Two unrelated patients with autosomal dominant omodysplasia and FRIZZLED2 mutations.

Presented are two patients with autosomal dominant omodysplasia and mutations in the FZD2 gene. The mutations identified have been recently reported, suggesting the possibility of recurrent mutations. The phenotypes of these patients overlap with what has been previously reported, though intellectual disability as seen in our patient is not typical.

Methods for surveillance of fetal alcohol syndrome: The Fetal Alcohol Syndrome Surveillance Network II (FASSNetII) - Arizona, Colorado, New York, 2009 - 2014.

Surveillance of fetal alcohol syndrome (FAS) is important for monitoring the effects of prenatal alcohol exposure and describing the public health burden of this preventable disorder. Building on the infrastructure of the Fetal Alcohol Syndrome Surveillance Network (FASSNet, 1997-2002), in 2009 the Centers for Disease Control and Prevention awarded 5-year cooperative agreements to three states, Arizona, Colorado, and New York, to conduct population-based surveillance of FAS. The Fetal Alcohol Syndrome Surveillance Network II (FASSNetII, 2009-2014) developed a surveillance case definition based on three clinical criteria: characteristic facial features, central nervous system abnormalities, and growth deficiency. FASSNetII modified the FASSNet methods in three important ways: (1) estimation of a period prevalence rather than birth prevalence; (2) surveillance of FAS among school-age children (ages 7-9 years) to better document the central nervous system abnormalities that are not apparent at birth or during infancy; and (3) implementation of an expert clinical review of abstracted data for probable and confirmed cases classified through a computerized algorithm. FASSNetII abstracted data from multiple sources including birth records, medical records from child development centers or other specialty clinics, and administrative databases such as hospital discharge and Medicaid. One challenge of FASSNetII was its limited access to non-medical records. The FAS prevalence that could be estimated was that of the population identified through an encounter with the healthcare system. Clinical and public health programs that identify children affected by FAS provide critical information for targeting preventive, medical and educational services in this vulnerable population.

Fetal alcohol syndrome among children aged 7-9 years - Arizona, Colorado, and New York, 2010.

Fetal alcohol syndrome (FAS) is a serious birth defect and developmental disorder caused by in utero exposure to alcohol. Assessment of the public health burden of FAS through surveillance has proven difficult; there is wide variation in reported prevalence depending on the study population and surveillance method. Generally, records-based birth prevalence studies report estimates of 0.2-1.5 per 1,000 live births, whereas studies that use in-person, expert assessment of school-aged children in a community report estimates of 6-9 per 1,000 population. The Fetal Alcohol Syndrome Surveillance Network II addressed some of the challenges in records-based ascertainment by assessing a period prevalence of FAS among children aged 7‒9 years in Arizona, Colorado, and New York. The prevalence across sites ranged from 0.3 to 0.8 per 1,000 children. Prevalence of FAS was highest among American Indian/Alaska Native children and lowest among Hispanic children. These estimates continue to be much lower than those obtained from studies using in-person, expert assessment. Factors that might contribute to this discrepancy include 1) inadequate recognition of the physical and behavioral characteristics of FAS by clinical care providers; 2) insufficient documentation of those characteristics in the medical record; and 3) failure to consider prenatal alcohol exposure with diagnoses of behavioral and learning problems. Addressing these factors through training of medical and allied health providers can lead to practice changes, ultimately increasing recognition and documentation of the characteristics of FAS.

Laterality defects in the national birth defects prevention study (1998-2007): birth prevalence and descriptive epidemiology.

Little is known epidemiologically about laterality defects. Using data from the National Birth Defects Prevention Study (NBDPS), a large multi-site case-control study of birth defects, we analyzed prevalence and selected characteristics in children born with laterality defects born from 1998 to 2007. We identified 517 nonsyndromic cases (378 heterotaxy, 73.1%; 139 situs inversus totalis [SIT], 26.9%) resulting in an estimated birth prevalence of 1.1 per 10,000 live births (95% confidence interval 1.0­1.2). Prevalence did not differ significantly across sites, over time, or by inclusion of pregnancy termination. Laterality defects were more common among preterm cases compared to term cases, and in children born to mothers who were non-white or younger than 20 years compared to white mothers or those age 25­29 years. The distribution of associated cardiac and extra-cardiac defects, excluding the expected heterotaxy anomalies, varied by type of laterality defect. Cases with heterotaxy were significantly more likely than those with SIT to have double outlet right ventricle, atrioventricular canal defects, pulmonary stenosis, non-tetralogy of Fallot pulmonary atresia with ventricular septal defect, totally and partially anomalous pulmonary venous return; also more likely to have orofacial clefts, esophageal atresia, bowel atresias, and omphalocele, though not reaching statistical significance. Relatively more common among cases with SIT were Dandy- Walker malformation, anotia/microtia, and limb deficiency. The similarity in the demographic characteristics of heterotaxy and SIT supports the hypothesis that they are part of a continuum of abnormal left-right axis patterning. These findings on laterality defects may help guide clinical care, future research, and prevention strategies.

Exploring the feasibility of using electronic health records in the surveillance of fetal alcohol syndrome.

BACKGROUND: Explore the use of electronic health records (EHRs) in fetal alcohol syndrome (FAS) surveillance systems. METHODS: Using EHRs we identified diagnoses and anthropometric measurements related to the FAS criteria developed by the Fetal Alcohol Syndrome Surveillance Network (FASSNet) among children aged 0 to 12 years. RESULTS: There were 143,393 distinct children aged between 0 and 12 years enrolled in Kaiser Permanente, Georgia, during the study period. Based on diagnoses and anthropometric measurements, 20,101 children met at least one criterion of interest, and when grouped into combinations of different criteria there were 2285 who met GROWTH+CNS criteria, 76 children who met GROWTH+FACE criteria, 107 children who met CNS+FACE criteria, and 93 children who met GROWTH+CNS+FACE criteria. The prevalence of FAS as defined by FASSNet is 1.92 per 1000 children. We linked 17,084 (85.0%) children to their mothers in the health plan; only 3% of mothers of children in the GROWTH+CNS+FACE group had an indication of alcohol or drugs use, but they had the highest rate of depression (39%). CONCLUSION: Data of utility in identification of FAS are readily available in EHRs and may serve as a basis for intervention with at-risk children and in planning of future FAS surveillance programs.

Long-term observation of a patient with dominant omodysplasia.

We report on the natural history of a female with dominant omodysplasia, a rare osteochondrodysplasia with short stature, rhizomelia of the extremities (upper extremities more affected), and short first metacarpals. The proband had normal molecular analysis of the glypican 6 gene (GPC6), which was recently reported as a candidate for autosomal recessive omodysplasia. The findings in this patient were compared to other known and suspected cases of autosomal dominant omodysplasia. Mild rhizomelic shortening of the lower extremities has not been previously reported.

A pilot study using residual newborn dried blood spots to assess the potential role of cytomegalovirus and Toxoplasma gondii in the etiology of congenital hydrocephalus.

BACKGROUND: Congenital hydrocephalus is a condition characterized by accumulation of cerebrospinal fluid in the ventricles of the brain. Prenatal infections are risk factors for some birth defects. This pilot study investigated whether residual dried blood spots (DBS) could be used to assess infections as risk factors for birth defects by examining the associations between prenatal infection with Toxoplasma gondii (T. gondii) or cytomegalovirus (CMV) with congenital hydrocephalus. METHODS: Case-infants with hydrocephalus (N=410) were identified among live-born infants using birth defects surveillance systems in California, North Carolina, and Texas. Control-infants without birth defects were randomly selected from the same geographic areas and time periods as case-infants (N=448). We tested residual DBS from case- and control-infants for T. gondii immunoglobulin M and CMV DNA. When possible, we calculated crude odds ratios (cORs) and confidence intervals (CIs). RESULTS: Evidence for prenatal T. gondii infection was more common among case-infants (1.2%) than control-infants (0%; p=0.11), and evidence for prenatal CMV infection was higher among case-infants (1.5%) than control-infants (0.7%; cOR: 2.3; 95% CI: 0.48, 13.99). CONCLUSIONS: Prenatal infections with T. gondii and CMV occurred more often among infants with congenital hydrocephalus than control-infants, although differences were not statistically significant. This pilot study highlighted some challenges in using DBS to examine associations between certain infections and birth defects, particularly related to reduced sensitivity and specimen storage conditions. Further study with increased numbers of specimens and higher quality specimens should be considered to understand better the contribution of these infections to the occurrence of congenital hydrocephalus.

Two extraordinarily severe cases of Treacher Collins syndrome.

Here, we report two extraordinarily severe cases of Teacher Collins syndrome. Initially, amniotic bands and plical fold disruption were considered, but downslanting eyes made us consider severe Treacher Collins syndrome. A TCOF1 mutation in exon 24 was identified in Patient 1 (c.4355_4356ins14, resulting in p.1456Thrfs*18). Patient 2, who expired on day 4, is so similar to Patient 1 that severe Treacher Collins syndrome may be inferred in this instance. Neither the TCOF1 mutation nor the well-known variability in the expression in affected families with Treacher Collins syndrome (∼40% of reported cases) can explain the severity of these cases; otherwise, we would be aware of such cases within families from time to time. We are unaware of any recent sporadic cases (∼60% of reported cases) exactly like ours either with a single exception in the case reported by Writzl et al. [2008] with a TCOF1 mutation. The case described by Otto in 1841 is spectacular. We propose several hypotheses to be considered in explaining this developmental amplification, including some promoter effect on the gene, some position effect on the gene, a polymorphism elsewhere in the gene, a point mutation elsewhere in the gene, a polymorphism in another gene, or a point mutation in another gene, such as POLR1C (which maps to 6p21.1) or POLR1D (which maps to13q12.2). We also review the etiology and pathogenesis of Treacher Collins syndrome, and discuss several other severe cases from the past.

Maternal age and prevalence of isolated congenital heart defects in an urban area of the United States.

Although maternal age has been associated with a number of birth defects in several reports, the literature on the association of maternal age with isolated congenital heart defect (CHD) phenotypes has been limited. We evaluated CHD prevalence based on a cohort of 5,289 infants and fetuses with isolated CHDs born during the period 1968-2005 and ascertained by the Metropolitan Atlanta Congenital Defects Program (MACDP) among residents of five central counties in Atlanta. For our denominator, we obtained information on births to residents of the same counties from vital records (n = 1,301,143). We calculated prevalence ratios for 23 CHD phenotypes by several maternal age categories, using the group 25-29 years of age as a reference group. We used Poisson regression models to estimate adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs), controlling for maternal race, infant sex, and birth cohort. A maternal age of 35 years or older was associated with an increased prevalence for several CHD phenotypes: laterality defects (aPR = 2.06; CI 1.22-3.48), all conotruncal defects (aPR = 1.30; CI 1.03-1.65), and specifically for dextro-transposition of the great arteries (aPR = 1.65; CI 1.10-2.48), coarctation of the aorta (aPR = 1.54; CI 1.10-2.16), ventricular septal defects (aPR = 1.20; CI 1.06-1.36), and atrial septal defects (aPR = 1.36; CI 1.05-1.77). Our findings suggest that the birth prevalence of specific isolated CHDs varies with maternal age. Further studies are warranted to corroborate these observations, taking into account potential confounding by known modifiable risk factors.

Descriptive study of nonsyndromic atrioventricular septal defects in the National Birth Defects Prevention Study, 1997-2005.

Nonsyndromic atrioventricular septal defects (AVSDs) are serious congenital heart defects for which information on prevalence and descriptive characteristics based on large, geographically, and ethnically diverse populations has been limited. To describe the birth prevalence and phenotype of nonsyndromic AVSDs, we used data from the National Birth Defects Prevention Study (NBDPS), a multisite, population-based case-control study aimed at identifying genetic and environmental risk factors for birth defects. For this analysis, infants born during the period 1997-2005 and meeting the NBDPS case definition for AVSDs were included. Infants with an AVSD associated with recognized or strongly suspected chromosomal abnormalities or single-gene disorders (syndromic case infants) were excluded. We identified 302 infants with a nonsyndromic AVSD for a birth prevalence of 0.83/10,000 livebirths. Over 20% of infants with an AVSD had an additional major birth defect, with gastrointestinal, renal or urinary, and central nervous system defects being the most common. A lower prevalence of AVSDs was seen among infants born to Hispanic mothers compared with those born to non-Hispanic White mothers [prevalence ratio = 0.63 (95% confidence interval: 0.46-0.86)]. Understanding the prevalence of nonsyndromic AVSDs, demographic factors associated with their occurrence, and associated defects could help guide clinical care, as well as contribute to a better understanding of pathogenesis.

Congenital heart defects and major structural noncardiac anomalies, Atlanta, Georgia, 1968 to 2005.

OBJECTIVE: To identify the proportion of major structural noncardiac anomalies identified with congenital heart defects (CHDs). STUDY DESIGN: Records of infants with CHDs in the Metropolitan Atlanta Congenital Defects Program who were born during the period 1968 through 2005 were classified as having isolated, syndromic, multiple CHD (ie, having an unrecognized pattern of multiple congenital anomalies or a recognized pattern of multiple congenital anomalies of unknown etiology), or laterality defects. Frequencies of associated noncardiac anomalies were obtained. RESULTS: We identified 7984 live-born and stillborn infants and fetuses with CHDs. Among them, 5695 (71.3%) had isolated, 1080 (13.5%) had multiple, 1048 (13.1%) had syndromic, and 161 (2.0%) had laterality defects. The percentage of multiple congenital anomalies was highest for case with atrial septal defects (18.5%), cardiac looping defects (17.2%), and conotruncal defects (16.0%), and cases with atrioventricular septal defects represented the highest percentages of those with syndromic CHDs (66.7%). CONCLUSIONS: Including those with syndromes and laterality defects, 28.7% of case infants with CHDs had associated major noncardiac malformations. Thus, infants with CHDs warrant careful examination for the presence of noncardiac anomalies.

Effect of specimen storage conditions on newborn dried blood spots used to assess Toxoplasma gondii immunoglobulin M (IgM).

BACKGROUND: Newborn screening programs store-under varying conditions-residual dried blood spots (DBS). Residual DBS were used to investigate the contribution of congenital infection with Toxoplasma gondii to the etiology of hydrocephalus and as a key step, we assessed the effect of storage conditions on the stability of newborn screening biomarkers. METHODS: Infants with hydrocephalus (410 cases) were identified using population-based birth defects surveillance systems in California, North Carolina, and Texas. Infants without birth defects (448 controls) were randomly selected from the same geographic areas and time periods. California stores DBS with controlled temperature, while North Carolina and Texas store DBS under ambient conditions. After removal of personal identifiers, DBS were tested for Toxo-specific immunoglobulin-M (Toxo-IgM). Because of poor elution of DBS stored in ambient conditions, additional biomarkers were tested on a specimen subset. RESULTS: Among 858 DBS tested, Toxo-IgM was found in 3 cases and no controls from California (N=515) and in no specimens from North Carolina or Texas (N=343). Among the 98 specimens tested for selected biomarkers, statistically significant differences were found for California vs. combined North Carolina and Texas DBS (thyroid stimulating hormone, phenylalanine, methionine, leucine and citrulline p<0.0001; tyrosine and valine p<0.001). CONCLUSIONS: Storage conditions for residual DBS had an effect on the ability to extract, recover, and accurately measure Toxo-IgM and other biomarkers from the filter paper matrix.

Long-term survival of infants with atrioventricular septal defects.

OBJECTIVE: To examine the variation in survival in infants with atrioventricular septal defects (AVSD) with demographic factors and clinical characteristics, including the presence of Down syndrome. STUDY DESIGN: We selected infants with all types of AVSD with Down syndrome (n = 177) and without Down syndrome (n = 161), born between Jan 1, 1979, and Dec 31, 2003 and identified through the Metropolitan Atlanta Congenital Defects Program (MACDP). Infants were classified by the complexity of their cardiac defects and presence of major non-cardiac malformations. Deaths (n = 111) were identified through 2004 with linkage with state vital records and the National Death Index. Kaplan-Meier survival probabilities and adjusted hazard ratios (HRs) were calculated in relation to demographic and clinical characteristics. RESULTS: Children with AVSD and Down syndrome had a similar overall survival probability (70%) as those without Down syndrome (69%). Mortality was higher in children with a complex AVSD (adjusted HR = 7.0; 95% CI, 3.1-15.5) and in children with > or =2 major non-cardiac malformations (adjusted HR = 3.4; 95% CI, 1.8-6.5) and was lower in children in the 1992 to 2003 birth cohort (adjusted HR = 0.6; 95% CI, 0.4-0.998). CONCLUSIONS: Down syndrome was not a prognostic factor. Our findings might be helpful in assessing the long-term prognosis of infants with AVSD.

Risk factors for non-syndromic holoprosencephaly in the National Birth Defects Prevention Study.

Holoprosencephaly (HPE) is a complex structural brain anomaly that results from incomplete cleavage of the forebrain. The prevalence of HPE at birth is low, and risk factors have been difficult to identify. Using data from a large multi-state population-based case-control study, we examined risk factors for non-syndromic HPE. Data from maternal telephone interviews were available for 74 infants with HPE and 5871 controls born between 1997 and 2004. Several characteristics and exposures were examined, including pregnancy history, medical history, maternal diet and use of nutritional supplements, medications, tobacco, alcohol, and illegal substances. We used chi(2)-tests and logistic regression (excluding women with pre-existing diabetes) to examine associations with HPE. Except for diet (year before pregnancy) and sexually transmitted infections (STIs) (throughout pregnancy), most exposures were examined for the time period from the month before to the third month of pregnancy. HPE was found to be associated with pre-existing diabetes (chi(2) = 6.0; P = 0.01), aspirin use [adjusted odds ratio (aOR) = 3.4; 95% confidence interval (CI) 1.6-6.9], lower education level (aOR = 2.5; 95%CI 1.1-5.6), and use of assisted reproductive technologies (ART) (crude OR = 4.2; 95%CI 1.3-13.7). Consistent maternal folic acid use appeared to be protective (aOR = 0.4; 95%CI 0.2-1.0), but the association was of borderline statistical significance. While some of these findings support previous observations, other potential risk factors identified warrant further study.

Orofacial clefts in the National Birth Defects Prevention Study, 1997-2004.

Orofacial clefts are among the most common types of birth defects, but their clinical presentation has not been well described in a geographically diverse US population. To describe the birth prevalence and phenotype of nonsyndromic clefts, we used data from the National Birth Defects Prevention Study (NBDPS), a multi-site, population-based, case-control study aimed at identifying genetic and environmental risk factors for birth defects. Included in the study were infants born during 1997-2004 with a cleft lip (CL), cleft lip with cleft palate (CLP), or cleft palate (CP). Infants with clefts associated with recognized single-gene disorders, chromosome abnormalities, holoprosencephaly, or amniotic band sequence were excluded. A total of 3,344 infants with nonsyndromic orofacial clefts were identified, including 751 with CL, 1,399 with CLP, and 1,194 with CP, giving birth prevalence estimates of 0.3, 0.5, and 0.4/1,000 live births, respectively. Among infants with CLP where cleft laterality was specified, about twice as many had unilateral vs. bilateral involvement, while for CL there were over 10 times as many with unilateral versus bilateral involvement. Involvement was most often left-sided. About one-quarter of infants with CP had Pierre Robin sequence. Over 80% of infants had an isolated orofacial cleft. Among infants with CL or CLP, heart, limb, and other musculoskeletal defects were most commonly observed, while heart, limb, and central nervous system defects were most common among infants with CP. Better understanding of the birth prevalence and phenotype may help guide clinical care as well as contribute to an improved understanding of pathogenesis.

Elements of morphology: standard terminology for the ear.

An international group of clinicians working in the field of dysmorphology has initiated the standardization of terms used to describe human morphology. The goals are to standardize these terms and reach consensus regarding their definitions. In this way, we will increase the utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients. Discussions with other workers in dysmorphology and related fields, such as developmental biology and molecular genetics, will become more precise. Here we introduce the anatomy of the ear and define and illustrate the terms that describe the major characteristics of the ear.

Setting a public health research agenda for Down syndrome: summary of a meeting sponsored by the Centers for Disease Control and Prevention and the National Down Syndrome Society.

On November 8-9, 2007, a meeting entitled "Setting a Public Health Research Agenda for Down Syndrome" was held to review current knowledge, identify gaps, and develop priorities for future public health research related to Down syndrome. Participants included experts in clinical and molecular genetics, pediatrics, cardiology, psychiatry, psychology, neuroscience, epidemiology, and public health. Participants were asked to identify key public health research questions and discuss potential strategies that could be used to address those questions. The following were identified as priority areas for future public health research: identification of risk and preventive factors for physical health and cognitive outcomes, focusing on understanding the reasons for previously recognized disparities; improved understanding of comorbid conditions, including their prevalence, clinical variability, natural history, and optimal methods for their evaluation and treatment; better characterization of the natural history of cognition, language, and behavior; identification of mental health comorbidities and of risk and protective factors for their development; identification of strategies to improve enrollment in research studies; development of strategies for conveying up-to-date information to parents and health professionals; identification of interventions to improve cognition, language, mental health, and behavior; understanding the impact of educational and social services and supports; identification of improved methods for diagnosis of and interventions for Alzheimer disease; and understanding the effects of different types of health care on outcomes. Participants strongly supported the development of population-based resources for research studies and resources useful for longitudinal studies. This agenda will be used to guide future public health research on Down syndrome.