21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia

21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia is a endocrine genetic disease caused by autosomal recessive variants in CYP21A2. It is not placed in the rankable burden order: only 2 of five axes are scored (cut: three of five), so the remaining 3 stay open [O], not guessed. Mechanism, scored axes, and treatment follow below.

21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia is inherited as autosomal recessive and acts by loss-of-function (biallelic; recessive) ([H]). Of the five burden axes, 2 are scored (O, S) and 3 are open [O] (P, M, D); because fewer than three are scored the disease is reported as “not placed — insufficient axis coverage” (rank null), not ranked on partial data.

Gene, inheritance, and molecular mechanism

21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia is inherited as Autosomal recessive inheritance [L] and is classified mechanistically as loss-of-function (biallelic; recessive) [H]. CYP21A2 encodes 21-hydroxylase, an adrenal cytochrome-P450 enzyme of cortisol and aldosterone synthesis. Biallelic deficiency blocks cortisol production; the lost negative feedback drives ACTH-stimulated adrenal hyperplasia and shunts steroid precursors into androgens.

Inheritance source: medgen:esummary:ModeOfInheritance:2026-06-17. Mechanism source: inference:recessive=>loss_of_function; basis=medgen_inheritance(recessive); corrob=clingen_AR(HI30):CYP21A2. These are observed, cited inputs; the classification is the reproducible analysis layer (C-D1).

In-scope clinical involvement

Classic 21-hydroxylase deficiency presents as salt-wasting or simple-virilising congenital adrenal hyperplasia: prenatal virilisation of affected females, and life-threatening neonatal salt-wasting crises in the salt-wasting form; a milder non-classic form presents later.

Organ systems [L] from HPO phenotype.hpoa v2026-06-06 (OMIM 201910,613815); P-aspect terms rolled up to HP:0000118 organ-system categories via hp.obo.

Burden axes and why this disease is not placed

For transparency the partial composite over the 2 scored axis/axes is raw_burden = 0.7500, but it is not used to rank the disease (below the ≥ 3-axis cut). The open axes (progression, mortality, disability) are graded [O] with a named obstacle, never imputed.

The natural-history registry passes lift onset (Orphanet, R6) and disability (GBD 2013 disability weights, R7) to registry [L] where an entity-anchored mapping exists, lift severity (HPO Severity-modifier subtree, R8) where the dominant sequela is annotated, and lift progression (curated PMC open-access literature with a frozen-R3-derived tier, R9) where a cited disease-level magnitude for the dominant untreated sequela exists. For some diseases the added disability axis was enough to cross the ≥ 3-axis cut and enter the placed residual order; for this one it was not — and its dominant sequela carries no open HPO severity annotation, so no registry severity tier is available (the open HPO severity annotations elsewhere are feature-level; the OMIM clinical synopsis, the disease-level alternative, is API-key-gated and the key is unobtainable for an individual researcher). Scoring three or more axes at registry grade (via published functional & survival literature) would let this disease enter the rankable residual order; until then it is reported here, never imputed.

Established treatment

The established disease-directed approach is glucocorticoid replacement with mineralocorticoid in salt-wasting forms. Mechanistically: corrects cortisol deficiency and suppresses ACTH-driven adrenal androgen excess; mineralocorticoid corrects salt-wasting [L]. Its effect on natural history is classified disease-modifying (substantial) (efficacy offset e = 0.5500, residual factor R_treat = 0.4500); this offset would apply to the burden score once the disease is placed.

Evidence tier: accession-dated to the GeneReviews NBK1171 Management section [L] (initial posting February 26, 2002; last revision February 4, 2016; retrieved 2026-06-18; corroborating term(s): “glucocorticoid, replacement, mineralocorticoid”).