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Neonatal Diabetes Mellitus and Neonatal Polycystic, Dysplastic Kidneys: Phenotypically Discordant Recurrence of a Mutation in the Hepatocyte Nuclear Factor-1ß Gene Due to Germline Mosaicism

Department of Pediatrics (T.Y., K.K., M.M., T.I., M.K., T.N.), Kyoto University Hospital, Kyoto 606-8507; Department of Pediatrics (Y.N.), Hiroshima Red Cross Hospital, Hiroshima 730-8619; and Departments of Urology (S.S.) and Endocrinology and Metabolism (Y.H.), Tokyo Metropolitan Kiyose Children’s Hospital, Tokyo 204-8567, Japan

Address all correspondence and requests for reprints to: Tohru Yorifuji, M.D., Ph.D., Department of Pediatrics, Kyoto University Hospital, 54 Shogoin Sakyo, Kyoto 606-8507, Japan. E-mail: yorif{at}kuhp.kyoto-u.ac.jp.

Mutations in the gene coding for hepatocyte nuclear factor-1ß (HNF-1ß) have been known to cause a form of maturity-onset diabetes of the young (MODY5), which is usually characterized by dominantly inherited adolescence-onset diabetes mellitus associated with renal cysts. This report, however, describes recurrence of a novel missense mutation in the HNF-1ß gene, S148W (C443G), in two sibs, one with neonatal diabetes mellitus and the other with neonatal polycystic, dysplastic kidneys leading to early renal failure. The former patient had only a few small renal cysts with normal renal functions, and the latter had only a transient episode of hyperglycemia, which resolved spontaneously. Interestingly, both parents were clinically unaffected, and PCR restriction fragment length polymorphism analysis showed that the mother was a low-level mosaic of normal and mutant HNF-1ß, which suggested that the recurrence was caused by germline mosaicism. This is the first report of permanent neonatal diabetes mellitus caused by a mutation of the HNF-1ß gene as well as the first report of germline mosaicism of this gene. In addition, the two cases described here show that additional factors, genetic or environmental, can have a significant influence on the phenotypic expression of HNF-1ß mutations.

Abbreviations: CMV, Cytomegalovirus; HNF-1ß, hepatocyte nuclear factor-1ß; MODY, maturity-onset diabetes of the young; MRI, magnetic resonance imaging; RFLP, restriction fragment length polymorphism.

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