Types of Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia comprises multiple distinct enzymatic defects in adrenal steroid biosynthesis, with 21-hydroxylase deficiency accounting for over 90% of cases, followed by rarer forms including 11β-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase deficiency, 17α-hydroxylase deficiency, and P450 oxidoreductase deficiency. 1, 2, 3
Primary Classification by Enzyme Deficiency
21-Hydroxylase Deficiency (Most Common)
- Represents >90% of all CAH cases and is the most common primary adrenal insufficiency in children and adolescents 1, 3
- Caused by mutations in the CYP21 (CYP21A2) gene, most arising from recombination with the nearby pseudogene CYP21P 3
- Subdivided into two severity categories based on residual enzyme activity:
Classic Form (Severe)
- Salt-wasting variant: Accounts for ~75% of classic cases, characterized by both cortisol and aldosterone deficiency leading to vomiting, dehydration, hypovolemia, and shock 4, 3
- Simple virilizing variant: Cortisol deficiency with preserved aldosterone synthesis, presenting with androgen excess but without salt-wasting crisis 5
- Female infants present with genital virilization and ambiguity at birth due to prenatal androgen exposure 4
- Male infants have normal external genitalia at birth but may exhibit hyperpigmentation 4
Nonclassical Form (Mild)
- Termed nonclassical 21-hydroxylase deficiency (NC21OHD), representing the most common autosomal recessive disorder in humans 5
- Highest ethnic-specific disease frequency in Ashkenazi Jews at 1/27 5
- Prenatal virilization does not occur; symptoms manifest later with premature adrenarche, growth acceleration, hirsutism, irregular menses, severe cystic acne, and potential infertility 5
11β-Hydroxylase Deficiency
- Second most common form of CAH 1
- Affects only adrenal steroidogenesis (not gonadal) 2
- Characterized by hypertension with hypokalemia, virilization in females, and elevated deoxycorticosterone (DOC), 11-deoxycortisol, and androgens 6, 7
3β-Hydroxysteroid Dehydrogenase Deficiency
- Rare form affecting both adrenal and gonadal steroid biosynthesis 1, 2
- Impacts production of all classes of steroid hormones due to the enzyme's role early in the biosynthetic pathway 2
17α-Hydroxylase Deficiency
- Rare form affecting both adrenal and gonadal steroidogenesis 2
- Presents with incomplete masculinization in males and primary amenorrhea in females 6, 7
- Associated with hypertension and hypokalemia due to mineralocorticoid excess 6
P450 Oxidoreductase Deficiency (ORD)
- Recently identified form with apparent combined 17α-hydroxylase and 21-hydroxylase deficiency 2
- Unique features distinguishing it from all other CAH variants: skeletal malformations (Antley-Bixler syndrome phenotype) and severe genital ambiguity in both sexes 2
- Paradoxical finding: females may present with virilized genitalia despite invariably low circulating androgens, explained by an alternative pathway in human androgen biosynthesis 2
- Mothers carrying affected fetuses may experience virilization during pregnancy 2
Clinical Severity Classification
CAH severity correlates with genotype and ranges from:
- Severe/Classic: Complete or near-complete enzyme deficiency requiring immediate treatment to prevent adrenal crisis and death 1, 3
- Mild/Nonclassical: Partial enzyme deficiency with later-onset symptoms of androgen excess without life-threatening salt-wasting 5
Diagnostic Approach by Type
For 21-hydroxylase deficiency: Elevated 17-hydroxyprogesterone (17-OHP) levels on newborn screening or ACTH stimulation testing, confirmed with CYP21A2 gene molecular genetic analysis 1, 5
For 11β-hydroxylase deficiency: Elevated DOC, 11-deoxycortisol, and androgens with low aldosterone 6, 7
For 17α-hydroxylase deficiency: Decreased androgens and estrogen with elevated deoxycorticosterone and corticosterone 6
For P450 oxidoreductase deficiency: Combined biochemical pattern of 17α-hydroxylase and 21-hydroxylase deficiency with skeletal abnormalities 2
Common Pitfall
The most critical error is failing to recognize that not all CAH presents in the newborn period—nonclassical forms may present in childhood, adolescence, or adulthood with symptoms of hyperandrogenism (hirsutism, acne, infertility) that are frequently misattributed to polycystic ovary syndrome, leading to missed diagnoses in dermatology and infertility clinics 5. Males with nonclassical CAH may appear asymptomatic but present with oligozoospermia or diminished fertility 5.