Familial juvenile hyperuricemic (gouty) nephropathy (HNFJ) is an autosomal dominant disorder characterized by elevated serum uric acid concentrations due to a low fractional excretion of uric acid, defective urinary concentrating ability, interstitial nephropathy, and progression to end-stage renal ... Familial juvenile hyperuricemic (gouty) nephropathy (HNFJ) is an autosomal dominant disorder characterized by elevated serum uric acid concentrations due to a low fractional excretion of uric acid, defective urinary concentrating ability, interstitial nephropathy, and progression to end-stage renal failure (summary by Piret et al., 2011). A form of medullary cystic kidney disease (MCKD2; 603860) is also caused by mutation in the UMOD gene, as is a form of glomerulocystic kidney disease (609886) with hyperuricemia and isosthenuria. - Genetic Heterogeneity of Familial Juvenile Hyperuricemic Nephropathy Familial juvenile hyperuricemic nephropathy-2 (HNFJ2; 613092) is caused by mutation in the renin gene (REN; 179820) on chromosome 1q32. HNFJ3 (614227) has been mapped to chromosome 2p22.1-p21. An atypical form of HNFJ, associated with renal cysts and diabetes, is caused by mutation in the HNF1B gene (189907) on chromosome 17q12.
Rosenbloom et al. (1967) described a family in which multiple males in 3 generations died from renal failure at a relatively early age. All had hyperuricemia early in the course and gout. No distinctive histologic findings were yielded ... Rosenbloom et al. (1967) described a family in which multiple males in 3 generations died from renal failure at a relatively early age. All had hyperuricemia early in the course and gout. No distinctive histologic findings were yielded by renal biopsy. Transmission from father to son excluded X-linked inheritance. See McKusick (1974) for pedigree of the family of Rosenbloom et al. (1967). Duncan and Dixon (1960), Van Goor et al. (1971), and Simmonds et al. (1980) reported families. Massari et al. (1980) described a family in which 9 had renal disease. Abnormalities of the urinary sediment were minimal. Hyperuricemia was noted in 3 other family members without evidence of renal disease. Three had gouty arthritis, which did not precede renal disease. Leumann (1972) and Leumann and Wegmann (1983) observed chronic interstitial nephropathy with disproportionate hyperuricemia in 2 girls and their mother. The mother suffered from gout beginning at age 20 years and required dialysis by age 34. The authors suggested that 'the severity of renal destruction by gout has been overestimated in the past and that families like the one described have been considered as gouty nephropathy.' Calabrese et al. (1990) and Cameron et al. (1990) reported further families. They emphasized the importance of investigating all sibs of such patients and of treatment with allopurinol of family members with a reduced fractional clearance of urate. Deterioration of renal function in patients who did not consistently take allopurinol and stability of renal function in compliers was the experience of Cameron et al. (1990) in 6 kindreds. Moro et al. (1991) found hyperuricemia associated with a grossly reduced fractional uric acid clearance in 2 children who did not yet have other signs of renal damage. They emphasized the usefulness of early recognition since allopurinol therapy in doses adjusted to the reduced renal function may ameliorate the progression of the renal lesion. Saeki et al. (1995) found autosomal dominant inheritance in a Japanese family. They reported on 2 sisters who had gout and renal insufficiency. McBride et al. (1997) stated that the Guy's Hospital group in London had identified 79 subjects with familial juvenile hyperuricemic nephropathy. They studied 36 children ranging in age from 3 to 17 years. Three were index cases. The other 33 were among 116 'healthy' relatives investigated from FJHN families in which the index case had presented initially with gout, renal disease, or both--generally with a strong family history spanning 2 or 3 generations (Moro et al., 1991). McBride et al. (1997) found a number of these children from FJHN kindreds who had hyperuricemia associated with a grossly reduced fractional uric acid clearance (FE(ur)) but normal renal function. (The FE(ur) is uric acid clearance factored by creatinine clearance x 100; mean for UK children = 18.4 +/- 5.1%.) The FE(ur) was 5.0 in affected children with normal or only mildly impaired renal function. These studies provided compelling evidence that hyperuricemia is a primary event in this type of nephropathy. The investigators underlined the importance of presymptomatic detection of FJHN, since in patients diagnosed before the onset of severe renal disease (creatinine clearance greater than 50 ml/min), allopurinol has ameliorated the hitherto rapid progression of the renal disease seen in earlier generations for up to 27 years (Moro et al., 1991). These studies demonstrated that screening of all family members of FJHN kindreds as essential. Stiburkova et al. (2003) studied 3 Belgian brothers (family 'BE2') who developed the first symptoms of hyperuricemia and gouty arthritis after the age of 30 years; allopurinol treatment was started at that time. They had onset of renal failure between 45 and 50 years of age, with renal echography showing small hyperechogenic kidneys; and between 55 and 60 years of age, arterial hypertension appeared as well as progressive preterminal renal failure with elevated creatinine levels. Vyletal et al. (2006) restudied family BE2 and reported that 2 of the 3 brothers had onset of disease at age 20 years. The eldest brother had undergone successful kidney transplantation at age 65 years, and the middle brother began hemodialysis at age 60 years. Dahan et al. (2003) reported 11 unrelated families with FJHN, 10 of which were of European descent and 1 of Moroccan descent. The 2 largest families had 11 and 7 affected individuals, respectively. At the time of examination, 17 patients had reached end-stage renal failure between ages 25 and 64 years, and 15 had chronic renal failure. Seven had preserved renal function, all of whom were younger than 34 years. Eighteen individuals had a history of gout with onset between 8 and 38 years. Renal biopsy, available from 6 individuals from 3 families, showed chronic interstitial nephritis with tubular atrophy and marked thickening of the tubular basement membrane. Renal imaging showed small cysts in 12 individuals with renal failure. Laboratory studies showed variably decreased urinary excretion of uromodulin compared to controls.
In 3 families with HNFJ and 1 family with medullary cystic kidney disease-2 (MCKD2; 603860), Hart et al. (2002) identified mutations in the UMOD gene, demonstrating that these disorders are allelic. Noting that hyperuricemia is not always present ... In 3 families with HNFJ and 1 family with medullary cystic kidney disease-2 (MCKD2; 603860), Hart et al. (2002) identified mutations in the UMOD gene, demonstrating that these disorders are allelic. Noting that hyperuricemia is not always present in HNFJ and medullary cysts are not always present in MCKD2, and that the 2 conditions result from mutations of the same gene, the authors suggested that it would be appropriate to designate these 2 conditions 'uromodulin-associated kidney disease.' In 5 unrelated kindreds with HNFJ, 2 from Austria and 3 from Spain, Turner et al. (2003) found 5 heterozygous missense mutations in the UMOD gene (191845.0005-191845.0009) that altered evolutionary conserved residues. These mutations were not found in 110 alleles from 55 unrelated normal individuals. Rampoldi et al. (2003) described missense mutations in 3 families with MCKD2 (603860)/HNFJ and demonstrated allelism (191845.0010) in 1 family with a glomerulocystic kidney disease variant (609886), showing association of cyst dilatation and collapse of glomeruli with some clinical features similar to MCKD2/FJHN such as hyperuricemia and impairment of urine-concentrating ability. In patients from 11 families with a HNFJ1, Dahan et al. (2003) identified 11 different heterozygous UMOD mutations, including 10 novel ones (see, e.g., 191845.0012). All of the mutations occurred at highly conserved residues in exon 4, and 5 of the mutations affected a conserved cysteine residue. The families were ascertained from a larger group of 25 families with a similar phenotype; thus, UMOD mutations were found in 44% of families. HNFJ1 patient kidney samples showed abnormal uromodulin immunostaining within enlarged or cystic profiles in tubules in the thick ascending loop, and not at the apical membrane as observed in controls. Mutant UMOD was not found in proximal tubules. Patients also showed decreased urinary excretion of wildtype uromodulin. The findings indicated that mutant uromodulin accumulates within renal tubular cells in patients with UMOD mutations. Vyletal et al. (2006) sequenced the UMOD gene in 19 families with characteristics of the HNFJ and MCKD phenotypes and identified mutations in 6 HNFJ families, 5 of which had been previously reported ('kindred 6' from McBride et al., 1998; kindreds 'A' and 'B' from Stiburkova et al., 2000; Fairbanks et al., 2002; and family 'BE2' from Stiburkova et al., 2003) (see, e.g., 191845.0006 and 191845.0011). Zaucke et al. (2010) identified 7 novel UMOD mutations among 44 families with nephropathy from western Europe and the United States. The number of UMOD-positive primary cilia in UMOD patients was significantly decreased compared with control samples.