Clinical, Genetic and Structural Basis of Congenital Adrenal Hyperplasia Due to 11β-Hydroxylase Deficiency

KHATTAB A; HAIDER S; KUMAR A; DHAWAN S; ALAM D; ROMERO R; BURNS J; MICHELLI D,; ESTATICO J; RAHI S; FATIMA S; ALZAHRANI A S; HAFEZ M; MUSA N; AZAR M; BEN CHARFEDDINE I; BILHARINHO DE MENDONCA B; BELGOROSKY A; DUMIC K; DUMIC M; AISENBERG J; KANDEMIR N; CHENG T; KUHNLE-KRAHL U; CAPPA M; HOLTERHUS P M; NOUR M; HOLTZMAN A; SUN L; ZAIDI M; YUEN T; NEW M

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2017

0027-8424

Congenital adrenal hyperplasia (CAH) owing to mutations inCYP11B1, a gene encoding 11β-hydroxylase, represents a rareautosomal recessive Mendelian disorder of aberrant sex steroidproduction. Unlike CAH due to 21-hydroxylase deficiency, thedisease is far more common in Arabic-speaking nations of theMiddle East and North Africa, where consanguinity is commonoften resulting in identical mutations. Clinically, affected femalenewborns are profoundly virilized (Prader score of 4/5), and bothgenders display significantly advanced bone ages and are oftentimeshypertensive. We find that 11-deoxycortisol, not frequentlymeasured, is the most robust biochemical marker for diagnosing11β-hydroxylase deficiency. Finally, computational modeling of 25missense mutations of CYP11B1 revealed that specific modificationsin the heme-binding (R374W and R448C) or substrate-binding(W116C) site of 11β-hydroxylase, or alterations in its stability(L299P and G267S), may predict severe disease. Thus, we reportclinical, genetic, hormonal and structural effects of CYP11B1 genemutations in the largest international cohort of 108 patients withsteroid 11β-hydroxylase deficiency CAH.