Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency

Summary

Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency (MONDO:0008730) is a disease caused by CYP17A1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: CYP17A1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 188
• Phenotypes (HPO): 41

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.1	Europe	Validated

Signs & symptoms

Clinical features (HPO)

41 HPO clinical features (Orphanet curated; top 41 by frequency):

HPO ID	Term	Frequency
HP:0000822	Hypertension	Very frequent (80-99%)
HP:0000837	Increased circulating gonadotropin level	Very frequent (80-99%)
HP:0008258	Congenital adrenal hyperplasia	Very frequent (80-99%)
HP:0031074	Abnormal response to ACTH stimulation test	Very frequent (80-99%)
HP:0032330	Increased urinary 11-deoxycorticosterone level	Very frequent (80-99%)
HP:0032362	Increased circulating corticosterone level	Very frequent (80-99%)
HP:0040171	Decreased serum testosterone concentration	Very frequent (80-99%)
HP:0500022	Abnormal serum dehydroepiandrosterone level	Very frequent (80-99%)
HP:0000026	Male hypogonadism	Frequent (30-79%)
HP:0000047	Hypospadias	Frequent (30-79%)
HP:0000138	Ovarian cyst	Frequent (30-79%)
HP:0000144	Decreased fertility	Frequent (30-79%)
HP:0000771	Gynecomastia	Frequent (30-79%)
HP:0000786	Primary amenorrhea	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0000858	Irregular menstruation	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0002900	Hypokalemia	Frequent (30-79%)
HP:0003351	Decreased circulating renin concentration	Frequent (30-79%)
HP:0004319	Decreased circulating aldosterone level	Frequent (30-79%)
HP:0008163	Decreased circulating cortisol level	Frequent (30-79%)
HP:0008187	Absence of secondary sex characteristics	Frequent (30-79%)
HP:0008197	Absence of pubertal development	Frequent (30-79%)
HP:0008232	Elevated circulating follicle stimulating hormone level	Frequent (30-79%)
HP:0008689	Bilateral cryptorchidism	Frequent (30-79%)
HP:0011749	Adrenocorticotropic hormone excess	Frequent (30-79%)
HP:0011969	Elevated circulating luteinizing hormone level	Frequent (30-79%)
HP:0031216	Increased circulating progesterone	Frequent (30-79%)
HP:0000033	Ambiguous genitalia, male	Occasional (5-29%)
HP:0000048	Bifid scrotum	Occasional (5-29%)
HP:0000054	Micropenis	Occasional (5-29%)
HP:0000151	Aplasia of the uterus	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002221	Absent axillary hair	Occasional (5-29%)
HP:0002555	Absent pubic hair	Occasional (5-29%)
HP:0003251	Male infertility	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0008207	Primary adrenal insufficiency	Occasional (5-29%)
HP:0008730	Female external genitalia in individual with 46,XY karyotype	Occasional (5-29%)
HP:0010465	Precocious puberty in females	Occasional (5-29%)
HP:0040314	Blind vagina	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency
Mondo ID	MONDO:0008730
OMIM	202110
Orphanet	90793
ICD-11	587903316
SNOMED CT	124220008
UMLS	C0268285
MedGen	82782
GARD	0001469
Is cancer (heuristic)	no

Also known as: 17-alpha-hydroxylase/17,20-lyase deficiency · CAH due to 17-alpha-hydroxylase deficiency · combined 17-hydroxylase/17,20-lyase deficiency · congenital adrenal hyperplasia type 5

Data availability: 188 ClinVar variants · 2 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 17-alpha-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 11-beta-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

188 retrieved; paginated sample, class counts are floors:

42 uncertain significance, 39 likely pathogenic, 36 pathogenic, 30 pathogenic/likely pathogenic, 21 likely benign, 12 conflicting classifications of pathogenicity, 5 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065950	NM_000102.4(CYP17A1):c.1117C>T (p.His373Tyr)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065951	NM_000102.4(CYP17A1):c.1117C>G (p.His373Asp)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066592	NM_000102.4(CYP17A1):c.1226C>T (p.Pro409Leu)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074306	NM_000102.4(CYP17A1):c.1072C>T (p.Arg358Ter)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1322182	NM_000102.4(CYP17A1):c.1226C>G (p.Pro409Arg)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1322183	NM_000102.4(CYP17A1):c.580G>T (p.Glu194Ter)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338524	NM_000102.4(CYP17A1):c.1319G>A (p.Arg440His)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1456799	NM_000102.4(CYP17A1):c.521C>A (p.Ala174Glu)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457632	NM_000102.4(CYP17A1):c.1306G>A (p.Gly436Arg)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1460105	NM_000102.4(CYP17A1):c.1117C>A (p.His373Asn)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1512295	NM_000102.4(CYP17A1):c.1345C>T (p.Arg449Cys)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1524567	NM_000102.4(CYP17A1):c.1486C>T (p.Arg496Cys)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709011	NM_000102.4(CYP17A1):c.438_439del (p.Ile146fs)	CYP17A1	Pathogenic	criteria provided, single submitter
1777	NM_000102.4(CYP17A1):c.1435_1438dup (p.Pro480fs)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1778	NM_000102.4(CYP17A1):c.157TTC[1] (p.Phe54del)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1780	NM_000102.4(CYP17A1):c.316T>C (p.Ser106Pro)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1782	NM_000102.4(CYP17A1):c.715C>T (p.Arg239Ter)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1785	NM_000102.4(CYP17A1):c.286C>T (p.Arg96Trp)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1787	NM_000102.4(CYP17A1):c.1040G>A (p.Arg347His)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1788	NM_000102.4(CYP17A1):c.1073G>A (p.Arg358Gln)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1794	NM_000102.4(CYP17A1):c.1039C>T (p.Arg347Cys)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1796	NM_000102.4(CYP17A1):c.1084C>T (p.Arg362Cys)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1797	NM_000102.4(CYP17A1):c.1216T>C (p.Trp406Arg)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1799	NM_000102.4(CYP17A1):c.1283C>T (p.Pro428Leu)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1802	NM_000102.4(CYP17A1):c.287G>A (p.Arg96Gln)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1803	NM_000102.4(CYP17A1):c.374G>A (p.Arg125Gln)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1804	NM_000102.4(CYP17A1):c.1247G>A (p.Arg416His)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136931	NM_000102.4(CYP17A1):c.362G>A (p.Trp121Ter)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2152094	NM_000102.4(CYP17A1):c.177dup (p.Tyr60fs)	CYP17A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2153178	NM_000102.4(CYP17A1):c.177del (p.Lys59fs)	CYP17A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CYP17A1	Strong	Autosomal recessive	congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP17A1	Orphanet:90793	Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency
CYP17A1	Orphanet:90796	46,XY difference of sex development due to isolated 17,20-lyase deficiency

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYP17A1	HGNC:2593	ENSG00000148795	P05093	Steroid 17-alpha-hydroxylase/17,20 lyase	gencc,clinvar
CYP17A1-AS1	HGNC:31671			CYP17A1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP17A1	Steroid 17-alpha-hydroxylase/17,20 lyase	A cytochrome P450 monooxygenase involved in corticoid and androgen biosynthesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYP17A1	Enzyme (other)	yes	1.14.14.19	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
CYP17A1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

Breadth distribution (Bgee present_calls)

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

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
CYP17A1	165	tissue_specific	yes	right adrenal gland, right adrenal gland cortex, left adrenal gland
CYP17A1-AS1

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYP17A1	2,720
CYP17A1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYP17A1	P05093	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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 CYP17A1 causes AH5	1	11420.0×	3e-04	CYP17A1
Androgen biosynthesis	1	1038.2×	0.001	CYP17A1
Glucocorticoid biosynthesis	1	878.5×	0.001	CYP17A1

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
cortisol biosynthetic process	1	2106.5×	0.001	CYP17A1
androgen biosynthetic process	1	1872.4×	0.001	CYP17A1
progesterone metabolic process	1	1685.2×	0.001	CYP17A1
glucocorticoid biosynthetic process	1	1532.0×	0.001	CYP17A1
hormone biosynthetic process	1	1404.3×	0.001	CYP17A1
sex differentiation	1	842.6×	0.002	CYP17A1
steroid biosynthetic process	1	601.9×	0.002	CYP17A1
steroid metabolic process	1	337.0×	0.003	CYP17A1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
CYP17A1	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP17A1	16	4
CYP17A1-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	CYP17A1
TESTOSTERONE PROPIONATE	4	CYP17A1
TIOCONAZOLE	4	CYP17A1
POSACONAZOLE	4	CYP17A1
KETOCONAZOLE	4	CYP17A1
ISOCONAZOLE	4	CYP17A1
ABIRATERONE	4	CYP17A1
ABIRATERONE ACETATE	4	CYP17A1
BIFONAZOLE	4	CYP17A1
OSILODROSTAT	4	CYP17A1
AMINOGLUTETHIMIDE	4	CYP17A1
ECONAZOLE	4	CYP17A1
MICONAZOLE	4	CYP17A1
ORTERONEL	3	CYP17A1
GALETERONE	3	CYP17A1
AZALANSTAT	2	CYP17A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CYP17A1	239	Binding:198, ADMET:37, Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP17A1	1.14.14.19, 1.14.14.32	steroid 17alpha-monooxygenase, 17alpha-hydroxyprogesterone deacetylase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CYP17A1	239

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

16 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)
CLOTRIMAZOLE	4	CYP17A1
TESTOSTERONE PROPIONATE	4	CYP17A1
TIOCONAZOLE	4	CYP17A1
POSACONAZOLE	4	CYP17A1
KETOCONAZOLE	4	CYP17A1
ISOCONAZOLE	4	CYP17A1
ABIRATERONE	4	CYP17A1
ABIRATERONE ACETATE	4	CYP17A1
BIFONAZOLE	4	CYP17A1
OSILODROSTAT	4	CYP17A1
AMINOGLUTETHIMIDE	4	CYP17A1
ECONAZOLE	4	CYP17A1
MICONAZOLE	4	CYP17A1
ORTERONEL	3	CYP17A1
GALETERONE	3	CYP17A1
AZALANSTAT	2	CYP17A1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYP17A1
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	1	CYP17A1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CYP17A1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.