Description

• Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by a defect in one of the five enzymatic steps in the production of cortisol.
  • The most common enzyme deficiency is 21-hydroxylase, which accounts for >90% of CAH cases.
  • 11-β-Hydroxylase deficiency accounts for ~5% of CAH cases.
  • Other rare causes include 17-α-hydroxylase deficiency, 3-β-hydroxylase deficiency, and lipoid CAH, which will not be discussed further here.
• CAH is subdivided into classical and nonclassical forms.
  • The enzymatic deficiency is defined as “classic” if the defect is severe enough to cause cortisol insufficiency or “nonclassical” if cortisol production is normal but with excessive precursor accumulation to overcome the partial enzymatic block.
  • The classic form can be subdivided into salt wasting (67%) and simple virilizing (33%). The nonclassical form has a milder phenotype.

Epidemiology

• 1/15,000 for the classic form of CAH
• 1/280 among Yupik Eskimo population
• Nonclassical form has a higher estimated incidence of 1/1,000 in Caucasians and up to 2% in inbred populations, such as Eastern European (Ashkenazi) Jews.

Etiology and Pathophysiology

• 21-Hydroxylase is one of the five enzymes involved in producing cortisol from cholesterol in the adrenal cortex.
  • 21-Hydroxylase converts 17-hydroxyprogesterone to 11-deoxycortisol in cortisol synthesis and progesterone and deoxycorticosterone in aldosterone synthesis.
• Without cortisol for negative feedback, increased ACTH is secreted by the pituitary, leading to hyperplasia of the adrenal cortex.
• This also results in accumulation of cortisol precursors, which are diverted to sex hormone biosynthesis.
  • Thus, levels of 17-hydroxyprogesterone are elevated for 21-hydroxylase deficiency.
• In salt-wasting CAH, cortisol and aldosterone production is defective due to total or near-total enzyme deficiency.
• In simple virilizing CAH, there is a partial enzyme deficiency resulting in reduced cortisol and aldosterone production.
• In nonclassical CAH, there is a mild enzyme deficiency with normal cortisol and aldosterone levels, but there is a mild increase in adrenal androgen production.

Genetics

• Autosomal recessive disorder with variable penetrance
• There are two 21-hydroxylase genes located on chromosome 6p21.3.
  • One is the active form and the other inactive. CAH is unusual among genetic disorders in that most of the mutant alleles (~90%) are generated by recombinations between the pseudo and active genes.
    • When deleterious sequences, normally present in the pseudogene, are transferred to the active gene, the latter becomes incapable of encoding a normal enzyme; this process is called gene conversion.
• >100 mutations are known.
• Mutations that result in large deletions or splicing that ablate enzyme activity result in salt-wasting CAH.
• Missense mutations with 1–2% enzyme activity correlate with simple virilizing CAH.
• Point mutations with 20–60% enzyme activity correlate with the nonclassical disorder.
• Most affected individuals are compound heterozygotes, and the clinical phenotype correlates with the less severely mutated allele.

Risk Factors

• Inbreeding
• Positive family history

Commonly Associated Conditions

• Upper urinary tract malformations, such as vesicoureteral reflux, hydronephrosis, or duplicated collecting system, are seen in children with CAH.
• Adrenal cortical tumors are thought to be secondary to higher levels of ACTH.
• Obesity, insulin resistance, polycystic ovaries
• Testicular adrenal rest tumors