Autosomal dominant medullary cystic disease: a disorder with variable clinical pictures and exclusion of linkage with the NPH1 locus.

BACKGROUND The nephronophthisis-medullary cystic disease (NPH/MCD) complex represents a heterogeneous group of hereditary tubulointerstitial nephritis. The most common variant is juvenile recessive NPH, for which a gene locus (NPH1) has been mapped on chromosome 2q13. MCD is a less common dominant condition usually recognized later in life, which resembles NPH in many aspects, still presenting remarkable clinical differences. Nothing is known about the chromosome locus of MCD. METHODS Five MCD families were studied. Diagnosis was made by inference from family history, type of inheritance, clinical signs and histology. Multipoint linkage analysis was performed by markers D2S293, D2S340 and D2S160 spanning the entire NPH1 locus. RESULTS Diagnosis of MCD was made in 28 affected members (16 males; 12 females), belonging to five families. Histological diagnosis was available in 10 patients; clinical diagnosis in 11; seven deceased relatives had diagnosis of chronic nephritis. The age at diagnosis ranged from 8 to 65 years. Renal medullary cysts were found in a minority of patients. In family 1, the disease was associated with hyperuricaemia and gouty arthritis. Progression of renal disease presented intra- and extra-family variability with members of the same family showing mild elevation of creatinine or terminal renal failure. The NPH1 locus associated to recessive NPH was excluded from linkage to the dominant MCD. CONCLUSIONS MCD might be more common than previously assumed. Variability in clinical presentation and absence of histopathological hallmarks contribute to make the diagnosis uncommon. The most remarkable clinical difference with NPH is the age of onset in some kindreds and a delayed progression towards renal failure. The exclusion of linkage to the NPH1 locus suggests the existence of an MCD responsible locus, still to be mapped.

[1]  L. Victorin,et al.  Nephrono-phthisis. A uremic disease with hypotonic urine. , 2009, Acta medica Scandinavica.

[2]  F. Hildebrandt,et al.  A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1 , 1997, Nature Genetics.

[3]  D. Le Paslier,et al.  Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis. , 1996, Human molecular genetics.

[4]  Cécile Fizames,et al.  The 1993–94 Généthon human genetic linkage map , 1994, Nature Genetics.

[5]  J. Beckmann,et al.  A gene for familial juvenile nephronophthisis (recessive medullary cystic kidney disease) maps to chromosome 2p , 1993, Nature Genetics.

[6]  F. Hildebrandt,et al.  The nephronophthisis complex: clinical and genetic aspects , 1992, The clinical investigator.

[7]  K. Schärer,et al.  Acquired cystic kidney disease before and after renal transplantation. , 1992, The Journal of pediatrics.

[8]  A. Cohen,et al.  Nephronophthisis. A primary tubular basement membrane defect. , 1986, Laboratory investigation; a journal of technical methods and pathology.

[9]  J. Ott,et al.  Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. , 1985, American journal of human genetics.

[10]  L. Garel,et al.  Juvenile nephronophthisis: sonographic appearance in children with severe uremia. , 1984, Radiology.

[11]  J. Burke,et al.  Juvenile nephronophthisis and medullary cystic disease--the same disease (report of a large family with medullary cystic disease associated with gout and epilepsy). , 1982, Clinical nephrology.

[12]  G. Thompson,et al.  Familial occurrence of hyperuricemia, gout, and medullary cystic disease. , 1978, Archives of internal medicine.

[13]  T. Murray,et al.  Chronic interstitial nephritis: etiologic factors. , 1975, Annals of internal medicine.

[14]  S. Sommers,et al.  Medullary cystic disease and familial juvenile nephronophthisis. , 1967, The New England journal of medicine.

[15]  J. Mongeau,et al.  Nephronophthisis and medullary cystic disease. , 1967, The American journal of medicine.

[16]  J. Graham,et al.  CONGENITAL MEDULLARY CYSTS OF THE KIDNEYS WITH SEVERE REFRACTORY ANEMIA , 1945 .

[17]  F. Hildebrandt,et al.  Late occurrence of cysts in autosomal dominant medullary cystic kidney disease. , 1997, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[18]  E. Leumann,et al.  Familial nephropathy with hyperuricemia and gout. , 1983, Nephron.

[19]  K. Gardner.  Evolution of clinical signs in adult-onset cystic disease of the renal medulla. , 1971, Annals of internal medicine.