creation date: 2026-06-10 01:57
tags: Pathologies
Congenital Adrenal Hyperplasia
Background
Definitions
Congenital adrenal hyperplasias (CAH) are autosomal recessive disorders resulting in a syndrome of signs and symptoms. Most (95%) cases arise from 21-hydroxylase deficiency (21OHD) which is discussed here.
Classic CAH: 21OHD present during neonatal period and early infancy; more severe
Nonclassic CAH: later onset of 21OHD (childhood or adulthood)
Pathophysiology
21-hydroxylase deficiency occurs due to pathogenic variants of CYP21A2
A deficiency in 21-hydroxylase results in impaired conversion of:
- 17-hydroxyprogesterone to 11-deoxycortisol
- Progesterone to 11-deoxycorticosterone
A decrease in cortisol synthesis causes a compensatory increase in ACTH which increases steroid production upstream of 21-hydroxylase, specifically adrenal-derived androgens.
Classic CAH results in only 0-2% of 21OH activity. This results in androgen excess in early infancy, causing salt wasting, adrenal insufficiency, and virilization.
Nonclassic CAH is less severe, in which 5-20% of enzyme activity is preserved. Preserved activity is sufficient to maintain normal glucocorticoid and mineralocorticoid production but excess adrenal steroid production is still present.
Clinical Presentation
Signs & Symptoms
Classic CAH
Classic CAH is diagnosed in the neonatal period, typically at 7-14 days of life.
- Neonatal screening/failure to thrive
- Dehydration
- Hyponatremia
- Hyperkalemia
In 25% of patients, small amounts of aldosterone produced allows for patient to escape the adrenal crisis as a neonate.
Females present with atypical genitalia:
- Fused labia
- Enlarged clitoris
- Urogenital sinus
At 2-4 years of age, early virilization presents with:
- Pubic hair
- Growth spurt
- Adult-type body odour
As an adult, CAH manifests as:
- Adrenocortical dysfunction (cortisol and glucocorticoid deficiency)
- Adrenomedullary dysfunction (cortisol and epinephrine deficiency)
- Poor glucose regulation
- Altered metabolic and hormonal response to stressors
- Hyperandrogenism (females)
- Hirsutism
- Acne
- Menstrual irregularity
- Neuropsychiatric features
- Females may have more male-typical childhood, play, activities
- Association with anxiety, depression, alcohol use disorder, suicidality
- Reproductive-related features
- Anovulation (hyperandrogenemia due to inadequate glucocorticoid therapy)
- Sexual dysfunction (anatomic factors)
- Reduced interest in motherhood
- Disease severity and poor fertility rate
- Ovarian adrenal rest tumours
- In males, testicular adrenal rest tumours are common
- Benign adrenal tumours
- Insulin resistance (cardiovascular and metabolic risk)
- Poor bone health (due to lifelong glucocorticoid therapy)
Nonclassic CAH
In nonclassic CAH, the degree of deficiency is less severe.
- Acne
- Hirsutism
- Menstrual irregularity (or primary amenorrhea)
- Infertility
- Alopecia
Heterozygote carriers are typically not clinically symptomatic but may be at higher risk of hirsutism and other hyperandrogenic symptoms. Male adults may present with acne but almost all remain asymptomatic.
History & Physical Exam
In infants, screening is done by blood sample. A physical examination of the genitalia may be performed.
In adults with nonclassic CAH, a presenting concern of oligomenorrhea and signs of hyperandrogenism should prompt review of other symptoms and further workup.
Diagnosis
Criteria
Classic CAH
Diagnosis is made via:
- Newborn heel-prick blood test with very high serum 17-hydroxyprogesterone (substrate for 21-hydroxylase)
- Confirmation with serum 17OHP and cortisol, and serum electrolytes
- ACTH stimulation test can be used for gold standard diagnosis, but often unnecessary
Nonclassic CAH
Screening is made with an early morning (before 8:30 AM), unstimulated serum 17-hydroxyprogesterone
- ≤6 nmol/L: excludes diagnosis
- 6-30 nmol/L: indeterminate
-
30 nmol/L: establishes diagnosis
For indeterminate screening, measure the following with ACTH stimulation:
- Serum 17-hydroxyprogesterone
- Cortisol (confirmed proper testing and checks for impaired cortisol production)
Work-up
Additional steroid intermediates
To define metabolic defect in infants with classic CAH, serum measurements are ordered, in order of priority:
- 11-deoxycortisol
- 17-hydroxypregnenolone
- Cortisol
- Androstenedione
- Dehydroepiandrosterone
Genetic testing
Genetic testing is not routine. For adults with nonclassic 21OHD pursuing fertility, genetic testing is indicated for preconception counselling.
Differential
Nonclassical 21OHD requires differentiation from:
- 11-hydroxylase deficiency (elevated mineralcorticoid levels is not feature of 21OHD)
- Polyendocrine metabolic ovarian syndrome (evaluate with ACTH stimulation)
There are several other, rarer forms of CAH (non-21OHD):
- CYP17A1 deficiencies
- 3-beta-hydroxysteroid dehydrogenase type 2 deficiency
- CYP11B1 deficiency (11OHD)
- Cytochrome P450-oxidoreductase deficiency
- Ferredoxin reductase deficiency
- Hexose-6-phosphate-dehydrogenase deficiency
- Phosphoadenosine phosphosulfate synthase type 2 deficiency
- Lipoid congenital adrenal hyperplasia
Red Flags / Complications
Management
Classic CAH
Goals of treatment is to prevent adrenal crisis and optimize growth, sexual maturation, and reproductive function.
Initial management consist of:
- IV normal saline for dehydration
- IV dextrose for hypoglycemia
- Hydrocortisone IM for adrenal crisis
If not in adrenal crisis:
- Hydrocortisone PO
- Fludrocortisone
- Sodium chloride PO
Glucocorticoid, mineralcorticoid, and salt replacement is continued. Monitoring is routine for blood pressure, skeletal growth, signs of androgen excess, and laboratory measurements (serum AM 17-OHP, androstenedione, sometimes testosterone):
- q 1 month until 6 months
- Then q 3 month until 12 month
- Then q 3-6 month in childhood
Nonclassic CAH
Goals of treatment are managing hyperandrogenic symptoms and regulating menstrual cycles.
Hirsutism and acne
- Combined oral contraceptives (preferred)
- Antiandrogen therapy (eg. spironolactone)
- Glucocorticoid therapy (only if unable to tolerate COCs or inadequate response)
Oligomenorrhea
- Combined oral contraceptives
- Glucocorticoid therapy (if pursuing fertility)
It should be noted that due to long-term glucocorticoid use, adrenal insufficiency is possible from HPA axis suppression. Stress-dose glucocorticoids should be counselled on for periods of acute stress.