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

Background. The nephronophthisis-medullary cysticdisease (NPH/MCD) complex represents a heterogeneous group of hereditarytubulointerstitial nephritis. The most common variant is juvenile recessiveNPH, for which a gene locus (NPH1) has been mapped on chromosome 2q13. MCDis a less common dominant condition usually recognized later in life, whichresembles NPH in many aspects, still presenting remarkable clinicaldifferences. Nothing is known about the chromosome locus of MCD.Methods. Five MCD families were studied. Diagnosis wasmade by inference from family history, type of inheritance, clinical signsand 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; 12females), belonging to five families. Histological diagnosis was availablein 10 patients; clinical diagnosis in 11; seven deceased relatives haddiagnosis of chronic nephritis. The age at diagnosis ranged from 8 to 65years. Renal medullary cysts were found in a minority of patients. Infamily 1, the disease was associated with hyperuricaemia and goutyarthritis. Progression of renal disease presented intra- and extra-familyvariability with members of the same family showing mild elevation ofcreatinine or terminal renal failure. The NPH1 locus associated torecessive NPH was excluded from linkage to the dominant MCD.Conclusions. MCD might be more common than previouslyassumed. Variability in clinical presentation and absence ofhistopathological hallmarks contribute to make the diagnosis uncommon. Themost remarkable clinical difference with NPH is the age of onset in somekindreds and a delayed progression towards renal failure. The exclusion oflinkage to the NPH1 locus suggests the existence of an MCD responsiblelocus, still to be mapped.