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-onsetdiabetes of the young (MODY5), which is usually characterizedby dominantly inherited adolescence-onset diabetes mellitusassociated with renal cysts. This report, however, describesrecurrence of a novel missense mutation in the HNF-1ßgene, S148W (C443G), in two sibs, one with neonatal diabetesmellitus and the other with neonatal polycystic, dysplastickidneys leading to early renal failure. The former patient hadonly a few small renal cysts with normal renal functions, andthe latter had only a transient episode of hyperglycemia, whichresolved spontaneously. Interestingly, both parents were clinicallyunaffected, and PCR restriction fragment length polymorphismanalysis showed that the mother was a low-level mosaic of normaland mutant HNF-1ß, which suggested that the recurrencewas caused by germline mosaicism. This is the first report ofpermanent neonatal diabetes mellitus caused by a mutation ofthe HNF-1ß gene as well as the first report of germlinemosaicism of this gene. In addition, the two cases describedhere show that additional factors, genetic or environmental,can have a significant influence on the phenotypic expressionof HNF-1ß mutations.
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