CONGENITAL ADRENAL HYPERPLASIA

✓ Medically ReviewedDISEASEID: MDBT0271🚨 TRIAGE: EMERGENCYICD-10: E25.0

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Definition

CLINICAL DEFINITION

Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders caused by mutations in genes encoding enzymes involved in adrenal steroidogenesis, leading to impaired cortisol synthesis and compensatory adrenocorticotropic hormone (ACTH) drive with resultant adrenal cortical hyperplasia. The most common form, accounting for over 90% of cases, is 21-hydroxylase deficiency (21-OHD), which is subclassified into classic (salt-wasting or simple virilising) and nonclassic phenotypes based on residual enzyme activity. Classic CAH presents in infancy with cortisol deficiency, variable aldosterone deficiency, and androgen excess; nonclassic CAH presents later with milder androgen excess.

IN PLAIN ENGLISH

Congenital adrenal hyperplasia (CAH) is an inherited condition where the adrenal glands cannot make enough of the hormones cortisol and sometimes aldosterone, while making too much of male-type hormones (androgens). This can cause serious salt loss and low blood sugar in babies, and can affect growth and development. Treatment involves replacing the missing hormones for life.

COMMON MISCONCEPTION / WHAT IT DOES NOT MEAN

Congenital adrenal hyperplasia is NOT a single disease but a family of enzyme deficiencies; 21-hydroxylase deficiency is the prototype but other enzyme defects (11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, etc.) produce distinct biochemical and clinical patterns. It is also NOT an acquired adrenal insufficiency; CAH is present from birth and requires lifelong management, whereas acquired adrenal insufficiency develops later.

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Word Breakdown

congenital-

=present from birth (from Latin 'congenitus')

adrenal

=adrenal — relating to the adrenal glands (from Latin 'ad-' near + 'renes' kidneys)

-hyperplasia

=overgrowth or excessive formation of cells (from Greek 'hyper-' over + 'plasis' formation)

Literal Meaning: A condition present from birth characterised by overgrowth (hyperplasia) of the adrenal glands

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Abbreviations

CAH=Congenital Adrenal Hyperplasia — the overarching term for this group of disorders

21-OHD=21-Hydroxylase Deficiency — the enzyme defect responsible for >90% of CAH cases

17-OHP=17-Hydroxyprogesterone — the key diagnostic biomarker, elevated in 21-OHD

DOC=Deoxycorticosterone — a mineralocorticoid precursor that accumulates in certain CAH subtypes

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Synonyms & Variants

Adrenogenital Syndrome›Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency›

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Category-Specific Context

As a Disease, congenital adrenal hyperplasia represents a defined group of inherited enzymatic defects with recognised diagnostic criteria (elevated 17-hydroxyprogesterone, characteristic steroid profiles, and genetic confirmation). It spans a severity spectrum from classic salt-wasting disease presenting in the neonatal period to nonclassic forms presenting in later childhood or adulthood with androgen excess. The category captures the pathological condition itself, encompassing its aetiologies, subtypes, and clinical consequences.

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Clinical Context & Usage

CLINICAL SETTINGS

Neonatal Intensive Care UnitPaediatric Endocrinology ClinicEmergency DepartmentGeneral Paediatrics WardAdult Endocrinology ClinicObstetrics and Gynaecology Clinic

USAGE & DOCUMENTATION NOTES

In clinical documentation, the term is often abbreviated to 'CAH' after first use, with the subtype specified (e.g., 'classic salt-wasting CAH due to 21-hydroxylase deficiency'). On newborn screening reports, an elevated 17-hydroxyprogesterone (17-OHP) is flagged as 'suggestive of CAH' and triggers urgent referral. In ward notes, clinicians document 'stress-dose hydrocortisone' during illness, and 'sick-day rules' are routinely referenced. Referral letters commonly state the enzyme defect, current glucocorticoid and mineralocorticoid doses, and the presence of salt-wasting.

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Primary Causes & Pathophysiology

PATHOPHYSIOLOGY

The adrenal cortex synthesises cortisol, aldosterone, and adrenal androgens from cholesterol through a sequence of enzymatic reactions. In 21-hydroxylase deficiency, the enzyme CYP21A2 is impaired, blocking the conversion of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol (the precursor of cortisol) and of progesterone to deoxycorticosterone (the precursor of aldosterone). The resulting cortisol deficiency removes negative feedback on the hypothalamus and pituitary, leading to increased corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secretion. Chronic ACTH stimulation causes adrenal cortical hyperplasia and shunts steroid precursors into the androgen pathway, producing excess adrenal androgens (androstenedione, testosterone, DHEA). In the salt-wasting subtype, aldosterone deficiency causes renal sodium loss, hyperkalaemia, hypovolaemia, and hypotension. In nonclassic CAH, residual enzyme activity is sufficient to avoid salt wasting and cortisol crisis, but androgen excess still occurs.

PRIMARY CAUSES

21-Hydroxylase deficiency (CYP21A2 mutations)

Impaired conversion of 17-OHP to 11-deoxycortisol and progesterone to deoxycorticosterone, causing cortisol and aldosterone deficiency with androgen excess; accounts for >90% of CAH.

11β-Hydroxylase deficiency (CYP11B1 mutations)

Blocked conversion of 11-deoxycortisol to cortisol and deoxycorticosterone to corticosterone, leading to cortisol deficiency, androgen excess, and accumulation of mineralocorticoid precursors causing hypertension and hypokalaemia.

3β-Hydroxysteroid dehydrogenase type 2 deficiency (HSD3B2 mutations)

Impaired conversion of pregnenolone, 17-hydroxypregnenolone, and DHEA to progesterone, 17-OHP, and androstenedione, causing combined cortisol, aldosterone, and androgen deficiency with ambiguous genitalia in both sexes.

17α-Hydroxylase/17,20-lyase deficiency (CYP17A1 mutations)

Blocked 17-hydroxylation and 17,20-lyase activity, impairing cortisol and sex steroid synthesis while shunting precursors to mineralocorticoids, causing hypertension, hypokalaemia, and undervirilisation in 46,XY individuals.

Lipoid congenital adrenal hyperplasia (StAR or CYP11A1 mutations)

Impaired cholesterol transport into mitochondria or cholesterol side-chain cleavage, blocking all steroidogenesis; causes severe salt wasting, cortisol deficiency, and complete lack of sex steroid synthesis.

P450 oxidoreductase deficiency (POR mutations)

Impaired electron transfer to multiple cytochrome P450 enzymes, causing combined partial deficiencies of 21-hydroxylase, 17α-hydroxylase, and aromatase, with variable genital ambiguity and skeletal features (Antley-Bixler syndrome).

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Drug-Induced Causes

💊 Danazol ↗

Mechanism: In utero exposure may transiently block steroid 21- and 11β-monooxygenases, producing a biochemical and clinical picture resembling salt-wasting CAH in the neonate.

→ Recognise as a transient, reversible cause; supportive care and monitoring of electrolytes and glucose; avoid danazol in pregnancy.

💊 Posaconazole ↗

Mechanism: Inhibits 11β-hydroxylase, producing reversible hypertension, hypokalaemia, and biochemical findings mimicking 11β-hydroxylase deficiency CAH.

→ Monitor blood pressure and potassium during therapy; consider alternative antifungal if clinically feasible; abnormalities resolve after discontinuation.

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Epidemiology

Prevalence:Classic CAH due to 21-hydroxylase deficiency has a global prevalence of approximately 1 in 14,000 to 1 in 18,000 live births based on newborn screening data. Regional variation exists, with higher rates in certain populations such as Yupik people in Alaska (approximately 1 in 280) and lower rates in New Zealanders of European descent (approximately 1 in 26,000). Nonclassic CAH is more common, with an estimated prevalence of 1 in 1,000 in the general population and up to 1 in 100–200 in certain ethnic groups.

Age Group:Classic CAH most commonly presents in neonates and infants (salt-wasting crisis or ambiguous genitalia). Nonclassic CAH often presents in later childhood, adolescence, or adulthood with signs of androgen excess (precocious pubarche, hirsutism, irregular menses, infertility).

Sex Predilection:Equal

Geographic Distribution:CAH occurs worldwide with variation by enzyme subtype and ethnicity. Classic 21-OHD is more prevalent in certain indigenous populations (e.g., Yupik people in Alaska) and in regions with higher consanguinity. Nonclassic 21-OHD is more common in Ashkenazi Jewish, Hispanic, and Mediterranean populations. Lipoid CAH is most prevalent in Japan and Korea, and 17α-hydroxylase deficiency has a higher prevalence in Brazil due to founder mutations.

Red Flags & Triage ★

TRIAGE LEVEL

🚨 EMERGENCY

DO NOT MISS — LIFE-THREATENING PRESENTATIONS

A neonate with ambiguous genitalia, non-palpable testes, vomiting, lethargy, or poor feeding may have salt-wasting CAH; obtain urgent electrolytes, glucose, and 17-OHP and initiate hydrocortisone without waiting for confirmatory results if adrenal crisis is suspected.
An infant or child with unexplained shock, hyponatraemia, hyperkalaemia, or hypoglycaemia should be evaluated for adrenal crisis due to CAH; delayed treatment can be fatal.

URGENT EVALUATION TRIGGERS

Neonate with ambiguous genitalia or non-palpable testes
Neonate with vomiting, diarrhoea, poor feeding, lethargy, or dehydration
Unexplained hypotension, hyponatraemia, hyperkalaemia, or hypoglycaemia in an infant or child
Positive newborn screen for CAH with elevated 17-OHP above the critical threshold
Acute illness with fever >38.5°C or gastroenteritis with dehydration in a patient with known CAH (requires stress-dose glucocorticoid)

Contraindications & Precautions

CONTRAINDICATIONS

Avoid chronic use of long-acting potent glucocorticoids (e.g.
dexamethasone) in growing children with classic CAH due to growth suppression; hydrocortisone is preferred.
Avoid oral hydrocortisone suspension in growing individuals due to unreliable dosing.
Avoid glucocorticoids that traverse the placenta (e.g.
dexamethasone) in pregnancy for maternal CAH treatment unless under specialist fetal therapy protocols.

SPECIAL PRECAUTIONS

Increase glucocorticoid dose (stress dosing) during febrile illness (>38.5°C)
gastroenteritis with dehydration
major surgery
or major trauma; mineralocorticoid dose is usually not increased.
Do not routinely increase glucocorticoid doses for everyday mental/emotional stress
minor illness
or routine exercise.
Monitor for signs of glucocorticoid excess (weight gain
hypertension
cushingoid features) and inadequate androgen control (virilisation
precocious puberty) at every visit.
Ensure all patients carry medical identification and an emergency glucocorticoid injection kit
with education on parenteral administration.
In pregnant women with CAH
continue prepregnancy hydrocortisone/prednisolone and fludrocortisone doses
with adjustments for insufficiency; stress-dose during labour and delivery.

Complications

DOWNSTREAM CLINICAL COMPLICATIONS

Adrenal crisis (life-threatening salt-wasting crisis with hypotension
hyponatraemia
hyperkalaemia
hypoglycaemia
and shock
especially in classic CAH during illness or stress)
Infertility and reproductive dysfunction (testicular adrenal rest tumours in males; oligo-ovulation and PCOS-like features in females)
Short stature and precocious puberty (from androgen excess and glucocorticoid over-treatment in childhood)
Metabolic syndrome and cardiometabolic risk (hypertension
obesity
insulin resistance
especially in adults on chronic glucocorticoid therapy)
Reduced bone mineral density (from prolonged glucocorticoid exposure)
Psychological and psychosexual morbidity (genital ambiguity
gender identity concerns
and quality-of-life impact)

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Reference Ranges

NORMAL RANGESerum 17-hydroxyprogesterone (17-OHP) reference ranges vary by age, assay, and gestational age. In adults, typical morning values are <220 ng/dL in males and <80 ng/dL (follicular phase) in females; preterm infants may have higher values, and values >1,000–1,500 ng/dL in a term infant are strongly suggestive of classic 21-OHD.

CRITICAL (PANIC) VALUEIn neonates, a 17-OHP level >1,500 ng/dL (or >15 ng/mL) on newborn screening is considered a critical value requiring urgent evaluation for classic CAH; delay in treatment can lead to salt-wasting crisis and death.

UNIT OF MEASUREMENTng/dL (or nmol/L for 17-OHP; SI conversion: 1 ng/dL = 0.0303 nmol/L)

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Confused With (LASA & DDx) ★

LEXICAL (LASA) — SIMILAR NAMES

Congenital Adrenal Hypoplasia

Sounds similar; adrenal hypoplasia congenita is a distinct X-linked disorder with adrenal insufficiency and hypogonadotropic hypogonadism, not enzyme-mediated hyperplasia.

Adrenogenital Syndrome

Often used interchangeably, but 'adrenogenital syndrome' is a broader historical term that may include other causes of virilisation; CAH is the specific enzymatic diagnosis.

CLINICAL DIFFERENTIAL DIAGNOSES (DDx)

11β-Hydroxylase Deficiency CAH

Key Distinguishing Feature: Hypertension and hypokalaemia (from DOC excess), with elevated 11-deoxycortisol and DOC; 17-OHP may be only modestly elevated.

3β-Hydroxysteroid Dehydrogenase Deficiency CAH

Key Distinguishing Feature: Virilisation is mild relative to the degree of salt wasting; elevated 17-hydroxypregnenolone and DHEA with low androstenedione.

X-linked Adrenal Hypoplasia Congenita

Key Distinguishing Feature: Occurs only in males; 17-OHP is low or normal (not elevated); associated with hypogonadotropic hypogonadism.

Polycystic Ovary Syndrome (PCOS)

Key Distinguishing Feature: In females with hirsutism/irregular menses, 17-OHP is typically normal or only mildly elevated; CAH is excluded by ACTH stimulation testing.

Exogenous Androgen Exposure

Key Distinguishing Feature: History of androgen exposure (maternal or iatrogenic); steroid profile normalises after withdrawal, and 17-OHP is not elevated.

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Clinical Pearls

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Newborn screening for CAH using 17-OHP is effective but can produce false positives, especially in preterm or stressed infants; confirmatory testing with LC-MS/MS or ACTH stimulation is essential before committing to lifelong therapy.

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In classic CAH, cortisol deficiency drives ACTH excess, which stimulates adrenal androgen production; treatment aims to normalise androgen levels without causing glucocorticoid excess, a narrow therapeutic window.

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Fludrocortisone is essential in salt-wasting CAH but is often omitted in simple virilising and nonclassic forms; monitor plasma renin to guide mineralocorticoid dosing.

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Stress dosing of hydrocortisone is required during febrile illness, surgery, or trauma, but not for minor psychological stress; educate families on sick-day rules and provide an emergency injection kit.

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Nonclassic CAH may present in adulthood with hirsutism, infertility, or PCOS-like features; it is far more common than classic CAH and is diagnosed by elevated 17-OHP on ACTH stimulation.

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Example Usage & SOAP

CLINICAL SENTENCE

"A 7-day-old term female infant presented with poor feeding, vomiting, and dehydration; examination revealed ambiguous genitalia and non-palpable testes, and initial investigations showed sodium 128 mmol/L, potassium 6.2 mmol/L, glucose 2.8 mmol/L, and 17-hydroxyprogesterone 1,850 ng/dL, consistent with salt-wasting congenital adrenal hyperplasia."

IN A SOAP NOTE

S: Neonate with poor feeding and vomiting since day 5 of life; mother reports no urine output for 12 hours. O: Weight 3.1 kg (birth weight 3.4 kg), heart rate 168 bpm, blood pressure 58/34 mmHg, sodium 127 mmol/L, potassium 6.5 mmol/L, glucose 2.6 mmol/L, 17-OHP 1,920 ng/dL. A: Suspected salt-wasting congenital adrenal hyperplasia with adrenal crisis. P: Administer IV sodium chloride 0.9% 20 mL/kg bolus, IV hydrocortisone 50 mg/m² stat, start fludrocortisone 0.1 mg daily, correct hypoglycaemia with IV dextrose, admit to NICU, and consult paediatric endocrinology.

DIFFERENTIAL DIAGNOSIS CONTEXT

Differential diagnosis for a neonate with ambiguous genitalia and salt wasting: (1) 21-hydroxylase deficiency CAH — elevated 17-OHP and androstenedione, low aldosterone, high renin; (2) 11β-hydroxylase deficiency CAH — hypertension, hypokalaemia, elevated DOC and 11-deoxycortisol; (3) 3β-hydroxysteroid dehydrogenase deficiency CAH — mild virilisation relative to salt wasting, elevated 17-hydroxypregnenolone; (4) lipoid CAH — complete lack of steroidogenesis, severe salt wasting, female genitalia in 46,XY; (5) X-linked adrenal hypoplasia congenita — males only, low 17-OHP, hypogonadotropic hypogonadism.

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Classifications & Scoring

SCORING TOOL

Steroidogenesis Score

A cascade logistic regression model using circulating steroid hormone levels to discriminate among the three most common CAH subtypes (21-hydroxylase, 11β-hydroxylase, and 17α-hydroxylase deficiencies) with high diagnostic accuracy.

Clinical Calculator ↗

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Prognosis

SHORT-TERM OUTCOME

With prompt diagnosis and appropriate glucocorticoid and mineralocorticoid replacement, short-term prognosis is good; salt-wasting crises can be prevented or treated effectively. Without treatment, classic CAH can be fatal in the neonatal period due to adrenal crisis.

LONG-TERM PROGNOSIS

Long-term prognosis depends on subtype and treatment adherence. Patients with classic CAH require lifelong hormone replacement and monitoring for complications of glucocorticoid excess and androgen control. With optimal care, near-normal adult height and quality of life are achievable; however, cardiometabolic risk, fertility challenges, and bone health require ongoing surveillance.

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References & Coding

ICD-10 DIAGNOSTIC CODE

E25.0

LITERATURE CITATIONS & GUIDELINES

[1]Speiser PW, Arlt W, Auchus RJ, et al. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043–4088. doi:10.1210/jc.2018-01865

[2]Yau M, Gujral J, New MI. Congenital Adrenal Hyperplasia: Diagnosis and Emergency Treatment. In: Feingold KR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. Updated 2019 Apr 16.

[3]NICE guideline NG243. Adrenal insufficiency: identification and management. 2024.

[4]Merke DP, Auchus RJ. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. N Engl J Med. 2020;383(13):1248–1261. doi:10.1056/NEJMra1909786

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