X-linked Adrenal Hypoplasia Congenita: report of two families and a new NR0B1 mutation

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 29-49-Congenital Adrenal Hyperplasia & Ectopic Cushing's
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-33
Bernardo Dias Pereira*1, Tiago Nunes Silva1, Henrique Vara Luiz1, Andreia Veloza1, Ana Catarina Matos1, Isabel Manita1, Maria Carlos Cordeiro1, Luísa Raimundo1, Joao M Goncalves Sr.2 and Jorge Portugal1
1Garcia de Orta Hospital, Almada, Portugal, 2National Institute of Health Dr. Ricardo Jorge, Lisboa, Portugal
Background: The rare X-linked Adrenal Hypoplasia Congenita tipically manifests as adrenal insufficiency (AI) in the newborn age and hypogonadotropic hypogonadism (HH) in males at puberty. It is caused by mutations in NR0B1 (present in Xp21.2), a critical gene in the development of adrenals and hypothalamic-pituitary-gonadal axis (HPGA) (1-3). We present two families with NR0B1mutations, one previously unreported.

Clinical case: The proband of family A presented with AI at day 19 of life. He had elevated ACTH (35pmol/L, reference for age - RA: <11), normal cortisol (221nmol/L, RA: 56-665) and androgens (17-OHP: 10nmol/L, RA: 8-25; 11-deoxycortisol: 84nmol/L, RA: 48-261), but beyond 2 yo serial steroid measurements rendered undetectable (17-OHP <0.3nmol/L; 11-deoxycortisol <0.2nmol/L). HPGA evaluation due to absent pubertal growth spurt confirmed HH (14 yo: FSH 0.9UI/L; LH <0.1UI/L; TT <0.5nmol/L; RA: 0.5-17.5). Molecular analysis of the NR0B1 gene revealed the mutation c.1084A>T, leading to a premature stop codon, p.Lys362*, in exon 1. His mother and sister were also asymptomatic carriers. This mutation, not previously described, leads probably to a non-functional truncated protein. Family B had two males manifesting AI at 14 (proband) and 16 days (brother) of life. The proband had elevated ACTH (193pmol/L, RA: <11), cortisol (634nmol/L, RA: 107-405) and 17-OHP (15nmol/L, RA: 1.6-5), which didn´t rose with tetracosactrin (peaks: cortisol-635nmol/L, 17-OHP-11.5nmol/L). Beyond 2.8 yo both siblings had undetectable androgen levels and delayed bone age. Prepubertal stage at 14 yo triggered HPGA surveys in both males (proband: FSH 2.61UI/L, LH <0.1UI/L, TT <0.5nmol/L, RA: 0.5-17.5; brother: FSH 0.4UI/L, LH <0.1UI/L, TT <0.5), proving HH. NR0B1molecular analysis allowed the identification of a nonsense mutation, c.234C>G; p.Tyr81*, in exon 1, present in the two affected males. Their mother and sister were asymptomatic carriers. 

Conclusion: Biochemical profiles, bone age and an apparently X-linked mode of inheritance led to a presumptive diagnosis. Molecular analysis of the NR0B1 gene allowed the identification of the defect in both families. Two different nonsense mutations in exon 1 were detected, one previously unreported, giving rise most probably to truncated non-functional proteins, confirming the disease severity and the clinical phenotype of the affected boys. Mutation identification was relevant for genetic counseling to parents and patient’s sisters.

(1) Lin L, Gu WX, Ozisik G, To WS, Owen CJ, Jameson JL, et al. J Clin Endocrinol Metab 2006; 91: 3048-3054. (2) Peter M, Viemann M, Partsch CJ, Sippell W. J Clin Endocrinol Metab 1998; 83: 2666-2674. (3)Jadhav U, Harris R, Jameson J. Mol Cell Biol 2011; 346: 65–73.

Nothing to Disclose: BDP, TNS, HVL, AV, ACM, IM, MCC, LR, JMG Sr., JP

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm