VACTERL is an acronym for vertebral anomalies (similar to those of spondylocostal dysplasia), anal atresia, cardiac malformations, tracheoesophageal fistula, renal anomalies (urethral atresia with hydronephrosis), and limb anomalies (hexadactyly, humeral hypoplasia, radial aplasia, and proximally placed thumb; see ... VACTERL is an acronym for vertebral anomalies (similar to those of spondylocostal dysplasia), anal atresia, cardiac malformations, tracheoesophageal fistula, renal anomalies (urethral atresia with hydronephrosis), and limb anomalies (hexadactyly, humeral hypoplasia, radial aplasia, and proximally placed thumb; see 192350). Some patients may have hydrocephalus, which is referred to as VACTERL-H (Briard et al., 1984).
Froster et al. (1996) suggested possible X-linked inheritance in the cases of 2 brothers with VACTERL and hydrocephalus. They described for the first time an additional feature of branchial arch defects. The parents were of average age and ... Froster et al. (1996) suggested possible X-linked inheritance in the cases of 2 brothers with VACTERL and hydrocephalus. They described for the first time an additional feature of branchial arch defects. The parents were of average age and unrelated. The first infant with multiple congenital anomalies noted at birth died at the age of 7 weeks. There were bilateral auricular malformation with atresia of the external auditory canal, dolichocephaly, cleft palate, hypertelorism, prominent philtrum, thin lips, retrognathia, and a short broad neck. There was bilateral radial aplasia with only 2 rays but a rudimentary thumb on the right hand; anal atresia (surgically corrected after birth), malrotation of the bowel; a bronchogenic cyst of the esophagus directly above the esophageal hiatus of the diaphragm, and incomplete lung lobation; agenesis of the pancreas, absence of the right kidney and a dysplastic double kidney on the left side, and a subaortic ventricular septal defect with a dextroverted aorta (Eisenmenger complex). There was internal hydrocephalus with thinning of the cortex and partial agenesis of the corpus callosum. The second affected sib was shown by prenatal ultrasound to have multiple defects, including bilateral radial agenesis and hydrocephalus. Termination of pregnancy at 24 weeks showed absence of the radii with short thumbs, defects of the third ray on both hands, malformed auricles with microtia on the right, and atresia of the ear canal. Autopsy findings included a hypoplastic pancreas, incomplete lung lobation, arteria lusoria, and agenesis of corpus callosum with hydrocephalus, without signs of Arnold-Chiari malformation. Both kidneys and the heart were normal. Lomas et al. (1998) reported a family with 4 affected males with symmetric radial ray abnormalities, renal anomalies, anal atresia, hypoplastic penis/abnormal testes, and cardiac abnormalities. They also had hydrocephalus due to aqueductal stenosis. One maternal female cousin of affected males had severe tracheoesophageal fistula, which may have represented partial manifestation in a female carrier. Chromosomes were apparently normal 46,XY with no spontaneous or excess induced breakages in one of the affected offspring and his mother. A confident ultrasonographic diagnosis was possible by 20 weeks in 2 cases in which testing was done. Wessels et al. (2010) reported a male infant with VACTERL association. He was born with anal atresia, laryngeal and esophageal atresia with tracheoesophageal fistula, dextroposition of the heart with persistent left superior vena cava, and unilateral multicystic kidney. Limb defects and hydrocephalus were not noted. He died 1 hour after birth. Wessels et al. (2010) noted the phenotypic overlap with X-linked heterotaxy (306955) caused by ZIC3 mutations. Chung et al. (2011) reported a 4-generation Italian family with X-linked recessive inheritance of clinical features overlapping both VACTERL-H and X-linked heterotaxy (HTX1; 306955). The proband was an asymptomatic woman who had abnormal fetal ultrasound necessitating termination at 23.2 weeks' gestation. The male fetus had complex cardiac anomalies, including atrial isomerism, atrioventricular septal defect, double-outlet right ventricle, transposition of the great arteries, and subvalvular pulmonary stenosis. He also had enlarged kidneys, imperforate anus, right-sided stomach and pancreas, bilateral trilobed lungs, and asplenia, consistent with heterotaxy. Neuropathology was normal. Family history revealed that 2 brothers of the proband had died soon after birth. Both had imperforate anus, and postmortem examination of 1 showed hydrocephalus, vertebral defects, limb deformities, fused kidneys, complex cardiac anomalies, and duplication of the descending colon. The brother of the maternal great-grandmother reportedly had imperforate anus and other abnormalities and died soon after birth. The proband also had a 3-year-old daughter with small ventricular septal defect that did not require surgery.
In a male infant with VACTERL association, Wessels et al. (2010) identified a de novo 6-bp in-frame insertion in exon 1 of the ZIC3 gene (300265.0010), resulting in the addition of 2 alanines within a polyalanine repeat. ... In a male infant with VACTERL association, Wessels et al. (2010) identified a de novo 6-bp in-frame insertion in exon 1 of the ZIC3 gene (300265.0010), resulting in the addition of 2 alanines within a polyalanine repeat. In a family in which affected males had a clinical phenotype ranging from VACTERL-H to X-linked heterotaxy, Chung et al. (2011) identified a 1.3-Mb deletion of chromosome Xq26.3 including the ZIC3 gene. The female proband, her mother, sister, grandmother, and daughter also carried the mutation. None of the females were affected, except perhaps the daughter, who had a small ventricular septal defect. The report demonstrated the wide intrafamilial phenotypic variability resulting from ZIC3 mutations.