The congenital adrenal hyperplasias (CAH) are a group of inherited disorders that result from loss-of-function mutations in one of several genes involved in adrenal steroid hormone synthesis. In the virilizing forms of CAH the mutations result in impairment of cortisol production and the consequent accumulation of steroid intermediates proximal to the defective enzyme. In the virilizing forms of CAH there is increased ACTH secretion which leads to elevated synthesis of adrenal androgens. In addition, there is adrenal cortical hyperplasia, the symptom that imparts the name to these disorders. All forms of CAH are inherited in an autosomal recessive manner.
There are two common and at least three rare forms of virilizing CAH. The common forms are caused by defects in either CYP21A2 (21-hydroxylase, also identified as just CYP21 or CYP21B) or CYP11B1 (11β-hydroxylase). The majority of CAH cases (90-95%) are the result of defects in CYP21A2 with a frequency of between 1 in 5,000 and 1 in 10,000. Three rare forms of virilizing CAH result from either defects in 3β-hydroxysteroid dehydrogenase (HSD3B2), placental aromatase (CYP19A1) or P450-oxidoreductase (POR). The typical signs of virilizing CAH are reflective of the androgen excess as well as the mineralocorticoid and glucocorticoid deficiencies. In general, the degree to which a given mutation results in reduction of enzyme activity is correlated to the level of glucocorticoid and mineralocorticoid deficiency.
An additional CAH is caused by mutations that affect either the 17β-hydroxylase, 17,20-lyase or both activities encoded in the CYP17A1 gene. Unlike the virilizing forms of CAH, in individuals harboring CYP17A1 mutations that result in severe loss of enzyme activity there is absent sex steroid hormone production accompanied by hypertension resulting from mineralocorticoid excess.
CYP21A2 deficiency: CAH resulting from deficiencies in the CYP21A2 gene represent the most commonly occurring forms (>95%) of the disease. The majority of the mutations in CYP21A2 that result in CAH have been identified and the severity of the disorder can be correlated to specific mutations and the consequent effect of the mutation on enzyme activity. Deficiencies in CYP21A2 result in decreased secretion and plasma concentration of cortisol. The reduced levels of cortisol result in a reduction in the negative feedback exerted by this hormone on the hypothalamic-pituitary axis. The reduced negative feedback leads to increased secretion of corticotropin releasing hormone (CRH) and ACTH. The resultant high plasma concentrations of ACTH are responsible for the adrenocortical hyperplasia characteristic of this disorder.
CAH resulting from CYP21A2 deficiencies is divided into three distinct clinical forms. The most severe enzyme impairment mutations result in the salt-losing form. Females with this form of the disease present at birth due to ambiguity in the external genitalia. Males with the salt-losing form present with acute adrenal crisis shortly after birth or in early infancy. Females who present with no acute adrenal crisis and only mild masculinization of the external genitalia and males who present with virilism early in life are considered be be suffering from the simple virilizing form of CAH. The final clinical form of CAH manifests only in females at puberty or shortly thereafter with symptoms of mild excess androgen development resulting in hirsutism, amenorrhea, and infertility. This form of the disorder is referred to as the attenuated form or the late onset or nonclassic form.
The 21-hydroxylase gene (CYP21A2, CYP21, CYP21B) is located within the class III region of the major histocompatibility complex (MHC) on chromosome 6. There are in fact, two CYP21 genes within this MHC locus but one of the two is a pseudogene and is identified as CYP21P. Older nomenclature identifies the CYP21P gene as the 21-hydroxylase A gene (or CYP21A1) and CYP21A2 as the 21-hydroxylase B gene. All 21-hydroxylase activity is synthesized from the mRNA encoded by the CYP21A2 gene. The CYP21A2 gene is located on chromosome 6p21.3 and is composed of 10 exons that generate two alternatively spliced mRNAs. The encoded proteins from these two mRNAs are identified as steroid 21-hydroxylase isoform a (495 amino acids) and steroid 21-hydroxylase isoform b (465 amino acids).
Salt-losing CYP21A2 deficiency: In the salt-losing form of this disorder the degree of loss of enzyme activity is severe to complete. As a result of the level of enzyme deficiency the synthesis of cortisol is negligible. Because CYP21A2 is also needed for the synthesis of aldosterone, which is a major hormone involved in Na+ retention by the kidney, there is excessive salt loss leading to hyponatremic dehydration which can be fatal if not treated. Although there is some aldosterone made, the level of salt loss exceeds the ability of the adrenal cortex to make sufficient aldosterone to compensate. The net result is an acute adrenal crisis. The near complete, or complete, loss in cortisol production results in maximal activity of the CRH-ACTH axis leading to maximal adrenal androgen secretion with the result being masculinization of the female genitalia. The first sign of CAH due to CYP21A2 deficiency is, in fact, the ambiguous female genitalia in neonates. The masculinization can be so extreme as to result in the fusion of the labia and the formation of a penile urethra. Diagnosis of the salt-losing form of this disorder is made in females born with masculinized genitalia, who are of normal 46,XX karyotype, with marked elevation in plasma 17α-hydroxyprogesterone and androstenedione, as well as serum chemistry showing hyponatremia, hypochloremia and hyperkalemic acidosis.
Simple virilizing CYP21A2 deficiency: In the simple virilizing form of the disorder the deficiency in CYP21A2 is not complete or as severe as in the salt-losing form. As a result the adrenal cortex can compensate for salt loss with increased aldosterone synthesis and release. In addition, the increased ACTH release result in normal plasma cortisol levels and thus, there is no glucocorticoid deficit. However, as in the salt-losing form the CRH-ACTH axis is hyperactive leading to excessive adrenal androgen synthesis with consequent masculinization of the female genitalia.
Attenuated CYP21A2 deficierncy: As the name of this form of disease implies, patients with the attenuated form exhibit only mild reductions in CYP21A2 activity. Symptoms associated with this form of the disorder manifest in females at puberty. There are no signs of masculinization of the genitalia in females with this form of the disease. Although females have relatively normal breast development, the androgen excess results in excessive body hair (hirsutism), amenorrhea and the development of small ovarian cysts.
Gene Reviews page on CYP21A2-deficient CAH
CYP11B1 deficiency: CAH due to deficiencies in 11β-hydroxylase (CYP11B1), although rare, are the second most commonly occurring forms of these disorders being found in approximately 5% of CAH patients. CYP11B1 deficiency was originally identified as a hypertensive form of CAH. Deficiency of CYP11B1 activity in the zona fasciculata results in impaired reductions in cortisol and corticosterone synthesis. In addition, the loss of negative feedback on the hypothalamic-pituitary axis leads to increased ACTH release with the consequent increase in production of deoxycorticosterone (DOC; 11-deoxycorticosterone), 11-deoxycortisol, and 18-hydroxy DOC. The hypertension seen in this form of CAH is due to the increased secretion of DOC is a weak mineralocorticoid activating the aldosterone receptor in the kidney (mineralocorticoid receptor) resulting dysregulation in the the renin-angiotensin-aldosterone system (RAAS). Because there is hypersecretion of ACTH and a block in the normal pathway to corticosteroid synthesis there is an androgen excess similar to that seen in the CYP21A2 deficiency forms of CAH. As a result, females exhibit masculinized genitalia.
The CYP11B1 gene is located on chromosome 8q21 spanning 6.5kbp and composed of 11 exons that generate two alternatively spliced mRNAs encoding isoform 1 (503 amino acids) ans isoform 2 (437 amino acids). Both isoforms encoded by the CYP11B1 gene include a 24 amino acid mitochondrial localization signal.
HSD3B2 deficiency: CAH due to deficiencies in 3β-hydroxysteroid dehydrogenase represent less than 1% of all cases. When the deficiency is severe there is a near total absence of adrenal steroids. Thus there are deficiencies in the glucocorticoids, mineralocorticoids, as well as adrenal androgens. The impaired corticosteroid synthesis results in symptoms of adrenal insufficiency that can be fatal if not treated during the neonatal period. Several steroid precursors accumulate including pregneneolone and DHEA as well as their hydroxylated derivatives. Females with this disorder will present with slight fusion of the labia and an enlarged clitoris, while males present with ambiguous genitalia. Correct diagnosis of this disorder can be made by measurement of the levels of DHEA, 17α-hydroxypregnenolone and 16α-hydroxy-DHEA in the urine and serum.
The HSD3B2 gene is located on chromosome 1p13.1 and is composed of 5 exons that generate two alternatively spliced mRNAs, both of which encode the same 372 amino acid protein.
POR deficiency: Cytochrome P450 oxidoreductase (POR) is a flavoprotein that donates electrons to all microsomal P450 enzymes. In the context of adrenal streroidogenesis, POR functions as the electron donor for CYP17A1, CYP21A2, and CYP19A1. Deficiencies in POR result in ambiguous genitalia in both males and females. Some of the skeletal malformations resulting from POR deficiency resemble Antley-Bixler syndrome (ABS), however ABS is not associated with disordered steroidogenesis. These skeletal malformations include midface hypoplasia, low set ears, craniosynostosis (premature fusion of the cranial sutures), choanal atresia (blockage in the back of the nasal passage), and fusion of the arm bones. CAH resulting from POR deficiencies are rare.
The POR gene is located on chromosome 7q11.2 and is composed of 16 exons that encode a 680 amino acid protein.
Placental aromatase (CYP19A1) deficiency: The aromatase gene (also called estrogen synthetase) is expressed in ovaries, placenta, and extragonadal tissues such as adipose tissue, liver, brain, muscle, and hair follicles. The activity of the enzyme is to convert androgens to estrogens. During fetal development the fetal adrenal glands secrete DHEA-S as the substrate for placental estrogen production. The loss of CYP19A1 activity results in decreased placental estrogen production and increased androgen precursors. Female infants may have masculinized external genitalia.
The CYP19A1 gene is located on chromosome 15q21.1 spanning 70kbp and composed of 13 exons that generate two alternatively spliced mRNAs, both of which encode the same 503 amino acid enzyme.
CYP17A1 deficiency: The CYP17A1 enzyme catalyzes both the 17α-hydroxylase and 17,20-lyase (side-chain removal) reactions of adrenal steroidogenesis. Similar to each of the above described CAH, the underlying clinical manifestations of CYP17A1 deficiency are due to the inability to produce normal levels of glucocorticoids with the consequences being a loss of the feedback inhibition of the hypothalamic-pituitary axis resulting in elevated ACTH secretion. However, symptoms in these patients are less severe than in other forms of CAH. Patients with 17α-hydroxylase deficiency do not make cortisol but do produce large amounts of corticosterone. Corticosterone does bind the glucocorticoid receptor but with an affinity 1/100th that of cortisol. Deoxycorticosterone (DOC), which serves as the precursor to corticosterone, exhibits significant mineralocorticoid activity. This fact explains the hypertension exhibited in 17α-hydroxylase deficient patients. A deficiency in the 17,20-lyase activity of CYP17A1 leads to loss of C-18 and C-19 steroids from C-21 precursors leading to impaired production of androgens and estrogens. Affected males have defective genital development in utero and present with ambiguous external genitalia at birth. Development of female genitalia in utero does not require endogenous sex steroid production thus, affected females present at birth with normal external genitalia. However, female patients will present at puberty with infantile breasts, primary amenorrhea, absent or scant axillary and pubic hair, and hypogonadism.
The CYP17A1 gene is located on chromosome 10q24.3 and is composed of 8 exons encoding a 508 amino acid enzyme. Deficiency in CYP17A1 is extremely rare with more than 90% of reported cases having deficiency in the both the 17α-hydroxylase and 17,20-lyase activities or just 17α-hydroxylase. The remainder of reported cases have deficiency in only the 17,20-lyase activity.