Abstract
Mutation in the orphan nuclear receptor DAX-1 gene causes X-linked adrenal hypoplasia congenita (AHC). Affected male children classically suffer a salt-losing crisis and adrenal insufficiency in their early infancy or, in some rare exceptions, with late-onset subtype. We report here a patient manifesting late-onset adrenal hypoplasia congenita caused by the premature truncation of the C-terminus of the DAX-1 molecule, which is essential for its function as a transcriptional repressor. A 12-year-old boy was referred to us after being afflicted with generalized skin pigmentation for about 3 years, fatigue and headache. Primary adrenal insufficiency was determined on the basis of a low plasma cortisol level (3.9 μg/dl) despite an extremely high ACTH level (1200 pg/ml). Replacement therapy with hydrocortisone and fludorocortisone acetate was initiated soon thereafter. Hypogonadotropic hypogonadism was confirmed at the age of 18 years, at which time sexual infantilism had become apparent. Direct sequencing of the peripheral lymphocyte-derived DNA revealed a novel 1033del13 mutation on the ligand-binding domain of the NR0B1 (DAX-1) gene, which generated a premature stop codon truncating the C-terminus. This mutation was considered de novo since we could not find it in his mother. This case demonstrates that even a truncated protein lacking the major functional domain of DAX-1 can present late-onset and latent adrenal failure.
Similar content being viewed by others
References
Habity RL, Boepple P, Nachtigall L, Sluss PM, Crowley WF Jr, Jameson JL (1996) Adrenal hypoplasia congenita with hypogonadotropic hypogonadism: evidence that DAX-1 mutations lead to combined hypothalamic and pituitary defects in gonadotropin production. J Clin Invest 98:1055–1062
Ito M, Yu R, Jameson JL (1997) DAX-1 inhibits SF-1-mediated transactivation via a carboxyl-terminal domain that is deleted in adrenal hypoplasia congenita. Mol Cell Biol 17(3):1476– 14 83, Mar
Loke KY, Larry KS, Lee YS, Peter M, Drop SL (2000) Prepubertal diagnosis of X-linked congenital adrenal hypoplasia presenting after infancy. Eur J Pediatr 159(9):671–675
Mantovani G, Ozisik G, Achermann JC, Romoli R, Borretta G, Persani L et al (2002) Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenita. J Clin Endocrinol Metab 87(1):41–43
Nakae J, Tajima T, Kusuda S, Kohda H, Okabe T, Shinohara N, Kato M, Murashita M, Mukai T, Imanaka K, Fujieda K (1996) Truncation at the C-terminus of the DAX-1 protein impairs its biological actions in patients with X-linked adrenal hypoplasia congenita. J Clin Endocrinol Metab 81:3680–3685
Phelan JK, McCabe ER (2001) Mutations in NR0B1 (DAX-1) and NR5A1 (SF1) responsible for adrenal hypoplasia congenita. Hum Mutat 18:472–487
Seminara SB, Achermann JC, Genel M, Jameson JL, Crowley WF Jr (1999) X-Linked adrenal hypoplasia congenita: A mutation in DAX1 expands the phenotypic spectrum in males and females. J Clin Endocrinol Metab 84:4501–4509
Tabarin A, Achermann JC, Recan D, Bex V, Bertagna X, Christin-Maitre S, Ito M, Jameson JL, Bouchard P (2000) A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism. J Clin Invest 105(3):321–328
Zanaria E, Muscatelli F, Bardoni B, Strom TM et al (1994) An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372:635–641
Zhang YH, Guo W, Wagner RL, Huang BL, McCabe L, Vilain E et al (1998) DAX-1 mutations map to putative structural domains in a deduced three-dimensional model. Am J Hum Genet 62(4):855–864
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yang, F., Hanaki, K., Kinoshita, T. et al. Late-onset adrenal hypoplasia congenita caused by a novel mutation of the DAX-1 gene. Eur J Pediatr 168, 329–331 (2009). https://doi.org/10.1007/s00431-008-0779-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-008-0779-x