BACKGROUND: Maturity-onset diabetes of the young type 5 (MODY5), a type of dominantly inherited diabetes mellitus and nephropathy, has been associated with mutations of the hepatocyte nuclear factor-1beta (HNF-1beta) gene, mostly generating truncated protein. Various phenotypes, including urogenital malformations, are related to HNF-1beta mutations. OBJECTIVE: To describe clinical and genetic findings in 13 patients with 8 novel HNF-1beta mutations. DESIGN: Multicenter, descriptive study. SETTING: 2 departments of diabetes, 1 department of internal medicine, and 1 department of nephrology. PARTICIPANTS: 8 probands with diabetes diagnosed before 40 years of age and nondiabetic kidney disease who were selected independent of their family history of diabetes, and 5 offspring. MEASUREMENTS: Characteristics of diabetes, renal function and structure, genital tract abnormalities, pancreas structure, insulin secretion, exocrine pancreas function, and liver test results. RESULTS: All mutations, including 5 missense changes, were found in the DNA-binding domain. Cosegregation of the mutation and MODY5 phenotype was observed in 4 families. Occurrence of a de novo mutation was demonstrated in 2 families. Diabetes was present in 10 of 13 mutation carriers. It was clinically overt in 5 participants and found by screening at age 19 to 38 years in 5 participants. Pancreas atrophy was observed in 5 of 6 probands, and pancreas exocrine insufficiency was observed in 6 of 7 probands. Renal involvement, consisting of structural changes and slowly progressive renal failure, was recognized in 9 patients at 18 to 41 years of age. Dysplastic kidneys were found by ultrasonography in 3 fetuses who subsequently showed transient neonatal renal failure. Genital tract abnormalities were present in 5 probands and liver enzyme levels were abnormal in 11 of 13 patients. LIMITATIONS: Since the study was small and not population-based, it could not estimate the prevalence of MODY5. Other phenotypes might be associated with HNF-1beta mutations. CONCLUSIONS: Maturity-onset diabetes of the young type 5 encompasses a wide clinical spectrum. Analysis for mutations of HNF-1beta is warranted, even without a family history of diabetes, in nonobese patients with diabetes and slowly progressive nondiabetic nephropathy, particularly when pancreatic atrophy or genital abnormalities are present.
BACKGROUND: Maturity-onset diabetes of the young type 5 (MODY5), a type of dominantly inherited diabetes mellitus and nephropathy, has been associated with mutations of the hepatocyte nuclear factor-1beta (HNF-1beta) gene, mostly generating truncated protein. Various phenotypes, including urogenital malformations, are related to HNF-1beta mutations. OBJECTIVE: To describe clinical and genetic findings in 13 patients with 8 novel HNF-1beta mutations. DESIGN: Multicenter, descriptive study. SETTING: 2 departments of diabetes, 1 department of internal medicine, and 1 department of nephrology. PARTICIPANTS: 8 probands with diabetes diagnosed before 40 years of age and nondiabetic kidney disease who were selected independent of their family history of diabetes, and 5 offspring. MEASUREMENTS: Characteristics of diabetes, renal function and structure, genital tract abnormalities, pancreas structure, insulin secretion, exocrine pancreas function, and liver test results. RESULTS: All mutations, including 5 missense changes, were found in the DNA-binding domain. Cosegregation of the mutation and MODY5 phenotype was observed in 4 families. Occurrence of a de novo mutation was demonstrated in 2 families. Diabetes was present in 10 of 13 mutation carriers. It was clinically overt in 5 participants and found by screening at age 19 to 38 years in 5 participants. Pancreas atrophy was observed in 5 of 6 probands, and pancreas exocrine insufficiency was observed in 6 of 7 probands. Renal involvement, consisting of structural changes and slowly progressive renal failure, was recognized in 9 patients at 18 to 41 years of age. Dysplastic kidneys were found by ultrasonography in 3 fetuses who subsequently showed transient neonatal renal failure. Genital tract abnormalities were present in 5 probands and liver enzyme levels were abnormal in 11 of 13 patients. LIMITATIONS: Since the study was small and not population-based, it could not estimate the prevalence of MODY5. Other phenotypes might be associated with HNF-1beta mutations. CONCLUSIONS: Maturity-onset diabetes of the young type 5 encompasses a wide clinical spectrum. Analysis for mutations of HNF-1beta is warranted, even without a family history of diabetes, in nonobese patients with diabetes and slowly progressive nondiabetic nephropathy, particularly when pancreatic atrophy or genital abnormalities are present.
Authors: Shazia Ashraf; Bethan E Hoskins; Hassan Chaib; Julia Hoefele; Andreas Pasch; Pawaree Saisawat; Friedrich Trefz; Hans W Hacker; Gudrun Nuernberg; Peter Nuernberg; Edgar A Otto; Friedhelm Hildebrandt Journal: Nephrol Dial Transplant Date: 2009-12-10 Impact factor: 5.992
Authors: Dagan Jenkins; Maria Bitner-Glindzicz; Louise Thomasson; Sue Malcolm; Stephanie A Warne; Sally A Feather; Sarah E Flanagan; Sian Ellard; Coralie Bingham; Lane Santos; Mark Henkemeyer; Andrew Zinn; Linda A Baker; Duncan T Wilcox; Adrian S Woolf Journal: J Pediatr Urol Date: 2007-02 Impact factor: 1.830