NR0B1 Frameshift Mutation in a Boy with Idiopathic Central Precocious PubertyShima H.a, e · Yatsuga S.f · Nakamura A.a · Sano S.a · Sasaki T.f · Katsumata N.a · Suzuki E.a · Hata K.b · Nakabayashi K.b · Momozawa Y.g · Kubo M.g · Okamura K.c · Kure S.e · Matsubara Y.d · Ogata T.h · Narumi S.a · Fukami M.a
Departments of aMolecular Endocrinology, bMaternal-Fetal Biology and cSystems BioMedicine, and dInstitute Director, National Research Institute for Child Health and Development, Tokyo, eDepartment of Pediatrics, Tohoku University School of Medicine, Sendai, fDepartment of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, gCenter for Integrative Medical Sciences, RIKEN, Yokohama, and hDepartment of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan
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NR0B1 is the causative gene for X-linked adrenal hypoplasia congenita, characterized by adrenal insufficiency, hypogonadotropic hypogonadism, and infertility. We identified an NR0B1 frameshift mutation in a boy with precocious puberty who had no signs of adrenal insufficiency. Blood examination revealed elevated testosterone levels and gonadotropin hyperresponses to gonadotropin releasing hormone (GnRH) stimulation, together with normal adrenal hormone levels. GnRH analog treatment partially ameliorated his clinical features. Molecular analysis identified a p.Glu3fsAla*16 in NR0B1. These results expand the clinical manifestations of NR0B1 mutations to include central precocious puberty without adrenal insufficiency. NR0B1 mutations likely underlie androgen overproduction via GnRH-dependent and -independent mechanisms.
© 2016 S. Karger AG, Basel
- Ahmad I, Paterson WF, Lin L, Adlard P, Duncan P, et al: A novel missense mutation in DAX-1 with an unusual presentation of X-linked adrenal hypoplasia congenita. Horm Res 68:32-37 (2007).
- Argente J, Ozisik G, Pozo J, Teresa Munoz M, Soriano-Guillen L, Larry Jameson J: A novel single base deletion at codon 434 (1301delT) of the DAX1 gene associated with prepubertal testis enlargement. Mol Genet Metab 78:79-81 (2003).
- Carel JC, Leger J: Clinical practice. Precocious puberty. N Engl J Med 358:2366-77 (2008).
- Darcan S, Goksen D, Ozen S, Ozkinay F, Durmaz B, Lalli E: Gonadotropin-dependent precocious puberty in a patient with X-linked adrenal hypoplasia congenita caused by a novel DAX-1 mutation. Horm Res Paediatr 75:153-156 (2011).
- Domenice S, Latronico AC, Brito VN, Arnhold IJ, Kok F, Mendonca BB: Adrenocorticotropin-dependent precocious puberty of testicular origin in a boy with X-linked adrenal hypoplasia congenita due to a novel mutation in the DAX1 gene. J Clin Endocrinol Metab 86:4068-4071 (2001).
- Durmaz E, Turkkahraman D, Berdeli A, Atan M, Karaguzel G, et al: A novel DAX-1 mutation presented with precocious puberty and hypogonadotropic hypogonadism in different members of a large pedigree. J Pediatr Endocrinol Metab 26:551-555 (2013).
- Izumi Y, Suzuki E, Kanzaki S, Yatsuga S, Kinjo S, et al: Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism. Fertil Steril 102:1130-1136 (2014).
- Jeffs B, Meeks JJ, Ito M, Martinson FA, Matzuk MM, et al: Blockage of the rete testis and efferent ductules by ectopic Sertoli and Leydig cells causes infertility in Dax1-deficient male mice. Endocrinology 142:4486-4495 (2001).
- Katoh-Fukui Y, Igarashi M, Nagasaki K, Horikawa R, Nagai T, et al: Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9. Mol Genet Genomic Med 3:550-557 (2015).
- Koh JW, Kang SY, Kim GH, Yoo HW, Yu J: Central precocious puberty in a patient with X-linked adrenal hypoplasia congenita and Xp21 contiguous gene deletion syndrome. Ann Pediatr Endocrinol Metab 18:90-94 (2013).
- Landau Z, Hanukoglu A, Sack J, Goldstein N, Weintrob N, et al: Clinical and genetic heterogeneity of congenital adrenal hypoplasia due to NR0B1 gene mutations. Clin Endocrinol (Oxf) 72:448-454 (2010).
- Loke KY, Poh LK, Lee WW, Lai PS: A case of X-linked adrenal hypoplasia congenita, central precocious puberty and absence of the DAX-1 gene: implications for pubertal regulation. Horm Res 71:298-304 (2009).
- Macedo DB, Silveira LF, Bessa DS, Brito VN, Latronico AC: Sexual precocity-genetic bases of central precocious puberty and autonomous gonadal activation. Endocr Dev 29:50-71 (2016).
- O'Shaughnessy PJ, Fleming LM, Jackson G, Hochgeschwender U, Reed P, Baker PJ: Adrenocorticotropic hormone directly stimulates testosterone production by the fetal and neonatal mouse testis. Endocrinology 144:3279-3284 (2003).
- Ozisik G, Mantovani G, Achermann JC, Persani L, Spada A, et al: An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita. J Clin Endocrinol Metab 88:417-423 (2003).
- Seminara SB, Achermann JC, Genel M, Jameson JL, Crowley WF Jr: X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females. J Clin Endocrinol Metab 84:4501-4509 (1999).
- Suntharalingham JP, Buonocore F, Duncan AJ, Achermann JC: DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best Pract Res Clin Endocrinol Metab 29:607-619 (2015).
- Takahashi T, Shoji Y, Shoji Y, Haraguchi N, Takahashi I, Takada G: Active hypothalamic-pituitary-gonadal axis in an infant with X-linked adrenal hypoplasia congenita. J Pediatr 130:485-488 (1997).
- Takahashi I, Takahashi T, Shoji Y, Takada G: Prolonged activation of the hypothalamus-pituitary-gonadal axis in a child with X-linked adrenal hypoplasia congenital. Clin Endocrinol (Oxf) 53:127-129 (2000).
- Teilmann G, Pedersen CB, Jensen TK, Skakkebaek NE, Juul A: Prevalence and incidence of precocious pubertal development in Denmark: an epidemiologic study based on national registries. Pediatrics 116:1323-1328 (2005).
- Yeste D, Gonzalez-Nino C, Perez de Nanclares G, Perez-Nanclares G, Audi L, et al: ACTH-dependent precocious pseudopuberty in an infant with DAX1 gene mutation. Eur J Pediatr 168:65-69 (2009).
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