Ventriculomegaly With Cystic Kidney Disease

A number sign (#) is used with this entry because of evidence that ventriculomegaly with cystic kidney disease (VMCKD) is caused by homozygous or compound heterozygous mutation in the CRB2 gene (609720) on chromosome 9q33.

Biallelic mutation in the CRB2 gene can also cause isolated focal segmental glomerulosclerosis-9 (FSGS9; 616220), a less severe disorder.

Description

Ventriculomegaly with cystic kidney disease is a severe autosomal recessive developmental disorder characterized by onset in utero of dilated cerebral ventricles and microscopic renal tubular cysts. The pregnancies of affected individuals are associated with increased alpha-fetoprotein (AFP). Most affected pregnancies have been terminated (summary by Slavotinek et al., 2015).

See also 602200 for a disorder characterized by ventriculomegaly and defects of the radius and kidney.

Clinical Features

Reuss et al. (1989) described a family in which in 2 consanguineous relationships a Cape Verdean man fathered 2 normal children and 6 infants or fetuses with hydrocephaly and cystic disease of the corticomedullary areas of the kidneys. All 6 affected infants were detected prenatally. The first was found at 32 weeks' gestation to have ventriculomegaly, normal-sized but echodense kidneys, and increased amniotic fluid, and was born stillborn at 32 weeks' gestation. The 5 other fetuses were found to be affected at 18 to 20 weeks' gestation, and were terminated during pregnancy. Amniocentesis during pregnancy in 5 of the 6 fetuses showed increased alpha-fetoprotein and acetylcholinesterase (AChE) levels. All had ventriculomegaly and normal-sized but echodense kidneys. Histologic studies of the kidneys showed cystic tubular dilatation in the corticomedullary area and renal medulla; the cysts contained eosinophilic amorphous proteinaceous material. One fetus had postaxial polydactyly, but no other limb anomalies were noted in any of the fetuses. The families lived in the Netherlands (ten Kate, 1991).

Slavotinek et al. (2015) reported 5 fetuses from 2 families and an unrelated infant with ventriculomegaly and cystic kidney disease. All pregnancies were abnormal and ascertained due to high AFP levels or abnormal ultrasound findings prior to the end of the second trimester; 5 of the affected pregnancies were terminated. Ultrasound showed severe cerebral ventriculomegaly and echogenic kidneys. Kidney examination showed numerous dilated tubules and microscopic cysts in the renal medulla. Electron microscopy of renal tissue from 1 fetus showed effacement of the epithelial foot processes and microvillous transformation of the podocytes. One affected infant, who was delivered at 35 weeks' gestation, died at age 7 months. This infant had massive ventriculomegaly, subependymal gray matter heterotopia, seizures, nephrotic syndrome, and small cardiac ventricular septal defect.

Inheritance

The transmission pattern of ventriculomegaly with cystic kidney disease in the family reported by Reuss et al. (1989) was consistent with autosomal recessive inheritance.

Molecular Genetics

In DNA from 3 fetuses from 2 families and a male infant from a third family with cerebral ventriculomegaly with cystic kidney disease, Slavotinek et al. (2015) identified homozygous or compound heterozygous mutations in the CRB2 gene (609720.0006-609720.0009). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There were 3 missense mutations and 1 truncating mutation, all of which occurred in the extracellular region of the protein; none of these mutations was predicted to affect polarity. Functional studies of the variants were not performed.