reported here. Discrepant features of the conditions (e.g., stature) and the young age of the patient may have made a clinical diagnosis more difficult in the absence of exome-wide genetic testing.

    View details for DOI 10.1101/mcs.a001388

    View details for PubMedID 28050602

  • The continuum of fetal alcohol spectrum disorders in a community in South Africa: Prevalence and characteristics in a fifth sample. Drug and alcohol dependence May, P. A., Marais, A., de Vries, M. M., Kalberg, W. O., Buckley, D., Hasken, J. M., Adnams, C. M., Barnard, R., Joubert, B., Cloete, M., Tabachnick, B., Robinson, L. K., Manning, M. A., Jones, K. L., Bezuidenhout, H., Seedat, S., Parry, C. D., Hoyme, H. E. 2016; 168: 274-286

    Abstract

    The prevalence and characteristics of the continuum of diagnoses within fetal alcohol spectrum disorders (FASD) were researched in a fifth sample in a South African community.An active case ascertainment approach was employed among all first grade learners in this community (n=862). Following individual examination by clinical geneticists/dysmorphologists, cognitive/behavioral testing, and maternal interviews, final diagnoses were made in multidisciplinary case conferences.Physical measurements, cardinal facial features of FAS, and total dysmorphology scores clearly differentiated diagnostic categories in a consistent, linear fashion, from severe to mild. Neurodevelopmental delays and behavioral problems were significantly worse for each of the FASD diagnostic categories, although not as consistently linear across diagnostic groups. Alcohol use was documented by direct report from the mother in 71% to 100% of cases in specific diagnostic groups. Significant distal maternal risk factors in this population are: advanced maternal age at pregnancy; low height, weight, and body mass index (BMI); small head circumference; low education; low income; and rural residence. Even when controlling for socioeconomic status, prenatal drinking correlates significantly with total dysmorphology score, head circumference, and five cognitive and behavioral measures. In this community, FAS occurs in 59-79 per 1,000 children, and total FASD in 170-233 per 1,000 children, or 17% to 23%.Very high rates of FASD continue in this community where entrenched practices of regular binge drinking co-exist with challenging conditions for childbearing and child development in a significant portion of the population.

    View details for DOI 10.1016/j.drugalcdep.2016.09.025

    View details for PubMedID 27736681

    View details for PubMedCentralID PMC5086258

  • Analysis of CYP1B1 in pediatric and adult glaucoma and other ocular phenotypes MOLECULAR VISION Reis, L. M., Tyler, R. C., Weh, E., Hendee, K. E., Kariminejad, A., Abdul-Rahman, O., Ben-Omran, T., Manning, M. A., Yesilyurt, A., McCarty, C. A., Kitchner, T. E., Costakos, D., Semina, E. V. 2016; 22: 1229-1238
  • Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders. Pediatrics Hoyme, H. E., Kalberg, W. O., Elliott, A. J., Blankenship, J., Buckley, D., Marais, A., Manning, M. A., Robinson, L. K., Adam, M. P., Abdul-Rahman, O., Jewett, T., Coles, C. D., Chambers, C., Jones, K. L., Adnams, C. M., Shah, P. E., Riley, E. P., Charness, M. E., Warren, K. R., May, P. A. 2016; 138 (2)

    Abstract

    The adverse effects of prenatal alcohol exposure constitute a continuum of disabilities (fetal alcohol spectrum disorders [FASD]). In 1996, the Institute of Medicine established diagnostic categories delineating the spectrum but not specifying clinical criteria by which diagnoses could be assigned. In 2005, the authors published practical guidelines operationalizing the Institute of Medicine categories, allowing for standardization of FASD diagnoses in clinical settings. The purpose of the current report is to present updated diagnostic guidelines based on a thorough review of the literature and the authors' combined expertise based on the evaluation of >10 000 children for potential FASD in clinical settings and in epidemiologic studies in conjunction with National Institute on Alcohol Abuse and Alcoholism-funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, and the Collaboration on FASD Prevalence. The guidelines were formulated through conference calls and meetings held at National Institute on Alcohol Abuse and Alcoholism offices in Rockville, MD. Specific areas addressed include the following: precise definition of documented prenatal alcohol exposure; neurobehavioral criteria for diagnosis of fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder; revised diagnostic criteria for alcohol-related birth defects; an updated comprehensive research dysmorphology scoring system; and a new lip/philtrum guide for the white population, incorporating a 45-degree view. The guidelines reflect consensus among a large and experienced cadre of FASD investigators in the fields of dysmorphology, epidemiology, neurology, psychology, developmental/behavioral pediatrics, and educational diagnostics. Their improved clarity and specificity will guide clinicians in accurate diagnosis of infants and children prenatally exposed to alcohol.

    View details for DOI 10.1542/peds.2015-4256

    View details for PubMedID 27464676

  • Breastfeeding and maternal alcohol use: Prevalence and effects on child outcomes and fetal alcohol spectrum disorders. Reproductive toxicology May, P. A., Hasken, J. M., Blankenship, J., Marais, A., Joubert, B., Cloete, M., de Vries, M. M., Barnard, R., Botha, I., Roux, S., Doms, C., Gossage, J. P., Kalberg, W. O., Buckley, D., Robinson, L. K., Adnams, C. M., Manning, M. A., Parry, C. D., Hoyme, H. E., Tabachnick, B., Seedat, S. 2016; 63: 13-21

    Abstract

    Determine any effects that maternal alcohol consumption during the breastfeeding period has on child outcomes.Population-based samples of children with fetal alcohol spectrum disorders (FASD), normally-developing children, and their mothers were analyzed for differences in child outcomes.Ninety percent (90%) of mothers breastfed for an average of 19.9 months. Of mothers who drank postpartum and breastfed (MDPB), 47% breastfed for 12 months or more. In case control analyses, children of MDPB were significantly lighter, had lower verbal IQ scores, and more anomalies in comparisons controlling for prenatal alcohol exposure and final FASD diagnosis. Utilizing a stepwise logistic regression model adjusting for nine confounders of prenatal drinking and other maternal risks, MDPB were 6.4 times more likely to have a child with FASD than breastfeeding mothers who abstained from alcohol while breastfeeding.Alcohol use during the period of breastfeeding was found to significantly compromise a child's development.

    View details for DOI 10.1016/j.reprotox.2016.05.002

    View details for PubMedID 27174445

    View details for PubMedCentralID PMC4987236

  • Fetal Alcohol Spectrum Disorders and Assessment of Maxillary and Mandibular Arc Measurements AMERICAN JOURNAL OF MEDICAL GENETICS PART A Abell, K., May, W., May, P. A., Kalberg, W., Hoyme, H. E., Robinson, L. K., Manning, M., Jones, K. L., Abdul-Rahman, O. 2016; 170 (7): 1763-1771

    Abstract

    Fetal alcohol spectrum disorders (FASD) comprise a range of physical differences and neurologic deficits from prenatal alcohol exposure. Previous studies suggest that relative maxillary growth deficiency can accompany FASD. Using the Fetal Alcohol Syndrome Epidemiologic Research (FASER) database, we investigated how maxillary and mandibular arcs and the ratio between them differ between FASD and non-FASD individuals. First, we established normative values for maxillary and mandibular arcs and maxillary-to-mandibular arc ratio. In our control group (545 males, 436 females), mean maxillary and mandibular arcs for males/females were 24.98/24.52 cm and 25.91/25.35 cm, respectively. The ratio was 0.9643 and 0.9676 for males and females, respectively. We then evaluated the effect of microcephaly, short stature, and low weight (<10th centile), individually on arcs in controls. Generally, arcs were reduced significantly but the ratio did not differ. We compared our controls to 138 male and 135 female FASD cases. We noted a significant difference in arcs in male and female groups, but not the ratio. We compared non-FAS controls with reduced growth parameters to similar cases with FASD. We did not find a significant difference in arc or ratio measurements. Therefore, we conclude the effect of prenatal alcohol exposure on maxillary and mandibular arc measurements is primarily on overall facial growth and less on asymmetric growth of the maxilla relative to the mandible, at least using this technique. © 2016 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ajmg.a.37656

    View details for Web of Science ID 000379948000007

    View details for PubMedID 27253440

  • Prenatally Diagnosed Cases of Binder Phenotype Complicated by Respiratory Distress in the Immediate Postnatal Period. Journal of ultrasound in medicine Blumenfeld, Y. J., Davis, A. S., Hintz, S. R., Milan, K., Messner, A. H., Barth, R. A., Hudgins, L., Chueh, J., Homeyer, M., Bernstein, J. A., Enns, G., Atwal, P., Manning, M. 2016; 35 (6): 1353-1358

    Abstract

    Binder phenotype, or maxillonasal dysostosis, is a distinctive pattern of facial development characterized by a short nose with a flat nasal bridge, an acute nasolabial angle, a short columella, a convex upper lip, and class III malocclusion. We report 3 cases of prenatally diagnosed Binder phenotype associated with perinatal respiratory impairment.

    View details for DOI 10.7863/ultra.15.02050

    View details for PubMedID 27162279

  • The continuum of fetal alcohol spectrum disorders in four rural communities in south africa: Prevalence and characteristics. Drug and alcohol dependence May, P. A., de Vries, M. M., Marais, A., Kalberg, W. O., Adnams, C. M., Hasken, J. M., Tabachnick, B., Robinson, L. K., Manning, M. A., Jones, K. L., Hoyme, D., Seedat, S., Parry, C. D., Hoyme, H. E. 2016; 159: 207-218

    Abstract

    Prevalence and characteristics of the continuum of diagnoses within fetal alcohol spectrum disorders (FASD) were researched in previously unstudied rural, agricultural, lower socioeconomic populations in South Africa (ZA).Using an active case ascertainment approach among first grade learners, 1354 (72.6%) were consented into the study via: height, weight, and/or head circumference ≤25th centile and/or random selection as normal control candidates. Final diagnoses were made following: examination by pediatric dysmorphologists/geneticists, cognitive/behavioral testing, and maternal risk factor interviews.FASD children were significantly growth deficient and dysmorphic: physical measurements, cardinal facial features of FAS, and total dysmorphology scores clearly differentiated diagnostic categories from severe to mild to normal in a consistent, linear fashion. Neurodevelopmental delays were also significantly worse for each of the FASD diagnostic categories, although not as consistently linear across groups. Alcohol use is well documented as the proximal maternal risk factor for each diagnostic group. Significant distal maternal risk factors in this population are: low body weight, body mass, education, and income; and high gravidity, parity, and age at birth of the index child. In this low SES, highly rural region, FAS occurs in 93-128 per 1000 children, PFAS in 58-86, and, ARND in 32-46 per 1000. Total FASD affect 182-259 per 1000 children or 18-26%.Very high rates of FASD exist in these rural areas and isolated towns where entrenched practices of regular binge drinking co-exist with challenging conditions for childbearing and child development.

    View details for DOI 10.1016/j.drugalcdep.2015.12.023

    View details for PubMedID 26774945

    View details for PubMedCentralID PMC4724497

  • in pediatric and adult glaucoma and other ocular phenotypes. Molecular vision Reis, L. M., Tyler, R. C., Weh, E., Hendee, K. E., Kariminejad, A., Abdul-Rahman, O., Ben-Omran, T., Manning, M. A., Yesilyurt, A., McCarty, C. A., Kitchner, T. E., Costakos, D., Semina, E. V. 2016; 22: 1229-1238

    Abstract

    The CYP1B1 gene encodes an enzyme that is a member of the cytochrome P450 superfamily. Mutations in CYP1B1 have been mainly reported in recessive pediatric ocular phenotypes, such as primary congenital glaucoma (PCG) and congenital glaucoma with anterior segment dysgenesis (CG with ASD), with some likely pathogenic variants also identified in families affected with adult-onset primary open angle glaucoma (POAG).We examined CYP1B1 in 158 pediatric patients affected with PCG (eight), CG with ASD (22), CG with other developmental ocular disorders (11), juvenile glaucoma with or without additional ocular anomalies (26), and ASD or other developmental ocular conditions without glaucoma (91); in addition, a large cohort of adult patients with POAG (193) and POAG-negative controls (288) was examined.Recessive pathogenic variants in CYP1B1 were identified in two PCG pedigrees, three cases with CG and ASD, and two families with CG and other ocular defects, such as sclerocornea in one patient and microphthalmia in another individual; neither sclerocornea nor microphthalmia has been previously associated with CYP1B1. Most of the identified causative mutations are new occurrences of previously reported pathogenic alleles with two novel variants identified: a c.1325delC, p.(Pro442Glnfs*15) frameshift allele in a family with PCG and a c.157G>A, p.(Gly53Ser) variant identified in a proband with CG, Peters anomaly, and microphthalmia. Analysis of the family history in the CYP1B1-positive families revealed POAG in confirmed or presumed heterozygous relatives in one family with PCG and two families with ASD/CG; POAG was associated with the c.1064_1076del, p.(Arg355Hisfs*69) allele in two of these pedigrees. Screening of an unrelated POAG cohort identified the same c.1064_1076del heterozygous allele in one individual with sporadic POAG but not in age- and ethnicity-matched POAG-negative individuals. Overall, there was no significant enrichment for mutant alleles in CYP1B1 within the POAG cases compared to the controls.In summary, these data expand the mutational and phenotypic spectra of CYP1B1 to include two novel alleles and additional developmental ocular phenotypes. The contribution of CYP1B1 to POAG is less clear, but loss-of-function variants in CYP1B1, especially c.1064_1076del, p.(Arg355Hisfs*69), may be associated with an increased risk for POAG.

    View details for PubMedID 27777502

  • RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans. American journal of human genetics Shamseldin, H., Alazami, A. M., Manning, M., Hashem, A., Caluseiu, O., Tabarki, B., Esplin, E., Schelley, S., Innes, A. M., Parboosingh, J. S., Lamont, R., Majewski, J., Bernier, F. P., Alkuraya, F. S. 2015; 97 (6): 862-8

    Abstract

    Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963(∗)] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration.

    View details for DOI 10.1016/j.ajhg.2015.10.012

    View details for PubMedID 26608784

  • RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans AMERICAN JOURNAL OF HUMAN GENETICS Shamseldin, H., Alazami, A. M., Manning, M., Hashem, A., Caluseiu, O., Tabarki, B., Esplin, E., Schelley, S., Innes, A. M., Parboosingh, J. S., Lamont, R., Majewski, J., Bernier, F. P., Alkuraya, F. S. 2015; 97 (6): 862-868

    Abstract

    Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963(∗)] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration.

    View details for DOI 10.1016/j.ajhg.2015.10.012

    View details for Web of Science ID 000368437900008

  • Prevalence and characteristics of fetal alcohol syndrome and partial fetal alcohol syndrome in a Rocky Mountain Region City. Drug and alcohol dependence May, P. A., Keaster, C., Bozeman, R., Goodover, J., Blankenship, J., Kalberg, W. O., Buckley, D., Brooks, M., Hasken, J., Gossage, J. P., Robinson, L. K., Manning, M., Hoyme, H. E. 2015; 155: 118-127

    Abstract

    The prevalence and characteristics of fetal alcohol syndrome (FAS) and partial FAS (PFAS) in the United States (US) are not well known.This active case ascertainment study in a Rocky Mountain Region City assessed the prevalence and traits of children with FAS and PFAS and linked them to maternal risk factors. Diagnoses made by expert clinical dysmorphologists in multidisciplinary case conferences utilized all components of the study: dysmorphology and physical growth, neurobehavior, and maternal risk interviews.Direct parental (active) consent was obtained for 1278 children. Averages for key physical diagnostic traits and several other minor anomalies were significantly different among FAS, PFAS, and randomly-selected, normal controls. Cognitive tests and behavioral checklists discriminated the diagnostic groups from controls on 12 of 14 instruments. Mothers of children with FAS and PFAS were significantly lower in educational attainment, shorter, later in pregnancy recognition, and suffered more depression, and used marijuana and methamphetamine during their pregnancy. Most pre-pregnancy and pregnancy drinking measures were worse for mothers of FAS and PFAS. Excluding a significant difference in simply admitting drinking during the index pregnancy (FAS and PFAS=75% vs. 39.4% for controls), most quantitative intergroup differences merely approached significance. This community's prevalence of FAS is 2.9-7.5 per 1000, PFAS is 7.9-17.7 per 1000, and combined prevalence is 10.9-25.2 per 1000 or 1.1-2.5%.Comprehensive, active case ascertainment methods produced rates of FAS and PFAS higher than predicted by long-standing, popular estimates.

    View details for DOI 10.1016/j.drugalcdep.2015.08.006

    View details for PubMedID 26321671

    View details for PubMedCentralID PMC4581993

  • A South African Mixed Race Lip/Philtrum Guide for Diagnosis of Fetal Alcohol Spectrum Disorders AMERICAN JOURNAL OF MEDICAL GENETICS PART A Hoyme, H. E., Hoyme, D. B., Elliott, A. J., Blankenship, J., Kalberg, W. O., Buckley, D., Abdul-Rahman, O., Adam, M. P., Robinson, L. K., Manning, M., Bezuidenhout, H., Jones, K. L., May, P. A. 2015; 167A (4): 752-755

    Abstract

    The adverse effects of maternal alcohol use during pregnancy represent a spectrum of growth restriction, facial dysmorphology, and neurocognitive challenges in the offspring. The continuum of diagnoses is referred to as fetal alcohol spectrum disorders (FASD). Short palpebral fissures, a smooth philtrum, and a thin vermilion border of the upper lip comprise the three cardinal facial features of FASD. Early attempts to define a smooth philtrum and thin vermilion border of the upper lip were subjective. Astley and colleagues introduced a 5-point Likert-scaled lip/philtrum guide based on Caucasian North American subjects as an objective tool for the evaluation of the facial dysmorphology in FASD. This Caucasian guide has been incorporated into all current diagnostic schemes for FASD. However, broad international clinical experience with FASD indicates racial and ethnic differences with respect to the facial morphology. Because of the substantial number of children with FASD in South Africa among the Cape Coloured (mixed race) population in the Western Cape Province, we developed a specific lip/philtrum guide for that population. The guide incorporates a 45-degree view of the philtrum that enables an enhanced 3-dimensional evaluation of philtral height not possible with a frontal view alone. The guide has proven to be a more specific and sensitive tool for evaluation of the facial dysmorphology of FASD in the Cape Coloured population than the use of the previous North American Caucasian guide and points to the utility of racial and ethnic-specific dysmorphology tools in the evaluation of children with suspected FASD.

    View details for DOI 10.1002/ajmg.a.37023

    View details for Web of Science ID 000352019000013

    View details for PubMedCentralID PMC4507499

  • Neonatal pulmonary arterial hypertension and Noonan syndrome: two fatal cases with a specific RAF1 mutation. American journal of medical genetics. Part A Hopper, R. K., Feinstein, J. A., Manning, M. A., Benitz, W., Hudgins, L. 2015; 167A (4): 882-885

    Abstract

    Mutations in RAF1 are associated with Noonan syndrome and hypertrophic cardiomyopathy. We present two infants with Noonan syndrome and an identical RAF1 mutation, p.Ser257Leu (c.770C>T), who developed severe pulmonary arterial hypertension (PAH) that proved to be fatal. The RAF1 gene encodes Raf-1 kinase, part of the Ras/mitogen-activated kinase (MAPK) signaling pathway, which has been linked to the development of PAH. This specific mutation has been associated with dephosphorylation of a critical serine residue and constitutive activation of the Raf-1 kinase. These two cases suggest that abnormal activation of the Ras/MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ajmg.a.37024

    View details for PubMedID 25706034

  • Neonatal Pulmonary Arterial Hypertension and Noonan Syndrome: Two Fatal Cases with a Specific RAF1 Mutation AMERICAN JOURNAL OF MEDICAL GENETICS PART A Hopper, R. K., Feinstein, J. A., Manning, M. A., Benitz, W., Hudgins, L. 2015; 167A (4): 882-885

    Abstract

    Mutations in RAF1 are associated with Noonan syndrome and hypertrophic cardiomyopathy. We present two infants with Noonan syndrome and an identical RAF1 mutation, p.Ser257Leu (c.770C>T), who developed severe pulmonary arterial hypertension (PAH) that proved to be fatal. The RAF1 gene encodes Raf-1 kinase, part of the Ras/mitogen-activated kinase (MAPK) signaling pathway, which has been linked to the development of PAH. This specific mutation has been associated with dephosphorylation of a critical serine residue and constitutive activation of the Raf-1 kinase. These two cases suggest that abnormal activation of the Ras/MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ajmg.a.37024

    View details for Web of Science ID 000352019000035

  • De Novo Nonsense Mutations in KAT6A, a Lysine Acetyl-Transferase Gene, Cause a Syndrome Including Microcephaly and Global Developmental Delay. American journal of human genetics Arboleda, V. A., Lee, H., Dorrani, N., Zadeh, N., Willis, M., Macmurdo, C. F., Manning, M. A., Kwan, A., Hudgins, L., Barthelemy, F., Miceli, M. C., Quintero-Rivera, F., Kantarci, S., Strom, S. P., Deignan, J. L., Grody, W. W., Vilain, E., Nelson, S. F. 2015; 96 (3): 498-506

    Abstract

    Chromatin remodeling through histone acetyltransferase (HAT) and histone deactylase (HDAC) enzymes affects fundamental cellular processes including the cell-cycle, cell differentiation, metabolism, and apoptosis. Nonsense mutations in genes that are involved in histone acetylation and deacetylation result in multiple congenital anomalies with most individuals displaying significant developmental delay, microcephaly and dysmorphism. Here, we report a syndrome caused by de novo heterozygous nonsense mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome sequencing (CES) in four independent families. The same de novo nonsense mutation (c.3385C>T [p.Arg1129(∗)]) was observed in three individuals, and the fourth individual had a nearby de novo nonsense mutation (c.3070C>T [p.Arg1024(∗)]). Neither of these variants was present in 1,815 in-house exomes or in public databases. Common features among all four probands include primary microcephaly, global developmental delay including profound speech delay, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. We further demonstrate that KAT6A mutations result in dysregulation of H3K9 and H3K18 acetylation and altered P53 signaling. Through histone and non-histone acetylation, KAT6A affects multiple cellular processes and illustrates the complex role of acetylation in regulating development and disease.

    View details for DOI 10.1016/j.ajhg.2015.01.017

    View details for PubMedID 25728775

  • Maternal risk factors for fetal alcohol spectrum disorders in a province in Italy. Drug and alcohol dependence Ceccanti, M., Fiorentino, D., Coriale, G., Kalberg, W. O., Buckley, D., Hoyme, H. E., Gossage, J. P., Robinson, L. K., Manning, M., Romeo, M., Hasken, J. M., Tabachnick, B., Blankenship, J., May, P. A. 2014; 145: 201-208

    Abstract

    Maternal risk factors for fetal alcohol spectrum disorders (FASD) in Italy and Mediterranean cultures need clarification, as there are few studies and most are plagued by inaccurate reporting of antenatal alcohol use.Maternal interviews (n = 905) were carried out in a population-based study of the prevalence and characteristics of FASD in the Lazio region of Italy which provided data for multivariate case control comparisons and multiple correlation models.Case control findings from interviews seven years post-partum indicate that mothers of children with FASD are significantly more likely than randomly-selected controls or community mothers to: be shorter; have higher body mass indexes (BMI); be married to a man with legal problems; report more drinking three months pre-pregnancy; engage in more current drinking and drinking alone; and have alcohol problems in her family. Logistic regression analysis of multiple candidate predictors of a FASD diagnosis indicates that alcohol problems in the child's family is the most significant risk factor, making a diagnosis within the continuum of FASD 9 times more likely (95%C.I. = 1.6 to 50.7). Sequential multiple regression analysis of the child's neuropsychological performance also identifies alcohol problems in the child's family as the only significant maternal risk variable (p < .001) when controlling for other potential risk factors.Underreporting of prenatal alcohol use has been demonstrated among Italian and other Mediterranean antenatal samples, and it was suspected in this sample. Nevertheless, several significant maternal risk factors for FASD have been identified.

    View details for DOI 10.1016/j.drugalcdep.2014.10.017

    View details for PubMedID 25456331

  • Prevalence and Characteristics of Fetal Alcohol Spectrum Disorders PEDIATRICS May, P. A., Baete, A., Russo, J., Elliott, A. J., Blankenship, J., Kalberg, W. O., Buckley, D., Brooks, M., Hasken, J., Abdul-Rahman, O., Adam, M. P., Robinson, L. K., Manning, M., Hoyme, H. E. 2014; 134 (5): 855-866

    Abstract

    To determine the prevalence and characteristics of fetal alcohol spectrum disorders (FASD) among first grade students (6- to 7-year-olds) in a representative Midwestern US community.From a consented sample of 70.5% of all first graders enrolled in public and private schools, an oversample of small children (≤ 25th percentile on height, weight, and head circumference) and randomly selected control candidates were examined for physical growth, development, dysmorphology, cognition, and behavior. The children's mothers were interviewed for maternal risk.Total dysmorphology scores differentiate significantly fetal alcohol syndrome (FAS) and partial FAS (PFAS) from one another and from unexposed controls. Alcohol-related neurodevelopmental disorder (ARND) is not as clearly differentiated from controls. Children who had FASD performed, on average, significantly worse on 7 cognitive and behavioral tests and measures. The most predictive maternal risk variables in this community are late recognition of pregnancy, quantity of alcoholic drinks consumed 3 months before pregnancy, and quantity of drinking reported for the index child's father. From the final multidisciplinary case findings, 3 techniques were used to estimate prevalence. FAS in this community likely ranges from 6 to 9 per 1000 children (midpoint, 7.5), PFAS from 11 to 17 per 1000 children (midpoint, 14), and the total rate of FASD is estimated at 24 to 48 per 1000 children, or 2.4% to 4.8% (midpoint, 3.6%).Children who have FASD are more prevalent among first graders in this Midwestern city than predicted by previous, popular estimates.

    View details for DOI 10.1542/peds.2013-3319

    View details for Web of Science ID 000344385900033

    View details for PubMedCentralID PMC4210790

  • Prevalence and characteristics of fetal alcohol spectrum disorders. Pediatrics May, P. A., Baete, A., Russo, J., Elliott, A. J., Blankenship, J., Kalberg, W. O., Buckley, D., Brooks, M., Hasken, J., Abdul-Rahman, O., Adam, M. P., Robinson, L. K., Manning, M., Hoyme, H. E. 2014; 134 (5): 855-866

    Abstract

    To determine the prevalence and characteristics of fetal alcohol spectrum disorders (FASD) among first grade students (6- to 7-year-olds) in a representative Midwestern US community.From a consented sample of 70.5% of all first graders enrolled in public and private schools, an oversample of small children (≤ 25th percentile on height, weight, and head circumference) and randomly selected control candidates were examined for physical growth, development, dysmorphology, cognition, and behavior. The children's mothers were interviewed for maternal risk.Total dysmorphology scores differentiate significantly fetal alcohol syndrome (FAS) and partial FAS (PFAS) from one another and from unexposed controls. Alcohol-related neurodevelopmental disorder (ARND) is not as clearly differentiated from controls. Children who had FASD performed, on average, significantly worse on 7 cognitive and behavioral tests and measures. The most predictive maternal risk variables in this community are late recognition of pregnancy, quantity of alcoholic drinks consumed 3 months before pregnancy, and quantity of drinking reported for the index child's father. From the final multidisciplinary case findings, 3 techniques were used to estimate prevalence. FAS in this community likely ranges from 6 to 9 per 1000 children (midpoint, 7.5), PFAS from 11 to 17 per 1000 children (midpoint, 14), and the total rate of FASD is estimated at 24 to 48 per 1000 children, or 2.4% to 4.8% (midpoint, 3.6%).Children who have FASD are more prevalent among first graders in this Midwestern city than predicted by previous, popular estimates.

    View details for DOI 10.1542/peds.2013-3319

    View details for PubMedID 25349310

  • Perinatal features of the RASopathies: Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome. American journal of medical genetics. Part A Myers, A., Bernstein, J. A., Brennan, M., Curry, C., Esplin, E. D., Fisher, J., Homeyer, M., Manning, M. A., Muller, E. A., Niemi, A., Seaver, L. H., Hintz, S. R., Hudgins, L. 2014; 164A (11): 2814-2821

    Abstract

    The RASopathies are a family of developmental disorders caused by heritable defects of the RAS/MAPK signaling pathway. While the postnatal presentation of this group of disorders is well known, the prenatal and neonatal findings are less widely recognized. We report on the perinatal presentation of 10 patients with Noonan syndrome (NS), nine with Cardiofaciocutaneous syndrome (CFCS) and three with Costello syndrome (CS), in conjunction with the results of a comprehensive literature review. The majority of perinatal findings in NS, CS, and CFCS are shared: polyhydramnios; prematurity; lymphatic dysplasia; macrosomia; relative macrocephaly; respiratory distress; hypotonia, as well as cardiac and renal anomalies. In contrast, fetal arrhythmia and neonatal hypoglycemia are relatively specific to CS. NS, CS, and CFCS should all be considered as a possible diagnosis in pregnancies with a normal karyotype and ultrasound findings of a RASopathy. Recognition of the common perinatal findings of these disorders should facilitate both their prenatal and neonatal diagnosis. © 2014 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ajmg.a.36737

    View details for PubMedID 25250515

  • Perinatal Features of the RASopathies: Noonan Syndrome, Cardiofaciocutaneous Syndrome and Costello Syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Myers, A., Bernstein, J. A., Brennan, M., Curry, C., Esplin, E. D., Fisher, J., Homeyer, M., Manning, M. A., Muller, E. A., Niemi, A., Seaver, L. H., Hintz, S. R., Hudgins, L. 2014; 164A (11): 2814-2821

    Abstract

    The RASopathies are a family of developmental disorders caused by heritable defects of the RAS/MAPK signaling pathway. While the postnatal presentation of this group of disorders is well known, the prenatal and neonatal findings are less widely recognized. We report on the perinatal presentation of 10 patients with Noonan syndrome (NS), nine with Cardiofaciocutaneous syndrome (CFCS) and three with Costello syndrome (CS), in conjunction with the results of a comprehensive literature review. The majority of perinatal findings in NS, CS, and CFCS are shared: polyhydramnios; prematurity; lymphatic dysplasia; macrosomia; relative macrocephaly; respiratory distress; hypotonia, as well as cardiac and renal anomalies. In contrast, fetal arrhythmia and neonatal hypoglycemia are relatively specific to CS. NS, CS, and CFCS should all be considered as a possible diagnosis in pregnancies with a normal karyotype and ultrasound findings of a RASopathy. Recognition of the common perinatal findings of these disorders should facilitate both their prenatal and neonatal diagnosis. © 2014 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ajmg.a.36737

    View details for Web of Science ID 000344187200019

  • Maternal alcohol consumption producing fetal alcohol spectrum disorders (FASD): Quantity, frequency, and timing of drinking DRUG AND ALCOHOL DEPENDENCE May, P. A., Blankenship, J., Marais, A., Gossage, J. P., Kalberg, W. O., Joubert, B., Cloete, M., Barnard, R., De Vries, M., Hasken, J., Robinson, L. K., Adnams, C. M., Buckley, D., Manning, M., Parry, C. D., Hoyme, H. E., Tabachnick, B., Seedat, S. 2013; 133 (2): 502-512

    Abstract

    Concise, accurate measures of maternal prenatal alcohol use are needed to better understand fetal alcohol spectrum disorders (FASD).Measures of drinking by mothers of children with specific FASD diagnoses and mothers of randomly-selected controls are compared and also correlated with physical and cognitive/behavioral outcomes.Measures of maternal alcohol use can differentiate maternal drinking associated with FASD from that of controls and some from mothers of alcohol-exposed normals. Six variables that combine quantity and frequency concepts distinguish mothers of FASD children from normal controls. Alcohol use variables, when applied to each trimester and three months prior to pregnancy, provide insight on critical timing of exposure as well. Measures of drinking, especially bingeing, correlate significantly with increased child dysmorphology and negative cognitive/behavioral outcomes in children, especially low non-verbal IQ, poor attention, and behavioral problems. Logistic regression links (p<.001) first trimester drinking (vs. no drinking) with FASD, elevating FASD likelihood 12 times; first and second trimester drinking increases FASD outcomes 61 times; and drinking in all trimesters 65 times. Conversely, a similar regression (p=.008) indicates that drinking only in the first trimester makes the birth of a child with an FASD 5 times less likely than drinking in all trimesters.There is significant variation in alcohol consumption both within and between diagnostic groupings of mothers bearing children diagnosed within the FASD continuum. Drinking measures are empirically identified and correlated with specific child outcomes. Alcohol use, especially heavy use, should be avoided throughout pregnancy.

    View details for DOI 10.1016/j.drugalcdep.2013.07.013

    View details for Web of Science ID 000328240900029

    View details for PubMedID 23932841

  • Maternal factors predicting cognitive and behavioral characteristics of children with fetal alcohol spectrum disorders. Journal of developmental and behavioral pediatrics May, P. A., Tabachnick, B. G., Gossage, J. P., Kalberg, W. O., Marais, A., Robinson, L. K., Manning, M. A., Blankenship, J., Buckley, D., Hoyme, H. E., Adnams, C. M. 2013; 34 (5): 314-325

    Abstract

    To provide an analysis of multiple predictors of cognitive and behavioral traits for children with fetal alcohol spectrum disorders (FASDs).Multivariate correlation techniques were used with maternal and child data from epidemiologic studies in a community in South Africa. Data on 561 first-grade children with fetal alcohol syndrome (FAS), partial FAS (PFAS), and not FASD and their mothers were analyzed by grouping 19 maternal variables into categories (physical, demographic, childbearing, and drinking) and used in structural equation models (SEMs) to assess correlates of child intelligence (verbal and nonverbal) and behavior.A first SEM using only 7 maternal alcohol use variables to predict cognitive/behavioral traits was statistically significant (B = 3.10, p < .05) but explained only 17.3% of the variance. The second model incorporated multiple maternal variables and was statistically significant explaining 55.3% of the variance. Significantly correlated with low intelligence and problem behavior were demographic (B = 3.83, p < .05) (low maternal education, low socioeconomic status [SES], and rural residence) and maternal physical characteristics (B = 2.70, p < .05) (short stature, small head circumference, and low weight). Childbearing history and alcohol use composites were not statistically significant in the final complex model and were overpowered by SES and maternal physical traits.Although other analytic techniques have amply demonstrated the negative effects of maternal drinking on intelligence and behavior, this highly controlled analysis of multiple maternal influences reveals that maternal demographics and physical traits make a significant enabling or disabling contribution to child functioning in FASD.

    View details for DOI 10.1097/DBP.0b013e3182905587

    View details for PubMedID 23751886

  • Axial spondylometaphyseal dysplasia with retinitis pigmentosa-a clinical report and diagnostic clues. Journal of applied genetics Reinstein, E., Okenfuss, E. B., Wadhawan, I., Wilnai, Y., Manning, M., Rimoin, D. L., Lachman, R. S. 2013; 54 (2): 231-234

    View details for DOI 10.1007/s13353-013-0136-2

    View details for PubMedID 23371363

  • Approaching the prevalence of the full spectrum of fetal alcohol spectrum disorders in a South african population-based study. Alcoholism, clinical and experimental research May, P. A., Blankenship, J., Marais, A., Gossage, J. P., Kalberg, W. O., Barnard, R., De Vries, M., Robinson, L. K., Adnams, C. M., Buckley, D., Manning, M., Jones, K. L., Parry, C., Hoyme, H. E., Seedat, S. 2013; 37 (5): 818-830

    Abstract

    The prevalence and characteristics of fetal alcohol spectrum disorders (FASD) were determined in this fourth study of first-grade children in a South African community.Active case ascertainment methods were employed among 747 first-grade pupils. The detailed characteristics of children within the continuum of FASD are contrasted with randomly selected, normal controls on (i) physical growth and dysmorphology; (ii) cognitive/behavioral characteristics; and (iii) maternal risk factors.The rates of specific diagnoses within the FASD spectrum continue to be among the highest reported in any community in the world. The prevalence (per 1,000) is as follows: fetal alcohol syndrome (FAS)-59.3 to 91.0; partial fetal alcohol syndrome (PFAS)-45.3 to 69.6; and alcohol-related neurodevelopmental disorder (ARND)-30.5 to 46.8. The overall rate of FASD is therefore 135.1 to 207.5 per 1,000 (or 13.6 to 20.9%). Clinical profiles of the physical and cognitive/behavioral traits of children with a specific FASD diagnosis and controls are provided for understanding the full spectrum of FASD in a community. The spectral effect is evident in the characteristics of the diagnostic groups and summarized by the total (mean) dysmorphology scores of the children: FAS = 18.9; PFAS = 14.3; ARND = 12.2; and normal controls, alcohol exposed = 8.2 and unexposed = 7.1. Documented drinking during pregnancy is significantly correlated with verbal (r = -0.253) and nonverbal ability (r = -0.265), negative behaviors (r = 0.203), and total dysmorphology score (r = 0.431). Other measures of drinking during pregnancy are significantly associated with FASD, including binge drinking as low as 3 drinks per episode on 2 days of the week.High rates of specific diagnoses within FASD were well documented in this new cohort of children. FASD persists in this community. The data reflect an increased ability to provide accurate and discriminating diagnoses throughout the continuum of FASD.

    View details for DOI 10.1111/acer.12033

    View details for PubMedID 23241076

  • Mutations in B3GALNT2 Cause Congenital Muscular Dystrophy and Hypoglycosylation of alpha-Dystroglycan AMERICAN JOURNAL OF HUMAN GENETICS Stevens, E., Carss, K. J., Cirak, S., Foley, R., Torelli, S., Willer, T., Tambunan, D. E., Yau, S., Brodd, L., Sewry, C. A., Feng, L., Haliloglu, G., Orhan, D., Dobyns, W. B., Enns, G. M., Manning, M., Krause, A., Salih, M. A., Walsh, C. A., Hurles, M., Campbell, K. P., Manzini, M. C., Stemple, D., Lin, Y., Muntoni, F. 2013; 92 (3): 354-365

    Abstract

    Mutations in several known or putative glycosyltransferases cause glycosylation defects in α-dystroglycan (α-DG), an integral component of the dystrophin glycoprotein complex. The hypoglycosylation reduces the ability of α-DG to bind laminin and other extracellular matrix ligands and is responsible for the pathogenesis of an inherited subset of muscular dystrophies known as the dystroglycanopathies. By exome and Sanger sequencing we identified two individuals affected by a dystroglycanopathy with mutations in β-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2). B3GALNT2 transfers N-acetyl galactosamine (GalNAc) in a β-1,3 linkage to N-acetyl glucosamine (GlcNAc). A subsequent study of a separate cohort of individuals identified recessive mutations in four additional cases that were all affected by dystroglycanopathy with structural brain involvement. We show that functional dystroglycan glycosylation was reduced in the fibroblasts and muscle (when available) of these individuals via flow cytometry, immunoblotting, and immunocytochemistry. B3GALNT2 localized to the endoplasmic reticulum, and this localization was perturbed by some of the missense mutations identified. Moreover, knockdown of b3galnt2 in zebrafish recapitulated the human congenital muscular dystrophy phenotype with reduced motility, brain abnormalities, and disordered muscle fibers with evidence of damage to both the myosepta and the sarcolemma. Functional dystroglycan glycosylation was also reduced in the b3galnt2 knockdown zebrafish embryos. Together these results demonstrate a role for B3GALNT2 in the glycosylation of α-DG and show that B3GALNT2 mutations can cause dystroglycanopathy with muscle and brain involvement.

    View details for DOI 10.1016/j.ajhg.2013.01.016

    View details for Web of Science ID 000316161700008

    View details for PubMedID 23453667

    View details for PubMedCentralID PMC3591840

  • ARTHROGRYPOSIS, RENAL DYSFUNCTION AND CHOLESTASIS (ARC) SYNDROME: A NEW PATIENT CASE REPORT Western Regional Meeting of the American-Federation-for-Medical-Research Brennan, M., SLATTERY, L., Esplin, E., Enns, G. M., Hudgins, L., Manning, M. LIPPINCOTT WILLIAMS & WILKINS. 2013: 188–88
  • Marked variability in the radiographic features of cartilage-hair hypoplasia: Case report and review of the literature AMERICAN JOURNAL OF MEDICAL GENETICS PART A Kwan, A., Manning, M. A., Zollars, L. K., Hoyme, H. E. 2012; 158A (11): 2911-2916

    Abstract

    Cartilage-hair hypoplasia (CHH) is a rare recessive metaphyseal chondrodysplasia characterized by severe short stature, ectodermal dysplasia, anemia in childhood, immune deficiency, susceptibility to malignancy, and normal intelligence. Short, thick long bones, metaphyseal flaring and irregularities, and globular epiphyses at the knees and ankles are the typical radiographic findings. The diagnosis is primarily made on the basis of clinical features, although mutations in the RMRP gene have recently been described in affected individuals, facilitating confirmation of the clinical diagnosis in atypical patients. We present a patient with two RMRP mutations whose stature and ectodermal features supported the diagnosis of CHH, but whose radiographic findings and other extraskeletal findings did not. We propose that the most consistent and reliable features of CHH are short stature of prenatal onset and ectodermal dysplasia, and suggest that the diagnosis of CHH be considered and mutation analysis pursued even when typical radiographic findings are absent.

    View details for DOI 10.1002/ajmg.a.35604

    View details for Web of Science ID 000310071700041

    View details for PubMedID 22987807

  • Report of Two Patients and Further Characterization of Interstitial 9p13 Deletion-A Rare But Recurrent Microdeletion Syndrome? AMERICAN JOURNAL OF MEDICAL GENETICS PART A Niemi, A., Kwan, A., Hudgins, L., Cherry, A. M., Manning, M. A. 2012; 158A (9): 2328-2335

    Abstract

    To date, an interstitial deletion of 9p13 has been described only two times in the medical literature. These reports were based on routine chromosomal analysis. We report on two additional patients with an interstitial deletion of 9p13 further defined on array CGH who share clinical features with the other two patients previously described. Our first patient is a 16-year-old girl with a 5.9 Mb deletion at 9p13.3-9p13.1, initially detected on routine karyotype analysis and further characterized on array CGH. Our second patient is a 7½-year-old boy with a 4.8 Mb deletion also at 9p13.3-9p13.1. Patients with 9p13 deletion appear to have mild to moderate developmental delay, social and interactive personality, behavior issues such as attention deficit-hyperactivity disorder, short stature, prominent antihelices, hypoplastic nails, and precocious/early puberty. Our 16-year-old patient is the oldest patient described thus far. This report further characterizes this condition and helps to delineate the long-term prognosis in these patients.

    View details for DOI 10.1002/ajmg.a.35536

    View details for Web of Science ID 000310068700037

    View details for PubMedID 22887577

  • Maternal risk factors predicting child physical characteristics and dysmorphology in fetal alcohol syndrome and partial fetal alcohol syndrome DRUG AND ALCOHOL DEPENDENCE May, P. A., Tabachnick, B. G., Gossage, J. P., Kalberg, W. O., Marais, A., Robinson, L. K., Manning, M., Buckley, D., Hoyme, H. E. 2011; 119 (1-2): 18-27

    Abstract

    Previous research in South Africa revealed very high rates of fetal alcohol syndrome (FAS), of 46-89 per 1000 among young children. Maternal and child data from studies in this community summarize the multiple predictors of FAS and partial fetal alcohol syndrome (PFAS).Sequential regression was employed to examine influences on child physical characteristics and dysmorphology from four categories of maternal traits: physical, demographic, childbearing, and drinking. Then, a structural equation model (SEM) was constructed to predict influences on child physical characteristics.Individual sequential regressions revealed that maternal drinking measures were the most powerful predictors of a child's physical anomalies (R² = .30, p < .001), followed by maternal demographics (R² = .24, p < .001), maternal physical characteristics (R²=.15, p < .001), and childbearing variables (R² = .06, p < .001). The SEM utilized both individual variables and the four composite categories of maternal traits to predict a set of child physical characteristics, including a total dysmorphology score. As predicted, drinking behavior is a relatively strong predictor of child physical characteristics (β = 0.61, p < .001), even when all other maternal risk variables are included; higher levels of drinking predict child physical anomalies.Overall, the SEM model explains 62% of the variance in child physical anomalies. As expected, drinking variables explain the most variance. But this highly controlled estimation of multiple effects also reveals a significant contribution played by maternal demographics and, to a lesser degree, maternal physical and childbearing variables.

    View details for DOI 10.1016/j.drugalcdep.2011.05.009

    View details for Web of Science ID 000297484200003

    View details for PubMedID 21658862

  • Ectopia Lentis as the Presenting and Primary Feature in Marfan Syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zadeh, N., Bernstein, J. A., Niemi, A. K., Dugan, S., Kwan, A., Liang, D., Hyland, J. C., Hoyme, H. E., Hudgins, L., Manning, M. A. 2011; 155A (11): 2661-2668

    Abstract

    Marfan syndrome (MFS) is a multisystem connective tissue disorder with primary involvement of the ocular, cardiovascular, and skeletal systems. We report on eight patients, all presenting initially with bilateral ectopia lentis (EL) during early childhood. These individuals did not have systemic manifestations of MFS, and did not fulfill the revised Ghent diagnostic criteria. However, all patients had demonstratable, disease-causing missense mutations in the FBN1 gene. Based on molecular results, cardiovascular imaging was recommended and led to the identification of mild aortic root changes in seven of the eight patients. The remaining patient had mitral valve prolapse with a normal appearing thoracic aorta. The findings presented in this paper validate the necessity of FBN1 gene testing in all individuals presenting with isolated EL. As we observed, these individuals are at increased risk of cardiovascular complications. Furthermore, we also noted that the majority of our patient cohort's mutations occurred in the 5' portion of the FBN1 gene, and were found to affect highly conserved cysteine residues, which may indicate a possible genotype-phenotype correlation. We conclude that in patients with isolated features of EL, FBN1 mutation analysis is necessary to aid in providing prompt diagnosis, and to identify patients at risk for potentially life-threatening complications. Additionally, knowledge of the type and location of an FBN1 mutation may be useful in providing further clinical correlation regarding phenotypic progression and appropriate medical management.

    View details for DOI 10.1002/ajmg.a.34245

    View details for PubMedID 21932315

  • Chromosome 22q11.2 Deletion Syndrome in African-American Patients: A Diagnostic Challenge AMERICAN JOURNAL OF MEDICAL GENETICS PART A Veerapandiyan, A., Abdul-Rahman, O. A., Adam, M. P., Lyons, M. J., Manning, M., Coleman, K., Kobrynski, L., Taneja, D., Schoch, K., Zimmerman, H. H., Shashi, V. 2011; 155A (9): 2186-2195

    Abstract

    Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with numerous and variable clinical manifestations including conotruncal heart abnormalities, palatal anomalies, hypoparathyroidism, immune deficiency, and cognitive deficits. The clinical suspicion of this syndrome is often heightened by the presence of characteristic facial features. A previous report highlighted the under-diagnosis of this condition in African Americans, thought to be related to a paucity of typical facial features. We ascertained the largest cohort (n = 50) of African-American individuals with 22q11DS reported thus far, across five genetics centers in the United States and report on their facial and other phenotypic features. About 3/4 of our cohort has at least one dysmorphic facial feature. Auricular abnormalities, especially small ears, are the most common dysmorphic facial feature followed by nasal and ocular abnormalities. Skeletal findings are seen in about 2/3 of our cohort, higher than the typical frequency reported in 22q11DS. Cardiac anomalies, developmental delay, and palatal abnormalities are seen at a lower frequency in our cohort. Thus, it is evident that the features traditionally associated with 22q11DS are difficult to recognize in African-American individuals with this syndrome, due to both altered frequencies of major anomalies and a non-classic facial appearance. Therefore, a high index of suspicion is needed to recognize 22q11DS in African-American individuals.

    View details for DOI 10.1002/ajmg.a.34226

    View details for Web of Science ID 000294182500023

    View details for PubMedID 21834039

  • Prevalence of Children with Severe Fetal Alcohol Spectrum Disorders in Communities Near Rome, Italy: New Estimated Rates Are Higher than Previous Estimates 7th International Symposium on Recent Advances in Environmental Health Research May, P. A., Fiorentino, D., Coriale, G., Kalberg, W. O., Hoyme, H. E., Aragon, A. S., Buckley, D., Stellavato, C., Gossage, J. P., Robinson, L. K., Jones, K. L., Manning, M., Ceccanti, M. MDPI AG. 2011: 2331–51

    Abstract

    To determine the population-based epidemiology of fetal alcohol syndrome (FAS) and other fetal alcohol spectrum disorders (FASD) in towns representative of the general population of central Italy.Slightly revised U.S. Institute of Medicine diagnostic methods were used among children in randomly-selected schools near Rome. Consented first grade children (n=976) were screened in Tier I for height, weight, or head circumference and all children≤10th centile on one of these measurements were included in the study. Also, teachers referred children for learning or behavioral problems. Children meeting either of these two criteria, along with randomly-selected controls, advanced to Tier II which began with a dysmorphology examination. Children with a possible FASD, and controls, advanced to Tier III for neurobehavioral testing, and their mothers were interviewed for maternal risks. Final diagnoses using indicators of dysmorphology, neurobehavior, and maternal risk were made in formally-structured, interdisciplinary case conferences.Case control comparisons of physical, neurobehavioral, and maternal risk variables are presented for 46 children with an FASD and 116 randomly-selected controls without a diagnosis on the FASD continuum. Rates of diagnoses within the FASD continuum are then estimated from these in-school data via three different methods. The range of rates of FAS produced by these methods is between 4.0 to 12.0 per 1,000; Partial FAS ranges from 18.1 to 46.3 per 1,000; and an FASD was found in 2.3% to 6.3% of the children.These rates are substantially higher than previous estimates of FAS and overall FASD for the general populations of Western Europe and the U. S., and raise questions as to the total impact of FASD on mental deficit in mainstream populations of Western Europe and the United States where the majority are middle class and are not believed to be characterized by heavy episodic drinking.

    View details for DOI 10.3390/ijerph8062331

    View details for Web of Science ID 000292022500034

    View details for PubMedID 21776233

    View details for PubMedCentralID PMC3138028

  • Fetal Alcohol Spectrum Disorders: Extending the Range of Structural Defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Jones, K. L., Hoyme, H. E., Robinson, L. K., del Campo, M., Manning, M. A., Prewitt, L. M., Chambers, C. D. 2010; 152A (11): 2731-2735

    Abstract

    Although the structural phenotype of fetal alcohol syndrome (FAS) is established, prenatal exposure to alcohol may produce a broader spectrum of defects, fetal alcohol spectrum disorder (FASD). Documenting the full spectrum of defects associated with FASD is critical to determining the true incidence of this disorder. We examined 831 children from the Collaborative Initiative on Fetal Alcohol Spectrum Disorders using a structured protocol for diagnosis of FAS using the cardinal facial and growth features, and assessment of additional structural defects thought to occur more often in children with prenatal alcohol exposure. Subjects were classified as FAS, Deferred (some characteristic features of FAS), or No FAS, Groups were compared on prevalence of additional features and number of additional features observed, stratified by diagnostic category, sex, race, and age. Prevalence of most additional features was greatest among subjects with FAS and least among No FAS. A higher frequency of additional features was observed among FAS and Deferred subjects ≥12 years of age than among those under 12. FAS and Deferred Whites had greater frequency of additional features than Cape Colored. Prenatal alcohol exposure may produce a broad spectrum of structural defects that goes beyond FAS with implications regarding the impact of alcohol on the developing fetus, a prerequisite for ultimate prevention of FASD.

    View details for DOI 10.1002/ajmg.a.33675

    View details for Web of Science ID 000284005700009

    View details for PubMedID 20949507

  • Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities GENETICS IN MEDICINE Manning, M., Hudgins, L. 2010; 12 (11): 742-745

    Abstract

    Laboratory evaluation of patients with developmental delay/intellectual disability, congenital anomalies, and dysmorphic features has changed significantly in the last several years with the introduction of microarray technologies. Using these techniques, a patient's genome can be examined for gains or losses of genetic material too small to be detected by standard G-banded chromosome studies. This increased resolution of microarray technology over conventional cytogenetic analysis allows for identification of chromosomal imbalances with greater precision, accuracy, and technical sensitivity. A variety of array-based platforms are now available for use in clinical practice, and utilization strategies are evolving. Thus, a review of the utility and limitations of these techniques and recommendations regarding present and future application in the clinical setting are presented in this study.

    View details for DOI 10.1097/GIM.0b013e3181f8baad

    View details for Web of Science ID 000284105800012

    View details for PubMedID 20962661

    View details for PubMedCentralID PMC3111046

  • Population Differences in Dysmorphic Features Among Children With Fetal Alcohol Spectrum Disorders JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS May, P. A., Gossage, J. P., Smith, M., Tabachnick, B. G., Robinson, L. K., Manning, M., Cecanti, M., Jones, K. L., Khaole, N., Buckley, D., Kalberg, W. O., Trujillo, P. M., Hoyme, H. E. 2010; 31 (4): 304-316

    Abstract

    To examine the variation in significant dysmorphic features in children from 3 different populations with the most dysmorphic forms of fetal alcohol spectrum disorders, fetal alcohol syndrome (FAS), and partial fetal alcohol syndrome (PFAS).Advanced multiple regression techniques are used to determine the discriminating physical features in the diagnosis of FAS and PFAS among children from Northern Plains Indian communities, South Africa, and Italy.Within the range of physical features used to identify children with fetal alcohol spectrum disorders, specifically FAS and PFAS, there is some significant variation in salient diagnostic features from one population to the next. Intraclass correlations in diagnostic features between these 3 populations is 0.20, indicating that about 20% of the variability in dysmorphology core features is associated with location and, therefore, specific racial/ethnic population. The highly significant diagnostic indicators present in each population are identified for the full samples of FAS, PFAS, and normals and also among children with FAS only. A multilevel model for these populations combined indicates that these variables predict dysmorphology unambiguously: small palpebral fissures, narrow vermillion, smooth philtrum, flat nasal bridge, and fifth finger clinodactyly. Long philtrum varies substantially as a predictor in the 3 populations. Predictors not significantly related to fetal alcohol spectrum disorders dysmorphology across the 3 populations are centile of height (except in Italy) strabismus, interpupilary distance, intercanthal distance, and heart murmurs.The dysmorphology associated with FAS and PFAS vary across populations, yet a particular array of common features occurs in each population, which permits a consistent diagnosis across populations.

    View details for DOI 10.1097/DBP.0b013e3181dae243

    View details for Web of Science ID 000277769600006

    View details for PubMedID 20431397

  • Developmental Pathogenesis of Short Palpebral Fissure Length in Children with Fetal Alcohol Syndrome BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY Jones, K. L., Hoyme, H. E., Robinson, L. K., del Campo, M., Manning, M. A., Bakhireva, L. N., Prewitt, L. M., Chambers, C. D. 2009; 85 (8): 695-699

    Abstract

    From the standpoint of normal embryologic development, the palpebral fissures are generally considered to be determined by and dependent on the underlying optic vesicles, outpouchings of the frontal area of the developing fetal brain. It has been suggested that short palpebral fissures are a reflection of an underlying defect in specific areas of forebrain development. Alternatively, short palpebral fissures, seen in a number of multiple malformation syndromes associated with small occipitofrontal circumference (OFC), such as the fetal alcohol syndrome (FAS), might be proportionally small as a reflection of the microcephaly. The purpose of this study was to examine whether short palpebral fissures are independent of or determined by the OFC.Age-specific palpebral fissure length (PFL) and OFC centiles were correlated in 273 children with FAS, 272 children with some features of FAS, and 385 children with no structural features characteristic of FAS.The OFC and PFL centiles demonstrated a statistically significant but weak correlation in all three study groups. Among children with FAS, only 10.2% of the total variation in PFL could be accounted for by OFC (p = 0.0001). A similar pattern was observed for children with some features of FAS (r(2) = 0.142; p = 0.0001) and children with no structural features of FAS (r(2) = 0.110; p = 0.0001).Palpebral fissure length is predominately independent of occipitofrontal circumference in children with and without features of FAS. Short palpebral fissures may well reflect a defect in forebrain development rather than being proportionally reduced in size as a reflection of microcephaly. Birth Defects Research (Part A) 2009. (c) 2009 Wiley-Liss, Inc.

    View details for DOI 10.1002/bdra.20585

    View details for Web of Science ID 000269377400005

    View details for PubMedID 19350654

  • PREVALENCE AND EPIDEMIOLOGIC CHARACTERISTICS OF FASD FROM VARIOUS RESEARCH METHODS WITH AN EMPHASIS ON RECENT IN-SCHOOL STUDIES DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS May, P. A., Gossage, J. P., Kalberg, W. O., Robinson, L. K., Buckley, D., Manning, M., Hoyme, H. E. 2009; 15 (3): 176-192

    Abstract

    Researching the epidemiology and estimating the prevalence of fetal alcohol syndrome (FAS) and other fetal alcohol spectrum disorders (FASD) for mainstream populations anywhere in the world has presented a challenge to researchers. Three major approaches have been used in the past: surveillance and record review systems, clinic-based studies, and active case ascertainment methods. The literature on each of these methods is reviewed citing the strengths, weaknesses, prevalence results, and other practical considerations for each method. Previous conclusions about the prevalence of FAS and total FASD in the United States (US) population are summarized. Active approaches which provide clinical outreach, recruitment, and diagnostic services in specific populations have been demonstrated to produce the highest prevalence estimates. We then describe and review studies utilizing in-school screening and diagnosis, a special type of active case ascertainment. Selected results from a number of in-school studies in South Africa, Italy, and the US are highlighted. The particular focus of the review is on the nature of the data produced from in-school methods and the specific prevalence rates of FAS and total FASD which have emanated from them. We conclude that FAS and other FASD are more prevalent in school populations, and therefore the general population, than previously estimated. We believe that the prevalence of FAS in typical, mixed-racial, and mixed-socioeconomic populations of the US is at least 2 to 7 per 1,000. Regarding all levels of FASD, we estimate that the current prevalence of FASD in populations of younger school children may be as high as 2-5% in the US and some Western European countries.

    View details for DOI 10.1002/ddrr.68

    View details for Web of Science ID 000270030100003

    View details for PubMedID 19731384

  • Clinical and molecular delineation of the 17q21.31 microdeletion syndrome JOURNAL OF MEDICAL GENETICS Koolen, D. A., Sharp, A. J., Hurst, J. A., Firth, H. V., Knight, S. J., Goldenberg, A., Saugier-Veber, P., Pfundt, R., Vissers, L. E., Destree, A., Grisart, B., Rooms, L., Van der Aa, N., Field, M., Hackett, A., Bell, K., Nowaczyk, M. J., Mancini, G. M., Poddighe, P. J., Schwartz, C. E., Rossi, E., De Gregori, M., Antonacci-Fulton, L. L., McLellan, M. D., Garrett, J. M., Wiechert, M. A., Miner, T. L., Crosby, S., Ciccone, R., Willatt, L., Rauch, A., Zenker, M., Aradhya, S., Manning, M. A., Strom, T. M., Wagenstaller, J., Krepischi-Santos, A. C., Vianna-Morgante, A. M., Rosenberg, C., Price, S. M., Stewart, H., Shaw-Smith, C., Brunner, H. G., Wilkie, A. O., Veltman, J. A., Zuffardi, O., Eichler, E. E., de Vries, B. B. 2008; 45 (11): 710-720

    Abstract

    The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation.We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome.We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10(-5)).Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

    View details for DOI 10.1136/jmg.2008.058701

    View details for Web of Science ID 000260535600004

    View details for PubMedID 18628315

    View details for PubMedCentralID PMC3071570

  • Sclerocornea associated with the chromosome 22q11.2 deletion syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Binenbaum, G., McDonald-McGinn, D. M., Zackai, E. H., Walker, B. M., Coleman, K., Mach, A. M., Adam, M., Manning, M., Alcorn, D. M., Zabel, C., Anderson, D. R., Forbes, B. J. 2008; 146A (7): 904-909

    Abstract

    Reported ocular findings in the 22q11.2 deletion syndrome (which encompasses the phenotypes of DiGeorge, velocardiofacial, and Takao (conotruncal-anomaly-face) syndromes) have included posterior embryotoxon (prominent, anteriorly displaced Schwalbe's line at the corneal limbus or edge), retinal vascular tortuosity, eyelid hooding, strabismus, and astigmatism. We present seven 22q11.2 patients from multiple centers with sclerocornea, an eye finding previously unreported in the literature. Four boys and three girls were identified with sclerocornea, systemic DGS/VCFS findings, and fluorescence in situ hybridization (FISH)-confirmed microdeletion at chromosome 22q11.2. FISH diagnosis was perinatal in six patients but at 2 years of age in one child. Sclerocornea was bilateral in five patients. Findings included descemetocele (five eyes), microophthalmos (one eye), iridocorneal adhesions (one bilateral case), and severe anterior segment dysgenesis (one eye). Two patients underwent bilateral corneal transplantation; another two were scheduled for possible unilateral transplant. Sclerocornea is a static congenital condition in which the cornea is opaque and vascularized and resembles the sclera. The novel finding of sclerocornea suggests that a genetic locus at 22q11.2 may be involved in anterior segment embryogenesis. In most of our patients, the diagnostic process was underway, but in one patient 22q11.2 deletion was not suspected until after the child had already been undergoing treatment for sclerocornea for 2 years. Sclerocornea should be added to the clinical manifestations of the 22q11.2 deletion syndrome. Ophthalmologists diagnosing sclerocornea in children with systemic findings suggestive of 22q11.2 deletion should ensure appropriate genetic referral.

    View details for DOI 10.1002/ajmg.a.32156

    View details for Web of Science ID 000254587400014

    View details for PubMedID 18324686

    View details for PubMedCentralID PMC2831198

  • 22q13.3 deletion syndrome: A recognizable malformation syndrome associated with marked speech and language delay AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS Cusmano-Ozog, K., Manning, M. A., Hoyme, H. E. 2007; 145C (4): 393-398

    Abstract

    The 22q13.3 deletion syndrome is a recognizable malformation syndrome associated with developmental delay, hypotonia, delayed or absent speech, autistic-like behavior, normal to accelerated growth and dysmorphic facies. The prevalence of this disorder is unknown, but it is likely under-diagnosed. Age at diagnosis has varied widely, from cases diagnosed prenatally to 46 years. Males and females are equally affected. The distal 22q deletion can be detected occasionally by routine or high resolution chromosome analysis; however, the majority of cases are detected by FISH analysis, associated with deletion of the ARSA (control) probe when performing a FISH analysis for the velocardiofacial syndrome (del 22q11.2). The 22q13.3 deletion syndrome can accompany a simple chromosome deletion, an unbalanced translocation, or a ring chromosome. Primary care physicians, in addition to numerous specialists, play an important role in caring for patients with this disorder. Although the dysmorphic features observed in this condition are nonspecific, it is an important consideration in the differential diagnosis of children with developmental delay, hypotonia, marked speech and language disability, autistic-like features, multiple minor anomalies, and normal growth and head circumference.

    View details for DOI 10.1002/ajmg.c.30155

    View details for Web of Science ID 000251230300009

    View details for PubMedID 17926345

  • Use of array-based technology in the practice of medical genetics GENETICS IN MEDICINE Manning, M., Hudgins, L. 2007; 9 (9): 650-653

    Abstract

    Mental retardation affects approximately 3% of the population, and the background birth defect rate is 3% to 4%. An underlying cause is identified less than 50% of the time. In the cases in which a cause is determined, a chromosomal anomaly is the cause in up to 40%. Laboratory evaluation routinely includes high-resolution karyotyping, subtelomeric fluorescence in situ hybridization analysis, and targeted fluorescence in situ hybridization analysis depending on the clinical features. There are technical limitations to these techniques, however. For example, anomalies less than 2 to 3 Mb in size are undetectable by karyotype, and subtelomeric fluorescence in situ hybridization analysis is a labor-intensive analysis with a relatively low yield. With completion of the Human Genome Project, diagnostic testing is moving toward the use of DNA-based techniques such as comparative genomic hybridization microarray analysis or array comparative genomic hybridization. Although this technology has been used in the evaluation of tumors and cancer patients in the past, it is now being applied in the assessment of patients demonstrating idiopathic mental retardation or developmental delay, dysmorphic features, congenital anomalies, and spontaneous abortions. As with other well-developed cytogenetic studies, there are technical limitations to array comparative genomic hybridization that must be acknowledged and addressed before its widespread use. A variety of array-based technologies are now available on a clinical basis. We discuss the utility and limitations of using this technology in the evaluation of individuals with mental retardation and malformations, citing the existing literature.

    View details for DOI 10.1097/GIM.0b013e31814cec3a

    View details for Web of Science ID 000249640800013

    View details for PubMedID 17873654

  • Whole-genome array-CGH identifies novel contiguous gene deletions and duplications associated with developmental delay, mental retardation, and dysmorphic features AMERICAN JOURNAL OF MEDICAL GENETICS PART A Aradhya, S., Manning, M. A., Splendore, A., Cherry, A. M. 2007; 143A (13): 1431-1441

    Abstract

    Cytogenetic imbalances are the most frequently identified cause of developmental delay or mental retardation, which affect 1-3% of children and are often seen in conjunction with growth retardation, dysmorphic features, and various congenital anomalies. A substantial number of patients with developmental delay or mental retardation are predicted to have cytogenetic imbalances, but conventional methods for identifying these imbalances yield positive results in only a small fraction of these patients. We used microarray-based comparative genomic hybridization (aCGH) to study a panel of 20 patients predicted to have chromosomal aberrations based on clinical presentation of developmental delay or mental retardation, growth delay, dysmorphic features, and/or congenital anomalies. Previous G-banded karyotypes and fluorescence in situ hybridization results were normal for all of these patients. Using both oligonucleotide-based and bacterial artificial chromosome (BAC)-based arrays on the same panel of patients, we identified 10 unique deletions and duplications ranging in size from 280 kb to 8.3 Mb. The whole-genome oligonucleotide arrays identified nearly twice as many imbalances as did the lower-resolution whole-genome BAC arrays. This has implications for using aCGH in a clinical setting. Analysis of parental DNA samples indicated that most of the imbalances had occurred de novo. Moreover, seven of the 10 imbalances represented novel disorders, adding to an increasing number of conditions caused by large-scale deletions or duplications. These results underscore the strength of high-resolution genomic arrays in diagnosing cases of unknown genetic etiology and suggest that contiguous genomic alterations are the underlying pathogenic cause of a significant number of cases of developmental delay.

    View details for DOI 10.1002/ajmg.a.31773

    View details for Web of Science ID 000247760600005

    View details for PubMedID 17568414

  • Fetal alcohol spectrum disorders: A practical clinical approach to diagnosis NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS Manning, M. A., Hoyme, H. E. 2007; 31 (2): 230-238

    Abstract

    In utero exposure to alcohol can have numerous adverse effects on a developing fetus. These effects represent a spectrum of structural anomalies and neurocognitive and behavioral disabilities that have recently been termed fetal alcohol spectrum disorders (FASD). Children at the most severe end of this spectrum and displaying the complete phenotype of characteristic facial anomalies, growth retardation and developmental abnormalities of the central nervous system are defined as having fetal alcohol syndrome (FAS). While FAS is the most readily clinically recognized form of FASD, other categories within the continuum of adverse effects due to prenatal alcohol exposure are becoming better defined. These include partial fetal alcohol syndrome (PFAS), alcohol-related birth defects (ARBD) and alcohol-related neurodevelopmental disorder (ARND). As more is learned regarding the exact manifestations of alcohol on brain development, these classifications may be expanded and/or refined. Because FASD represents a major public health concern, early recognition of at-risk children is important for initiating interventional strategies. Thus, the purpose of this report is to educate practicing physicians about the recognizable phenotypes of FASD in order to accurately identify these children and implement the most appropriate management plans.

    View details for DOI 10.1016/j.neubiorev.2006.06.016

    View details for Web of Science ID 000244763100009

    View details for PubMedID 16962173

  • Nablus mask-like facial syndrome is caused by a microdeletion of 8q detected by array-based comparative genomic hybridization. American journal of medical genetics. Part A Shieh, J. T., Aradhya, S., Novelli, A., Manning, M. A., Cherry, A. M., Brumblay, J., Salpietro, C. D., Bernardini, L., Dallapiccola, B., Hoyme, H. E. 2006; 140 (12): 1267-1273

    Abstract

    In 2000, Teebi reported on a 4-year-old boy with a distinctive pattern of malformation, which he termed the "Nablus mask-like facial syndrome" (OMIM# 608156). Characterization of this syndrome has been difficult because of the paucity of patients described in the medical literature and its unknown etiology and pathogenesis. We present two patients with Nablus mask-like facial syndrome who both display a microdeletion in the 8q21-8q22 region detected by array-based comparative genomic hybridization. Patient 1, a boy, has a distinct facial appearance characterized by severe blepharophimosis, tight-appearing glistening facial skin, sparse and unruly hair, a flat and broad nose, and distinctive ears that are triangular in shape with prominent antihelices. He also demonstrates camptodactyly, contractures, unusual dentition, cryptorchidism, mild developmental delay, and a happy demeanor. Patient 2, a girl with a strikingly similar phenotype, was previously described in a report by Salpietro et al. 2003. She has distinctive ears, dental anomalies, and developmental delay. The etiology of her pattern of malformation was not identified at that time. Although high-resolution chromosome and subtelomeric FISH analyses were normal, array-based comparative genomic hybridization revealed an approximately 4 Mb deletion involving the 8q21.3-8q22.1 region in both patients. This region encompasses a number of genes that may contribute to this unique phenotype. These results demonstrate a chromosomal microdeletion as the etiology of Nablus mask-like facial syndrome and emphasize the diagnostic utility of array-based comparative genomic hybridization in the evaluation of multiple malformation syndromes of previously unrecognized causation.

    View details for PubMedID 16691576

  • Nablus mask-like facial syndrome is caused by a microdeletion of 8q detected by array-based comparative genomic hybridization AMERICAN JOURNAL OF MEDICAL GENETICS PART A Shieh, J. T., Aradhya, S., Novelli, A., Manning, M. A., Cherry, A. M., Brumblay, J., Salpietro, C. D., Bernardini, L., Dallapiccola, B., Hoyme, H. E. 2006; 140A (12): 1267-1273

    Abstract

    In 2000, Teebi reported on a 4-year-old boy with a distinctive pattern of malformation, which he termed the "Nablus mask-like facial syndrome" (OMIM# 608156). Characterization of this syndrome has been difficult because of the paucity of patients described in the medical literature and its unknown etiology and pathogenesis. We present two patients with Nablus mask-like facial syndrome who both display a microdeletion in the 8q21-8q22 region detected by array-based comparative genomic hybridization. Patient 1, a boy, has a distinct facial appearance characterized by severe blepharophimosis, tight-appearing glistening facial skin, sparse and unruly hair, a flat and broad nose, and distinctive ears that are triangular in shape with prominent antihelices. He also demonstrates camptodactyly, contractures, unusual dentition, cryptorchidism, mild developmental delay, and a happy demeanor. Patient 2, a girl with a strikingly similar phenotype, was previously described in a report by Salpietro et al. 2003. She has distinctive ears, dental anomalies, and developmental delay. The etiology of her pattern of malformation was not identified at that time. Although high-resolution chromosome and subtelomeric FISH analyses were normal, array-based comparative genomic hybridization revealed an approximately 4 Mb deletion involving the 8q21.3-8q22.1 region in both patients. This region encompasses a number of genes that may contribute to this unique phenotype. These results demonstrate a chromosomal microdeletion as the etiology of Nablus mask-like facial syndrome and emphasize the diagnostic utility of array-based comparative genomic hybridization in the evaluation of multiple malformation syndromes of previously unrecognized causation.

    View details for DOI 10.1002/ajmg.a.31262

    View details for Web of Science ID 000237990400003

  • A report of three patients with an interstitial deletion of chromosome 15q24. American journal of medical genetics. Part A Cushman, L. J., Torres-Martinez, W., Cherry, A. M., Manning, M. A., Abdul-Rahman, O., Anderson, C. E., Punnett, H. H., Thurston, V. C., Sweeney, D., Vance, G. H. 2005; 137 (1): 65-71

    Abstract

    Partial monosomy of the q2 region of chromosome 15 has been infrequently reported. Moreover, interstitial deletions involving 15q22-q24 have been described in only nine patients to date. The phenotype of these reported individuals is subject to the extent of the deletion but typically includes altered muscle tone and significant developmental delays. In addition, eye abnormalities, such as strabismus, microphthalmia, or colobomas, ear abnormalities including cleft earlobe and preauricular tags, and urogenital defects are common features. Congenital heart defects, diaphragmatic hernia, abnormalities of the central nervous system, and skeletal anomalies have been reported but appear to be less frequent clinical manifestations. In this report, we describe three new patients with interstitial deletions involving 15q24, two with cryptic deletions identified by fluorescence in situ hybridization (FISH) with a probe for the PML gene and one with a cytogenetically visible deletion of 15q22.3-q24. The clinical presentation of these individuals is similar to those previously described and includes global developmental delays, hypotonia, and genital abnormalities in the males. The identification of these three cases demonstrates that the above clinical features are associated with a new cytogenetic deletion syndrome. Furthermore, we suggest that FISH analysis with a probe for the PML gene be performed in patients with these physical findings.

    View details for PubMedID 16007617

  • A report of three patients with an interstitial deletion of chromosome 15q24 AMERICAN JOURNAL OF MEDICAL GENETICS PART A Cushman, L. J., Torres-Martinez, W., Cherry, A. M., Manning, M. A., Abdul-Rahman, O., Anderson, C. E., Punnett, H. H., Thurston, V. C., Sweeney, D., Vance, G. H. 2005; 137A (1): 65-71

    Abstract

    Partial monosomy of the q2 region of chromosome 15 has been infrequently reported. Moreover, interstitial deletions involving 15q22-q24 have been described in only nine patients to date. The phenotype of these reported individuals is subject to the extent of the deletion but typically includes altered muscle tone and significant developmental delays. In addition, eye abnormalities, such as strabismus, microphthalmia, or colobomas, ear abnormalities including cleft earlobe and preauricular tags, and urogenital defects are common features. Congenital heart defects, diaphragmatic hernia, abnormalities of the central nervous system, and skeletal anomalies have been reported but appear to be less frequent clinical manifestations. In this report, we describe three new patients with interstitial deletions involving 15q24, two with cryptic deletions identified by fluorescence in situ hybridization (FISH) with a probe for the PML gene and one with a cytogenetically visible deletion of 15q22.3-q24. The clinical presentation of these individuals is similar to those previously described and includes global developmental delays, hypotonia, and genital abnormalities in the males. The identification of these three cases demonstrates that the above clinical features are associated with a new cytogenetic deletion syndrome. Furthermore, we suggest that FISH analysis with a probe for the PML gene be performed in patients with these physical findings.

    View details for DOI 10.1002/ajmg.a.30836

    View details for Web of Science ID 000231009900012

  • Terminal 22q deletion syndrome: A newly recognized cause of speech and language disability in the autism spectrum PEDIATRICS Manning, M. A., Cassidy, S. B., Clericuzio, C., Cherry, A. M., Schwartz, S., Hudgins, L., Enns, G. M., Hoyme, H. E. 2004; 114 (2): 451-457

    Abstract

    Cryptic subtelomeric chromosome rearrangements account for 6% to 10% of idiopathic mental retardation. As cytogenetic and molecular techniques have become more sophisticated, the number of genetic syndromes attributed to these microdeletions has increased. To date, 64 patients have been described in the literature with a more recently recognized microdeletion syndrome, del 22q13.3. The purpose of this study is to present 11 new cases of this recently described syndrome to delineate further the phenotype and to alert the clinician to another genetic condition that should be considered in the differential diagnosis of early hypotonia, delayed speech acquisition, and autistic behavior.Eleven patients were evaluated in 3 academic institutions. Clinical features and results of cytogenetic testing were recorded and tabulated. Reasons for referral for genetic evaluation included developmental delay, severe expressive speech and language delay, and dysmorphic features.Age of presentation ranged from 5 months to 46 years. There were 10 female patients and 1 male patient. All of the patients exhibited delayed motor development, some degree of hypotonia, and severe expressive speech and language delay. Dysmorphic facial features included epicanthal folds, large cupped ears, underdeveloped philtrum, loss of cupid's bow, and full supraorbital ridges. Six patients exhibited autistic-like behaviors. Microscopically visible chromosome deletions were observed in 6 patients. In the remainder, the deletion was detected with the use of fluorescence in situ hybridization.Hypotonia and developmental delay are nonspecific findings observed in many malformation and genetic syndromes. However, in association with severe speech and language delay and autistic-like behavior, this phenotype may be a significant indication to consider the 22q13 deletion syndrome as a potential cause.

    View details for PubMedID 15286229

  • Neu-Laxova syndrome: Detailed prenatal diagnostic and post-mortem findings and literature review AMERICAN JOURNAL OF MEDICAL GENETICS PART A Manning, M. A., Cunniff, C. M., Colby, C. E., El-Sayed, Y. Y., Hoyme, H. E. 2004; 125A (3): 240-249

    Abstract

    Neu-Laxova syndrome (NLS) is a lethal, autosomal recessive multiple malformation syndrome with many features resulting from severe skin restriction and decreased fetal movement. It is characterized by ichthyosis, marked intrauterine growth restriction (IUGR), microcephaly, short neck, central nervous system (CNS) anomalies, limb deformities, hypoplastic lungs, edema, and abnormal facial features including severe proptosis with ectropion, hypertelorism, micrognathia, flattened nose, and malformed ears. We present two new patients with NLS with striking prenatal diagnostic findings and detailed post-mortem examinations and review the previously described cases in the literature. Data from these patients suggest that the NLS represents a heterogeneous phenotype. Prenatal ultrasound findings of marked ocular proptosis in a growth restricted, edematous fetus should prompt consideration of a diagnosis of the NLS.

    View details for DOI 10.1002/ajmg.a.20467

    View details for Web of Science ID 000189316800004

    View details for PubMedID 14994231

  • Head imaging abnormalities in dihydropyrimidine dehydrogenase deficiency JOURNAL OF INHERITED METABOLIC DISEASE Enns, G. M., Barkovich, A. J., van Kuilenburg, A. B., Manning, M., Sanger, T., Witt, D. R., Van Gennip, A. H. 2004; 27 (4): 513-522

    Abstract

    Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of pyrimidine metabolism. Patients may present with a wide range of neurological symptoms during the first years of life. Head imaging abnormalities have been reported only rarely and include diffuse cerebral atrophy and white-matter hyperintensity. The pathogenesis of the white-matter abnormalities is unknown, although environmental factors and altered energy metabolism may be involved. To further understanding of the spectrum of brain abnormalities associated with DPD deficiency, we report a 17-month-old girl, born to a consanguineous Pakistani couple, who had a history of encephalopathy, prolonged hypoventilation, developmental delay and failure to thrive. Head MRI showed prominent sulci and abnormal T2 prolongation in the cerebral white matter and brainstem. Thus, DPD deficiency may feature prominent brain abnormalities involving the cerebral white matter and brainstem. Anoxic stress may have contributed to the clinical presentation and brain findings in this case. In order to define more clearly the contribution of DPD deficiency to the pathogenesis of these MRI abnormalities, we recommend performing detailed analysis of urine pyrimidine metabolites in patients who have such findings.

    View details for Web of Science ID 000223177000010

    View details for PubMedID 15303009

  • Methotrexate/misoprostol embryopathy: Report of four cases resulting from failed medical abortion Bryan D Hall Festschrift 2003 Adam, M. P., Manning, M. A., Beck, A. E., Kwan, A., Enns, G. M., Clericuzio, C., Hoyme, H. E. WILEY-LISS. 2003: 72–78

    Abstract

    Methotrexate, a methyl derivative of aminopterin, is a folic acid antagonist and a known human teratogen; misoprostol is a synthetic prostaglandin E1 analog that causes uterine contractions. Recently, there has been resurgence in the use of methotrexate in combination with misoprostol or of methotrexate alone for the treatment of unwanted or ectopic pregnancies, respectively. This report documents the findings in four infants who were exposed prenatally to methotrexate alone or in combination with misoprostol in a failed attempt at medical abortion or treatment of ectopic pregnancy. All patients demonstrated growth deficiency, with growth parameters <10th centile, and all displayed features consistent with methotrexate and/or misoprostol embryopathy. Since an increasing number of medical abortions are being performed, it is important for physicians to recognize the associated teratogenic effects of these abortifacients. Data from the patients herein described should prompt obstetricians and other health care practitioners who prescribe these medications to counsel their patients regarding these risks, especially if the treatment regimen fails to induce an abortion.

    View details for DOI 10.1002/ajmg.a.20503

    View details for PubMedID 14556250

  • Uncommon FBN1 mutation in Marfan syndrome family with severe ectopia lentis 53rd Annual Meeting of the American-Society-of-Human-Genetics Manning, M., Hyland, J., Kwan, A., Liang, D., Hudgins, L. CELL PRESS. 2003: 293–93
  • Severe liver disease in urea cycle disorders. Western Regional Meeting of the American-Federation-for-Medical-Research Traynor, J. D., Tuchman, M., Manning, M. A., Goodman, S. I., Enns, G. M. LIPPINCOTT WILLIAMS & WILKINS. 2003: S118–S118
  • Diagnosis and management of the adolescent boy with Klinefelter syndrome. Adolescent medicine (Philadelphia, Pa.) Manning, M. A., Hoyme, H. E. 2002; 13 (2): 367-?

    Abstract

    Klinefelter syndrome is the most common sex chromosome disorder, affecting approximately 1/500 to 1/1000 males. The condition results when one or more extra X chromosomes are present in the cells of XY fetuses. Although the clinical presentation is variable, all males with Klinefelter syndrome demonstrate hypogonadism, impaired spermatogenesis, and androgen deficiency. Treatment options include testosterone replacement for correction of the androgen deficiency and tailoring of school curricula to address specific areas of learning difficulties. Adolescence can be a challenging time for any child, but for boys with Klinefelter syndrome who receive proper guidance the transition through puberty should not be a time for undue anxiety, Most boys with Klinefelter syndrome do not differ vastly from their peers. Several manifestations of the syndrome, however, should be monitored during adolescence and require the primary care physician's attention.

    View details for PubMedID 11986043

  • Intracranial hemorrhage in infants and children with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) PEDIATRICS Morgan, T., McDonald, J., Anderson, C., Ismail, M., Miller, F., Mao, R., Madan, A., Barnes, P., Hudgins, L., Manning, M. 2002; 109 (1)

    Abstract

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Most cases are caused by mutations in the endoglin gene on chromosome 9 (HHT type 1) or the activin receptor-like kinase 1 gene on chromosome 12 (HHT type 2), which leads to telangiectases and arteriovenous malformations (AVM) of the skin, mucosa, and viscera. Epistaxis is the most frequent presentation. Visceral involvement includes pulmonary, gastrointestinal, and cerebral AVMs, which have been reported predominantly in adults. The purpose of this article is to describe 9 children who presented with intracranial hemorrhage (ICH) secondary to cerebral AVM. None of these children was suspected of having HHT before the incident, despite family histories of the disease.We report the first case of an ICH secondary to a cerebral AVM in a neonate confirmed to have HHT type 1 by molecular analysis. We also describe a series of 8 additional cases of ICH secondary to cerebral AVM in children presumed to have HHT. Examination of multiple affected members from each of these families, using well-accepted published criteria, confirmed the diagnosis of HHT. In addition, genetic linkage studies and/or mutation analysis identified endoglin as the disease-causing gene in 6 of these families. Autopsy, imaging studies, and/or surgery confirmed the presence of cerebral AVMs and ICH in all 9 cases.Our report shows that infants and children with a family history of HHT are at risk for sudden and catastrophic ICH. A preemptive diagnosis may potentially identify and prevent more serious sequelae.

    View details for PubMedID 11773580

  • Intracranial hemorrhage in children with hereditary hemorrhagic telangiectasia. Manning, M., Morgan, T., McDonald, J., Anderson, C., Ismail, M., Miller, F., Madan, A., Barnes, P., Hudgins, L. CELL PRESS. 2001: 221–21