congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

Summary

congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (MONDO:0013310) is a disease caused by POR (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: POR (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 803
• Phenotypes (HPO): 108

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.75	Europe	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0031074	Abnormal response to ACTH stimulation test	Very frequent (80-99%)
HP:0000924	Abnormality of the skeletal system	Very frequent (80-99%)
HP:0000811	Abnormal external genitalia	Frequent (30-79%)
HP:0000055	Abnormality of female external genitalia	Frequent (30-79%)
HP:0000032	Abnormality of male external genitalia	Frequent (30-79%)
HP:0003154	Increased circulating ACTH level	Frequent (30-79%)
HP:0008163	Decreased circulating cortisol level	Frequent (30-79%)
HP:0031213	Elevated circulating 17-hydroxyprogesterone	Frequent (30-79%)
HP:0031216	Increased circulating progesterone	Frequent (30-79%)
HP:0031187	Abnormality of circulating pregnenolone level	Frequent (30-79%)
HP:0031215	Decreased circulating dehydroepiandrosterone-sulfate level	Frequent (30-79%)
HP:0031083	Abnormal response to human chorionic gonadotrophin stimulation test	Frequent (30-79%)
HP:0000798	Oligozoospermia	Frequent (30-79%)
HP:0000144	Decreased fertility	Frequent (30-79%)
HP:0001007	Hirsutism	Frequent (30-79%)
HP:0003070	Elbow ankylosis	Frequent (30-79%)
HP:0001377	Limited elbow extension	Frequent (30-79%)
HP:0002987	Elbow flexion contracture	Frequent (30-79%)
HP:0000927	Abnormality of skeletal maturation	Frequent (30-79%)
HP:0008214	Decreased serum estradiol	Frequent (30-79%)
HP:0008221	Adrenal hyperplasia	Frequent (30-79%)
HP:0031065	Abnormal ovarian morphology	Frequent (30-79%)
HP:0000147	Polycystic ovaries	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0011911	Abnormality of metacarpophalangeal joint	Occasional (5-29%)
HP:0011800	Midface retrusion	Occasional (5-29%)
HP:0001363	Craniosynostosis	Occasional (5-29%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000262	Turricephaly	Occasional (5-29%)
HP:0001760	Abnormal foot morphology	Occasional (5-29%)
HP:0001155	Abnormality of the hand	Occasional (5-29%)
HP:0001166	Arachnodactyly	Occasional (5-29%)
HP:0030084	Clinodactyly	Occasional (5-29%)
HP:0012385	Camptodactyly	Occasional (5-29%)
HP:0001440	Metatarsal synostosis	Occasional (5-29%)
HP:0009701	Metacarpal synostosis	Occasional (5-29%)
HP:0003019	Abnormality of the wrist	Occasional (5-29%)
HP:0001838	Rocker bottom foot	Occasional (5-29%)
HP:0001883	Talipes	Occasional (5-29%)
HP:0002974	Radioulnar synostosis	Occasional (5-29%)
HP:0003041	Humeroradial synostosis	Occasional (5-29%)
HP:0000062	Ambiguous genitalia	Occasional (5-29%)
HP:0040253	Increased size of the clitoris	Occasional (5-29%)
HP:0025486	Fused labia majora	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000054	Micropenis	Occasional (5-29%)
HP:0030349	Decreased circulating androgen level	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000786	Primary amenorrhea	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency
Mondo ID	MONDO:0013310
OMIM	613571
Orphanet	95699
DOID	DOID:0080925
ICD-11	497412536
NCIT	C174439
SNOMED CT	715733000
UMLS	C1860042
MedGen	348008
GARD	0012664
Is cancer (heuristic)	no

Also known as: congenital adrenal hyperplasia due to cytochrome POR deficiency · disordered steroidogenesis due to cytochrome P450 oxidoreductase · POR deficiency · PORD

Data availability: 803 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 cytochrome P450 oxidoreductase 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, congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency, spondylocostal dysostosis-anal and genitourinary malformations syndrome, 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

600 retrieved; paginated sample, class counts are floors:

376 likely benign, 116 uncertain significance, 49 pathogenic, 26 likely pathogenic, 11 conflicting classifications of pathogenicity, 10 benign, 9 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1411407	NM_001395413.1(POR):c.1033del (p.Val345fs)	LOC126860075	Pathogenic	criteria provided, single submitter
16902	NM_001395413.1(POR):c.850G>C (p.Ala284Pro)	LOC126860075	Pathogenic	criteria provided, multiple submitters, no conflicts
2706311	NM_001395413.1(POR):c.955dup (p.His319fs)	LOC126860075	Pathogenic	criteria provided, single submitter
2730681	NM_001395413.1(POR):c.1044del (p.Asn349fs)	LOC126860075	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2785905	NM_001395413.1(POR):c.981_988dup (p.Leu330fs)	LOC126860075	Pathogenic	criteria provided, single submitter
1324955	NM_001395413.1(POR):c.1816C>T (p.Gln606Ter)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1379019	NM_001395413.1(POR):c.1676_1679dup (p.Leu561fs)	POR	Pathogenic	criteria provided, multiple submitters, no conflicts
1405328	NM_001395413.1(POR):c.723-2A>T	POR	Pathogenic	criteria provided, multiple submitters, no conflicts
1454425	NM_001395413.1(POR):c.1837C>T (p.Arg613Ter)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454456	NM_001395413.1(POR):c.1406_1407del (p.Val469fs)	POR	Pathogenic	criteria provided, single submitter
16904	NM_001395413.1(POR):c.1813G>T (p.Val605Phe)	POR	Pathogenic	no assertion criteria provided
16906	NM_001395413.1(POR):c.532T>G (p.Tyr178Asp)	POR	Pathogenic	no assertion criteria provided
16907	NM_001395413.1(POR):c.1361G>A (p.Arg454His)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16910	NM_001395413.1(POR):c.1320dup (p.Ile441fs)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16915	NM_001395413.1(POR):c.1606G>A (p.Gly536Arg)	POR	Pathogenic	criteria provided, multiple submitters, no conflicts
1723238	NM_001395413.1(POR):c.821+1G>A	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1920714	NM_001395413.1(POR):c.64_65del (p.Leu22fs)	POR	Pathogenic	criteria provided, single submitter
1941965	NM_001395413.1(POR):c.768del (p.Lys257fs)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2065334	NM_001395413.1(POR):c.1795C>T (p.Gln599Ter)	POR	Pathogenic	criteria provided, single submitter
2626788	NM_001395413.1(POR):c.1675dup (p.Glu559fs)	POR	Pathogenic	no assertion criteria provided
2695460	NM_001395413.1(POR):c.697del (p.Val233fs)	POR	Pathogenic	criteria provided, single submitter
2707022	NM_001395413.1(POR):c.1631_1634del (p.Ile544fs)	POR	Pathogenic	criteria provided, single submitter
2713901	NM_001395413.1(POR):c.1807-1G>A	POR	Pathogenic	criteria provided, single submitter
2715315	NM_001395413.1(POR):c.40G>T (p.Glu14Ter)	POR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2733599	NM_001395413.1(POR):c.385_386dup (p.Asp129fs)	POR	Pathogenic	criteria provided, single submitter
2735032	NM_001395413.1(POR):c.251dup (p.Tyr84Ter)	POR	Pathogenic	criteria provided, single submitter
2735033	NM_001395413.1(POR):c.658C>T (p.Arg220Ter)	POR	Pathogenic	criteria provided, single submitter
2735034	NM_001395413.1(POR):c.1178CCTCGGAGC[1] (p.Pro396_Glu398del)	POR	Pathogenic	criteria provided, single submitter
2735035	NM_001395413.1(POR):c.1613dup (p.Pro539fs)	POR	Pathogenic	criteria provided, single submitter
2735036	NM_001395413.1(POR):c.1792del (p.Glu598fs)	POR	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 4 · 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
POR	Strong	Autosomal recessive	congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency	7
PORCN	Strong	Autosomal recessive	congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PORCN	Orphanet:2092	Focal dermal hypoplasia
PORCN	Orphanet:98938	Colobomatous microphthalmia
POR	Orphanet:63269	Antley-Bixler syndrome with genital anomaly and disorder of steroidogenesis
POR	Orphanet:95699	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PORCN	HGNC:17652	ENSG00000102312	Q9H237	Protein-serine O-palmitoleoyltransferase porcupine	gencc,clinvar
POR	HGNC:9208	ENSG00000127948	P16435	NADPH–cytochrome P450 reductase	gencc,clinvar
TMEM120A	HGNC:21697	ENSG00000189077	Q9BXJ8	Transmembrane protein 120A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PORCN	Protein-serine O-palmitoleoyltransferase porcupine	Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1(9Z)), to Wnt proteins.
POR	NADPH–cytochrome P450 reductase	This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes.
TMEM120A	Transmembrane protein 120A	Multifunctional protein involved in mechanosensation, and plays an essential role in lipid metabolism and adipocyte differentiation.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PORCN	Enzyme (other)	yes	2.3.1.250	MBOAT_fam, LPLAT_7/PORCN-like
POR	Enzyme (other)	yes	1.6.2.4	Flavdoxin-like, OxRdtase_FAD/NAD-bd, Flavoprot_Pyr_Nucl_cyt_Rdtase
TMEM120A	Other/Unknown	no		TMEM120A/B

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right adrenal gland	2
right adrenal gland cortex	2
lower esophagus mucosa	1
adrenal tissue	1
right lobe of liver	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PORCN	184	ubiquitous	marker	lower esophagus mucosa, right adrenal gland cortex, right adrenal gland
POR	266	ubiquitous	marker	adrenal tissue, right lobe of liver, right adrenal gland
TMEM120A	238	ubiquitous	marker	right testis, left testis, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POR	2,263
PORCN	802
TMEM120A	651

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POR	P16435	9
PORCN	Q9H237	7
TMEM120A	Q9BXJ8	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
LGK974 inhibits PORCN	1	2855.0×	0.002	PORCN
Cytochrome P450 - arranged by substrate type	1	356.9×	0.008	POR
WNT ligand biogenesis and trafficking	1	211.5×	0.009	PORCN
Phase I - Functionalization of compounds	1	109.8×	0.014	POR
Biological oxidations	1	64.9×	0.018	POR
Metabolism	1	5.8×	0.165	POR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nitrate catabolic process	1	5617.3×	0.002	POR
positive regulation of growth plate cartilage chondrocyte proliferation	1	5617.3×	0.002	POR
positive regulation of steroid hormone biosynthetic process	1	5617.3×	0.002	POR
protein palmitoleylation	1	2808.7×	0.002	PORCN
nitric oxide catabolic process	1	2808.7×	0.002	POR
organofluorine metabolic process	1	2808.7×	0.002	POR
Wnt protein secretion	1	1872.4×	0.002	PORCN
P450-containing electron transport chain	1	1872.4×	0.002	POR
demethylation	1	1404.3×	0.003	POR
protein lipidation	1	1123.5×	0.003	PORCN
carnitine metabolic process	1	802.5×	0.004	POR
flavonoid metabolic process	1	702.2×	0.004	POR
lipid modification	1	624.1×	0.004	PORCN
electron transport chain	1	510.7×	0.005	POR
cellular response to follicle-stimulating hormone stimulus	1	468.1×	0.005	POR
response to dexamethasone	1	401.2×	0.005	POR
glycoprotein metabolic process	1	374.5×	0.005	PORCN
detection of mechanical stimulus involved in sensory perception of pain	1	374.5×	0.005	TMEM120A
fatty acid oxidation	1	351.1×	0.005	POR
protein heterooligomerization	1	351.1×	0.005	TMEM120A
cellular response to peptide hormone stimulus	1	280.9×	0.006	POR
positive regulation of chondrocyte differentiation	1	267.5×	0.006	POR
nitric oxide biosynthetic process	1	234.1×	0.006	POR
regulation of postsynaptic membrane neurotransmitter receptor levels	1	165.2×	0.009	PORCN
response to hormone	1	144.0×	0.009	POR
positive regulation of smoothened signaling pathway	1	140.4×	0.009	POR
response to nutrient	1	98.5×	0.013	POR
antiviral innate immune response	1	75.9×	0.016	TMEM120A
monoatomic ion transmembrane transport	1	69.3×	0.017	TMEM120A
fat cell differentiation	1	60.4×	0.019	TMEM120A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 3 of 3 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
PORCN	2	2
POR	1	2
TMEM120A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
WNT-974	2	PORCN
LAPACHONE	2	POR
ETC-159	1	PORCN

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PORCN	31	Binding:31
POR	21	ADMET:14, Binding:7
TMEM120A	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PORCN	2.3.1.250	[Wnt protein] O-palmitoleoyl transferase
POR	1.6.2.4	NADPH-hemoprotein reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
WNT-974	2	PORCN
LAPACHONE	2	POR
ETC-159	1	PORCN

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	2	PORCN, POR
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TMEM120A

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)
TMEM120A	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.