Oesophageal atresia, related malformations, and medical problems: A family study

Abstract

Oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) are life-threatening malformations of generally undefined cause. Previous reports of familial cases suggest a genetic contribution. The pattern of inheritance appears non-Mendelian, i.e., multifactorial. Individuals with OA/TOF often have other malformations and medical problems. The aim of this study was to determine the association in OA/TOF cases and healthy control subjects of associated malformations, midline defects, and medical conditions. We also investigate the relationships of these conditions in the relatives of the cases and controls. The results show that infants with OA/TOF frequently have VACTERL anomalies (vertebral, 17%; anal, 12%; cardiac, 20%; renal, 16%; limb, 10%) and other midline defects (cleft lip and palate, 2%; sacral dysgenesis, 2%; urogenital anomalies, 5%). The following medical problems were also reported: oesophageal dysmotility, 21%; gastro-oesophageal reflux, 22%; chest infections, 6%; and autonomic dysfunction, 0.5%. The first-degree relatives of children with OA are much more likely to have one of the aforementioned malformations or medical conditions when compared with the control group: one or more VACTERL anomalies (P < 0.01), gastro-oesophageal reflux (P < 0.05), recurrent respiratory infections (P < 0.05), and autonomic dysfunction (P < 0.001). The more distant relatives also show an increased incidence of such problems although in this case the data must be viewed with caution. The results confirm that the associated malformations and related medical problems occur significantly more frequently in the relatives of individuals with OA/TOF. These families may prove valuable for linkage analysis in an attempt to determine the genetics of OA/TOF.

Esophageal atresia

“…Brown et al [13] carried out a study to determine the incidence of at least one component of the VACTERL (vertebral defects, imperforate anus, tracheoesophageal fistula, and radial and renal dysplasia; see below) association among first-degree relations of patients with esophageal atresia. Of 1700 families contacted, 579 (34%) responded (from the Tracheoesophageal Fistula Support Group and KEKS-the German equivalent).…”

Genetic players in esophageal atresia and tracheoesophageal fistula

“…Recurrence of VACTERL association (vertebral anomalies, anal atresia, cardiac defects, TEF, radial anomalies and limb defects) in a family is extremely rare and it is reasonable to assume that this is normally a nongenetic condition. However, one recent study found that firstdegree relatives of children with EA were more likely to have one or more VACTERL anomalies, implying possible genetic predisposition [5]. Analysis of mouse models suggests that defects of either sonic hedgehog (shh) or GLI signaling might cause VACTERL-type abnormalities [6].…”

Genetics of gastrointestinal atresias

“…The most common are the trisomies and in particular trisomy 13, 18 and 21 mosaic trisomy 8 and triploidy (Beasley et al, 1997;Bianca et al, 2002;Brown et al, 1999;Brunner and van Bokhoven, 2005;DePaepe et al, 1993;Robert et al, 1993;Shaw-Smith, 2006;Torfs et al, 1995;Warren et al, 1979). EA is also found in patients with chromosomal deletions such as 17q22-q23.3, 22q11 and rarely 12q24.3, 13q13-qter 16q24.1, and 5p deletions (Digilio et al, 1999;Doray et al, 2002;Marsh et al, 2000;POSSUM, 2004;Stankiewicz et al, 2009).…”

“…Recurrence of VACTERL association in families is extremely rare, and it is reasonable to assume that it is normally a non-genetic condition. Results from a family study have shown that first degree relatives of children with EA are more likely to have one or more of the VACTERL association anomalies, implying a possible genetic cause (Brown et al, 1999). Several genetic disorders show similar phenotypes (e.g.…”