Hnf1b-Related Autosomal Dominant Tubulointerstitial Kidney Disease

Renal cysts and diabetes syndrome (RCAD) is a rare form of maturity-onset diabetes of the young (MODY; see this term) characterized clinically by heterogeneous cystic renal disease and early-onset familial non-autoimmune diabetes. Pancreatic atrophy, liver dysfunction and genital tract anomalies are also features of the syndrome.

Epidemiology

RCAD accounts for 1-5% of MODY cases, depending on whether cases are ascertained in those with renal disease. There is an equal female to male ratio.

Clinical description

Patients with RCAD typically present with diabetes between 10 and 40 years of age. Unlike patients with HNF1A mutations, they are not sensitive to sulphonylureas. Most patients progress fairly rapidly to insulin treatment. Pancreatic structural abnormalities such as atrophy or hypoplasia and exocrine dysfunction are reported in around 10% and 6% of patients, respectively. Renal abnormalities usually present early and include renal cysts, renal dysplasia, unilateral renal agenesis (see these terms), collecting system malformations, hypoplastic glomerulonephritic kidney disease, and rarely, Fanconi syndrome or chromophobe renal cell carcinoma (see this term). Half of affected patients have impaired renal function and 12% have end-stage renal failure. Male and female genital tract abnormalities, elevated liver enzymes or structural liver anomalies, hyperuricemia and increased PTH levels have also been reported.

Etiology

RCAD is caused by heterozygous mutations in the human transcription factor 2 gene (HNF1B; 17q12), which encodes hepatocyte nuclear factor 1 beta. It is expressed during the development of the pancreas, liver and genitourinary tract, which explains the phenotype of this disorder.

Genetic counseling

Early-onset of diabetes, maintained endogenous insulin production and family history of diabetes associated with renal cystic disease should trigger molecular testing for HNF1B mutations. Whole gene or exon deletions form a high proportion of RCAD cases. RCAD follows an autosomal dominant pattern of inheritance. Cascade screening of family members is therefore recommended.