Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency

Summary

Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency (MONDO:0008727) is a disease caused by HSD3B2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HSD3B2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 170
• Phenotypes (HPO): 36

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		68	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0008258	Congenital adrenal hyperplasia	Very frequent (80-99%)
HP:0000033	Ambiguous genitalia, male	Frequent (30-79%)
HP:0000047	Hypospadias	Frequent (30-79%)
HP:0000061	Ambiguous genitalia, female	Frequent (30-79%)
HP:0000127	Renal salt wasting	Frequent (30-79%)
HP:0000771	Gynecomastia	Frequent (30-79%)
HP:0000848	Increased circulating renin level	Frequent (30-79%)
HP:0000953	Hyperpigmentation of the skin	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:0004319	Decreased circulating aldosterone level	Frequent (30-79%)
HP:0008163	Decreased circulating cortisol level	Frequent (30-79%)
HP:0008665	Clitoral hypertrophy	Frequent (30-79%)
HP:0011749	Adrenocorticotropic hormone excess	Frequent (30-79%)
HP:0012041	Decreased fertility in males	Frequent (30-79%)
HP:0025380	Increased circulating androstenedione concentration	Frequent (30-79%)
HP:0030088	Increased serum testosterone level	Frequent (30-79%)
HP:0031213	Elevated circulating 17-hydroxyprogesterone	Frequent (30-79%)
HP:0040171	Decreased serum testosterone concentration	Frequent (30-79%)
HP:0500022	Abnormal serum dehydroepiandrosterone level	Frequent (30-79%)
HP:0000027	Azoospermia	Occasional (5-29%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000037	Male pseudohermaphroditism	Occasional (5-29%)
HP:0000808	Penoscrotal hypospadias	Occasional (5-29%)
HP:0001007	Hirsutism	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0008730	Female external genitalia in individual with 46,XY karyotype	Occasional (5-29%)
HP:0008734	Decreased testicular size	Occasional (5-29%)
HP:0012412	Premature adrenarche	Occasional (5-29%)
HP:0012768	Neonatal asphyxia	Occasional (5-29%)
HP:0012881	Abnormality of the labia majora	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency
Mondo ID	MONDO:0008727
MeSH	C538236
OMIM	201810
Orphanet	90791
ICD-11	929626064
NCIT	C131088
SNOMED CT	54470008
UMLS	C0342471
MedGen	452446
GARD	0009152
Is cancer (heuristic)	no

Also known as: 3-beta HSD deficiency · 3b-hydroxysteroid dehydrogenase deficiency · adrenal hyperplasia II · CAH due to 3-beta-hydroxysteroid dehydrogenase deficiency · HSD3B deficiency · type II 3-beta-hydroxysteroid dehydrogenase deficiency

Data availability: 170 ClinVar variants · 3 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase 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, classic congenital adrenal hyperplasia due to 21-hydroxylase 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

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

170 retrieved; paginated sample, class counts are floors:

65 uncertain significance, 27 likely pathogenic, 21 conflicting classifications of pathogenicity, 20 likely benign, 16 pathogenic/likely pathogenic, 13 pathogenic, 6 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12186	NM_000198.4(HSD3B2):c.[742_743delinsAA;745C>T]		Pathogenic	no assertion criteria provided
1070043	NM_000198.4(HSD3B2):c.244G>A (p.Ala82Thr)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070432	NM_000198.4(HSD3B2):c.340del (p.Ala114fs)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073403	NM_000198.4(HSD3B2):c.965C>A (p.Ser322Ter)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12184	NM_000198.4(HSD3B2):c.512G>A (p.Trp171Ter)	HSD3B2	Pathogenic	criteria provided, multiple submitters, no conflicts
12185	NM_000198.4(HSD3B2):c.558dup (p.Thr187fs)	HSD3B2	Pathogenic	criteria provided, multiple submitters, no conflicts
12187	NM_000198.4(HSD3B2):c.745C>T (p.Arg249Ter)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12190	NM_000198.4(HSD3B2):c.424G>A (p.Glu142Lys)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12191	NM_000198.4(HSD3B2):c.664C>A (p.Pro222Thr)	HSD3B2	Pathogenic	criteria provided, multiple submitters, no conflicts
12192	NM_000198.4(HSD3B2):c.776C>T (p.Thr259Met)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12193	NM_000198.4(HSD3B2):c.867del (p.Met290fs)	HSD3B2	Pathogenic	criteria provided, multiple submitters, no conflicts
12194	NM_000198.4(HSD3B2):c.1022C>T (p.Pro341Leu)	HSD3B2	Pathogenic	no assertion criteria provided
1451753	NM_000198.4(HSD3B2):c.792_796del (p.Tyr264_Asn266delinsTer)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451900	NM_000198.4(HSD3B2):c.65dup (p.Leu22fs)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456146	NM_000198.4(HSD3B2):c.829del (p.Leu277fs)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1513071	NM_000198.4(HSD3B2):c.35G>A (p.Gly12Glu)	HSD3B2	Pathogenic	criteria provided, multiple submitters, no conflicts
1722337	NM_000198.4(HSD3B2):c.665C>A (p.Pro222Gln)	HSD3B2	Pathogenic	criteria provided, multiple submitters, no conflicts
2202833	NM_000198.4(HSD3B2):c.540C>A (p.Tyr180Ter)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674668	NM_000198.4(HSD3B2):c.687_713del (p.Trp230_Ala238del)	HSD3B2	Pathogenic	criteria provided, single submitter
2761538	NM_000198.4(HSD3B2):c.424G>T (p.Glu142Ter)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
517183	NM_000198.4(HSD3B2):c.1064G>A (p.Trp355Ter)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
586031	NM_000198.4(HSD3B2):c.818_819del (p.Lys273fs)	HSD3B2	Pathogenic	criteria provided, multiple submitters, no conflicts
597649	NM_000198.4(HSD3B2):c.1003C>T (p.Arg335Ter)	HSD3B2	Pathogenic	criteria provided, multiple submitters, no conflicts
937691	NM_000198.4(HSD3B2):c.931C>T (p.Gln311Ter)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
944811	NM_000198.4(HSD3B2):c.518T>G (p.Leu173Arg)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
946461	NM_000198.4(HSD3B2):c.9G>A (p.Trp3Ter)	HSD3B2	Pathogenic	criteria provided, multiple submitters, no conflicts
956384	NM_000198.4(HSD3B2):c.1000C>T (p.Gln334Ter)	HSD3B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076441	NM_000198.4(HSD3B2):c.15C>A (p.Cys5Ter)	LOC109029530	Pathogenic	criteria provided, multiple submitters, no conflicts
2961055	NM_000198.4(HSD3B2):c.131_132del (p.Glu44fs)	LOC109029530	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12189	NM_000198.4(HSD3B2):c.1119A>C (p.Ter373Cys)	HSD3B2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
HSD3B2	Strong	Autosomal recessive	congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HSD3B2	Orphanet:90791	Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase 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
HSD3B2	HGNC:5218	ENSG00000203859	P26439	3 beta-hydroxysteroid dehydrogenase/Delta 5–>4-isomerase type 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HSD3B2	3 beta-hydroxysteroid dehydrogenase/Delta 5–>4-isomerase type 2	3-beta-HSD is a bifunctional enzyme, that catalyzes the oxidative conversion of Delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids.

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)
HSD3B2	Enzyme (other)	yes	1.1.1.145	3Beta_OHSteriod_DH/Estase, NAD(P)-bd_dom_sf, Lipid_A_modif_metabolic_enz

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
adrenal cortex	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HSD3B2	157	tissue_specific	yes	right adrenal gland, right adrenal gland cortex, adrenal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSD3B2	2,968

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HSD3B2	P26439	94.30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Mineralocorticoid biosynthesis	1	1427.5×	0.003	HSD3B2
Androgen biosynthesis	1	1038.2×	0.003	HSD3B2
Glucocorticoid biosynthesis	1	878.5×	0.003	HSD3B2
Metabolism of steroid hormones	1	519.1×	0.003	HSD3B2
Metabolism of steroids	1	137.6×	0.010	HSD3B2
Metabolism of lipids	1	31.6×	0.037	HSD3B2
Metabolism	1	11.6×	0.086	HSD3B2

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
C21-steroid hormone metabolic process	1	3370.4×	8e-04	HSD3B2
androgen biosynthetic process	1	1872.4×	8e-04	HSD3B2
steroid biosynthetic process	1	601.9×	0.002	HSD3B2

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HSD3B2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HSD3B2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HSD3B2	1.1.1.145, 5.3.3.1	3beta-hydroxy-DELTA5-steroid dehydrogenase, steroid DELTA-isomerase

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	HSD3B2
E	Difficult family or no structure, no drug	0

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)
HSD3B2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.