Meckel Syndrome, Type 7

A number sign (#) is used with this entry because of evidence that Meckel syndrome type 7 (MKS7) is caused by homozygous mutation in the NPHP3 gene (608002) on chromosome 3q22.

Description

This autosomal recessive disorder is designated Meckel syndrome type 7 based on the classic phenotypic triad of (1) cystic renal disease; (2) a central nervous system abnormality, and (3) hepatic abnormalities, as defined by Meckel (1822), Salonen (1984), and Logan et al. (2011). According to these criteria, polydactyly is a variable feature.

Herriot et al. (1991) and Al-Gazali et al. (1996) concluded that Dandy-Walker malformation can be the phenotypic manifestation of a central nervous system malformation in MKS.

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

Clinical Features

Goldston et al. (1963) reported 3 neonate sibs with cystic renal dysplasia, 2 of whom also had Dandy-Walker malformation. Liver and pancreatic abnormalities were not reported (Hunter et al., 1991).

Kudo et al. (1985) reported 2 unrelated premature infants with Dandy-Walker malformation, congenital hepatic fibrosis, and generalized cystic dysplastic kidneys. The authors noted that similar renal lesions had been reported in Meckel syndrome and Goldston syndrome, but suggested a distinction from Meckel syndrome due to the presence of Dandy-Walker malformation and the absence of polydactyly and occipital meningoencephalocele. However, the cases did resemble Goldston syndrome.

Gloeb et al. (1989) reported a 17-week-old fetus with marked dilatation of the fourth ventricle and cystic renal dysplasia. Postmortem examination showed evidence of the oligohydramnios syndrome and microscopic lesions in the liver. Gloeb et al. (1989) considered this to be a case of Goldston syndrome, which they defined as cystic renal dysplasia and Dandy-Walker malformation.

Tsuru et al. (1980) reported an autopsied case with renal dysplasia, tapetoretinal degeneration, and Dandy-Walker malformation.

Hunter et al. (1991) described a male neonate with Potter facies, and pulmonary hypoplasia born of a pregnancy complicated by oligohydramnios. He died 15 minutes after birth due to respiratory insufficiency. Postmortem examination showed malrotation of the gut, Dandy-Walker malformation, markedly enlarged cystic kidneys, and congenital hepatic fibrosis with dysgenetic bile ducts. The pancreas was grossly normal, but microscopic examination showed ductal dysgenesis. A sib in a subsequent pregnancy was found to have Dandy-Walker malformation and multicystic kidneys, and the pregnancy was terminated. The authors concluded that their patients most closely resembled the sibs reported by Goldston et al. (1963), although liver and pancreatic abnormalities were not described in those patients. Hunter et al. (1991) also suggested phenotypic overlap with the patients reported by Kudo et al. (1985), Gloeb et al. (1989), and Tsuru et al. (1980). Hunter et al. (1991) noted phenotypic overlap with Meckel syndrome, but concluded that these patients had a distinct autosomal recessive disorder. Hunter et al. (1991) also commented that pancreatic dysplasia may not always be present, that it may not be studied or reported, and that pancreatic changes may be subtle.

Walpole et al. (1991) described a family in which 3 nonviable brothers had a variant of Dandy-Walker malformation associated with enlarged cystic dysplastic kidneys and hepatic fibrosis with biliary duct proliferation. Absence of the spleen was noted in 1 fetus. The presence of these abnormalities in all 3 sibs in the absence of polydactyly and encephalocele suggested that this was distinct from Meckel syndrome. Walpole et al. (1991) noted the phenotypic similarities to the sibs reported by Goldston et al. (1963).

Gulcan et al. (2001) reported a case of Goldston syndrome in a prematurely born male neonate. They defined the disorder as a combination of renal lesions, Dandy-Walker malformation, and congenital hepatic fibrosis. According to the authors, this was the second reported patient in whom the disorder had been diagnosed prenatally.

Moerman et al. (1993) described 2 sib fetuses with a combination of CNS malformations, renal dysplasia, and hepatic ductal malformation. The first fetus had absent cerebellar vermis, congenital hepatic fibrosis with ductal plate malformation, large cystic kidneys, and Dandy-Walker cyst. There was no encephalocele and no polydactyly. Based on the occurrence of a cerebellar Dandy-Walker malformation, the diagnosis of Goldston syndrome was proposed. The other sib showed typical Meckel syndrome with occipital encephalocele, hepatic ductal plate malformation, and cystic renal dysplasia. Both fetuses had cranium bifidum with 2 defects in the squamous part of the occipital bone. Neither fetus had pancreatic abnormalities. Moerman et al. (1993) concluded that Goldston syndrome is not a distinct entity, but rather is a variant of Meckel syndrome, of which the Dandy-Walker malformation can be a component.

Karmous-Benailly et al. (2005) concluded that the association of Dandy-Walker malformation, cystic kidneys, and hepatic fibrosis without bile duct proliferation, sometimes described as the 'Meckel-like' syndrome, belongs to the clinical spectrum of Bardet-Biedl syndrome (BBS; 209900).

Bergmann et al. (2008) reported 2 Turkish sibs, 1 of whom died at age 23 weeks' gestation and the other in the perinatal period, with enlarged multicystic dysplastic kidneys, oligohydramnios, and hepatic ductal plate malformation. One had Dandy-Walker malformation; it was not determined whether the other had a central nervous system defect. The pancreas was normal in 1 and defects were not determined in the other. Bergmann et al. (2008) concluded that the phenotype was consistent with a Meckel-like syndrome, here designated MKS7.

Bergmann et al. (2008) also reported 2 African sibs with enlarged multicystic dysplastic kidneys and liver abnormalities: 1 had liver cysts and the other had ductal plate malformation. One died in the perinatal period and was found to have a hypoplastic calvarium, large fontanel, and cystic pancreas. The other, who died at age 49 days, was neurologically abnormal, with hypertonia, a cyst on the floor of the right ventricle, and bilateral choroid plexus cysts.

Molecular Genetics

In 2 Turkish sibs with a phenotype consistent with Meckel syndrome, Bergmann et al. (2008) identified a homozygous truncating mutation in the NPHP3 gene (608002.0004). They also identified homozygosity for a truncating mutation in the NPHP3 gene (608002.0005) in 2 African sibs with a renal-hepatic-pancreatic dysplasia and brain anomalies, representing phenotypic overlap between MKS7 and RHPD (208540).

Nomenclature

There has been controversy about whether the classic description by Goldston et al. (1963) of renal dysplasia with Dandy-Walker malformation represents a distinct entity or is a form of Meckel syndrome because occipital encephalocele and polydactyly, which are often present in Meckel syndrome, have not been described in Goldston syndrome (Walpole et al., 1991). Moerman et al. (1993) concluded that Goldston syndrome is a variant of Meckel syndrome, of which the Dandy-Walker malformation can be a component.