Congenital adrenal hyperplasia

CAH comprises a classic and a non-classic form, with phenotypic severity reflecting the residual enzyme activity. The classic form of 21-hydroxylase deficiency (21-OHD), which accounts for more than 90% of CAH, manifests at birth or in the first weeks of life. Prenatal exposure to adrenal androgens virilises the external genitalia of 46,XX neonates, frequently producing genital ambiguity. Approximately 75% of classic cases have the salt-wasting form, in which inadequate aldosterone production causes life-threatening adrenal crises with hyponatraemia, hyperkalaemia, and vascular collapse within the first 1-4 weeks of life; the remaining ~25% have the simple virilising form. Untreated androgen excess drives advanced bone age, premature epiphyseal fusion, and reduced adult stature, and may compromise fertility and contribute to testicular adrenal rest tumours in males. The non-classic form presents postnatally with signs of hyperandrogenism (premature pubarche, hirsutism, menstrual irregularity); affected females are not virilised at birth.

The estimated prevalence of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CYP21A2) is approximately 1:10,000–1:20,000. Other, rarer forms of congenital adrenal hyperplasia are substantially less frequent and vary depending on the underlying genetic defect.

Reported carrier frequencies for CYP21A2 variants are typically in the range of 1:50–1:70 in European populations, although estimates vary depending on the population studied and the spectrum of variants included. Frequencies may be substantially higher when milder (non-classic) variants are taken into account.

CAH is genetically heterogeneous, with biallelic germline pathogenic variants in any of the 7 steroidogenic genes implicated to date. The leading genes are CYP21A2 (~90% of cases, 21-hydroxylase deficiency) and CYP11B1 (~5%, 11β-hydroxylase deficiency); rarer forms arise from variants in HSD3B2, CYP17A1, STAR, CYP11A1, and POR. Loss of enzyme function impairs cortisol synthesis, releases ACTH from negative feedback, and drives adrenal hyperplasia; precursor steroids are shunted into intact adjacent pathways, generating androgen excess (21-OHD, 11β-OHD, 3β-HSD) and either mineralocorticoid deficiency with salt wasting (21-OHD, 3β-HSD, STAR) or mineralocorticoid excess with hypertension (11β-OHD, 17α-OHD).

CAH is inherited in an autosomal recessive manner. Parents of an affected individual are obligate heterozygous carriers; the recurrence risk for siblings is 25%. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

Diagnosis of 21-OHD CAH rests on a markedly elevated serum 17-hydroxyprogesterone (17-OHP), which exceeds 10,000 ng/dL (300 nmol/L) in classic disease. Adrenal androgens (Δ4-androstenedione, DHEA, 21-deoxycortisol, testosterone) are elevated; plasma renin activity is high with inappropriately low aldosterone in the salt-wasting form. Newborn screening uses filter-paper 17-OHP immunoassay, with liquid chromatography-tandem mass spectrometry as a recommended second-tier test. For the non-classic form, the 60-minute ACTH stimulation test plotted on a 17-OHP nomogram is the functional reference standard.

Main differential diagnoses include:

• 11β-hydroxylase-deficient CAH: androgen excess and virilisation with low-renin hypertension from deoxycorticosterone accumulation rather than salt wasting; CYP11B1
• 3β-hydroxysteroid dehydrogenase type 2 deficiency: mild virilisation in females and undervirilisation in males with salt wasting; characteristic elevation of Δ5-steroids (17-OH pregnenolone, DHEA); HSD3B2
• Cytochrome P450 oxidoreductase deficiency: apparent combined partial 17α- and 21-hydroxylase deficiency on urinary steroid profiling; spectrum extends to Antley-Bixler syndrome with craniosynostosis and skeletal anomalies; POR

• The diagnosis should be confirmed at the molecular level when the clinical and biochemical findings are compatible.
• Providing the prerequisite for individualised clinical management, including avoidance of disease-specific risks; further measures are determined by the treating physicians in consultation with the affected individual.
• Enabling testing of at-risk family members once the familial pathogenic variants have been identified.

• Nimkarn S, Gangishetti PK, Yau M, New MI. 21-hydroxylase-deficient congenital adrenal hyperplasia. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: .
• Mallappa A, Merke DP. Management challenges and therapeutic advances in congenital adrenal hyperplasia. Nat Rev Endocrinol. 2022;18(6):337-352. PMID: .
• Neumann U, van der Linde A, Krone RE, Krone NP, Güven A, Güran T, et al. Treatment of congenital adrenal hyperplasia in children aged 0-3 years: a retrospective multicenter analysis of salt supplementation, glucocorticoid and mineralocorticoid medication, growth and blood pressure. Eur J Endocrinol. 2022;186(5):587-596. PMID: .
• Leusink QM, Verploegen EEW, Adriaansen BPH, Chin X, Stikkelbroeck NMML, Span PN, et al. Current insights into monitoring of congenital adrenal hyperplasia. Front Endocrinol (Lausanne). 2026;17:1774145. PMID: .