Array-based molecular karyotyping in 115 VATER/VACTERL and VATER/VACTERL-like patients identifies disease-causing copy number variations.

BACKGROUND: The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CF): vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia, renal malformations (R), and limb defects (L). Patients presenting with at least three CFs are diagnosed as having VATER/VACTERL association while patients presenting with only two CFs are diagnosed as having VATER/VACTERL-like phenotypes. Recently, rare causative copy number variations (CNVs) have been identified in patients with VATER/VACTERL association and VATER/VACTERL-like phenotypes. METHODS: To detect further causative CNVs we performed array based molecular karyotyping in 75 VATER/VACTERL and 40 VATER/VACTERL-like patients. RESULTS: Following the application of stringent filter criteria, we identified 13 microdeletions and seven microduplications in 20 unrelated patients all of which were absent in 1,307 healthy inhouse controls (n < 0.0008). Among these, microdeletion at 17q12 was confirmed to be de novo. Three microdeletions at 5q23.1, 16q23.3, 22q11.21, and one microduplication at 10q11.21 were all absent in the available parent. Microdeletion of chromosomal region 22q11.21 was previously found in VATER/VACTERL patients rendering it to be causative in our patient. The remaining 15 CNVs were inherited from a healthy parent. CONCLUSION: In two of 115 patients' causative CNVs were found (2%). The remaining identified rare CNVs represent candidates for further evaluation. Rare inherited CNVs may constitute modifiers of, or contributors to, multifactorial VATER/VACTERL or VATER/VACTERL-like phenotypes. Birth Defects Research 109:1063-1069, 2017. © 2017 Wiley Periodicals, Inc.

Prenatal Diagnosis and Evaluation of Sonographic Predictors for Intervention and Adverse Outcome in Congenital Pulmonary Airway Malformation.

OBJECTIVE: To describe antenatal findings and evaluate prenatal risk parameters for adverse outcome or need for intervention in fetuses with congenital pulmonary airway malformation (CPAM). METHODS: In our retrospective study all fetuses with a prenatal diagnosis of CPAM detected in our tertiary referral center between 2002 and 2013 were analyzed. Sonographic findings were noted and measurements of mass-to-thorax-ratio (MTR), congenital pulmonary airway malformation volume-ratio (CVR) and observed to expected lung-to head-ratio (o/e LHR) were conducted and correlated to fetal or neonatal morbidity and mortality and/or need for prenatal intervention. RESULTS: 67 fetuses with CPAM were included in the study. Hydropic fetuses were observed in 16.4% (11/67) of cases, prenatal intervention was undertaken in 9 cases; 7 pregnancies were terminated. The survival rate of non-hydropic fetuses with conservatively managed CPAM was 98.0% (50/51), the survival rate for hydropic fetuses with intention to treat was 42.9% (3/7). 10 (18.2%) children needed respiratory assistance. Fetuses with a CVR of <0.91 were significantly less likely to experience adverse outcome or need for prenatal intervention with sensitivity, specificity and positive/negative predictive value of 0.89, 0.71, 0.62 and 0.93, respectively. A MTR (mass-to-thorax-ratio) of < 0.51 had a positive predictive value of 0.54 and a negative predictive value of 0.96 of adverse events with a sensitivity of 0.95 and a specificity of 0.63. The negative predictive value for o/e LHR of 45% was 0.84 with sensitivity, specificity and positive predictive value of 0.73, 0.68 and 0.52, respectively. CONCLUSIONS: The majority of cases with CPAM have a favorable outcome. MTR and CVR are able to identify fetuses at risk, the o/e LHR is less sensitive.

Second study on the recurrence risk of isolated esophageal atresia with or without trachea-esophageal fistula among first-degree relatives: no evidence for increased risk of recurrence of EA/TEF or for malformations of the VATER/VACTERL association spectrum.

BACKGROUND: Esophageal atresia with/without trachea-esophageal fistula (EA/TEF) denotes a spectrum of severe congenital malformations. The aim of this systematic study was to determine both the recurrence risk for EA/TEF, and the risk for malformations of the VATER/VACTERL association spectrum, in first-degree relatives of patients with isolated EA/TEF. METHODS: A total of 108 unrelated patients with isolated EA/TEF were included. These individuals had 410 first-degree relatives including 194 siblings. The presence of EA/TEF and malformations of the VATER/VACTERL association spectrum in relatives was systematically assessed. Data from the EUROCAT network were used for comparison. RESULTS: None of the first-degree relatives displayed any form of EA/TEF. In two families, a first-degree relative presented with malformations from the VATER/VACTERL association spectrum. However, no increase in the risk for malformations of the VATER/VACTERL association spectrum was found compared with the control cohort (p = 0.87). In three families, one more distantly related relative presented with EA/TEF. CONCLUSION: In contrast to previous studies, our results suggest a very low recurrence risk for isolated EA/TEF and/or for malformations of the VATER/VACTERL association spectrum among first-degree relatives.

Nine new twin pairs with esophageal atresia: a review of the literature and performance of a twin study of the disorder.

BACKGROUND: Isolated esophageal atresia (EA) is a rare congenital malformation whose etiology remains largely unknown. Nine twin pairs with EA were identified from our clinical service, prompting the performance of a systematic review of the literature and the first reported twin study of isolated EA. METHODS: A total of 330 twin pairs with EA were identified from the literature. The zygosity, concordance, and malformation (isolated vs. nonisolated) status of all 339 twin pairs were evaluated. A total of 72 twin pairs (4 of 9 / 68 of 330) fulfilled the criteria for inclusion in a classic twin study of isolated EA. RESULTS: The pairwise concordance rates were 50% (95% confidence interval [CI], 34-66%) for monozygous (MZ) twin pairs and 26% (95% CI, 15-42%) for dizygous (DZ) twin pairs (p = 0.033). The probandwise concordance rates were 67% (95% CI, 53-78%) for MZ twin pairs and 42% (95% CI, 29-56%) for DZ twin pairs (p = 0.011). The MZ/DZ ratios were 1.9 for pairwise analysis and 1.6 for probandwise analysis. The familial risk ratios for MZ and DZ twin pairs were 1700 and 900, respectively. CONCLUSION: The observation of higher concordance rates for MZ compared to DZ twin pairs indicates that genetic factors contribute to isolated EA.

Esophageal atresia and severe respiratory failure--cuffed pediatric tracheal tubes as an additional therapeutic option?

This article describes the use of a cuffed pediatric endotracheal tube occluding selectively the air leakage resulting from tracheoesophageal fistula in a preterm neonate with esophageal atresia and severe respiratory failure due to respiratory distress syndrome. The gastric distension resolved completely within 4 hours. Surgical correction was performed on the third day of life after respiratory stabilization.