What are the causes of congenital adrenal hyperplasia (CAH)?

Updated: Oct 06, 2020
  • Author: Thomas A Wilson, MD; Chief Editor: Sasigarn A Bowden, MD  more...
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The defects that cause congenital adrenal hyperplasia are autosomal recessive disorders due to deficient activity of a protein involved in cortisol synthesis, aldosterone synthesis, or both.

  • In most cases, this disorder is due to a mutation or deletion of the gene that codes for the involved protein. When both genes carry the same mutation or deletion, the condition is homozygous. When the 2 affected genes carry different mutations or deletions, the patient is said to be a compound heterozygote. In general, the clinical severity reflects the least affected allele. Carriers or heterozygotes who carry only one abnormal gene are asymptomatic.

  • Many of the genes involved in cortisol and aldosterone synthesis code for CYP proteins. The best-studied gene is the 21-hydroxylase gene (CYP21, CYP21A). The 21-hydroxylase gene is located on chromosomal band 6p21.3 among genes that code for proteins that determine human leukocyte antigen (HLA) types. The gene for 21-hydroxylase has a pseudogene (CYP21P) 30 kb away from CYP21 that is 98% homologous in structure to CYP21A; however, it is rendered inactive because of minor differences in the gene. The proximity of CYP21P with CYP21A is thought to predispose the CYP21A gene to crossovers in meiosis between CYP21A and CYP21P, resulting in loss of genetic function.

  • Other defects occur because of gene deletions or mutations. Among abnormalities of CYP21A, approximately 95% are thought to be due to recombinations with CYP21P, 20% are thought to represent deletions, and 70% are point mutations. The phenotype depends on the function of the less-severely affected gene rather than on the more severely affected gene because the former determines the level of enzyme activity. In general, genotype-phenotype correlations are strong, although exceptions occur. Because aldosterone secretion is approximately 1000-fold less than cortisol secretion, the enzyme activity required for aldosterone synthesis is less than that required for cortisol synthesis. Therefore, patients with only the most severe loss of function of CYP21A have salt wasting.

  • The 11-beta-hydroxylase gene (CYP11B1) is on chromosomal band 8q21. CYP11B1 has no pseudogene, and no HLA association is found. CYP11B1 catalyzes the conversion of 11-deoxycortisol to cortisol in the glucocorticoid pathway and the conversion of deoxycorticosterone to corticosterone in the mineralocorticoid pathway. A neighboring gene codes for CYP11B2, or aldosterone synthetase, which catalyzes the conversion of corticosterone to aldosterone in the zona glomerulosa. Mutations and deletions of the CYP11B2 gene result in diminished aldosterone synthesis. Therefore, individuals with CYP11B2 deficiency develop hyponatremia, hyperkalemia, and dehydration. Sexual differentiation occurs normally because sex steroid synthesis and cortisol synthesis are not impaired. The genes for CYP11B1 and CYP11B2 share 95% sequence homology for coding sequences. Nonetheless, gene conversion from chromosomal crossover at meiosis does not appear to play a major role in the mutations and deletions thatrendereither gene inactive.

  • Two tissue forms of 3-beta-hydroxysteroid dehydrogenase are described. Type I occurs primarily in the adrenal and gonad, whereas type II occurs primarily in the placenta and liver. The genes for both forms reside on chromosomal band 1p13. The classic form of 3-beta-hydroxysteroid dehydrogenase deficiency results from mutations or deletions in the gene for the adrenal form of the enzyme.

  • Some patients appear to have nonclassic forms of this disease, as evidenced by symptoms and signs of virilization such as hirsutism, oligomenorrhea, and infertility. Laboratory studies may reveal mildly abnormal precursors-to-product ratios (ie, increased ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone and of dehydroepiandrosterone to androstenedione). These patients have not had mutations or deletions in any of the genes that code for adrenal 3-beta-hydroxysteroid dehydrogenase. The molecular basis for this disorder remains undefined. Clinical and hormonal findings of this condition and polycystic ovary disease overlap considerably. Some patients benefit from suppression of adrenal steroidogenesis with dexamethasone.

  • 17-alpha-hydroxylase activity and 17,20-desmolase activities are thought to be due to a single protein (CYP17) with separate enzymatic activity sites.

  • Some patients with lipoid adrenal hyperplasia, which was originally thought to be due to deficiency of CYP450 side-chain cleavage (scc) enzyme activity, have had mutations in a gene that codes for StAR. This protein appears to be involved in the transport of cholesterol across the mitochondrial membrane, where CYP450 scc can act on it. This enzyme converts cholesterol to pregnenolone, which is then processed in the various steroidogenic tissues into cortisol, aldosterone, or sex steroids. Thus, a deficiency of StAR results in a global steroid deficiency state. Affected 46 XY individuals may have female external genitalia, and affected 46 XX individuals have normal female genitalia. Both develop signs of adrenal insufficiency with onset from early infancy to age 6 months.

  • A curious observation is that females with this disorder who survived as the result of early replacement of glucocorticoids and mineralocorticoid have developed breasts and spontaneous nonovulatory menses at puberty. Researchers postulate that the accumulation of cholesterol esters in steroidogenic cells, which results from StAR deficiency, is eventually toxic to the steroidogenic cells. According to this theory, some ovarian function is preserved because ovarian steroidogenesis does not occur until puberty, and then steroidogenesis occurs in only one follicle at a time, thereby allowing some preservation of steroidogenesis.

  • Mutations in the gene that code for CYP oxidoreductase were recently found to cause deficiencies of several enzymes involved in steroidogenesis. CYP oxidoreductase facilitates electron transfer from nicotinamide adenine dinucleotide phosphate (NADPH) reduced form to the 21-hydroxylase and 17-hydroxylase enzymes required in steroidogenesis (Online Mendelian Inheritance in Man [OMIM] 201750 and 124015). [17] Some individuals with these mutations have craniosynostosis and skeletal abnormalities known as the Antley-Bixler syndrome (OMIM 207410). [18] However, mutations in the fibroblast growth factor receptor-2 can also cause the phenotypic picture of Antley-Bixler syndrome without problems in steroidogenesis.

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