Adrenal Hyperplasia

Overview

Adrenal hyperplasia refers to enlargement of the adrenal glands, most commonly due to Congenital Adrenal Hyperplasia (CAH) - a group of autosomal recessive disorders caused by enzyme defects in the cortisol biosynthetic pathway. The fundamental defect is inadequate cortisol synthesis, which triggers compensatory ACTH hypersecretion, causing adrenal gland enlargement (hyperplasia) and accumulation of steroid precursors proximal to the enzymatic block.

Steroidogenesis Pathway

The diagram below shows the complete adrenal and gonadal steroidogenesis pathway, illustrating where each enzyme acts:

Five enzymes are involved in cortisol biosynthesis. A defect in any one of them can result in CAH:

Cholesterol side-chain cleavage enzyme (CYP11A1 / StAR)
3β-hydroxysteroid dehydrogenase (HSD3B2)
17α-hydroxylase (CYP17A1)
21-hydroxylase (CYP21A2) - most common
11β-hydroxylase (CYP11B1) - second most common

Types of CAH by Enzyme Deficiency

1. 21-Hydroxylase Deficiency (95% of CAH cases)

Gene: CYP21A2, chromosome 6p21.3 (within the HLA complex); autosomal recessive
Incidence: 1 in 5,000-15,000 in the US/Europe; highest in Yupik Alaskan Eskimos (1 in 490)
Over 200 mutations reported; ~10 mutations account for 90-95% of alleles

Clinical subtypes:

Subtype	Frequency	Features
Salt-wasting	75% of classic	Virilization + aldosterone deficiency; risk of adrenal crisis
Simple virilizing	25% of classic	Virilization without salt loss
Non-classic (late onset)	Most common autosomal recessive disorder (1:100)	Partial deficiency; hyperandrogenism only

Clinical features in females:

Virilization begins in utero at 10 weeks gestation (when external genitalia form)
Clitoromegaly, labial fusion, urogenital sinus (vagina + urethra sharing a common opening)
Severity classified by Prader staging (I-V)
Müllerian structures (uterus, fallopian tubes) are typically NORMAL

Non-classic form in females: Hirsutism, oligo-amenorrhea, male-pattern baldness, polycystic ovaries Non-classic form in males: Oligospermia, subfertility (reversible with glucocorticoid therapy)

Diagnosis:

Markedly elevated plasma 17-hydroxyprogesterone (17-OHP) - key diagnostic marker
Elevated urinary 17-ketosteroids and pregnanetriol
Pelvic ultrasound confirms müllerian structures (in ambiguous genitalia)
Neonatal ultrasound may show enlarged, "cerebriform"-appearing adrenal glands
Neonatal screening (elevated 17-OHP on dried blood spot) - mandatory in all 50 US states and 40+ countries

2. 11β-Hydroxylase Deficiency (~5% of CAH cases)

Gene: CYP11B1, chromosome 8q (NOT HLA-linked)
Results in accumulation of 11-deoxycortisol and deoxycorticosterone (DOC)
Key distinguishing feature: Hypertension (due to mineralocorticoid effect of elevated DOC)
Classic form: virilization as severe as 21-OH deficiency
Late-onset form: mild virilization in prepubertal/postpubertal patients
Diagnosis: Elevated plasma 11-deoxycortisol and 11-deoxycorticosterone
Treatment: glucocorticoids (same as for 21-OH deficiency)

3. 3β-Hydroxysteroid Dehydrogenase Deficiency (rare)

Affects early steroidogenesis in both adrenal glands AND gonads
Impairs synthesis of aldosterone, cortisol, AND sex steroids
Affected females: mild clitoromegaly + labial fusion + aldosterone/cortisol deficiency
Affected males: undervirilization (because testosterone synthesis also impaired)

4. Other Forms (rare)

17α-hydroxylase deficiency: Hypertension + hypokalemia + sexual infantilism; 46,XX females present with primary amenorrhea; 46,XY males present as phenotypic females
StAR / cholesterol side-chain cleavage deficiency (lipoid CAH): Most severe form; no steroid hormones produced; lipid accumulation destroys adrenal cortex

Pathophysiology Summary

Enzyme Defect
    ↓
↓ Cortisol synthesis
    ↓
Hypothalamus ↑ CRH → Pituitary ↑ ACTH
    ↓
Adrenal glands become HYPERPLASTIC
Steroid precursors accumulate proximal to the block
    ↓
Precursors shunted → Androgens (virilization)

Treatment

Glucocorticoid replacement is the cornerstone of treatment for all forms of CAH:

Suppresses excess ACTH → reduces adrenal hyperplasia and precursor accumulation
Hydrocortisone (cortisol) is preferred in children (minimizes growth suppression)
Stress dosing ("sick day rules") is required to prevent adrenal crisis

Mineralocorticoid replacement (fludrocortisone) + salt supplementation:

Required in salt-wasting 21-OH deficiency

Non-classic CAH: Lower doses of glucocorticoid; treatment only when symptomatic (hirsutism, infertility)

Surgical management (in virilized females):

Clitoral recession/reduction and vaginoplasty for significant genital ambiguity
Timing is debated; often done in infancy or deferred to adolescence

Prenatal treatment:

Maternal dexamethasone (crosses placenta) given early in pregnancy to an at-risk fetus can reduce virilization in affected 46,XX females
Requires genetic confirmation; ethical considerations involved

Adrenal Medullary Hyperplasia (separate entity)

This is a distinct condition - bilateral enlargement of the adrenal medulla, associated with MEN2 syndromes and predisposing to pheochromocytoma. It is NOT a cortisol synthesis defect.

Key Points Summary

Feature	21-OH Deficiency	11β-OH Deficiency
Frequency	95% of CAH	~5% of CAH
Gene	CYP21A2 (chr 6)	CYP11B1 (chr 8)
HLA linkage	Yes	No
Salt wasting	Yes (75%)	No
Hypertension	No	Yes (DOC excess)
Virilization	Yes	Yes
Elevated marker	17-OHP	11-deoxycortisol, DOC
Treatment	GC + MC (if salt-wasting)	GC alone

Goldman-Cecil Medicine, p. 2515-2516
Campbell Walsh Wein Urology, pp. 1290-1294

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