Disorders of Sex Development of Adrenal Origin

Abstract

Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.

Adrenal hyperplasias in childhood: An update

“…Approximately 75% of classic CAHs represent life-threatening salt-wasting forms and they are a result of large gene conversions, nonsense or frameshift mutations or complete deletions leading to complete absence of 21OH activity. Production of mineralocorticoids and glucocorticoids is ceased resulting in life-threatening adrenal crises in the first two weeks of life ( 72 ). When CAH is suspected, then aldosterone, serum electrolytes and plasma renin should be measured.…”

“…The expected abnormalities are low aldosterone levels, hyperkalemia and elevated renin; however, because renin levels are age-specific appropriate references should be used ( 73 ). On the other hand, the NCCAH forms are more often associated with missense variants and they retain some enzymatic activity and thus are able to maintain a relatively normal amount of aldosterone and cortisol at the expense of mild to moderate excess of sex hormone precursors salt balance ( 72 ); they present with premature pubarche during childhood; however cases have been described as early as six months old ( 74 ). Females most commonly present during adolescence with hirsutism, acne and menstrual abnormalities or infertility, findings similar to polycystic ovarian syndrome (PCOS) while males often remain undiagnosed until they undergo pre-conception genetic screening or after having an affected offspring ( 74 ).…”

“…About 0.2-8% of all CAH cases are due to 11βOHD (OMIM#202010) ( 72 ). 11βOH encoded by CYP11B1 , catalyzes the conversion of 11-deoxycortisol and 11-deoxycorticosterone (DOC) to cortisol and corticosterone, respectively.…”

“…This form of CAH is very rare accounting for <0.5% of the cases (OMIM#201810) ( 80 ). 3β-hydroxysteroid dehydrogenase exists in two isoforms; 3βHSD1, encoded by HSD3B1 (the homologous type I gene) and is expressed in the placenta and peripheral tissue (liver, skin, brain) and 3βHSD2, encoded by HSD3B2 and is found in the adrenals and gonads ( 72 ). Inactivating variants in HSD3B2 impair steroidogenesis in both gonads and adrenals, leading to deficiency of glucocorticoids and mineralocorticoids as well as overproduction of dehydroepiandrosterone (DHEA).…”

Ectopic Prostate Tissue in the Uterine Cervix of a Female with Non-Classic Congenital Adrenal Hyperplasia—A Case Report

“…Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH 21-OHD) is an autosomal recessive disorder and one of the most common forms of DSD [ 6 ]. It is characterized by cortisol deficiency and an adrenocorticotropic hormone (ACTH)-driven adrenal androgen excess [ 7 ].…”