A number sign (#) is used with this entry because of evidence that Meckel syndrome-8 (MKS8) is caused by homozygous mutation in the TCTN2 gene (613846) on chromosome 12q24. One such family has been reported.

Meckel-Gruber syndrome is a severe autosomal recessive ciliopathy classically defined by the triad of encephalocele, polydactyly, and renal and biliary ductal dysplasia. Clinical heterogeneity exists even within families (summary by Shaheen et al., 2011).

For a general phenotypic description and a discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (249000).

Shaheen et al. (2011) described a multiplex consanguineous Saudi family in which 5 individuals had Meckel-Gruber syndrome defined as the presence of encephalocele and any of the following: biliary ductal dysplasia, renal dysplasia, or polydactyly. One child died at 2 hours of age and was found to have encephalocele, polydactyly, and renal anomalies by report. A second child was delivered at 36 weeks' gestation to a 26-year-old healthy gravida-5/para-4 mother and a 31-year-old father. Antenatal ultrasound scan revealed anhydramnios, grossly enlarged echogenic kidneys, polydactyly, and encephalocele. Apgar scores were 3 and 2 at 1 and 5 minutes, respectively. Examination showed dysmorphic features consisting of occipital encephalocele, broad forehead, flat hypoplastic nose, anophthalmia, cleft lip and palate, low-set malformed ears, short neck, polydactyly of both hands and feet with equinovarus deformity, grossly distended abdomen due to bilateral renal enlargement, and normal female genitalia. She died at 30 minutes of age. A third child was born at term and by history had genital ambiguity, large encephalocele, 4-limb polydactyly, and renal anomalies; she died within 1 hour of delivery. A fourth child was diagnosed antenatally at 23 weeks' gestation with severe microcephaly, large occipital encephalocele, abnormal intracranial structures, bilateral enlarged polycystic kidneys, narrow chest, and 4-limb polydactyly. The mother was induced and the fetus was delivered dead at 24 weeks. Examination revealed severe microcephaly, microphthalmia, cleft palate, large occipital encephalocele, distended abdomen, and 4-limb polydactyly. One pregnancy was terminated at 15 weeks following the ultrasonographic finding of occipital encephalocele, bilateral polycystic kidneys, pericardial effusion, fixed lower limbs, and polydactyly.

In affected members of a consanguineous Arab family with Meckel-Gruber syndrome, Shaheen et al. (2011) identified homozygosity for a splice site mutation in the TCTN2 gene (613846.0001) that completely abolished normal splicing and created 2 aberrant transcripts. The mutation was found to segregate with disease in the family in homozygosity and was not observed in 192 ethnically matched controls.