Nephronophthisis 11

A number sign (#) is used with this entry because nephronophthisis-11 (NPHP11) is caused by homozygous or compound heterozygous mutation in the TMEM67 gene (609884) on chromosome 8q22.

Mutations in the TMEM67 gene can also cause Meckel syndrome-3 (MKS3; 607361), Joubert syndrome-6 (JBTS6; 610688), and COACH syndrome (216360), all of which show more severe yet overlapping clinical features with NPHP.

For a general phenotypic description and a discussion of genetic heterogeneity of NPHP, see NPHP1 (256100).

Clinical Features

Boichis et al. (1973) described an association of nephronophthisis and congenital hepatic fibrosis in sibs. Five had demonstrated renal disease. Two died of renal failure at ages 7 and 15, and a third was maintained on hemodialysis. Approximately 5% of patients with NPHP have hepatic fibrosis (Otto et al., 2009).

Otto et al. (2009) described a consanguineous Turkish family in which 3 sibs had nephronophthisis and hepatic fibrosis. The diagnosis of NPHP was based on (1) characteristic clinical signs of NPHP including chronic renal failure, polyuria, polydipsia, anemia, and growth retardation; (2) renal ultrasound or renal biopsy compatible with the diagnosis; and (3) a pedigree compatible with autosomal recessive inheritance. After initial investigation, several other affected individuals were identified from a larger cohort of 60 probands. All patients developed end-stage renal disease (ESRD) between the age of 6 and 14 years and all had liver fibrosis. Three patients had ocular symptoms, including strabismus/nystagmus, retinal degeneration, and anisocoria, respectively. Patients had no or only mild neurologic involvement, and none had brain MRI abnormalities. One patient had mild 'statomotoric' retardation and another had psychomotor retardation.

Molecular Genetics

In patients with nephronophthisis and hepatic fibrosis, Otto et al. (2009) identified homozygous or compound heterozygous missense mutations in the TMEM67 gene (see, e.g., 609884.0018-609884.0021). Mutations in the TMEM67 gene were not found in 105 NPHP patients without liver fibrosis, suggesting that liver fibrosis is a specific feature of TMEM67 mutations. Otto et al. (2009) concluded that mutations in TMEM67 can cause NPHP in patients with additional liver fibrosis, normal brain imaging, and no neurologic involvement, and that NPHP11, MKS3, and JBTS6 represent a spectrum of allelic disorders. However, mutations were only identified in 8% of patients with NPHP and hepatic fibrosis, indicating genetic heterogeneity for this combination of features.