Congenital Adrenal Hyperplasia



Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders that have in common deficiency of an enzyme needed for cortisol biosynthesis. The disease exists along a spectrum of severity and is typically subdivided into “classic” (severe) and “nonclassic” (milder) forms.

  • There are five specific causes of CAH:
    • 21-hydroxylase deficiency (21OHase)
    • 11-hydroxylase deficiency
    • 3β-hydroxysteroid dehydrogenase deficiency
    • 17α-hydroxylase deficiency
    • Congenital lipoid hyperplasia (stAR mutation)
  • The vast majority of cases of CAH (~95%) are due to 21OHase deficiency, which will therefore be the focus of this chapter. The 21OHase enzyme is in the glucocorticoid and mineralocorticoid biosynthetic pathways.


  • The incidence of classic CAH is 1:10,000 to 1:20,000 live births.
    • More common in certain ethnic groups and in remote areas
    • Approximately 75% of cases are characterized by overt salt wasting due to mineralocorticoid deficiency, whereas the remaining cases are described as simply virilizing.
  • The prevalence of nonclassic CAH (also called late onset) is approximately 1:1,000.
    • More common in some ethnicities such as Ashkenazi, Italian, and persons from the former Yugoslav Republic and may be as common as 1:50 individuals in these groups

Risk Factors


  • CAH is caused by mutations in the CYP21A2 gene, which is located on chromosome 6p21.3 and encodes for the 21OHase enzyme. This locus is characterized by many overlapping transcripts and a high rate of recombination.
  • Most mutations involve large deletions or arise from the transfer of small sequences of the nearby pseudogene CYP21A1P during meiosis. >100 different CYP21A2 mutations have been reported. Most patients are compound heterozygotes, with the phenotype reflecting the milder mutation.
  • Approximately 1% of mutations are estimated to arise de novo and uniparental disomy has been reported. Although genotype–phenotype correlations are generally high, the genetic complexity of CAH renders them sometimes problematic.


  • The enzymatic block in cortisol biosynthesis results in diminished negative feedback at the level of the hypothalamus and pituitary gland with a subsequent increase in corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH). Precursor buildup proximal to the block results in increased adrenal androgen production (Appendix, Table 13).
  • Variable degrees of mineralocorticoid deficiency cause salt wasting and contribute to the risk of adrenal crisis. The clinical consequences of this process vary according to gender and to the severity of the CAH.
  • Classic CAH; genetic females
    • Androgen excess during early prenatal life (first trimester) results in ambiguous genitalia. Typical features include elongation of the urethra, development of a urogenital sinus, and enlargement of the clitoris.
    • Internal reproductive structure development is unaffected.
    • If not diagnosed and treated early, progressive virilization occurs postnatally. Girls with salt-wasting CAH are also at risk for an adrenal crisis.
  • Classis CAH; genetic males
    • Prenatal androgen exposure has no clinical consequence in infant boys with CAH. However, infant boys with salt-wasting CAH are at risk for an adrenal crisis.
    • As with girls, if not diagnosed and treated early, progressive virilization occurs postnatally.
  • Nonclassic CAH; females
    • The far milder degree of androgen excess in nonclassic CAH has no effect during embryologic development but can result in symptoms of hyperandrogenism during childhood, adolescence, or adulthood.
  • Nonclassic CAH; males
    • Symptoms of androgen excess can occur during childhood, adolescence, or adulthood.

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