Melanie Manning, MD

  • Melanie Ann Manning


Medical Genetics

Clinical Cytogenetics

Trabajo y Educación

Formación Profesional

Eastern VA Medical School, Norfolk, VA, 1997


Maricopa Medical Center, Phoenix, AZ, 1998


Maricopa Medical Center, Phoenix, AZ, 2000

Stanford University School of Medicine Registrar, Palo Alto, CA, 2002


Stanford University School of Medicine Registrar, Palo Alto, CA, 2003

Certificaciones Médicas

Clinical Cytogenetics, American Board of Medical Genetics and Genomics

Clinical Genetics, American Board of Medical Genetics and Genomics

Pediatrics, American Board of Pediatrics

Todo Publicaciones

Variable clinical course of identical twin neonates with Alstrm 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


Alstrm 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)


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)


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

View details for PubMedCentralID PMC5171698

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


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

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
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


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

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)


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 >10000 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

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


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 24.98/24.52cm and 25.91/25.35cm, 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


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


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

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


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): 862-868


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 7bp 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


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

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
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
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


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

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


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


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

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
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
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


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

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


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


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


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


Mutations in several known or putative glycosyltransferases cause glycosylation defects in -dystroglycan (-DG), an integral component of the dystrophin glycoprotein complex. The hypoglycosylation reduces the ability of -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 -1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2). B3GALNT2 transfers N-acetyl galactosamine (GalNAc) in a -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 -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

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: 18888
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


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


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 5.9Mb deletion at 9p13.3-9p13.1, initially detected on routine karyotype analysis and further characterized on array CGH. Our second patient is a 7-year-old boy with a 4.8Mb 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


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 (R = .30, p < .001), followed by maternal demographics (R = .24, p < .001), maternal physical characteristics (R=.15, p < .001), and childbearing variables (R = .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 ( = 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


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 Web of Science ID 000297199700009

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


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: 233151


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 children10th 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

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


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

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


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

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


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


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



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


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


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


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


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


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


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


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
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


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
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


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 Web of Science ID 000223040000017

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


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


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: 7278


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 Web of Science ID 000186239400010

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: 29393
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: S118S118
Diagnosis and management of the adolescent boy with Klinefelter syndrome. Adolescent medicine (Philadelphia, Pa.) Manning, M. A., Hoyme, H. E. 2002; 13 (2): 367-?


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)


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 Web of Science ID 000173006600012

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: 22121