Congenital Adrenal Hyperplasia

Overview
  • Congenital Adrenal Hyperplasias (CAHs) are clinical syndromes caused by inborn errors of metabolism which result in inappropriate secretion of adrenal androgens, specifically DHEA and androstenedione. Below we describe common pathogenic and biochemical features of CAH diseases and then discuss unique features of specific disease entities.
Pathogenesis
  • CAHs are caused by mutations in particular enzymes required for biosynthesis of cortisol and are inherited in an autosomal recessive pattern. The resultant absence of plasma cortisol lifts feedback inhibition of ACTH secretion from the anterior pituitary, yielding elevated levels of ACTH (See: Glucocorticoid Physiology). Because ACTH is a trophic factor for the adrenal cortex, the adrenal cortices undergo hypertrophy in these diseases thus providing their namesake. A variety of different mutations can result in different degrees of reduced enzyme functionality; consequently the clinical manifestations of these diseases vary considerably in their seriousness. The extreme end of the clinical spectrum is described below.
Biochemistry
  • As described in Adrenocortical Hormone Biosynthesis, corticosteroids are synthesized through step-wise modification of cholesterol by a defined set of enzymes. In the normal scenario, different complements of enzymes are present in each adrenocortical zone, resulting in each zone synthesizing a distinct corticosteroid. As discussed, CAHs result due to specific enzyme defects required for corticosteroid biosynthesis. When an enzyme no longer functions the upstream intermediates of the pathway begin to accumulate and because of their hydrophobic nature can easily diffuse into adjacent adrenocortical zones where they enter that zone's biosynthetic pathway. Consequently, the clinical consequences of CAHs arise from an insufficiency of certain corticosteroids and excesses of others.
21-hydroxylase Deficiency
  • Biochemistry
    • Defects of 21-hydroxylase prevent synthesis of aldosterone and cortisol. Hormone intermediates are shunted into the pathway for DHEA and androstenedione and thus excess levels of adrenal androgens result.
  • Clinical Consequences
    • In both genders aldosterone and cortisol deficiency results in symptomology associated with chronic adrenocortical insufficiency. Excess adrenal androgens do not produce significant symptomology in males; however, female neonates may display virilization of genitalia at birth.
17-Hydroxylase Deficiency
  • Biochemistry Basis
    • Defects of 17-hydroxylase prevent synthesis of cortisol and adrenal androgens. Hormone intermediates are shunted into the pathway for aldosterone and thus excess levels of aldosterone result.
  • Clinical Consequences
    • In both genders hyperaldosteronism arises as well as cortisol deficiency which manifests as hypoglycemia along with certain other symptoms associated with chronic adrenocortical insufficiency. In women deficiencies of adrenal androgens results in an absence of axillary hair and pubic hair.