Nephrolithiasis, X-Linked Recessive, With Renal Failure

A number sign (#) is used with this entry because X-linked recessive nephrolithiasis with renal failure is caused by mutation in the CLCN5 gene (300008) on chromosome Xp11.22.

Description

X-linked recessive nephrolithiasis with renal failure is a form of X-linked hypercalciuric nephrolithiasis, which comprises a group of disorders characterized by proximal renal tubular reabsorptive failure, hypercalciuria, nephrolithiasis, and renal insufficiency. These disorders have also been referred to as the 'Dent disease complex' (Scheinman, 1998; Gambaro et al., 2004). For a general discussion of Dent disease, see 300009.

Clinical Features

Frymoyer et al. (1991) reported a large kindred living in the St. Lawrence valley of northern New York, descendants of 19th century Irish immigrants, with nephrolithiasis inherited in an X-linked recessive pattern. Nine affected males had onset in childhood of calcium nephrolithiasis and proteinuria, with progression to nephrocalcinosis and renal insufficiency. Renal biopsies showed tubular atrophy, interstitial fibrosis, and glomerulosclerosis. Renal biopsies were abnormal even in younger members, but abnormalities in the renal excretion of calcium, phosphate, potassium, and uric acid were found only in affected adults. In 1 patient who had a renal transplant for 7 years, the disease had not recurred. Frymoyer et al. (1992) pointed out that patients with X-linked recessive nephrocalcinosis differed from Dent disease by having normal growth, no evidence of bone disease, and sometimes absence of hypercalciuria despite the presence of nephrocalcinosis, recurrent calcium nephrolithiasis, or both. Furthermore, all could acidify their urine to a pH below 5.6.

Mapping

In the family reported by Frymoyer et al. (1991) as having X-linked recessive nephrolithiasis, Scheinman et al. (1993) found linkage to chromosome Xp11.22 (maximum lod score of 5.91 at marker DXS255). Multilocus analysis indicated that the mutant gene was distal to DXS255 but proximal to the DMD (300377) locus.

Molecular Genetics

In affected members from 2 unrelated North American families with X-linked recessive nephrolithiasis, Lloyd et al. (1996) identified 2 different mutations in the CLCN5 gene (300008.0005; 300008.0006).

In affected members of a kindred with X-linked recessive nephrolithiasis, Schurman et al. (1998) identified a mutation in the CLCN5 gene (300008.0011). The disease had occurred in males in first, third, and fifth generations, with the carrier females in the intervening second and fourth generations. Individuals at risk were screened with renal ultrasonography and measurement of urinary excretion of low molecular weight proteins and calcium.

Nomenclature

Scheinman et al. (1993) suggested the symbol 'XRN' (for X-linked recessive nephrolithiasis) for this disorder; NPHL1 was the locus symbol assigned by the human gene nomenclature committee.