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Abstract

Abstract 

  1. Congenital adrenal hyperplasia (CAH, MIM 300200) is a group of diseases whose common feature is an enzymatic defect in the steroidogenic pathway leading to the biosynthesis of cortisol. This relative decrease in cortisol production causes an increase in adrenocorticotropic hormone (ACTH) secretion and consequent hyperplasia of the adrenal cortex. All forms of CAH are inherited in an autosomal recessive manner. The variable phenotypes are determined by the effects produced by deficient hormones and by excess production of steroids unaffected by the enzymatic block.

  2. The biochemical pathways of adrenal steroid production are interrelated. The three zones of the adrenal cortex produce three classes of steroid hormones: glucocorticoids and androgens (zona fasciculata/reticularis) and mineralocorticoids (zona glomerulosa). All but one of the enzymatic steps are mediated by members of the cytochrome P450 (CYP) family of mixed-function oxidases. The first step in the production of all steroid hormones, mediated by CYP11A, is the conversion of cholesterol to pregnenolone. Pregnenolone may then be acted on by CYP17 to form 17-hydroxypregnenolone and then dehydroepiandrosterone (DHEA), or it may be converted to progesterone by the non-P450 enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD). 3β-HSD also converts 17-hydroxypregnenolone to 17-hydroxyprogesterone and DHEA to androstenedione, an androgen precursor. Progesterone and 17-hydroxyprogesterone are then converted by CYP21 to 11-deoxycorticosterone (a mineralocorticoid) and 11-deoxycortisol, respectively. These two products are then converted by CYP11B1 to corticosterone and cortisol (the major glucocorticoid), respectively. Aldosterone, the major mineralocorticoid, is produced from corticosterone by the enzyme CYP11B2 (aldosterone synthase).

  3. Control of adrenal steroid production is multifaceted. Glucocorticoid production is stimulated primarily by the anterior pituitary hormone ACTH, which itself is controlled by the hypothalamic corticotropin-releasing hormone (CAH). Aldosterone secretion is modulated by the renin-angiotensin system. Adrenal androgen secretion is stimulated by excessive ACTH, but physiologic control is through an unidentified factor.

  4. In keeping with their different physiologic regulations, the secretion rates of the various adrenocortical hormones vary independently. The cortisol secretion rate is approximates 12 mg/m2 of body surface area per day. This rate is somewhat higher—but quite variable—in newborn infants and significantly higher during periods of physiologic stress, such as fever and surgery. The aldosterone secretion rate (approximately 100 μg/day) remains fairly constant throughout life. Adrenal androgen secretion is quite low during infancy and childhood and increases gradually to maximal levels during puberty and early adulthood, with age-related declines thereafter.

  5. 21-Hydroxylase (CYP21) deficiency is the most common form of CAH, accounting for over 90 percent of cases. The incidence varies from 1 in 10,000 to 18,000 live births. There is a continuum of degrees of CYP21 deficiency that results in a continuum of severity of clinical presentations. The most marked deficiency results in the salt-losing form of CAH, characterized by both mineralocorticoid and glucocorticoid deficiencies. The steroid precursors prior to the enzymatic block (progesterone and 17-hydroxyprogesterone) accumulate due to excessive ACTH stimulation of the gland and are shunted into the androgen biosynthetic pathway, which is unaffected by the block. The resulting androgen excess produces prenatal masculinization (ambiguous genitalia) in females and postnatal virilization in both sexes. In the simple virilizing form, milder CYP21 deficiency results in androgen excess (prenatal masculinization in females and postnatal virilization in both sexes), but salt loss does not occur. In the attenuated or late onset form, minimal CYP21 deficiency results in androgen excess that becomes clinically significant only in pubertal or adult females. Genetic studies in CYP21 deficiency have identified two 21-hydroxylase genes within the class III region of the major histocompatibility complex on chromosome 6p. The disease is therefore HLA-linked. The active gene (CYP21) and the pseudogene (CYP21P) lie in tandem duplication with the genes encoding the C4A and C4B complement proteins. Most of the mutations in CYP21 deficiency are caused by events to which duplicated loci are predisposed, such as unequal crossovers and gene conversions.

  6. 11β-Hydroxylase (CYP11B1) deficiency is the second most common form of CAH, representing approximately 5 percent of cases. Deficiency of CYP11B1 causes accumulation of the mineralocorticoid 11-deoxycorticosterone, resulting in hypertension. In the glucocorticoid pathway, 11-deoxycortisol accumulates. The androgen pathway is unaffected by the enzymatic deficiency; thus prenatal masculinization occurs in females, and postnatal virilization occurs in both sexes. A late onset form exists that is similar in its clinical presentation to attenuated CYP21 deficiency. Genetic studies in CYP11B1 deficiency have mapped two homologous genes, CYP11B1 and CYP11B2, to chromosome 8q. The product of CYP11B1 catalyzes 11β-hydroxylation in the glucocorticoid pathway in the zona fasciculata/reticularis, and the product of CYP11B2 (aldosterone synthase) converts corticosterone to aldosterone in the zona glomerulosa. Mutations of CYP11B1 cause CAH due to 11β-hydroxylase deficiency; mutations of CYP11B2, which do not impair glucocorticoid production, cause autosomal recessive aldosterone deficiencies without CAH; and intergenic recombinations producing fusion of the 5′ end of CYP11B1 and the 3′ end of CYP11B2 produce autosomal dominant glucocorticoid-remediable aldosteronism.

  7. CAH due to CYP17 deficiency occurs less frequently than that due to CYP11B1 deficiency, and the clinical features vary depending on the enzymatic activity affected. In severe CYP17 deficiency, both 17β-hydroxylase and 17,20-lyase activities are reduced or absent. This results in mineralocorticoid excess and hypertension and in absent sex steroid production in both the adrenal and gonad, producing female external genitalia in all patients. Partial CYP17 deficiencies may cause ambiguous sexual development in genetic males. Mutations within specific regions of CYP17, a single-copy gene on chromosome 10q, produce deleterious effects on 17β-hydroxylase and/or 17,20-lyase activities.

  8. Deficiency of 3β-HSD is a rare cause of CAH, and the varying degrees of defective enzymatic activity produce a continuum of clinical effects. In severe 3β-HSD deficiency, there is absent production of all three classes of steroid hormones, with accumulation of 17-hydroxypregnenolone and DHEA. Patients suffer from renal salt loss, insufficient cortisol, and deficient sex steroid production. Excess DHEA can act as the substrate for peripheral conversion to androgen, which may cause some virilization in females; however, there is insufficient androgen production for normal virilization in male patients. Although it has been reported that mild 3β-HSD deficiency can cause a late onset form of CAH in postpubertal females with symptoms of excessive androgen derived from DHEA, mutations in the different 3β-HSD genes have not been demonstrated; thus the pathogenesis of late onset 3β-HSD deficiency remains unknown.

  9. There are no reported cases of CAH due to CYP11A deficiency. This may reflect the obligatory requirement for steroidogenesis by the fetal component of the placenta in maintaining pregnancy. A phenotype closely resembling that predicted for deficiency of CYP11A, however, is seen in patients with congenital lipoid adrenal hyperplasia (lipoid CAH), which results from mutations in the gene encoding the steroidogenic acute regulatory protein (StAR). These patients have established definitively that StAR is essential for the delivery of substrate cholesterol into the steroidogenic pathway. There is no production of steroid hormones, and cholesterol accumulates in the adrenocortical cells, producing lipoid adrenal hyperplasia. Patients have renal salt loss, cortisol deficiency, and sex steroid deficiency; thus all patients have a female phenotype.

  10. The mainstay of treatment in all forms of CAH is glucocorticoid replacement therapy, which corrects the cortisol deficiency and reverses the abnormal hormonal patterns resulting from excessive ACTH secretion. Patients with deficiencies of mineralocorticoids and sex steroids require the appropriate replacement therapies. Glucocorticoid replacement must be increased during periods of stress. The majority of female patients with prenatal masculinization require surgical correction. Heterozygous carrier detection, prenatal diagnosis, and prenatal therapy are routinely available in families with CYP21 deficiency and are often used in CYP11B1 deficiency. They are being explored in other forms of CAH.

  11. Long-term follow-up studies of large numbers of patients are limited to results in CYP21 deficiency. These studies show normal adult health and subnormal adult stature in both sexes, normal fertility in males, and some degree of decreased fertility in females. A prenatal effect of androgens on the developing female brain is suspected. There may be an increased prevalence of homosexuality among females with CYP21 deficiency.

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