Types of Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia comprises several distinct enzyme deficiency disorders, with 21-hydroxylase deficiency accounting for over 90-95% of all cases, followed by 11β-hydroxylase deficiency as the second most common type, and rare forms including 3β-hydroxysteroid dehydrogenase deficiency, 17-hydroxylase deficiency, and lipoid CAH. 1, 2, 3
Primary Types by Frequency
21-Hydroxylase Deficiency (>90-95% of cases)
Classic forms present in two variants: salt-wasting (approximately 75% of classic cases) with both cortisol and aldosterone deficiency leading to hypovolemia and shock, and simple virilizing type with cortisol deficiency but preserved aldosterone production 3, 4
Non-classic form presents later in childhood or adulthood with symptoms of premature adrenarche, growth acceleration, hirsutism, and irregular menses 1
Caused by mutations in the CYP21 (CYP21A2) gene, with most mutations arising from recombination between CYP21 and the nearby pseudogene CYP21P 3
Newborn screening with elevated 17-hydroxyprogesterone levels enables early diagnosis in the United States 1
11β-Hydroxylase Deficiency (Second most common)
Results from CYP11B1 deficiency causing inability to produce cortisol and aldosterone with excessive adrenal androgen production 2
Key distinguishing feature: Unlike 21-hydroxylase deficiency, mineralocorticoid deficiency findings are NOT observed despite the biochemical aldosterone deficiency 2
Clinical and laboratory features otherwise resemble 21-hydroxylase deficiency with virilization 2
Rare Forms (<1% combined)
3β-Hydroxysteroid Dehydrogenase Deficiency:
- Incidence less than 1/1,000 live births 2
- Impairs both adrenal and gonadal steroid biosynthesis very early in the steroidogenic pathway 2
- Presents with inadequate virilization in 46,XY individuals and varying degrees of virilization in 46,XX individuals 2
- May manifest as salt-wasting crisis in infancy or delayed puberty in both sexes 2
17-Hydroxylase Deficiency:
- Characterized by 46,XY disorders of sex development in genetic males 2
- Genetic females present with immature pubertal development and primary amenorrhea due to estrogen deficiency throughout adolescence 2
Lipoid CAH (Steroidogenic Acute Regulatory Protein Deficiency):
- Typically presents with salt wasting in the first year of life 2
- Complete or near-complete deficiency of all adrenal and gonadal steroid hormones 2
- Progressive accumulation of cholesterol esters in the adrenal gland is pathognomonic 2
Classification Context
When evaluating primary adrenal insufficiency, CAH represents one category within the broader genetic causes listed in diagnostic algorithms 5
The etiologic workup distinguishes CAH from other causes of primary adrenal insufficiency including autoimmune disease (85% of adult cases in Western Europe), infections, bleeding, and other genetic disorders like adrenoleukodystrophy 5
Clinical Implications
Phenotype generally correlates with genotype in 21-hydroxylase deficiency, allowing prognostic information from genetic testing 3
All classic CAH patients require lifelong glucocorticoid replacement (typically hydrocortisone in children), with most also requiring mineralocorticoid (fludrocortisone) 1, 3
Long-term comorbidities include cardiometabolic risk factors, impaired cognitive function, adrenal rest tumors, and bone health effects, necessitating ongoing monitoring 1, 6