Congenital omphalocele and cleft palate in two fetuses

Abstract

An omphalocele is described as a midline defect in the anterior abdominal wall through which abdominal viscera herniates into the base of the umbilical cord. The birth prevalence of omphalocele has been reported to be 1.2 to 2.7 per 10 000 live births (Marshall et al. 2015). Omphalocele occurs either as an isolated malformation or in association with other defects. However, co-occurrence of omphalocele and cleft palate has been previously described only once in the literature (Czeizel 1983). We herein report two unrelated fetuses born to non-consanguineous parents with omphalocele and cleft palate reinforcing the existence of omphalocele-cleft palate syndrome. Two primigravida were referred at about 12 weeks of gestation with antenatal ultrasound showing an abdominal wall defect. Both were in a non-consanguineous marriage and no significant family history was noted. Ultrasonography in case 1 disclosed herniation of abdominal contents, liver and stomach bubble outside the abdominal wall suggestive of omphalocele (Fig. 1b) and in case 2 showed the presence of omphalocele containing intestinal loops covered with a membrane. The umbilical cord was seen attached on the top of the sac in both cases. The couples opted for medical termination of pregnancy after counseling. A detailed autopsy was carried out for both fetuses. The study has approval of institutional ethics committee. Case 1 was a male fetus and on external examination showed retrognathia (Fig. 1a) and cleft soft palate with cleft uvula (Fig. 1c). Omphalocele (Fig. 1a) with liver, stomach, spleen, pancreas, small intestine and part of the large intestine as its contents was seen. Radiographs and karyotype of the fetus were normal. Case 2, also a male fetus was aborted at about 15 weeks of gestation. Examination showed unilateral cleft lip (Fig. 1e) on right side and complete cleft palate (Fig. 1f). Omphalocele was noted with bowel loops (part of jejunum, ileum and colon) as its contents (Fig. 1d). There was bilateral congenital talipes equinovarus (Fig. 1d) in the fetus. Radiographs of the fetus were normal. Fetal karyotype could not be obtained. However, karyotypes of the parents were normal. Association of omphalocele with cleft palate has previously been reported as omphalocele-cleft palate syndrome, lethal (OMIM 258320) in three siblings of normal unrelated parents (Czeizel 1983). One of the siblings had omphalocele, posterior cleft palate and uterus bicornuatus; the second had omphalocele, cleft uvula and hydrocephalus and the third had omphalocele and cleft palate. They died at the age of 2 months, 4 months and at 1 year, respectively. Chromosomal abnormalities in antenatally detected cases of omphalocele vary from 22% in isolated cases to more than 80% in the presence of associated abnormalities (De Veciana et al. 1994). Abnormal chromosomes mainly trisomy 13 and trisomy 18 have been observed in 20% to 50% of cases of omphalocele (Havalad et al. 1979). The various known syndromes with omphalocele and cleft palate include Beckwith-Wiedemann syndrome, thoracoabdominal syndrome (Pentalogy of Cantrell), otopalatodigital syndrome, hydrolethalus syndrome and Pallister-Killian syndrome. It has also been infrequently described in cases of midline defects like holoprosencephaly. Few mechanisms have been elucidated recently that provide a likely explanation for the co-occurrence of omphalocele and cleft palate. Dysregulation Hedgehog (Hh) signaling pathway is known to cause digital, urogenital, brain and craniofacial anomalies including cleft palate. Recently, the involvement of ectopic SHH signaling in ventral body wall malformation has been demonstrated in mouse mutants (Matsumaru et al. 2011). Another evidence for co-occurrence of these two malformations comes from a recent GAD65/GAD67 double knockout mouse model (Kakizaki et al. 2015). It has been shown that double knockout mice for glutamate decarboxylase (GAD65 and GAD67), the GABA-synthesizing enzymes, and their transporter, vesicular GABA transporter (VGAT) has almost 100% incidence of omphalocele and cleft palate, suggesting that GABAergic transmission is involved in palate and abdominal wall formation. Mutational analysis for these genes could not be done in both fetuses due to non-availability of preserved tissue. Reports of the above two cases of co-occurrence of omphalocele and cleft palate raise the possibility of a new syndrome. However, further delineation of cases and unraveling of the genetic basis is warranted for this disorder. The authors are grateful to the patients for consenting to participate in the study. The work was supported by a grant from Indian Council of Medical Research (BMS No. 54/5/2010). None