Clinical perspectives in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Abstract

Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency is a rare autosomal recessive genetic disorder. It is caused by reduced or absent activity of 11β-hydroxylase (CYP11B1) enzyme and the resultant defects in adrenal steroidogenesis. The most common clinical features of 11 beta-hydroxylase deficiency are ambiguous genitalia, accelerated skeletal maturation and resultant short stature, peripheral precocious puberty and hyporeninemic hypokalemic hypertension. The biochemical diagnosis is based on raised serum 11-deoxycortisol and 11-deoxycorticosterone levels together with increased adrenal androgens. More than 100 mutations in CYP11B1 gene have been reported to date. The level of in-vivo activity of CYP11B1 relates to the degree of severity of 11 beta-hydroxylase deficiency. Clinical management of 11 beta-hydroxylase deficiency can pose a challenge to maintain adequate glucocorticoid dosing to suppress adrenal androgen excess while avoiding glucocorticoid-induced side effects. The long-term outcomes of clinical and surgical management are not well studied. This review article aims to collate the current available data about 11 beta-hydroxylase deficiency and its management.

Next-Generation Sequencing Identifies Different Genetic Defects in 2 Patients with Primary Adrenal Insufficiency and Gonadotropin-Independent Precocious Puberty

“…Mutations of the CYP11B1 gene (chromosome 8q24.3) reduce or abolish the activity of 11β-hydroxylase enzyme that catalyzes, in the zona fasciculata of the adrenal cortex, the conversion of 11-deoxycortisol and deoxycorticosterone (DOC) to cortisol and corticosterone, respectively. The low cortisol levels activate the negative feedback of the pituitary-adrenal axis, leading to increased ACTH production, which causes adrenal cortex hyperplasia [2, 3, 15]. Classical CAH due to 11β-hydroxylase deficiency (MIM#202010) is characterized by low cortisol levels and excessive adrenal androgen production starting during fetal life, with prenatal virilization of the female fetus.…”

“…Classical CAH due to 11β-hydroxylase deficiency (MIM#202010) is characterized by low cortisol levels and excessive adrenal androgen production starting during fetal life, with prenatal virilization of the female fetus. After birth, the excessive androgen production causes in both sexes an acceleration of growth and skeletal maturation, virilization in females and gonadotropin-independent precocious puberty in males [2, 3, 15]. Clinical manifestation of mineralocorticoid disorder in 11β-hydroxylase-deficient CAH can be biphasic, ranging from severe deficiency (salt-wasting crisis) in early infancy to excess of mineralocorticoid precursors as DOC, causing hyporeninemic hypokalemic hypertension in late childhood or adult life [2, 3, 15].…”

“…In particular, mutations of CYP21A2 (encoding 21-hydroxylase) and CYP11B1 (encoding 11β-hydroxylase) cause congenital adrenal hyperplasia (CAH) characterized by a block in cortisol and aldosterone biosynthesis, with ensuing accumulation of androgen precursors [2]. Male patients classically present with early symptoms of PAI followed by gonadotropin-independent (peripheral) precocious puberty [2, 3]. …”

Diagnostic approach to low‐renin hypertension

“…The excessive androgens production results in various degrees of virilization of female external genitalia and pseudoprecocious pubertal development in males, together with accelerated somatic growth, but premature closure of growth plates resulting in short stature in adulthood. Due to DOC excess, that act as a mineralocorticoid (Figure ), two‐thirds of the affected subjects display hypertension at diagnosis, together with suppressed renin, low‐aldosterone levels and hypokalaemia (however, present in a minority of the cases) . The goal of therapy is to replace deficient cortisol synthesis, reduce ACTH excess as well as DOC and androgens overproduction.…”

“…Standard treatment is therefore based on chronic glucocorticoid treatment, at the lowest effective dose to avoid cushingoid side effects . If hypertension is not well controlled by glucocorticoids alone, a MRA can be administered …”