Patterns of multiple congenital anomalies in the National Birth Defect Prevention Study: Challenges and insights.

BACKGROUND: About 20%-30% of children with birth defects have multiple major birth defects in more than one organ system, often referred to as multiple congenital anomalies (MCAs). Evaluating the patterns of MCAs can provide clues to the underlying causes, pathogenic mechanisms, and developmental pathways. We sought to explore selected patterns of MCAs within the National Birth Defects Prevention Study (NBDPS), a population-based, case-control study that excluded cases attributed to known chromosomal or single-gene abnormalities. METHODS: We defined MCAs as having two or more NBDPS-eligible birth defects and calculated the adjusted observed-to-expected ratio for all observed MCA patterns using co-occurring defect analysis. RESULTS: Of the 50,186 case infants eligible for NBDPS, 2,734 (3.7%) had at least two eligible birth defects. We observed 209 distinct 2-way combinations of birth defects, 297 distinct 3-way combinations, 179 distinct 4-way combinations, and 69 distinct 5-way combinations. Sacral agenesis had the largest proportion of cases with MCAs (70%), whereas gastroschisis had the lowest (3%). Among the cases with MCAs, 63% had a heart defect, 23% had an oral cleft, and 21% had anorectal atresia/stenosis. Of the patterns with adjusted observed-to-expected ratios in the top 20%, most were consistent with the known associations or syndromes, including VATER/VACTERL association and CHARGE syndrome. CONCLUSIONS: Most but not all patterns that had the highest adjusted observed-to-expected ratios were instances of known syndromes or associations. These findings highlight the importance of considering birth defect combinations that suggest syndromic patterns in the absence of a formal syndromic diagnosis. New approaches for screening for sequences and associations, and VATER/VACTERL in particular, in surveillance systems with limited resources for manual review may be valuable for improving surveillance system quality. The observed MCA patterns within NBDPS may help focus future genetic studies by generating case groups of higher yield.

Familial colloid cysts: not a chance occurrence.

PURPOSE: Colloid cysts are rare, benign brain tumors of the third ventricle with an estimated population prevalence of 1 in 5800. Sudden deterioration and death secondary to obstructive hydrocephalus are well-described presentations in patients with a colloid cyst. Although historically conceptualized as driven by sporadic genetic events, a growing body of literature supports the possibility of an inherited predisposition. METHODS: A prospective registry of patients with colloid cysts was maintained between 1996 and 2021. Data pertaining to a family history of colloid cyst was collected retrospectively; self-reporting was validated in each case by medical record or imaging review. Frequency of patients with a documented first-degree family member with a colloid cyst based on self-reporting was calculated. The rate of familial co-occurrence within our series was then compared to a systematic literature review and aggregation of familial case studies, as well as population-based prevalence rates of sporadic colloid cysts. RESULTS: Thirteen cases with affected first-degree relatives were identified in our series. Of the entire cohort, 19/26 were symptomatic from the lesion (73%), 12/26 (46.2%) underwent resection, and 2/26 (7.7%) had sudden death from presumed obstructive hydrocephalus. The majority of transmission patterns were between mother and child (9/13). Compared with the estimated prevalence of colloid cysts, our FCC rate of 13 cases in 383 (3.4%) estimates a greater-than-chance rate of co-occurrence. CONCLUSION: Systematic screening for FCCs may facilitate early recognition and treatment of indolent cysts, thereby preventing the rapid deterioration that can occur with an unrecognized third ventricular tumor. Furthermore, identifying a transmission pattern may yield more insight into the molecular and genetic underpinnings of colloid cysts.

Descriptive and risk factor analysis of infantile cataracts: National Birth Defects Prevention Study, 2000-2011.

Using National Birth Defects Prevention Study (NBDPS) data, we sought to estimate birth prevalence, describe clinical characteristics, and examine risk factors for infantile cataracts. We calculated birth prevalence using the numbers of NBDPS-eligible cataract cases and live births in the study area. We described case infants by the presence of associated ipsilateral eye defects (IEDs) and non-eye-related major birth defects. Using maternal exposure information collected via telephone interview, we conducted logistic regression analyses among the interviewed cases and controls. Birth prevalence of infantile cataracts was 1.07/10,000 live births. Unilateral cataracts were more often associated with IEDs, while infants with bilateral cataracts were more often preterm, full-term with low birth weight, or had non-eye-related major birth defects. Unilateral cataracts were positively associated with maternal nulliparity (adjusted odds ratio [aOR] = 1.61, 95% confidence interval [CI] = 1.18, 2.20; reference: multiparity), whereas bilateral cataracts were positively associated with maternal education <12 years (aOR = 2.08, 95% CI = 1.13, 3.82; reference: education >12 years), and foreign-born nativity (aOR = 1.92, 95% CI = 1.04, 3.52; reference: U.S.-born nativity). The current analysis can inform future epidemiological studies aimed at identifying mechanisms underlying the associations between infantile cataracts and complex maternal exposures, such as lower levels of education and foreign-born nativity.

Rapid genotype imputation from sequence with reference panels.

Inexpensive genotyping methods are essential to modern genomics. Here we present QUILT, which performs diploid genotype imputation using low-coverage whole-genome sequence data. QUILT employs Gibbs sampling to partition reads into maternal and paternal sets, facilitating rapid haploid imputation using large reference panels. We show this partitioning to be accurate over many megabases, enabling highly accurate imputation close to theoretical limits and outperforming existing methods. Moreover, QUILT can impute accurately using diverse technologies, including long reads from Oxford Nanopore Technologies, and a new form of low-cost barcoded Illumina sequencing called haplotagging, with the latter showing improved accuracy at low coverages. Relative to DNA genotyping microarrays, QUILT offers improved accuracy at reduced cost, particularly for diverse populations that are traditionally underserved in modern genomic analyses, with accuracy nearly doubling at rare SNPs. Finally, QUILT can accurately impute (four-digit) human leukocyte antigen types, the first such method from low-coverage sequence data.

Descriptive and risk factor analysis of nonsyndromic sacral agenesis: National Birth Defects Prevention Study, 1997-2011.

Sacral agenesis is a rare birth defect characterized by partial or complete absence of the sacrum. We sought to (a) describe case characteristics, (b) estimate birth prevalence, and (c) identify risk factors for nonsyndromic sacral agenesis using data from the National Birth Defects Prevention Study (NBDPS). The NBDPS was a population-based, case-control study involving pregnancies with estimated dates of delivery from October 1997 through December 2011. We estimated birth prevalence using all NBDPS eligible cases. Using self-reported maternal exposure information, we conducted multivariable logistic regression analysis to identify potential risk factors overall and among women without diabetes. The birth prevalence of sacral agenesis was 2.6/100,000 live births. In the multivariable analysis, multifetal pregnancy, pre-existing Type 1 diabetes, and pre-existing Type 2 diabetes were positively and significantly associated with sacral agenesis, albeit estimates were imprecise. Preexisting Type 1 diabetes was the strongest risk factor (adjusted odds ratio = 96.6, 95% confidence interval = 43.5-214.7). Among women without diabetes, periconceptional smoking was positively and significantly associated with sacral agenesis. Our findings underscore the importance of smoking cessation programs among women planning pregnancy and the importance of better understanding the role of glycemic control before and during pregnancy when designing interventions for primary prevention of sacral agenesis.

Descriptive epidemiology of cerebellar hypoplasia in the National Birth Defects Prevention Study.

BACKGROUND: Cerebellar hypoplasia is a rare disorder of cerebellar formation in which the cerebellum is not completely developed, smaller than it should be, or completely absent. The prevalence of cerebellar hypoplasia at birth is unknown, and little is known about epidemiological risk factors. Using data from the National Birth Defects Prevention Study (NBDPS), a population-based, case-control study, we analyzed clinical features and potential risk factors for nonsyndromic cerebellar hypoplasia. METHODS: The NBDPS included pregnancies with estimated delivery dates from 1997-2011. We described clinical features of cerebellar hypoplasia cases from the study area. We explored risk factors for cerebellar hypoplasia (case characteristics, demographics, pregnancy characteristics, maternal health conditions, maternal medication use, and maternal behavioral exposures) by comparing cases to non-malformed live born control infants. We calculated crude odds ratios (ORs) and 95% confidence intervals using logistic regression models. RESULTS: We identified 87 eligible cerebellar hypoplasia cases and 55 mothers who participated in the NBDPS. There were no differences in clinical features between interviewed and non-interviewed cases. Cerebellar hypoplasia cases were more likely than controls to be from a multiple pregnancy, be born preterm, and have low birth weight. Cerebellar hypoplasia cases were more likely to be born in or after 2005, as opposed to earlier in NBDPS. We found elevated ORs that were not statistically significant for maternal use of vasoactive medications, non-Hispanic black mothers, and mothers with a history of hypertension. CONCLUSIONS: Although unadjusted, our findings from a large, population-based study can contribute to new hypotheses regarding the etiology of cerebellar hypoplasia.

Linking the degree of virilization in females with congenital adrenal hyperplasia to genotype.

Mutations of CYP21A2 variably decrease 21-hydroxylase activity and result in a spectrum of disease expressions in patients with congenital adrenal hyperplasia (CAH). We examined the association between CYP21A2 mutations and virilization (Prader score) in females with CAH. The study population included 187 CAH females with fully characterized CYP21A2 mutations. One hundred fifty-eight patients were sorted into groups by expected enzyme activity (percent of normal activity) of the less severely affected allele: (A) null, 0%; (B) I2G, 1%; (C) I172N, 2%; and (D) V281L, >2%. We observed an inverse relationship between virilization and residual enzyme activity (P < 0.001). Subjects in group A or B had a significantly higher likelihood (unadjusted odds ratio: 16; P < 0.001) of developing severe virilization compared with those in group C. Surprisingly, 24% of group D patients, whose mutation is usually associated with nonclassical (NC) CAH, had severe virilization. Among subjects with the NC P30L mutation, 66% expressed unexpected virilization. Virilization, usually leading to extensive reconstructive surgery, is highly likely in patients with null or I2G mutations; however, NC mutations (P30L/V281L) may also lead to unexpected virilization. These findings have implications for prenatal counseling and highlight the need for additional investigations into other factors that influence virilization in CAH.

Rapidly progressive mitral valve stenosis in patients with acromelic dysplasia.

Acromelic dysplasias are a group of skeletal dysplasias characterised by short-limbed short stature with other distinctive phenotypic features including small hands and feet and stiff joints. Geleophysic dysplasia is an acromelic dysplasia that is associated with characteristic facial features, progressive cardiac valvular thickening, and tracheal stenosis. Owing to overlapping clinical features with other types of short-limbed skeletal dysplasias, it is important to make a precise diagnosis as they have different cardiac morbidity and mortality. We present the cases of three patients with geleophysic dysplasia and progressive mitral valve disease to emphasise the natural history of this disorder and provide guidance regarding cardiac health supervision in these individuals.

Respiratory Care Received by Individuals With Duchenne Muscular Dystrophy From 2000 to 2011.

BACKGROUND: Duchenne muscular dystrophy (DMD) causes progressive respiratory muscle weakness and decline in function, which can go undetected without monitoring. DMD respiratory care guidelines recommend scheduled respiratory assessments and use of respiratory assist devices. To determine the extent of adherence to these guidelines, we evaluated respiratory assessments and interventions among males with DMD in the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) from 2000 to 2011. METHODS: MD STARnet is a population-based surveillance system that identifies all individuals born during or after 1982 residing in Arizona, Colorado, Georgia, Hawaii, Iowa, and western New York with Duchenne or Becker muscular dystrophy. We analyzed MD STARnet respiratory care data for non-ambulatory adolescent males (12-17 y old) and men (≥18 y old) with DMD, assessing whether: (1) pulmonary function was measured twice yearly; (2) awake and asleep hypoventilation testing was performed at least yearly; (3) home mechanical insufflation-exsufflation, noninvasive ventilation, and tracheostomy/ventilators were prescribed; and (4) pulmonologists provided evaluations. RESULTS: During 2000-2010, no more than 50% of both adolescents and men had their pulmonary function monitored twice yearly in any of the years; 67% or fewer were assessed for awake and sleep hypoventilation yearly. Although the use of mechanical insufflation-exsufflation and noninvasive ventilation is probably increasing, prior use of these devices did not prevent all tracheostomies, and at least 18 of 29 tracheostomies were performed due to acute respiratory illnesses. Fewer than 32% of adolescents and men had pulmonologist evaluations in 2010-2011. CONCLUSIONS: Since the 2004 publication of American Thoracic Society guidelines, there have been few changes in pulmonary clinical practice. Frequencies of respiratory assessments and assist device use among males with DMD were lower than recommended in clinical guidelines. Collaboration of respiratory therapists and pulmonologists with clinicians caring for individuals with DMD should be encouraged to ensure access to the full spectrum of in-patient and out-patient pulmonary interventions.

Fluconazole use and birth defects in the National Birth Defects Prevention Study.

BACKGROUND: Low-dose fluconazole is used commonly to treat vulvovaginal candidiasis, a condition occurring frequently during pregnancy. Conflicting information exists on the association between low-dose fluconazole use among pregnant women and the risk of major birth defects. OBJECTIVE: We used data from the National Birth Defects Prevention Study to examine this association. STUDY DESIGN: The National Birth Defects Prevention Study is a multisite, population-based, case-control study that includes pregnancies with estimated delivery dates from 1997 to 2011. Information on fluconazole use in early pregnancy was collected by self-report from 31,645 mothers of birth defect cases and 11,612 mothers of unaffected controls. Adjusted odds ratios and 95% confidence intervals were estimated for birth defects with 5 or more exposed cases; crude odds ratios and exact 95% confidence intervals were estimated for birth defects with 3-4 exposed cases. RESULTS: Of the 43,257 mothers analyzed, 44 case mothers and 6 control mothers reported using fluconazole. Six exposed infants had cleft lip with cleft palate, 4 had an atrial septal defect, and each of the following defects had 3 exposed cases: hypospadias, tetralogy of Fallot, d-transposition of the great arteries, and pulmonary valve stenosis. Fluconazole use was associated with cleft lip with cleft palate (odds ratio = 5.53; confidence interval = 1.68-18.24) and d-transposition of the great arteries (odds ratio = 7.56; confidence interval = 1.22-35.45). CONCLUSIONS: The associations between fluconazole and both cleft lip with cleft palate and d-transposition of the great arteries are consistent with earlier published case reports but not recent epidemiologic studies. Despite the larger sample size of the National Birth Defects Prevention Study, fluconazole use was rare. Further investigation is needed in large studies, with particular emphasis on oral clefts and conotruncal heart defects.

A human homeotic transformation resulting from mutations in PLCB4 and GNAI3 causes auriculocondylar syndrome.

Auriculocondylar syndrome (ACS) is a rare, autosomal-dominant craniofacial malformation syndrome characterized by variable micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic "question-mark" ear malformation. Careful phenotypic characterization of severely affected probands in our cohort suggested the presence of a mandibular patterning defect resulting in a maxillary phenotype (i.e., homeotic transformation). We used exome sequencing of five probands and identified two novel (exclusive to the patient and/or family studied) missense mutations in PLCB4 and a shared mutation in GNAI3 in two unrelated probands. In confirmatory studies, three additional novel PLCB4 mutations were found in multigenerational ACS pedigrees. All mutations were confirmed by Sanger sequencing, were not present in more than 10,000 control chromosomes, and resulted in amino-acid substitutions located in highly conserved protein domains. Additionally, protein-structure modeling demonstrated that all ACS substitutions disrupt the catalytic sites of PLCB4 and GNAI3. We suggest that PLCB4 and GNAI3 are core signaling molecules of the endothelin-1-distal-less homeobox 5 and 6 (EDN1-DLX5/DLX6) pathway. Functional studies demonstrated a significant reduction in downstream DLX5 and DLX6 expression in ACS cases in assays using cultured osteoblasts from probands and controls. These results support the role of the previously implicated EDN1-DLX5/6 pathway in regulating mandibular specification in other species, which, when disrupted, results in a maxillary phenotype. This work defines the molecular basis of ACS as a homeotic transformation (mandible to maxilla) in humans.

Risk for cognitive deficit in a population-based sample of U.S. children with autism spectrum disorders: variation by perinatal health factors.

BACKGROUND: From 30% to 60% of children with an autism spectrum disorder (ASD) have an IQ measure that falls in the intellectual disability (ID) range. It is not well studied whether, for children within this ASD subgroup, there is variation in the risk for low IQ based on a child's perinatal risk factors. OBJECTIVE/HYPOTHESES: We assessed whether preterm delivery and term small-for-gestational-age (tSGA) were associated with various measures of cognitive deficit among children with ASDs. METHODS: A sample of 1129 singleton children born in 1994 and identified through school and health record review as having an ASD by age 8 years were selected from a U.S. population-based surveillance network. Mean IQ and dichotomous IQ outcomes indicating various levels of ID were examined according to whether a child was preterm (<37 weeks' gestation) or tSGA (term delivery and birth weight <10th percentile for gestational age of a U.S. referent). Results for the total sample and within race-ethnicity/maternal education strata were adjusted for child sex and ASD subtype classification. RESULTS: Mean IQ was significantly (p < .05) lower in children delivered preterm (69.5) than term (74.5) and tSGA (69.3) than term appropriate-for gestational age (75.3). In stratified analyses, the preterm-IQ association was significant only among non-Hispanic white (NHW) children with maternal education at birth of high school or less; adjusted mean IQ was 8 points lower among those delivered preterm (65.4) than term (73.8). Term-SGA was associated with a significant 8-point deficit in adjusted mean IQ (75.5 vs. 83.8) in NHW children with maternal education greater than high school and a 6-point deficit that approached significance (68.4 vs. 74.5, p=0.10) in NHW children with maternal education of high school or less. Non-Hispanic black children in both maternal education groups had significantly lower mean IQs than NHW children with little variation by preterm or tSGA. CONCLUSIONS: In children with ASDs, the risk for concurrent ID or IQ deficit is associated with both preterm delivery and tSGA; these associations may vary by race-ethnicity and SES. Further studies of ASD-ID co-occurrence and the effectiveness of intervention strategies should consider both perinatal and sociodemographic factors.

Advanced parental age and the risk of autism spectrum disorder.

This study evaluated independent effects of maternal and paternal age on risk of autism spectrum disorder. A case-cohort design was implemented using data from 10 US study sites participating in the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring Network. The 1994 birth cohort included 253,347 study-site births with complete parental age information. Cases included 1,251 children aged 8 years with complete parental age information from the same birth cohort and identified as having an autism spectrum disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. After adjustment for the other parent's age, birth order, maternal education, and other covariates, both maternal and paternal age were independently associated with autism (adjusted odds ratio for maternal age > or =35 vs. 25-29 years = 1.3, 95% confidence interval: 1.1, 1.6; adjusted odds ratio for paternal age > or =40 years vs. 25-29 years = 1.4, 95% confidence interval: 1.1, 1.8). Firstborn offspring of 2 older parents were 3 times more likely to develop autism than were third- or later-born offspring of mothers aged 20-34 years and fathers aged <40 years (odds ratio = 3.1, 95% confidence interval: 2.0, 4.7). The increase in autism risk with both maternal and paternal age has potential implications for public health planning and investigations of autism etiology.

Neu-Laxova syndrome: detailed prenatal diagnostic and post-mortem findings and literature review.

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.