Familial juvenile hyperuricaemic nephropathy in a Caucasian family associated with inborn malformations
Peter Kotanko,
Eva Gebetsroither and
Falko Skrabal
Department of Internal Medicine, Krankenhaus der Barmherzigen Brüder, Graz, Austria
 |
Introduction
|
---|
Familial juvenile hyperuricaemic nephropathy (FJHN; OMIM 162000) is considered a rare cause of end-stage renal disease (ESRD). FJHN is characterized by hyperuricaemia and gout after adolescence and the slow development of renal insufficiency, leading to ESRD in adulthood. The disorder is characterized by a renal under-secretion of urate, which may be detected already during early childhood [1]. The histological lesions in affected subjects are characterized by unspecific tubulo-interstitial nephropathy. FJHN is inherited in an autosomal dominant pattern with a high penetrance. Recently, the gene(s) for FJHN was localized to a candidate interval at the short arm of chromosome 16 [2,3].
 |
Case
|
---|
We report a Caucasian four-generation family with FJHN without consanguinity between spouses and a clustering of various malformations (Figure 1
). Tests of renal function, serum uric acid levels, and fractional uric acid excretion (FEua) were done in all 18 living consanguineous family members (Table 1
) and seven spouses (data not shown). The serum and urine concentrations of uric acid or creatinine (Sua, Uua, Scr, Ucr, respectively) were determined by using an autoanalyser (Cobas Integra 700) while the patients were not on a purine-restricted diet. FEua was calculated in per cent as (UuaxScrx100%)/(SuaxUcr). The diagnosis of FJHN was based on a history of hyperuricaemia or gout and/or the finding of an FEua below 6.6% in men, below 7.0% in women, and below 8.2% in children [1].

View larger version (13K):
[in this window]
[in a new window]
|
Fig. 1. Pedigree of a Caucasian family with FJHN. Squares indicate males, and circles indicate females. Unblackened symbols indicate unaffected individuals, and blackened symbols indicate affected individuals with ESRD. Blackened right upper quadrant denotes individuals with reduced FEua, blackened right lower quadrant denotes individuals with gout. Blackened left lower quadrant denotes individuals with renal insufficiency. Deceased individuals are shown by diagonal bars across the square or circle.
|
|
The index case (III:6) was referred to our hospital with gout and a renal insufficiency (Scr 2.2 mg/dl, creatinine clearance 70 ml/min). His FEua was grossly reduced (2.9%). The family history revealed a clustering of ESRD. His grandmother (I:2) died of ESRD at the age of 40 years; his mother (II:5) and one of his aunts (II:9) suffered from gouty arthritis, both died with renal failure at the age of 44 and 29 years, respectively. Three alive aunts have gout and ESRD (II:2, II:8, II:11), one cousin (III:14) has gout and ESRD. Two cousins (III:1, III:4) have hyperuricaemia, a low FEua, and renal function is impaired in one of them (III:4). The siblings of the index case have no evidence of gout, low FEua, or renal insufficiency. As pregnancy is known to lower Sua, the studies on renal uric acid handling in one of his sisters (III:8) may have been influenced by the concurrent pregnancy (second trimester). Despite that shortcoming we believe from her past history, that she is not affected by FJHN. This patient died postpartum because of endocarditis in another hospital and no further studies are available.
Seven affected patients underwent renal ultrasound studies, renal cysts were revealed in the native kidneys of subject II:2 (diameter <1 cm; investigation 1999), subject II:11 (investigation 1989), subject III:4 (two cysts, diameter 1.5 and 2.4 cm, respectively; investigation 1999), and subject III:6 (two cysts, diameter <1 cm; investigation 2002), no renal cysts could be demonstrated in subjects II:8, III:1, and III:14.
In the described family various somatic malformations were observed. The index case (III:6) suffered from severe congenital pulmonary stenosis and underwent cardiac surgery at the age of 9 years. His mother (II:5), who suffered from gouty arthritis and ESRD, had grade III aortic valve stenosis, necessitating valve replacement. His sister (III:8), who was to the best of our knowledge not affected by FJHN, had congenital aortic valve stenosis and pulmonary stenosis and underwent balloon dilatation during early infancy. Cardiac ultrasound studies revealed no valvular disease in other subjects with FJHN (II:2, II:8, III:1, III:4, III:14) and in two healthy siblings (III:9, III:10) of the index case. During childhood a cousin (III:1) of the index case had idiopathic portal vein thrombosis with consecutive esophageal varices and repeated variceal bleedings. Cytogenetic studies in the index case were unremarkable, renal biopsy was rejected by him.
Patients III:1 and III:4 were treated with allopurinol 300 mg/day without improvement of FEua. FEua increased from 2.5 to 7.6% in subject III:1 after benzbromarone was added (100 mg/day). The index case (III:6) was given allopurinol (150 mg/day) and benzbromarone (100 mg/day), his FEua rose initially from 2.9 to 7.7%. A careful history revealed that the consecutive decline of the FEua (Table 1
) was probably due to poor compliance. With the combination therapy of allopurinol and benzbromarone uric acid normalized in all treated patients and none experienced further gout attacks.
Three patients were successfully kidney grafted at the age of 46 (II:2), 34 (II:8), and 40 years (II:11). Patient II:2 returned to haemodialysis (HD) 2 years post-transplant, the two other patients have functioning grafts 16 and 6 years post-transplant, respectively. The low FEua observed in the two subjects with functioning renal transplants (II:8, II:11) is most probably due to the cyclosporine therapy. One patient (III:14) is on HD since 29 years of age and awaits renal transplantation.
 |
Discussion
|
---|
We presented a large Caucasian family with FJHN. The diagnosis of FJHN was based on a history of hyperuricaemia or gout and/or the finding of a reduced FEua. Recently, a possible link between FJHN and autosomal dominant medullary cystic kidney disease type 2 (MCKD 2) has been postulated [4]. Ultrasound studies revealed renal cysts in four out of seven patients studied. Although it may well be that these cysts represent an unspecific sequel of renal insufficiency, MCKD 2 cannot be excluded on clinical and biochemical grounds. It has been suggested that the combination of an uricosuric agent with allopurinol might be effective in FJHN and increase FEua [5,6]. This notion is supported by the observations made by us. The combination therapy with allopurinol and benzbromarone increased the FEua to a near normal range and therefore may possibly help to avoid ESRD in FJHN. It appeared in line with previous reports that patients with FJHN can be successfully treated with renal transplantation.
Hitherto unreported is a clustering of cardiac malformations in a FJHN family. In the general population congenital heart disease, with the commonest form being ventricular septal defect, occurs in approximately 1% of liveborn children [7]. It cannot be excluded that the observed association between cardiac malformations occurred by chance, as one subject with congenital aortic valve stenosis and pulmonary stenosis (III:8) did not have FJHN. Nevertheless, the occurrence of congenital heart disease in two patients (II:5, III:6) with FJHN may aid the search for the FJHN gene locus. Congenital valve defects have been located to many other chromosomes beside the sex chromosomes (e.g. chromosomes 1, 4, 5, 7, 8, 10, 20, and 22) but to the best of our knowledge not to chromosome 16, which carries a candidate region for FJHN. To further elucidate that issue we suggest that in patients with congenital valvular heart disease and a family history of hyperuricaemia and/or ESRD determination of FEua may be worthwhile.
 |
Notes
|
---|
Correspondence and offprint requests to: Peter Kotanko, Department of Internal Medicine, Krankenhaus der Barmherzigen Brüder, Teaching Hospital Karl-Franzens-University, Graz, Austria. Email: kotanko1{at}eunet.at 
 |
References
|
---|
- McBride MB, Rigden S, Haycock GB et al. Presymptomatic detection of familial juvenile hyperuricaemic nephropathy in children. Pediatr Nephrol1998; 12: 357364[ISI][Medline]
- Kamatani N, Moritani M, Yamanaka H, Takeuchi F, Hosoya T, Itakura M. Localization of a gene for familial juvenile hyperuricemic nephropathy causing underexcretion-type gout to 16p12 by genome-wide linkage analysis of a large family. Arhritis Rheum2000; 43: 925929
- Stiburkova B, Majewski J, Sebesta I, Zhang W, Ott J, Kmoch S. Familial juvenile hyperuricemic nephropathy: localization of the gene on chromosome 16p11.2and evidence for genetic heterogeneity. Am J Hum Genet2000; 66: 19891994[ISI][Medline]
- Dahan K, Fuchshuber A, Adamis S et al. Familial juvenile hyperuricemic nephropathy and autosomal dominant medullary cystic kidney disease type 2: two facets of the same disease? J Am Soc Nephrol2001; 12: 23482357[Abstract/Free Full Text]
- Hisatome I, Kosaka H, Ohtahara K et al. Renal handling of urate in a patient with familial juvenile gouty nephropathy. Intern Med1996; 35: 564568[ISI][Medline]
- Lhotta K, Gruber J, Sgonc R, Fend F, König P. Apoptosis of tubular epithelial cells in familial juvenile gouty nephropathy. Nephron1998; 79: 340344[ISI][Medline]
- Hoffman, JI. Congenital heart disease: incidence and inheritance. Ped Clin North Am1990; 37: 2543[ISI][Medline]