Omphalocele, Autosomal

A number sign (#) is used with this entry because of evidence that isolated omphalocele can be caused by duplication of genes on chromosome 1p31.

Description

An omphalocele is an abdominal wall defect limited to an open umbilical ring, and is characterized by the herniation of membrane-covered internal organs into the open base of the umbilical cord. Omphalocele is distinguished from gastroschisis (230750), in which the abdominal wall defect is located laterally to a normally closed umbilical ring with herniation of organs that are uncovered by membranes (summary by Bugge, 2010). On the basis of clinical manifestations, epidemiologic characteristics, and the presence of additional malformations, Yang et al. (1992) concluded that omphalocele and gastroschisis are casually and pathogenetically distinct abdominal wall defects.

Omphalocele can be a feature of genetic disorders, such as Beckwith-Wiedemann syndrome (130650) and the Shprintzen-Goldberg syndrome (182210).

Clinical Features

DiLiberti (1982) reported a family with multiple cases of omphalocele and abdominal wall hernias in an apparent autosomal dominant pedigree pattern. Males in 3 successive generations had umbilical hernia, sometimes with inguinal hernia, and 2 girls in the most recent (fourth) generation had omphalocele. DiLiberti (1982) provided a review of the literature and noted that cases of familial omphalocele had a much lower incidence of associated nongastrointestinal malformation than did sporadic cases.

Pryde et al. (1992) described a woman in which infants born of each of 5 consecutive pregnancies (by 2 separate nonconsanguineous partners) were complicated by omphalocele as an isolated defect. Neither the woman nor her partners had a history of relatives with omphalocele, although the woman's brother and his son had 'large umbilical hernia' requiring repair in infancy. One of the 5 pregnancies resulted in spontaneous abortion at 16 weeks. The other 4 were associated with precocious labor and prematurity, with the longest survival being 5 months.

Inheritance

Familial occurrence of omphalocele has been reported. Osuna and Lindham (1976) reported 4 cases of isolated omphalocele in 2 generations of a family. Rott and Truckenbrodt (1974) observed uncomplicated omphalocele in a brother and sister. Kapur et al. (1980) described omphalocele in half sibs, a boy and girl born to unrelated mothers and a phenotypically normal father. They concluded that this malformation, when independent of other abnormalities, is probably multifactorial. Lurie and Ilyina (1984) reported 3 cases of familial omphalocele and noted that recurrence risk is likely lower than that seen in their series as it is based on families referred for genetic counseling.

Based on data from the Hungarian Congenital Malformation Register between 1970 and 1976, Czeizel (1979) reported that after isolated omphalocele the recurrence risk in families is less than 1%. Based on epidemiologic reports, Lowry and Baird (1982) concluded that the recurrence risk in families is extremely low.

Using a population-based analysis of 82 cases of omphalocele, Yang et al. (1992) concluded that an autosomal recessive pattern of inheritance could be applied to families with isolated omphalocele. However, for families of infants with multiple defects, a sporadic or nongenetic model fit best.

Kanagawa et al. (2002) reported a family with 9 individuals over 3 generations affected with an omphalocele requiring surgical intervention within the first few days of life. Because of the vertical transmission and male-to-male inheritance, the authors concluded that an autosomal dominant gene was responsible.

Population Genetics

Calzolari et al. (1995) reported that a total of 732 cases of omphalocele and 274 cases of gastroschisis (230750) were registered in 21 regional registers in Europe (EUROCAT registers) during the period 1980 to 1990. The total prevalence rates were 2.52 per 10,000 and 0.94 per 10,000, respectively. There was significant geographic heterogeneity in the prevalence rates. Consistently higher than average rates of omphalocele were found in the 5 centers in the British Isles. This was in large part the result of the association between omphalocele and neural tube defects. They observed a significant female excess among the cases of omphalocele associated with neural tube defects, in comparison with an insignificant male excess for other cases of omphalocele. Geographic differences in the prevalence of gastroschisis was partly explained by differences in maternal age distributions in the populations surveyed. Omphalocele was an isolated malformation in 46% of cases; gastroschisis was isolated in 79% of cases. Prenatal diagnosis leading to termination of pregnancy was reported in 33.2% of omphalocele and in 26.5% of gastroschisis cases, demonstrating the considerable impact of prenatal screening programs during the period of observation. On the basis of clinical manifestations, epidemiologic considerations, and the presence and type of additional malformations, both omphalocele and gastroschisis could be considered heterogeneous conditions.

From a population-based registry covering 2 decades (1970 to 1989) in Denmark, Bugge (2010) identified 7 pairs of twins with omphalocele in at least 1 twin. There were 2 monozygotic (MZ), 2 dizygotic (DZ), and 3 same-sex pairs of unknown zygosity. All pairs were discordant for omphalocele except for a pair of conjoined twins. The 8 infants with omphalocele represented 3.1% of the 253 infants from the registry with omphalocele. Three infants had isolated omphalocele, and 5 had omphalocele with associated congenital malformations. The occurrence of twins with omphalocele was not significantly different from the occurrence of twins in the Danish population in the same period, but the study was too small to allow other conclusions for the role of genetic factors in omphalocele.

Cytogenetics

Yatsenko et al. (2003) observed a patient with omphalocele, dysmorphic features, and mild developmental delay associated with a chromosomal aberration. The propositus carried a maternally derived unbalanced translocation resulting in trisomy for region 3q27.3-qter and monosomy for 4q32.3-qter. Because the association between dup3q and omphalocele had been reported in several instances, Yatsenko et al. (2003) analyzed the data on 93 previously reported patients with partial trisomy for the long arm of chromosome 3. The imbalance of chromosome 3 in their patient was further defined by FISH using bacterial artificial chromosome (BAC) clones. A specific BAC clone was identified as spanning the breakpoint in the patient and his mother. Based on comparative analysis, they defined the smallest region of overlap (SRO) associated with omphalocele to be between the breakpoint-identifying BAC clone and 3qter. Yatsenko et al. (2003) hypothesized that this SRO contains a gene or genes important in normal abdominal wall development and is worthy of further investigation.

Mapping

In a 5-generation family, previously reported by Kanagawa et al. (2002), in which 9 members over 3 generations had isolated omphalocele, Radhakrishna et al. (2012) performed a genomewide linkage scan and found significant evidence of linkage at marker rs937805 on chromosome 1p31.3 (p = 0.0001). Eleven SNP markers spanning a 2.74-Mb region showed nonparametric lod scores of 6.9. Haplotype analysis and recombination events defined the 2.74-Mb omphalocele candidate region, flanked by rs2886770 proximally and by rs1343981 distally.

Molecular Genetics

Using oligonucleotide microsphere hybridization in a 5-generation family in which 9 members over 3 generations had isolated omphalocele mapping to chromosome 1p31, Radhakrishna et al. (2012) identified an approximately 710-kb duplication at 1p31.3, with the proximal border at 63.5 Mb, proximal to the FOXD3 gene (611539), and the distal border within the ROR1 gene (602336). The duplication was present in all 8 available affected individuals but was absent in 2 unaffected family members. Multipoint linkage analysis using the duplication as a marker yielded a maximum lod score of 3.2 at 1p31.3 under a dominant model; the best-fitted parametric model was a dominant model with 99% penetrance and a disease-allele frequency of 0.0001. The duplicated region contained 7 genes: FOXD3, ALG6 (604566), ITGB3BP (605494), PGM1 (171900), DLEU2L, KIAA1799, and ROR1.