22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome.

PURPOSE: Phelan-McDermid syndrome is a developmental disability syndrome with varying deletions of 22q13 and varying clinical severity. We tested the hypothesis that, in addition to loss of the telomeric gene SHANK3, specific genomic regions within 22q13 are associated with important clinical features. METHODS: We used a customized oligo array comparative genomic hybridization of 22q12.3-terminus to obtain deletion breakpoints in a cohort of 70 patients with terminal 22q13 deletions. We used association and receiver operating characteristic statistical methods in a novel manner and also incorporated protein interaction networks to identify 22q13 genomic locations and genes associated with clinical features. RESULTS: Specific genomic regions and candidate genes within 22q13.2q13.32 were associated with severity of speech/language delay, neonatal hypotonia, delayed age at walking, hair-pulling behaviors, male genital anomalies, dysplastic toenails, large/fleshy hands, macrocephaly, short and tall stature, facial asymmetry, and atypical reflexes. We also found regions suggestive of a negative association with autism spectrum disorders. CONCLUSION: This work advances the field of research beyond the observation of a correlation between deletion size and phenotype and identifies candidate 22q13 loci, and in some cases specific genes, associated with singular clinical features observed in Phelan-McDermid syndrome. Our statistical approach may be useful in genotype-phenotype analyses for other microdeletion or microduplication syndromes.

Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome).

BACKGROUND: The clinical features of Phelan-McDermid syndrome (also known as 22q13 deletion syndrome) are highly variable and include hypotonia, speech and other developmental delays, autistic traits and mildly dysmorphic features. Patient deletion sizes are also highly variable, prompting this genotype-phenotype association study. METHODS: Terminal deletion breakpoints were identified for 71 individuals in a patient cohort using a custom-designed high-resolution oligonucleotide array comparative genomic hybridisation platform with a resolution of 100 bp. RESULTS: Patient deletion sizes were highly variable, ranging from 0.22 to 9.22 Mb, and no common breakpoint was observed. SHANK3, the major candidate gene for the neurologic features of the syndrome, was deleted in all cases. Sixteen features (neonatal hypotonia, neonatal hyporeflexia, neonatal feeding problems, speech/language delay, delayed age at crawling, delayed age at walking, severity of developmental delay, male genital anomalies, dysplastic toenails, large or fleshy hands, macrocephaly, tall stature, facial asymmetry, full brow, atypical reflexes and dolichocephaly) were found to be significantly associated with larger deletion sizes, suggesting the role of additional genes or regulatory regions proximal to SHANK3. Individuals with autism spectrum disorders (ASDs) were found to have smaller deletion sizes (median deletion size of 3.39 Mb) than those without ASDs (median deletion size 6.03 Mb, p=0.0144). This may reflect the difficulty in diagnosing ASDs in individuals with severe developmental delay. CONCLUSIONS: This genotype-phenotype analysis explains some of the phenotypic variability in the syndrome and identifies new genomic regions with a high likelihood for causing important developmental phenotypes such as speech delay.

Long term maintenance of neural tube defects prevention in a high prevalence state.

OBJECTIVE: To assess the efficacy of folic acid (FA) supplementation and fortification in preventing neural tube defects (NTDs) in a high prevalence region of the United States. STUDY DESIGN: Active and passive surveillance methods were used to identify all fetuses/infants affected with an NTD in South Carolina. Prevalence rates were compared with FA intake to determine the effects of increased intake on NTD occurrence and recurrence. RESULTS: From 1992 to 2009, 916 NTD cases occurred in South Carolina, with isolated defects comprising 79% of cases. The NTD rate decreased 58% during this period. There was one NTD-affected pregnancy in 418 subsequent pregnancies (0.2%) in mothers with earlier NTD-affected pregnancies who consumed periconceptional FA supplements, and there were 4 NTDs in 66 pregnancies (6.1%) in which the mother did not take FA supplements. FA supplementation increased from 8% to 35% from 1992 to 2007, and knowledge of the protective benefits of FA increased from 8% to 65% in women of childbearing age. CONCLUSIONS: Increased periconceptional intake of FA appeared to reduce NTDs in a high-prevalence region. The rate of spina bifida and anencephaly in South Carolina is now essentially the same (0.69 cases per 1000 live births and fetal deaths) as the 1998 to 2005 US rate (0.69).

Reduction in rate of epilepsy from neurocysticercosis by community interventions: the Salamá, Honduras study.

PURPOSE: Epilepsy is highly prevalent in developing countries like Honduras, with few studies evaluating this finding. This population-based study evaluated the impact of an 8-year public health and educational intervention program in reducing symptomatic epilepsies in rural Salamá, Honduras. METHODS: We used the capture and recapture method including review of charts, previous databases, key informants from the community, and a second house-to-house survey for epilepsy. Epilepsy incidence and prevalence day after the interventions was May 5, 2005. Residents with active epilepsy with onset after May 1997 were offered neurologic evaluation, electroencephalography, and brain tomography. New data over 8 years were compared to preintervention data from the initial baseline 1997 study utilizing prevalence ratios and confidence intervals. Other calculations utilized chi square or Fisher's exact tests. KEY FINDINGS: Thirty-three of 36 patients with onset of active epilepsy after 1997 accepted evaluations to determine etiology. Symptomatic etiology was found in 58.3%. Neurocysticercosis (NCC) was again the most frequent cause (13.9%), followed by perinatal insults (11.1%). Epilepsy secondary to NCC was significantly reduced from 36.9% in 1997 (p = 0.02). The incidence (35.7/100,000) and prevalence (11.8/1,000) of active epilepsy were not significantly reduced when compared to the incidence (92.7/100,000) and prevalence (15.4/1,000) of active epilepsy in 1997. SIGNIFICANCE: Our cohort appears to indicate that health and educational community interventions can reduce preventable epilepsy from NCC in a hyperendemic population in a low-resource, developing country. Plans are underway for the Honduran Government to institute this rural model countrywide.

United States head circumference growth reference charts: birth to 21 years.

OBJECTIVE: To produce a more reliable, continuous set of occipitofrontal head circumference (OFC) growth reference charts for males and females from birth to adulthood in the United States. STUDY DESIGN: After investigating the strengths and shortcomings of previous reports, we combined the most recent statistically reliable reports of OFC growth reference data into a locally weighted regression analysis to estimate percentile curves. We used cross-sectional prospective local pediatric data to validate our results. RESULTS: We present new age- and sex-appropriate US OFC growth charts from birth to adulthood that include 3rd and 97th percentile cutoff values. Our local pediatric data validate that our new proposed OFC growth charts' assessment of attained OFC growth is comparable with previous references. CONCLUSIONS: We have eliminated disagreements between multiple current references by unifying previously reported US OFC data into a single set of smoothed male and female growth reference charts from birth to adulthood. This will reduce confusion or errors in interpretation of normal versus abnormal measurements currently encountered by primary care clinicians and subspecialists when using OFC growth charts for the US pediatric population.

Updated National Birth Prevalence estimates for selected birth defects in the United States, 2004-2006.

BACKGROUND: The National Birth Defects Prevention Network collects state-specific birth defects surveillance data for annual publication of prevalence estimates and collaborative research projects. In 2006, data for 21 birth defects from 1999 through 2001 were presented as national birth prevalence estimates. The purpose of this report was to update these estimates using data from 2004 through 2006. METHODS: Population-based data from 11 active case-finding programs, 6 passive case-finding programs with case confirmation, and 7 passive programs without case confirmation were used in this analysis. Pooled birth prevalence estimates for 21 birth defects, stratified by case ascertainment approach, were calculated. National prevalence estimates, adjusted for maternal race/ethnicity and maternal age (trisomy 13, trisomy 18, and Down syndrome only) were determined using data from 14 programs. The impact of pregnancy outcomes on prevalence estimates was also assessed for five specific defects. RESULTS: National birth defects prevalence estimates ranged from 0.72 per 10,000 live births for common truncus to 14.47 per 10,000 live births for Down syndrome. Stratification by type of surveillance system showed that active programs had a higher prevalence of anencephaly, anophthalmia/microphthalmia, cleft lip with or without cleft palate, reduction defect of upper limbs, and trisomy 18. The birth prevalence of anencephaly, trisomy 13, and trisomy 18 also varied substantially with inclusion of elective terminations. CONCLUSION: Accurate and timely national estimates of the prevalence of birth defects are needed for monitoring trends, assessing prevention efforts, determining service planning, and understanding the burden of disease due to birth defects in the United States.

The c.940G variant of the Microcephalin (MCPH1) gene is not associated with microcephaly or mental retardation.

It was reported that positive selection has acted upon a gene involved in autosomal recessive primary microcephaly, Microcephalin (MCPH1/BRIT1), located at chromosome 8p23. We tested if the reported diagnostic single nucleotide polymorphism (SNP) (G37995C or c.940G > C) of a derived haplogroup of the MCPH1 gene had significantly different frequencies in mental retardation (MR) patients and in MR patients with microcephaly as compared to MR patients without microcephaly and controls in African-American and Caucasian populations in South Carolina, US. Our results suggest that there is little or no association between the MCPH1 c.940G allele and either microcephaly or MR. However, we found highly significant racial differences in the c.940G > C SNP allele frequencies between African-American and Caucasian populations.

Detailed assessment of the ear in Cornelia de Lange syndrome: comparison with a control sample using the new dysmorphology guidelines.

The literature abounds with reports of malformation syndromes in which human external ears are variously described as dysplastic, abnormal, large/small, low set, typical, or in some way unusual. Rarely is the ear well illustrated or described in meaningful detail. With few exceptions, such as Down syndrome, there is no real understanding of the degree to which ear morphology is affected in a specific syndrome. This paper describes a retrospective attempt to apply the recently published Morphological Definitions of the ear to compare a control sample of convenience with a group of patients with Cornelia de Lange syndrome (CdLS) (all six papers in this issue are available online, open access at http://www3.interscience.wiley.com/journal/121641055/issue). Although this study has a number of limitations, it demonstrates that the method can be successfully applied and is capable of producing data that can be subjected to statistical analysis. The ears of the patients with CdLS were significantly different from the controls over a number of descriptors, the most significant of which included more frequent apparent posterior rotation, a shorter more serpiginous antihelical stem and sharper antihelical to inferior crus angle, a shorter crus helix, a more V-shaped incisura, and a smaller lobe.

Pediatric convulsive status epilepticus in Honduras, Central America.

Convulsive status epilepticus (SE) in children is an important public health problem, particularly in low-resource countries. A surveillance study was performed with consecutive enrollment of all children presenting with convulsive SE to Hospital Escuela Materno-Infantil Emergency Department in Tegucigalpa, Honduras over a 13-week period in 2003. In the 47 children with SE, the mean age was 4.5 years and the median seizure duration was 95 min. Mortality and morbidity were higher in children from rural locations, with all six deaths and three cases of new neurologic abnormalities occurring in rural children who had acute symptomatic SE. We conclude that childhood SE is common in the low-resource developing country of Honduras. Given the long delays in obtaining initial treatment in pediatric emergency facilities, availability of prehospital treatment may be of particular importance in this setting.

Public health projects for preventing the recurrence of neural tube defects in the United States.

BACKGROUND: The recurrence risk for neural tube defects (NTDs) in subsequent pregnancies is approximately 3%, or 40 times the background risk. Prevention projects target these high-risk women to increase their folic acid consumption during the periconceptional period, a behavior which decreases their recurrence risk by at least 85%. This study surveyed birth defect surveillance programs to assess their NTD recurrence prevention activities and to identify components of intervention projects that might be implemented in states with limited resources. METHODS: In 2005, the National Birth Defects Prevention Network developed and distributed an online survey to primary state birth defects surveillance contacts for the purpose of gathering information on NTD recurrence prevention activities in the United States. RESULTS: Responses came from 37 contacts in 34 states and Puerto Rico. There were 13 active NTD recurrence prevention projects, four past projects, and three planned projects. Fifteen past and present projects recommended that women with a prior NTD-affected birth take 4.0 mg of folic acid daily, and four projects provided folic acid to the women. Reasons given for not having an NTD recurrence prevention project included staffing limitations (53%), lack of funds (47%), lack of priority (18%), and confidentiality/privacy concerns (6%). CONCLUSIONS: Only 15 states and Puerto Rico had or were planning NTD recurrence prevention projects. An NTD recurrence prevention project using minimal resources should consist of timely case ascertainment, educational materials, and mechanisms for disseminating these materials.

Adherence and complementary and alternative medicine use among Honduran people with epilepsy.

Adherence to antiepileptic drugs (AEDs) and use of complementary and alternative medicine (CAM) among Hondurans with epilepsy were evaluated. Our epilepsy cohort of 274 outpatients was surveyed to determine demographics, epilepsy treatment history, adherence, and use of CAM. Nonadherence to epilepsy therapy was reported by 121, with unavailability of AEDs (48%) the most common reason. CAM was reportedly used by 141, with prayer, herbs, and potions being common. Forty-nine rural Miskito Hondurans without epilepsy were also interviewed to gain an understanding of their beliefs and longstanding practices regarding epilepsy. Seventeen (34.7%) attributed epilepsy to the supernatural; only three knew of an AED. Widespread nonadherence to evidence-based epilepsy treatments in Honduras can be attributed to inadequate education, AED unavailability, insufficient resources, cultural beliefs, and wide use of CAM. A comprehensive epilepsy education program and improved access to evidence-based AEDs represent initial priorities to improve the Honduran epilepsy treatment gap.

Prenatal diagnostic accuracy in South Carolina demonstrated by autopsy.

Fully 150 consecutive fetal/neonatal autopsies were reviewed to determine to what extent they confirmed or altered the impressions gained through prenatal ultrasonographic fetal examination. Distinctions were made between features that may or may not be assessable by prenatal ultrasound. Analyses of weights and measures were based on recently published regressions derived from a worldwide review of normative data. Our analysis indicated a high level of correspondence between prenatal ultrasound findings and later observations of independent persons at autopsy (85% positive predictive value and 44% sensitivity). We concluded that skills of maternal-fetal medicine specialists, located at several geographically divergent centers, are confirmed by a high level of correspondence between prenatal ultrasound and autopsy findings. The low sensitivity was due in large part to the relatively subtle nature of many autopsy findings that had not been predicted by prenatal examination.

Fragile X syndrome detection in newborns-pilot study.

PURPOSE: Fragile X syndrome is the most common form of hereditary intellectual disability. Detection of the fragile X phenotype in the prepubertal period is very difficult, and early detection might assist in early developmental intervention and reproductive counseling. A pilot study was conducted to establish the feasibility of newborn screening for fragile X syndrome. METHODS: A prospective study was done contacting mothers postdelivery in two hospitals in upstate South Carolina from 2005 to 2006. With their permission, blood samples were obtained from the male infants via heelstick and analyzed. RESULTS: A total of 1,459 newborns were tested, and 5 abnormal results were obtained. The results included one sex chromosome aneuploidy (47, XXY), two premutations, and two full mutations. CONCLUSIONS: Our study establishes the potential feasibility of such a screening process. However, more complete studies assessing a larger population and risk-benefit analyses are necessary before any universal application of this test. Our detection rate for fragile X syndrome (1:730) was inexplicably greater than anticipated but likely represents a chance occurrence among the small number of infants tested.

Evidence that SIZN1 is a candidate X-linked mental retardation gene.

An estimated 1-3% of individuals within the United States are diagnosed with mental retardation (MR), yet the cause is unknown in nearly 50% of the patients. While several environmental, genetic and combined teratogenetic etiologies have been identified, many causative genes remain to be identified. Furthermore, the pathogenetic mechanisms underlying MR are known for very few of these genes. Males have a much higher incidence of MR implicating genes on the X-chromosome. We have recently identified a novel gene, SIZN1, on the X-chromosome and showed that it functions in modulating the BMP signaling pathway. Furthermore, we have shown this gene is necessary for basal forebrain cholinergic neuron (BFCN) specific gene expression. Given that cognitive function is impaired when BFCNs are lost or functionally disrupted, we undertook a screen of cognitively impaired males for SIZN1 mutations. We report on four different sequence variants in SIZN1 in 11 individuals with nonsyndromic X-linked mental retardation (XLMR). Our data implicate SIZN1 as a candidate gene for XLMR and/or as a neurocognitive functional modifier.

Trends in the postfortification prevalence of spina bifida and anencephaly in the United States.

BACKGROUND: The prevalence of NTDs in the US declined significantly after mandatory folic acid fortification; however, it is not known if the prevalence of NTDs has continued to decrease in recent years relative to the period immediately following the fortification mandate. METHODS: Population-based data from 21 birth defects surveillance systems were used to examine trends in the birth prevalence of spina bifida and anencephaly during 1999-2000, 2001-2002, and 2003-2004. Prevalence data were stratified by non-Hispanic White, non-Hispanic Black, and Hispanic race or ethnicity. Prevalence ratios were calculated by dividing the birth prevalences during the later time periods (2001-2002 and 2003-2004) by the birth prevalences during 1999-2000. RESULTS: During 1999-2004, 3,311 cases of spina bifida and 2,116 cases of anencephaly were reported. Hispanic infants had the highest prevalences of NTDs for all years. For all infants, the combined birth prevalences of spina bifida and anencephaly decreased 10% from the 1999-2000 period to the 2003-2004 period. The decline in spina bifida (3%) was not significant; however the decline in anencephaly (20%) was statistically significant. CONCLUSIONS: While the prevalences of spina bifida and anencephaly in the United States have declined since folic acid fortification in the food supply began, these data suggest that reductions in the prevalence of anencephaly continued during 2001-2004 and that racial and ethnic and other disparities remain.

Quantitative standards for fetal and neonatal autopsy.

Growth curves are essential for determining whether growth parameters lie within normal ranges. In the case of fetal and neonatal autopsy, relevant data are scattered across many publications, and few sources examine a large enough sample to be considered definitive. To ameliorate these inadequacies, regressions were created incorporating data from multiple sources both to increase accuracy and to condense available data into a single standard. When measurements were not well studied, the best available published standards are given. These regressions provide a valuable tool for clinicians who need to understand the significance of measurements obtained during autopsy.

Bootstrap calibration of TRANSMIT for informative missingness of parental genotype data.

Informative missingness of parental genotype data occurs when the genotype of a parent influences the probability of the parent's genotype data being observed. Informative missingness can occur in a number of plausible ways and can affect both the validity and power of procedures that assume the data are missing at random (MAR). We propose a bootstrap calibration of MAR procedures to account for informative missingness and apply our methodology to refine the approach implemented in the TRANSMIT program. We illustrate this approach by applying it to data on hypertensive probands and their parents who participated in the Framingham Heart Study.