Session: SUN 29-49-Congenital Adrenal Hyperplasia & Ectopic Cushing's
Poster Board SUN-33
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.
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
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