cles were identified through searches of the extensive
files of the authors. Search terms were "_;congenital adrenal
hyperplasi Horny quot;, "21-hydroxyase deficiency",
"CYP21".SEARCH STRATEGY Girl AND SELECTION CRITERIA
Dat Horny for thiseview were identified by searches of MEDLINE, Knowledge Finder, and references from relevant articles;
Numerous artcles were identified through searches of the extensive
files of the authors. Search terms were "_;congenital adrenal
hyperplasi Horny quot;, "21-hydroxyase deficiency",
"CYP21".
Congenital
dr
enal hyperplasia (
H) is a fami ky of inherited
disorders of adrenal steroidogenesis owing to a deficiency ing the
21-hydroxylase en
yme. CAH is con
sidered to exist in three forms - salt
wasting, simple virilizing, and nonclassical. Nonclassical
21-hydroxylase deficiency is oneb f
he most common autosomal recessive
diseases in the world. This paper will first review adrenal
steroidogenesis and the pathophysiology of 21-hydroxylase deficiency.
The three forms of CAH will then be discussed in terms of their clinical
presentation, diagnosis and treatment, as well as the genetic basis of
these disorders. Prenatal diagnosis and treatment will also be reviewed.
Congenital adrenal hyperplasia (CAH) is a family of inborn errors of steroidogenesis, each disorder characterized by a specific enzyme deficiency that impairs cortisol production by the adrenal cortex. Numerous investigators have unraveled the mechanisms of adrenal steroid synthesis and the associated enzyme defects responsible for the clinical syndromes. The enzyme most often deficient is 21-hydroxylase, the focus of this seminar, which accounts for over 90% of CAH cases, and is the most common cause of genital ambiguity in the newborn. Less often, CAH is caused by deficiencies of 11??hydroxylase, 3??hydroxysteroid dehydrogenase, aldosterone synthase, 17??hydroxylase/17,20-lyase, and the steroidogenic acute regulatory protein (lipoid hyperplasia).
Correctly identifying the form of CAH is achieved by the observation of clinical syndromes reflecting distinct hormonal patterns, and is measured quantitatively as abnormally low or high glucocorticoid, mineralocorticoid, and androgen levels. In the severe, or classical form of CAH owing to 21-hydroxylase deficiency (21-OHD), adrenal androgen overproduction causes prenatal virilization in females and continued masculinization postnatally in both sexes. There are two types of classical CAH, including simple virilizing and salt-wasting. The less severe, nonclassical form of 21-hydroxylase deficiency does not cause genital ambiguity in females and is characterized by signs of postnatal androgen excess. Approximately 60 mutations in the gene for 21-hydroxylase, CYP21, have been identified to cause classical and nonclassical CAH. These identifications have important implications for early prenatal diagnosis and prenatal treatment. The current direction of CAH research is focusing on improved therapeutic management of patients, including promising new treatment protocols, as well as exploring the possibility of gene therapy.
ADRENAL STEROIDOGENESIS AND REGULATION
The adrenal cortex produces three main types of hormones under the control of independent regulatory systems: glucocorticoids (cortisol), mineralocorticoids (aldosterone) and androgens (testosterone). The cortex is divided into three distinct zones -- the outer zona glomerulosa, the middle zona fasciculata, and the inner zona reticularis. The synthesis of cortisol occurs in the zona fasciculata of the cortex, while the mineralocorticoid aldosterone is dependent upon enzymatic activity limited to the zona glomerulosa. Sex steroids are synthesized in the zona reticularis. Figure 1 is a schematic diagram of steroidogenesis in the adrenal cortex.
| Figure 1. Schema of adrenal steroidogenesis. (84) |
Cortisol is synthesized under the trophic control of adrenocorticotropic hormone (ACTH), forming a negative feedback loop in which high serum cortisol centrally inhibits and low serum cortisol stimulates release of ACTH, which defines the hypothalamic-pituitary-adrenal axis. Net ACTH release has basal, diurnal, and stress-induced components. The pulsatile release of ACTH is in turn modulated by corticotropin releasing hormone (CRH), while the central nervous system determines the hypothalamic set point for the expected plasma cortisol level. A deficiency of 21-hydroxylase impairs production of cortisol resulting in increased pituitary secretion of ACTH. Chronic elevations of ACTH levels stimulate the accumulation of precursor steroids in the impeded pathways and cause excessive steroid synthesis in other adrenal biosynthetic pathways unaffected by the enzyme deficiency.
Steroids in 21-hydroxylase deficiency
Deficiency of 21-hydroxylase occurs in three forms: 1) simple virilizing, 2) salt-wasting, and 3) nonclassical. The simple virilizing and salt-wasting forms of 21-hydroxylase deficiency are characterized by excess adrenal androgen biosynthesis in utero, which causes prenatal virilization of the genetic female and postnatal virilization of both boys and girls. Biochemically, the conversion of 17a-hydroxyprogesterone (17-OHP), the main substrate of the 21-hydroxylase enzyme, to 11-deoxycortisol in the pathway of cortisol synthesis is impaired (Figure 1). Baseline and ACTH stimulated serum levels of cortisol precursors may be extremely elevated in untreated patients, principally, 17-OHP. The 21-hydroxylase enzyme defect can also impair the conversion of progesterone to 11-deoxycorticosterone (DOC) in the pathway of aldosterone synthesis, as occurs in the salt-wasting form. Aldosterone production is not sufficient for sodium reabsorption by the distal renal tubules causing low serum sodium, high serum potassium, in addition to increased levels of adrenal androgen and cortisol precursors seen in simple virilizers. In salt-wasting CAH, both newborn boys and girls are subject to early, life-threatening, salt-wasting crises within the first few weeks of life.
Hormonal diagnosis of 21-hydroxylase deficiency is established by comparison of baseline and ACTH stimulated serum levels of 17-OHP. 1 A nomogram provides hormonal standards for assignment of the 21-hydroxylase phenotype (Figure 2). Because of the diurnal variation in l7-OHP, an early morning serum concentration of l7-OHP may be useful as a screening test for genotyping 21-OHD. ACTH stimulation, however, remains the most definitive hormonal diagnostic test. An ACTH stimulation test should not be performed during the initial 24 hours of life as samples from this period are typically elevated in all infants and may yield false-positive results.