MODY5

MODY5, also known as HNF1B-MODY or RCAD syndrome (renal cysts and diabetes), is a form of Maturity-Onset Diabetes of the Young caused by heterozygous mutations in the HNF1B gene. It is inherited in an autosomal dominant pattern with variable expressivity.

Genetic basis and gene function: MODY5 results from mutations in HNF1B, which encodes hepatocyte nuclear factor 1 beta, a transcription factor essential for the development and function of multiple organs, including the pancreas, kidneys, liver, and reproductive tract. Mutations include missense, nonsense, frameshift, and splice-site changes, as well as whole-gene deletions. The clinical spectrum ranges from isolated diabetes to a multi-organ RCAD syndrome with renal involvement.

Clinical features: Diabetes typically presents in adolescence or early adulthood and may require insulin. Extra-pancreatic features are common and include renal anomalies such as cysts, dysplasia, and chronic kidney disease, as well as urinary tract abnormalities and, less frequently, liver or genital tract anomalies. There is substantial phenotypic heterogeneity; some individuals have diabetes without kidney disease, while others have significant renal involvement.

Diagnosis and management: Diagnosis is established through genetic testing for HNF1B variants. Management emphasizes glycemic control and monitoring for kidney disease and other organ involvement. Treatment of hyperglycemia may involve insulin or oral agents, with variable response. Regular surveillance of renal function, blood pressure, and potential urogenital abnormalities is recommended.

Prognosis and epidemiology: MODY5 is a rare form of monogenic diabetes. Penetrance is high but expressivity is variable, leading to a range of outcomes from mild disease to progressive kidney disease. Family history often supports autosomal dominant inheritance.

See also: Maturity-Onset Diabetes of the Young, HNF1B, RCAD syndrome, monogenic diabetes.