Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3.

Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome metabolism resulting from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, although milder phenotypes are increasingly being identified. It is commonly caused by defects in the peroxisome transporter, PEX7 (RCDP1), and less frequently due to defects in the peroxisomal enzymes required to initiate plasmalogen synthesis, GNPAT (RCDP2) and AGPS (RCDP3). PEX7 transports AGPS into the peroxisome, where AGPS and GNPAT partner on the luminal membrane surface. The presence of AGPS is thought to be required for GNPAT activity. We present six additional probands with RCDP2 and RCDP3, and the novel mutations identified in them. Using cell lines from these and previously reported patients, we compared the amounts of both AGPS and GNPAT proteins present for the first time. We used protein modeling to predict the structural consequences of AGPS mutations and transcript analysis to predict consequences of GNPAT mutations, and show that milder RCDP phenotypes are likely to be associated with residual protein function. In addition, we propose that full GNPAT activity depends not only on the presence of AGPS, but also on the integrity of substrate channeling from GNPAT to AGPS.

Variation in the prevalence of congenital heart defects by maternal race/ethnicity and infant sex.

OBJECTIVE: To determine the prevalence of major congenital heart defects (CHD) by ethnicity and sex. STUDY DESIGN: Data from the Florida Birth Defects Registry was used to conduct a retrospective cohort study with 8029 singleton infants with 11 CHDs born 1998-2003 to resident non-Hispanic (NH) white, NH-black, and Hispanic women aged 15 to 49. Defect-specific prevalence rates, ratios, and 95% confidence intervals were calculated. Poisson regression was used to calculate adjusted ethnic-specific rate ratios (RR) for each CHD. Statistical significance was P < .0001. RESULTS: Compared with NH-whites, NH-black males had significantly increased rates of pulmonary valve atresia/stenosis (RR = 1.66) but lower prevalence of aortic valve atresia/stenosis (RR = 0.33) and ventricular septal defect (VSD; RR = 0.78). Hispanic males had lower rates of aortic valve atresia/stenosis (RR = 0.28), coarctation of the aorta (RR = 0.61) and VSD (RR = 0.79). NH-black females had statistically significantly lower rates of VSD (RR = 0.75), and Hispanic females had lower rates of tetralogy of Fallot (RR = 0.54), VSD (RR = 0.84) and atrioventricular septal defects (RR = 0.53) compared with NH-whites. CONCLUSIONS: We found differences in ethnic susceptibilities to CHD by sex, but the cause remains unclear.

Left outflow tract anomalies in children.

PURPOSE OF REVIEW: To provide a discussion of the current knowledge of the genetics of left outflow tract of the heart, including the aortic stenosis, in children. It addresses the available means of diagnosis for syndromic and nonsyndromic left outflow tract abnormalities and implications for at-risk family members. Options for prenatal testing and recommendations for cardiac follow-up are presented. RECENT FINDINGS: Left outflow tract cardiac anomalies in children present as a varied spectrum among and within families. Even nonsyndromic forms can be inherited in an autosomal dominant pattern. These can lead to significant complications in asymptomatic individuals, making diagnosis a challenge and underscoring the importance of evaluation of at-risk family members. SUMMARY: Improved understanding of the genetics of both syndromic and nonsyndromic left outflow tract disorders is hoped to lead to improved identification of affected children and greater ongoing cardiac follow-up for those potentially at risk.

Is the prevalence of specific types of congenital heart defects different for non-Hispanic white, non-Hispanic black and Hispanic infants?

BACKGROUND: Our purpose was to determine the prevalence of specific types of CHD among non-Hispanic (NH)-Black, NH-White, and Hispanic infants. METHODS: We conducted a retrospective cohort study with 9,352 singleton infants diagnosed with conotruncal, right or left obstructive or septal CHDs from the Florida Birth Defects Registry, born 1998-2003 to resident NH-White, NH-Black, and Hispanic women aged 15-49. Defect-specific prevalence rates, prevalence ratios and P-values were calculated for each type of CHD and by number of defects for each racial/ethnic group. RESULTS: Compared to NH-Whites, NH-Blacks had higher rates of pulmonary valve atresia/stenosis but lower frequency of aortic valve atresia/stenosis and ventricular septal defect. Hispanics had lower rates of aortic valve atresia/stenosis and atrioventricular septal defects than NH-Whites. CONCLUSIONS: Although few racial/ethnic differences in prevalence are present among infants with major CHD, observed differences are clinically meaningful. However, the underlying etiologies for the observed differences remain unknown.

Are black and Hispanic infants with specific congenital heart defects at increased risk of preterm birth?

Congenital heart defects (CHDs) are a leading cause of infant morbidity and mortality. Infants with CHDs have increased risk of preterm birth (PTB) compared to infants without birth defects. Although non-Hispanic (NH) Blacks are more likely to be born preterm and Hispanics have rates similar to those of PTB to NH-Whites, it is unknown if this pattern is present for infants with specific types of CHDs. Our intent was to determine if defect-specific risk of PTB varies by maternal race/ethnicity among infants with CHDs. We conducted a retrospective cohort study with 14,888 singleton infants from the Florida Birth Defects Registry, born in 1998-2003 to resident NH-White, NH-Black, and Hispanic women aged 15-49, diagnosed with 11 CHDs. Covariates were taken from Florida live birth certificates. PTB was defined as 20-36 weeks of gestation. Odds ratios (OR) and P-values were calculated from defect-specific multivariable logistic regression models; statistical significance was set at P < 0.002. The greatest risk of PTB was for NH-Black infants with conotruncal CHDs. NH-Blacks with common truncus, transposition of the great vessels, and tetralogy of Fallot had increased risk of PTB compared to NH-Whites (OR = 4.8, P = 0.015; OR = 3.1, P = 0.004; and OR = 2.0, P = 0.005, respectively). Hispanics with conotruncal CHDs had almost a twofold risk of PTB compared to NH-Whites (P > 0.002). NH-Blacks with tricuspid valve atresia/stenosis had 4.1 times (P = 0.034) and Hispanics had 2.1 times (P = 0.314) the risk for PTB compared to NH-Whites. NH-Blacks with hypoplastic left heart syndrome had 2.0 times (P = 0.047) the risk for PTB as NH-Whites. Both NH-Black and Hispanic infants with CHDs may be at increased risk of PTB, depending on the type of CHD, but the etiology is unknown. Future research is needed to further examine this complex relationship.

A patient with an interstitial duplication of chromosome 5p11-p13.3 further confirming a critical region for 5p duplication syndrome.

Partial or complete trisomy 5p has been associated with characteristic facial features, developmental delay, seizures, congenital heart defects, and respiratory compromise. We present a child with developmental delay, seizures, and congenital cardiac anomalies found to have a previously unreported de novo interstitial duplication of chromosome 5p, 46,XX,dup(5) (p11p13.3). The breakpoints of the duplication were further confirmed by fluorescence in situ hybridization analysis using bacterial artificial chromosome probes specific for the affected region. Comparison with previously reported cases of patients with duplications of 5p suggests loci of interest for both congenital heart anomalies and seizures.

Fetal growth among infants with congenital heart defects by maternal race/ethnicity.

PURPOSE: Congenital heart defects (CHDs) are the most prevalent birth defects. Infants with CHDs more often are small-for-gestational age (SGA) than infants without CHD; however, little is known about racial/ethnic variations in prevalence of SGA or large-for-gestational age (LGA) for infants born with CHDs. This study determined the risk of SGA and LGA for non-Hispanic (NH)-black and Hispanic infants with CHDs. METHODS: Data from the Florida Birth Defects Registry were used in a retrospective cohort study of 10,027 live-born infants to resident NH-White, NH-Black, and Hispanic women ages 15-49 years from January 1, 1998, to December 31, 2003, and diagnosed with 11 CHDs. Defect-specific odds ratios and 95% confidence intervals were computed for risk of SGA and LGA by race/ethnicity and adjusted for covariates using multinomial logistic regression. RESULTS: After adjusting for covariates, we found there were no statistically significant racial/ethnic differences in risk of SGA. However, NH-Blacks with ventricular septal defect had increased risk of LGA and NH-Blacks with tetralogy of Fallot had decreased risk of LGA compared to NH-Whites. CONCLUSIONS: Very few racial/ethnic differences in fetal growth are present among infants with CHD. Further elucidation of the factors involved in fetal growth and the impact of CHD itself on fetal development is needed.

Familial thoracic aortic dilation and bicommissural aortic valve: a prospective analysis of natural history and inheritance.

The autosomal dominant inheritance of bicommissural aortic valve (BAV) (Online Mendelian Inheritance in Man #109730) in some families is well-documented; however, the inheritance of BAV with thoracic aortic aneurysm (TAA) is less clear. Whether the aneurysm is secondary to hemodynamic perturbation related to the valve abnormality or a primary manifestation of the disorder remains controversial. Guidelines are needed regarding the follow-up and treatment of these patients and their families. Thirteen families with at least one individual with TAA and BAV (BAV/TAA) were evaluated prospectively by standard echocardiographic methods or clinical history. Affected status was determined by the presence of BAV or TAA or a history of dissection, rupture, or surgical repair. Six of 13 families had at least two family members with both BAV and TAA, often in successive generations. Informatively, all 13 families had at least one family member with TAA in the absence of BAV. Thirty-five percent (39/110) of family members had BAV/TAA or TAA, and the majority of families (11/13) had maximal dilatation above the sinotubular junction (STJ). Vascular dissection or rupture occurred in seven of 13 families and in individuals with structurally normal aortic valves. Two families had non-manifesting, obligate carriers. Three families have members with other left heart outflow tract anomalies. This study confirms autosomal dominant inheritance with incomplete penetrance for BAV/TAA in these families. Furthermore, our data suggest that the component features, BAV and TAA, are independent manifestations of a single gene defect. To avoid the risk of early death, it is essential that all first-degree relatives receive echocardiographic follow-up at regular intervals regardless of the presence or absence of a BAV. This assessment must include imaging of the aortic region above the STJ.

Association between fetal lymphedema and congenital cardiovascular defects in Turner syndrome.

OBJECTIVES: Turner syndrome (TS) is associated with congenital cardiovascular defects (CCVDs), most commonly bicuspid aortic valve (BAV) and aortic coarctation (COARC), congenital renal anomalies, and fetal lymphedema. It has been theorized that compressive or obstructive effects of fetal lymphedema may actually cause cardiovascular and renal dysmorphogenesis in TS. The objective of this study was to determine whether there is a specific association between a history of fetal lymphedema and CCVDs in monosomy X, or TS, independent of karyotype or general severity of the phenotype. METHODS: This was a prospective study of 134 girls and women who have TS (mean age: 30 years) and were clinically evaluated for evidence of fetal lymphedema, classified as central (signified by the presence of neck webbing) or peripheral (current or perinatal, or dysplastic fingernails). The presence of BAV and/or COARC was detected by magnetic resonance imaging combined with echocardiography, and renal anomalies were determined by ultrasound. RESULTS: There is a strong association between developmental central lymphedema, signified by neck webbing, and the presence of BAV (chi2 = 10) and COARC (chi2 = 8). The association between webbed neck and CCVDs was independent of karyotype. There was, in contrast, no significant association between renal anomalies and webbed neck or CCVDs. CONCLUSIONS: The strong, statistically significant association between neck webbing and the presence of BAV and COARC in TS suggests a pathogenetic connection between fetal lymphatic obstruction and defective aortic development. The presence of neck webbing in TS should alert the clinician to the possibility of congenital cardiovascular defects.