Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency

Summary

Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency (MONDO:0008729) is a disease caused by CYP11B1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: CYP11B1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 397
• Phenotypes (HPO): 32

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.75	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.47	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0000062	Ambiguous genitalia	Very frequent (80-99%)
HP:0000822	Hypertension	Very frequent (80-99%)
HP:0001507	Growth abnormality	Very frequent (80-99%)
HP:0002900	Hypokalemia	Very frequent (80-99%)
HP:0003351	Decreased circulating renin concentration	Very frequent (80-99%)
HP:0005616	Accelerated skeletal maturation	Very frequent (80-99%)
HP:0008163	Decreased circulating cortisol level	Very frequent (80-99%)
HP:0025380	Increased circulating androstenedione concentration	Very frequent (80-99%)
HP:0030348	Increased circulating androgen concentration	Very frequent (80-99%)
HP:0031213	Elevated circulating 17-hydroxyprogesterone	Very frequent (80-99%)
HP:0032330	Increased urinary 11-deoxycorticosterone level	Very frequent (80-99%)
HP:0000040	Long penis	Frequent (30-79%)
HP:0000061	Ambiguous genitalia, female	Frequent (30-79%)
HP:0000826	Precocious puberty	Frequent (30-79%)
HP:0000858	Irregular menstruation	Frequent (30-79%)
HP:0000953	Hyperpigmentation of the skin	Frequent (30-79%)
HP:0001007	Hirsutism	Frequent (30-79%)
HP:0001061	Acne	Frequent (30-79%)
HP:0003154	Increased circulating ACTH level	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0008236	Isosexual precocious puberty	Frequent (30-79%)
HP:0008665	Clitoral hypertrophy	Frequent (30-79%)
HP:0012411	Premature pubarche	Frequent (30-79%)
HP:0012412	Premature adrenarche	Frequent (30-79%)
HP:0000127	Renal salt wasting	Occasional (5-29%)
HP:0000147	Polycystic ovaries	Occasional (5-29%)
HP:0000771	Gynecomastia	Occasional (5-29%)
HP:0001596	Alopecia	Occasional (5-29%)
HP:0025451	Testicular adrenal rest tumor	Occasional (5-29%)
HP:0030088	Increased serum testosterone level	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Very rare (<1-4%)
HP:0010314	Premature thelarche	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency
Mondo ID	MONDO:0008729
MeSH	C535978
OMIM	202010
Orphanet	90795
ICD-11	791376680
NCIT	C131085
SNOMED CT	124214007
UMLS	C0268292
MedGen	82783
GARD	0005658
MedDRA	10000002
Is cancer (heuristic)	no

Also known as: adrenal hyperplasia hypertensive form · adrenal hyperplasia IV · adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency · CAH due to 11-beta-hydroxylase deficiency · CYP11B1 deficiency

Data availability: 397 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › congenital adrenal hyperplasia due to 11-beta-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, classic congenital adrenal hyperplasia due to 21-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

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

ClinVar germline variants

397 retrieved; paginated sample, class counts are floors:

156 uncertain significance, 61 likely pathogenic, 39 conflicting classifications of pathogenicity, 37 pathogenic, 34 pathogenic/likely pathogenic, 26 benign, 23 likely benign, 20 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1264342	NM_000497.3:c.[1024C>T];[1012dup]		Pathogenic	criteria provided, single submitter
1030831	NM_000497.4(CYP11B1):c.1343G>C (p.Arg448Pro)	CYP11B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073771	NM_000497.4(CYP11B1):c.421C>T (p.Arg141Ter)	CYP11B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1171	NM_000497.4(CYP11B1):c.1343G>A (p.Arg448His)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1173	NM_000497.4(CYP11B1):c.953C>T (p.Thr318Met)	CYP11B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1176	NM_000497.4(CYP11B1):c.347G>A (p.Trp116Ter)	CYP11B1	Pathogenic	no assertion criteria provided
1179	NM_000497.4(CYP11B1):c.124C>T (p.Pro42Ser)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184	CYP11B1, CYP11B1/CYP11B2 CHIMERA	CYP11B1	Pathogenic	no assertion criteria provided
1186	NM_000497.4(CYP11B1):c.281C>T (p.Pro94Leu)	CYP11B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1187	NM_000497.4(CYP11B1):c.1103C>A (p.Ala368Asp)	CYP11B1	Pathogenic	no assertion criteria provided
1384166	NM_000497.4(CYP11B1):c.449C>A (p.Ser150Ter)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1403418	NM_000497.4(CYP11B1):c.1179_1180dup (p.Asn394fs)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454795	NM_000497.4(CYP11B1):c.907del (p.Ala303fs)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459491	NM_000497.4(CYP11B1):c.1342C>T (p.Arg448Cys)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1481332	NM_000497.4(CYP11B1):c.596-2A>T	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687503	NM_000497.4(CYP11B1):c.913A>T (p.Lys305Ter)	CYP11B1	Pathogenic	criteria provided, single submitter
2112958	NM_000497.4(CYP11B1):c.706C>T (p.Gln236Ter)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674651	NM_000497.4(CYP11B1):c.359_363dup (p.His122fs)	CYP11B1	Pathogenic	criteria provided, single submitter
2674652	NM_000497.4(CYP11B1):c.381_382dup (p.Gly128fs)	CYP11B1	Pathogenic	criteria provided, single submitter
2674655	NM_000497.4(CYP11B1):c.760_776delinsGG (p.Lys254_Ala259delinsGly)	CYP11B1	Pathogenic	criteria provided, single submitter
2674662	NM_000497.4(CYP11B1):c.1466T>C (p.Leu489Ser)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3684024	NM_000497.4(CYP11B1):c.1345del (p.Gln449fs)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4294084	NM_000497.4(CYP11B1):c.239+1G>C	CYP11B1	Pathogenic	criteria provided, single submitter
447227	NM_000497.4(CYP11B1):c.841_842insACAGTACACCA (p.Ser281fs)	CYP11B1	Pathogenic	criteria provided, multiple submitters, no conflicts
550599	NM_000497.4(CYP11B1):c.235T>A (p.Phe79Ile)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551876	NM_000497.4(CYP11B1):c.317_344del (p.Leu106fs)	CYP11B1	Pathogenic	criteria provided, multiple submitters, no conflicts
551998	NM_000497.4(CYP11B1):c.372del (p.His125fs)	CYP11B1	Pathogenic	no assertion criteria provided
552238	NM_000497.4(CYP11B1):c.1151G>A (p.Arg384Gln)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
552695	NM_000497.4(CYP11B1):c.412C>T (p.Arg138Cys)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
555090	NM_000497.4(CYP11B1):c.780G>A (p.Trp260Ter)	CYP11B1	Pathogenic	criteria provided, single submitter

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
CYP11B1	Definitive	Autosomal recessive	congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP11B1	Orphanet:403	Familial hyperaldosteronism type I
CYP11B1	Orphanet:90795	Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency

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
CYP11B1	HGNC:2591	ENSG00000160882	P15538	Cytochrome P450 11B1, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP11B1	Cytochrome P450 11B1, mitochondrial	A cytochrome P450 monooxygenase involved in the biosynthesis of adrenal corticoids.

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)
CYP11B1	Enzyme (other)	yes	1.14.15.4	Cyt_P450, Cyt_P450_mitochondrial, Cyt_P450_CS

Expression context

Cohort genes with no expression data: 0.

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
CYP11B1	137		yes	right adrenal gland cortex, right adrenal gland, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYP11B1	1,596

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYP11B1	P15538	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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 CYP11B1 causes AH4	1	5710.0×	0.002	CYP11B1
Glucocorticoid biosynthesis	1	878.5×	0.005	CYP11B1
Metabolic disorders of biological oxidation enzymes	1	878.5×	0.005	CYP11B1
Cytochrome P450 - arranged by substrate type	1	713.8×	0.005	CYP11B1
Metabolism of steroid hormones	1	519.1×	0.005	CYP11B1
Endogenous sterols	1	393.8×	0.006	CYP11B1
Phase I - Functionalization of compounds	1	219.6×	0.008	CYP11B1
Metabolism of steroids	1	137.6×	0.011	CYP11B1
Biological oxidations	1	129.8×	0.011	CYP11B1
Diseases of metabolism	1	80.4×	0.016	CYP11B1
Metabolism of lipids	1	31.6×	0.037	CYP11B1
Disease	1	13.1×	0.083	CYP11B1
Metabolism	1	11.6×	0.086	CYP11B1

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
aldosterone biosynthetic process	1	3370.4×	0.002	CYP11B1
cortisol metabolic process	1	2808.7×	0.002	CYP11B1
cortisol biosynthetic process	1	2106.5×	0.002	CYP11B1
C21-steroid hormone biosynthetic process	1	1872.4×	0.002	CYP11B1
glucocorticoid biosynthetic process	1	1532.0×	0.002	CYP11B1
cellular response to potassium ion	1	1053.2×	0.002	CYP11B1
sterol metabolic process	1	842.6×	0.002	CYP11B1
cellular response to peptide hormone stimulus	1	842.6×	0.002	CYP11B1
cellular response to hormone stimulus	1	383.0×	0.004	CYP11B1
regulation of blood pressure	1	221.7×	0.006	CYP11B1
cholesterol metabolic process	1	195.9×	0.006	CYP11B1
glucose homeostasis	1	130.6×	0.008	CYP11B1
immune response	1	47.1×	0.021	CYP11B1

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
CYP11B1	FLUCONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP11B1	13	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FLUCONAZOLE	4	CYP11B1
POSACONAZOLE	4	CYP11B1
LETROZOLE	4	CYP11B1
KETOCONAZOLE	4	CYP11B1
ABIRATERONE	4	CYP11B1
OSILODROSTAT	4	CYP11B1
ETOMIDATE	4	CYP11B1
METYRAPONE	4	CYP11B1
BAXDROSTAT	3	CYP11B1
VOROZOLE	2	CYP11B1
DEXFADROSTAT	2	CYP11B1
AZALANSTAT	2	CYP11B1
FADROZOLE	2	CYP11B1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CYP11B1	113	Binding:95, ADMET:16, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP11B1	1.14.15.4	steroid 11beta-monooxygenase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CYP11B1	113

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

13 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)
FLUCONAZOLE	4	CYP11B1
POSACONAZOLE	4	CYP11B1
LETROZOLE	4	CYP11B1
KETOCONAZOLE	4	CYP11B1
ABIRATERONE	4	CYP11B1
OSILODROSTAT	4	CYP11B1
ETOMIDATE	4	CYP11B1
METYRAPONE	4	CYP11B1
BAXDROSTAT	3	CYP11B1
VOROZOLE	2	CYP11B1
DEXFADROSTAT	2	CYP11B1
AZALANSTAT	2	CYP11B1
FADROZOLE	2	CYP11B1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYP11B1
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: 0.