{"id":3126801,"date":"2020-07-10T20:23:00","date_gmt":"2020-07-11T00:23:00","guid":{"rendered":"https:\/\/myendoconsult.com\/learn\/?p=3126801"},"modified":"2023-03-16T06:18:18","modified_gmt":"2023-03-16T11:18:18","slug":"non-classical-adrenal-hyperplasia","status":"publish","type":"post","link":"https:\/\/myendoconsult.com\/learn\/non-classical-adrenal-hyperplasia\/","title":{"rendered":"Non classical adrenal hyperplasia"},"content":{"rendered":"

Congenital adrenal hyperplasia (CAH)<\/strong> refers to a group of inherited enzymatic defects in cortisol biosynthesis. Impairment in cortisol production lifts the classic negative effect of cortisol on the hypothalamus and the pituitary gland<\/a>.<\/p>\n

Subsequently, this results in the secretion of corticotropin-releasing hormone (CRH) and ACTH, by the hypothalamus and anterior pituitary gland respectively, resulting in hyperplasia of the adrenal cortex. 21-hydroxylase deficiency (21OHD) also known as classic CAH accounts for almost 90% of CAH cases. Non classical adrenal hyperplasia<\/strong> is relatively less common and contributes to hyperandrogenemia.<\/p>\n

Classification of Congenital adrenal hyperplasia<\/h2>\n

It is worth noting that 21OHD is grouped into classic and nonclassic forms, based on the presence or absence of cortisol insufficiency (adrenal insufficiency). Furthermore, the classic subtype of 21OHD is further dichotomized into \u201csalt-wasting\u201d and \u201csimple virilizing\u201d variants, depending on whether or not mineralocorticoid synthesis is sufficiently impaired.<\/p>\n

The nonclassic 21OHD (NCCAH) is a much more frequent cause of clinical hyperandrogenemia, occurring in about 1 in 1,000 Caucasians. The prevalence is highly variable, depending on the ethnic group – Ashkenazi Jews (1:27), Hispanics (1:53), Yugoslavs (1:62), and Italians (1:300). The difference between the classic and non-classic forms is that girls who suffer from the latter do not develop either cortisol deficiency or overt clinical virilization (a sign of hyperandrogenemia).<\/p>\n

Pathophysiology of Congenital adrenal hyperplasia<\/h2>\n

Steroidogenesis in the adrenal gland<\/a> is dependent on the expression of enzymes in specific zones of the gland (review this simple mnemonic for remembering adrenal steroidogenesis here<\/a>). This results in the synthesis of various adrenal steroids including aldosterone, cortisol, and dehydroepiandrosterone sulfate.\u00a0 The primary defect in CAH is an adrenal steroidogenic enzyme defect, which results in low levels of serum cortisol. The loss of negative feedback control activates the hypothalamic-pituitary-adrenal axis, which results in increased Adrenocorticotropic hormone (ACTH) production. ACTH stimulates the buildup and subsequent shunting of precursor steroids into either adrenal androgens or mineralocorticoid production[1].\u00a0Distinguishing between non classic and classic congenital adrenal hyperplasia? [2]\n\n\n\n\n\n\n\n
Classic CAH<\/td>\nNon classic CAH (mild form of CAH)<\/td>\n<\/tr>\n
Large gene deletion involving the CYP21A2 gene.<\/td>\nUsually, a point mutation (70% of patients) in the CYP21A2 gene.<\/td>\n<\/tr>\n
Loss of 21-hydroxylase enzyme activity by 95-100%<\/td>\nLoss of 21-hydroxylase enzyme activity by 20-50%<\/td>\n<\/tr>\n
Early onset (detected at birth)<\/td>\nLate onset (detected in the reproductive years)<\/td>\n<\/tr>\n
Ambiguous genitalia in females<\/td>\nNormal genitals in females<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Other forms of CAH<\/h2>\n

The primary defect in CAH is an adrenal steroidogenic enzyme deficiency, which results in low levels of serum cortisol. The loss of negative feedback control activates the hypothalamic-pituitary-adrenal axis, which results in increased Adrenocorticotropic hormone (ACTH) production. ACTH stimulates the buildup and subsequent shunting of precursor steroids into either androgen or mineralocorticoid production[1].\u00a0The steroidogenic acute regulatory protein<\/strong> (StAR), at the level of the adrenal gland, mobilizes cholesterol from the outer to the inner mitochondrial membrane. The cytochrome P450 side-cleavage enzyme (P450scc) in the inner mitochondrial membrane converts cholesterol to pregnenolone; this is the rate-limiting step of adrenal steroidogenesis. The downstream effects of StAR are under trophic stimulation by both ACTH and luteinizing hormone (LH)[3].\u00a0Pregnenolone is then converted to progesterone by 3beta-hydroxysteroid dehydrogenase type 2<\/strong> (HSD3B2), in the zona glomerulosa. Progesterone is then converted through a series of enzymatic steps involving 21 hydroxylase<\/strong> (CYP21A2) and aldosterone synthase<\/strong> into aldosterone.<\/p>\n

In the zona fasciculata, pregnenolone is hydroxylated into 17-hydroxypregnenolone by CYP17A1 (17-alpha-hydroxylase enzyme\/17,20 lyase). HSD3B2, CYP21A2, and CYP11B1 (11 beta-hydroxylase) are then involved in downstream reactions leading to the production of cortisol.\u00a0In the zona reticularis, CYP17A1 and HSD3B2 are involved in the eventual formation of androgen precursors such as dehydroepiandrosterone (DHEA) and androstenedione[4].<\/p>\n

Some of the types of CAH outlined below are rare disorders.<\/p>\n

    \n
  1. Congenital lipoid hyperplasia (CLH)<\/b><\/em>. CLH is due to an autosomal recessive mutation in the gene encoding StAR. Clinical features include severe adrenal insufficiency (both mineralocorticoid and glucocorticoid deficiency) and external female genitalia in male infants. It is a severe form of CAH[5].<\/li>\n
  2. 3beta-hydroxysteroid dehydrogenase type 2 deficiency<\/b>. <\/em>The clinical spectrum of 3BHSD varies from a presentation akin to CLH (both mineralocorticoid and glucocorticoid deficiency) to an even less severe subtype characterized by the absence of salt-wasting [6].<\/li>\n
  3. 17 hydroxylase deficiency.<\/b><\/em> A genetic mutation in CYP17A1 impairs steroidogenesis in both the adrenal glands and gonads[7]. Genetic females have normal-appearing female external genitalia at birth but subsequently present with delayed puberty. Male infants, on the other hand, are unable to synthesize testosterone, critical in developing male external genitalia. This results in the formation of female appearing external genitalia]8,9]. Also, males do not have internal Mullerian structures (uterus and fallopian tubes) since their anatomic testes continue to produce anti-Mullerian hormone. Despite patients being mildly glucocorticoid deficient, they seldom develop overt adrenal crises. This is because of the accumulation of precursors such as corticosterone and 11-deoxycorticosterone (DOC) not only activates the mineralocorticoid receptor to maintain blood pressure but also contributes to hypertension in affected patients[10].<\/li>\n
  4. 11 beta-hydroxylase deficiency.<\/b><\/em> A genetic mutation in CYP11B1 results in a defective 11beta hydroxylase<\/strong>, a critical enzyme in cortisol synthesis[11,12]. There is, therefore, an accumulation of proximal precursors such as DOC <\/strong>and 11-deoxycortisol<\/strong>. DOC has intrinsic mineralocorticoid activity and accounts for hypertension and hypokalemia observed in these patients[13]. There is an additional shunting of more proximal steroids into androgen production (DHEA, DHEA-S, and androstenedione). Genetic males have enlarged penile shafts at birth due to hyperandrogenemia. Genetic females have ambiguous genitalia due to exposure to elevated serum androgens during intrauterine life[13,14].<\/li>\n
  5. 21 hydroxylase deficiency.<\/b><\/em> This is a classical form of CAH – a genetic mutation in CYP21A2 results in a defective 21 hydroxylase enzyme. 21-hydroxylation of progesterone (mineralocorticoid synthesis pathway) and 17-hydroxyprogesterone (glucocorticoid synthesis pathway) is therefore impaired. There is a subsequent diversion of proximal steroidogenic precursors into androgen production. Newborns with more deleterious mutations in the CYP21A2 gene are hemodynamically unstable due to impaired glucocorticoid and mineralocorticoid synthesis. Genetic females present with ambiguous genitalia[15].<\/li>\n<\/ol>\n

    Clinical features of non classic CAH<\/h2>\n

    Non classic CAH accounts for up to 2% of cases of hyperandrogenemia involving women in their reproductive years[16]. The clinical presentation of this condition is variable. A few clinical features include :<\/p>\n