Infants with Bochdalek diaphragmatic hernia: Sibling precurrence and monozygotic twin discordance in a hospital‐based malformation surveillance program

Abstract

Congenital diaphragmatic hernia (CDH) is a common and often devastating birth defect. In order to learn more about possible genetic causes, we reviewed and classified 203 cases of the Bochdalek hernia type identified through the Brigham and Women's Hospital (BWH) Active Malformation Surveillance Program over a 28-year period. Phenotypically, 55% of the cases had isolated CDH, and 45% had complex CDH defined as CDH in association with additional major malformations or as part of a syndrome. When classified according to likely etiology, 17% had a Recognized Genetic etiology for their CDH, while the remaining 83% had No Apparent Genetic etiology. Detailed analysis using this largest cohort of consecutively collected cases of CDH showed low precurrence among siblings. Additionally, there was no concordance for CDH among five monozygotic twin pairs. These findings, in conjunction with previous reports of de novo dominant mutations in patients with CDH, suggest that new mutations may be an important mechanism responsible for CDH. The twin data also raise the possibility that epigenetic abnormalities contribute to the development of CDH.

Candidate genes for congenital diaphragmatic hernia from animal models: sequencing of FOG2 and PDGFRα reveals rare variants in diaphragmatic hernia patients

“…2 CDH can occur as an isolated birth defect (isolated CDH) or it can be associated with additional physical anomalies (CDH with additional anomalies or non-isolated CDH), either with or without a recognizable underlying genetic syndrome. 3 In both types of CDH, there is substantial evidence implicating genetic factors in pathogenesis and for genetic heterogeneity, 4 but there are little data on the causative genes to date. In humans, only one mutation has been demonstrated, occurring in the FOG2 gene in a female patient with posterior diaphragmatic eventration.…”

Genetics of Congenital Diaphragmatic Hernia

“…Those defects include dextroposition of the heart, a small compressed heart, tricuspid or mitral valve regurgitation, pulmonary hypoplasia, a patent foramen ovale or ductus arteriosus, malrotation or incomplete rotation of bowel, undescended testes and accessory spleen (Pober, 2008). The recurrence risk of isolated CDH in an sibling is 1-2% (Czeizel & Kovacs, 1985;Pober et al, 2005).…”

“…Findings in the literature show that the majority of monozygotic twin pairs described in case reports or as part of a small series are concordant for CDH (Abe et al, 2001;Chao et al, 1997;Eichelberger et al, 1980;Gallot et al, 2003;Gencik et al, 1982;Gibbs et al, 1997;Lucas Talan et al, 1998;Machado et al, ;Mishalany & Gordo, 1986;Watanatittan, 1983). In contrast, most twin pairs reported as part of a consecutive series are discordant (David & Illingworth, 1976;Jancelewicz et al, 2010;Pober et al, 2005;Robert et al, 1997;Tonks et al, 2004;Torfs et al, 1992). Pober and coworkes hypothesized that there is overreporting of concordantly affected twins in case reports and that CDH, even though it can be present in both members of a monozygous twin pair, it more frequently affects only one.…”

Copy number detection in discordant monozygotic twins of Congenital Diaphragmatic Hernia (CDH) and Esophageal Atresia (EA) cohorts

“…In the literature, 77 twin pairs have been described for CDH of which 53 were recognized as MZ. [17][18][19][20] Twelve pairs were concordant for the CDH phenotype.…”