Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Summary

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (MONDO:0008728) is a disease caused by CYP21A2 (GenCC Definitive), with 1 cohort gene and 5 clinical trials. Top therapeutic interventions include hydrocortisone, hydrocortisone cypionate, and tildacerfont.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: CYP21A2 (GenCC Definitive)
• Cohort genes: 1
• Phenotypes (HPO): 56
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

11 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	7	Europe	Validated
Prevalence at birth	1-9 / 100 000	6.4	France	Validated
Prevalence at birth	1-9 / 100 000	8.7	Sweden	Validated
Prevalence at birth	1-9 / 100 000	6.2	United States	Validated
Prevalence at birth	1-9 / 100 000	4.2	New Zealand	Validated
Prevalence at birth	1-9 / 100 000	6.4	Croatia	Validated
Prevalence at birth	1-9 / 100 000	6.2	Estonia	Validated
Prevalence at birth	1-9 / 100 000	4.5	Singapore	Validated
Prevalence at birth	1-9 / 100 000	6.5	Switzerland	Validated
Prevalence at birth	1-9 / 100 000	7	Worldwide	Not yet validated
Prevalence at birth	1-9 / 100 000	9.2	Italy	Not yet validated

Signs & symptoms

Clinical features (HPO)

56 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0008163	Decreased circulating cortisol level	Very frequent (80-99%)
HP:0030348	Increased circulating androgen concentration	Very frequent (80-99%)
HP:0031074	Abnormal response to ACTH stimulation test	Very frequent (80-99%)
HP:0031213	Elevated circulating 17-hydroxyprogesterone	Very frequent (80-99%)
HP:0031216	Increased circulating progesterone	Very frequent (80-99%)
HP:0000127	Renal salt wasting	Frequent (30-79%)
HP:0000140	Abnormality of the menstrual cycle	Frequent (30-79%)
HP:0000144	Decreased fertility	Frequent (30-79%)
HP:0000811	Abnormal external genitalia	Frequent (30-79%)
HP:0000841	Hyperactive renin-angiotensin system	Frequent (30-79%)
HP:0000876	Oligomenorrhea	Frequent (30-79%)
HP:0001007	Hirsutism	Frequent (30-79%)
HP:0001061	Acne	Frequent (30-79%)
HP:0001507	Growth abnormality	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0001944	Dehydration	Frequent (30-79%)
HP:0001998	Neonatal hypoglycemia	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002153	Hyperkalemia	Frequent (30-79%)
HP:0002615	Hypotension	Frequent (30-79%)
HP:0002902	Hyponatremia	Frequent (30-79%)
HP:0003113	Hypochloremia	Frequent (30-79%)
HP:0003154	Increased circulating ACTH level	Frequent (30-79%)
HP:0003639	Elevated urinary epinephrine	Frequent (30-79%)
HP:0004012	Premature fusion of the radial epiphyseal plates	Frequent (30-79%)
HP:0004319	Decreased circulating aldosterone level	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0005616	Accelerated skeletal maturation	Frequent (30-79%)
HP:0005976	Hyperkalemic metabolic acidosis	Frequent (30-79%)
HP:0008207	Primary adrenal insufficiency	Frequent (30-79%)
HP:0008665	Clitoral hypertrophy	Frequent (30-79%)
HP:0011106	Hypovolemia	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012411	Premature pubarche	Frequent (30-79%)
HP:0012417	Hypocapnia	Frequent (30-79%)
HP:0012605	Hypernatriuria	Frequent (30-79%)
HP:0025380	Increased circulating androstenedione concentration	Frequent (30-79%)
HP:0030088	Increased serum testosterone level	Frequent (30-79%)
HP:0031066	Abnormal ovarian physiology	Frequent (30-79%)
HP:0500022	Abnormal serum dehydroepiandrosterone level	Frequent (30-79%)
HP:0000040	Long penis	Occasional (5-29%)
HP:0000044	Hypogonadotropic hypogonadism	Occasional (5-29%)
HP:0000061	Ambiguous genitalia, female	Occasional (5-29%)
HP:0000062	Ambiguous genitalia	Occasional (5-29%)
HP:0000098	Tall stature	Occasional (5-29%)
HP:0000151	Aplasia of the uterus	Occasional (5-29%)
HP:0002292	Frontal balding	Occasional (5-29%)
HP:0005268	Spontaneous abortion	Occasional (5-29%)
HP:0008734	Decreased testicular size	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Mondo ID	MONDO:0008728
MeSH	C535979
OMIM	201910
Orphanet	90794
NCIT	C131087
SNOMED CT	124221007, 717261006
UMLS	C4273964
MedGen	903755
GARD	0012665
Is cancer (heuristic)	no

Also known as: 21 hydroxylase deficiency · 21-OHD · adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency · classic 21-OHD CAH · classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency · congenital adrenal hyperplasia due to 21-hydroxylase deficiency · CYP21 deficiency

Data availability: 3 GenCC gene-disease records · 17 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Related subtypes (29): pelvic organ prolapse, cortisone reductase deficiency, physiological sexual disorder, gonadal disorder, female reproductive system disorder, male reproductive system disorder, pituitary gland disorder, infertility disorder, hypospadias, reproductive system neoplasm, dysplasia of cervix, female genital tuberculosis, habitual spontaneous abortion, aromatase excess syndrome, hand-foot-genital syndrome, mullerian duct anomalies-limb anomalies syndrome, Currarino triad, double uterus-hemivagina-renal agenesis syndrome, congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency, congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency, congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency, spondylocostal dysostosis-anal and genitourinary malformations syndrome, congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, estrogen resistance syndrome, short stature, microcephaly, and endocrine dysfunction, diethylstilbestrol syndrome, sexually transmitted disease, NR5A1-related sex development disorder

Subtypes (2): classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CYP21A2	Definitive	Autosomal recessive	classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP21A2	Orphanet:315306	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form
CYP21A2	Orphanet:315311	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYP21A2	HGNC:2600	ENSG00000231852	P08686	Steroid 21-hydroxylase	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP21A2	Steroid 21-hydroxylase	A cytochrome P450 monooxygenase that plays a major role in adrenal steroidogenesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYP21A2	Enzyme (other)	yes	1.14.14.16	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYP21A2	130	tissue_specific	marker	right adrenal gland, left adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYP21A2	28

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYP21A2	P08686	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CYP21A2 causes AH3	1	5710.0×	7e-04	CYP21A2
Mineralocorticoid biosynthesis	1	1427.5×	0.001	CYP21A2
Glucocorticoid biosynthesis	1	878.5×	0.002	CYP21A2
Endogenous sterols	1	393.8×	0.003	CYP21A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mineralocorticoid biosynthetic process	1	4213.0×	0.001	CYP21A2
cortisol biosynthetic process	1	2106.5×	0.001	CYP21A2
glucocorticoid biosynthetic process	1	1532.0×	0.001	CYP21A2
sterol metabolic process	1	842.6×	0.002	CYP21A2
steroid biosynthetic process	1	601.9×	0.002	CYP21A2
steroid metabolic process	1	337.0×	0.003	CYP21A2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CYP21A2	KETOCONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP21A2	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KETOCONAZOLE	4	CYP21A2
ABIRATERONE	4	CYP21A2
ORTERONEL	3	CYP21A2
GALETERONE	3	CYP21A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CYP21A2	15	Binding:10, ADMET:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP21A2	1.14.14.16	steroid 21-monooxygenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

4 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
KETOCONAZOLE	4	CYP21A2
ABIRATERONE	4	CYP21A2
ORTERONEL	3	CYP21A2
GALETERONE	3	CYP21A2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYP21A2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE1/PHASE2	1
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00519818	PHASE1/PHASE2	COMPLETED	Comparison of Two Forms of Hydrocortisone in Patients With Congenital Adrenal Hyperplasia
NCT05128942	PHASE2	TERMINATED	A Phase 2 Study to Evaluate the Safety, Efficacy and PK of Tildacerfont in Children Aged 2-17 Years With CAH
NCT01495910	PHASE1	COMPLETED	A Study Examining Doses of Abiraterone Acetate in Adult Women With 21-Hydroxylase Deficiency
NCT00542841	Not specified	COMPLETED	Examining Genetic Differences Among People With 21-Hydroxylase Deficiency
NCT01862380	Not specified	UNKNOWN	Adrenocortical Functions in Women With Nonclassical 21-hydroxylase Deficiency.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
HYDROCORTISONE	4	2
HYDROCORTISONE CYPIONATE	4	1
TILDACERFONT	2	1