ESPE Abstracts (2016) 86 RFC15.2

NR0B1 Frameshift Mutation in a Boy with Precocious Puberty and Normal Adrenal Function

Hirohito Shimaa, Shuichi Yatsugab, Akie Nakamuraa, Shinichiro Sanoa, Takako Sasakib, Noriyuki Katsumataa, Erina Suzukia, Tsutomu Ogatac & Maki Fukamia


aDepartments of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan; bDepartment of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan; cDepartment of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan


Background: While hemizygous NR0B1 (DAX1) mutations usually lead to adrenal crisis during infancy or early childhood, p.Gln37*, p.Trp39*, and some other mutations result in late-onset or latent adrenal insufficiency. A small percentage of boys with NR0B1 mutations develops precocious puberty in addition to adrenal insufficiency.

Objective and hypotheses: To report a boy with an NR0B1 mutation who exhibited central precocious puberty without adrenal insufficiency.

Method: A 4-year-old boy presented with pubic hair, testicular enlargement, and advanced bone age. Blood examinations revealed increased testosterone levels and hyperresponses of gonadotropins to GnRH stimulation. The patient was clinically diagnosed with idiopathic central precocious puberty. GnRH analog treatment partially ameliorated the hormonal abnormalities, but did not improve the physical findings. On his latest visit at 7 years and 6 months of age, the patient showed no clinical or laboratory signs of adrenal insufficiency. The patient was subjected to mutation screening of 32 genes known to control the hypothalamic-pituitary-gonadal axis.

Results: Molecular analysis identified a maternally-inherited hemizygous 1-bp deletion in exon 1 (p.Glu3fsAla*16) of NR0B1. The mutation was predicted to encode an N-terminally truncated hypomorphic protein, similar to that produced by p.Gln37*and p.Trp39*. No pathogenic mutations were found in other tested genes.

Conclusion: These findings expand the clinical manifestations of NR0B1 mutations to include male central precocious puberty without adrenal insufficiency. NR0B1 mutations likely underlie testosterone overproduction through both GnRH-dependent and -independent mechanisms.

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