Aromatase deficiency

Summary

Aromatase deficiency (MONDO:0013301) is a disease caused by CYP19A1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CYP19A1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 197
• Phenotypes (HPO): 26

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		38	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000938	Osteopenia	Very frequent (80-99%)
HP:0000939	Osteoporosis	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001513	Obesity	Very frequent (80-99%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0002663	Delayed epiphyseal ossification	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0002857	Genu valgum	Very frequent (80-99%)
HP:0003077	Hyperlipidemia	Very frequent (80-99%)
HP:0003251	Male infertility	Very frequent (80-99%)
HP:0003782	Eunuchoid habitus	Very frequent (80-99%)
HP:0008072	Maternal virilization in pregnancy	Very frequent (80-99%)
HP:0008222	Female infertility	Very frequent (80-99%)
HP:0008675	Enlarged polycystic ovaries	Very frequent (80-99%)
HP:0010458	Female pseudohermaphroditism	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000061	Ambiguous genitalia, female	Very frequent (80-99%)
HP:0000098	Tall stature	Very frequent (80-99%)
HP:0000786	Primary amenorrhea	Very frequent (80-99%)
HP:0000815	Hypergonadotropic hypogonadism	Very frequent (80-99%)
HP:0000855	Insulin resistance	Frequent (30-79%)
HP:0000956	Acanthosis nigricans	Frequent (30-79%)
HP:0001397	Hepatic steatosis	Frequent (30-79%)
HP:0002050	Macroorchidism, postpubertal	Frequent (30-79%)
HP:0002230	Generalized hirsutism	Frequent (30-79%)
HP:0005978	Type II diabetes mellitus	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	aromatase deficiency
Mondo ID	MONDO:0013301
MeSH	C537436
OMIM	613546
Orphanet	91
ICD-11	260189446
NCIT	C120144
UMLS	C1960539
MedGen	743307
GARD	0000365
Is cancer (heuristic)	no

Also known as: aromatase deficiency · congenital estrogen deficiency · congenital oestrogen deficiency

Data availability: 197 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited primary ovarian failure › aromatase deficiency

Related subtypes (40): blepharophimosis, ptosis, and epicanthus inversus syndrome, congenital lipoid adrenal hyperplasia due to STAR deficency, ataxia telangiectasia, classic galactosemia, 46 XX gonadal dysgenesis, premature ovarian failure 2A, premature ovarian failure 2B, premature ovarian failure 1, Satoyoshi syndrome, premature ovarian failure 3, osteosclerosis-ichthyosis-premature ovarian failure syndrome, premature ovarian failure 5, premature ovarian failure 6, premature ovarian failure 7, premature ovarian failure 8, premature ovarian failure 9, 46,XX ovarian dysgenesis-short stature syndrome, premature ovarian failure 11, premature ovarian failure 12, Perrault syndrome, trisomy X, Turner syndrome, tetrasomy X, X small rings, premature ovarian failure 17, premature ovarian failure 18, premature ovarian failure 20, premature ovarian failure 19, premature ovarian failure 16, premature ovarian failure 13, premature ovarian failure 10, premature ovarian failure 14, premature ovarian failure 15, premature ovarian failure 4, premature ovarian failure 21, premature ovarian failure 22, premature ovarian failure 23, premature ovarian failure 24, premature ovarian failure 25, premature ovarian failure 26

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

197 retrieved; paginated sample, class counts are floors:

85 uncertain significance, 26 benign, 26 likely pathogenic, 25 likely benign, 16 conflicting classifications of pathogenicity, 10 pathogenic, 8 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076833	NM_000103.4(CYP19A1):c.256C>T (p.Arg86Ter)	CYP19A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2780299	NM_000103.4(CYP19A1):c.1263+1G>A	CYP19A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2863693	NM_000103.4(CYP19A1):c.671G>A (p.Trp224Ter)	CYP19A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4816277	NM_000103.4(CYP19A1):c.744-2A>G	CYP19A1	Pathogenic	criteria provided, single submitter
930859	NM_000103.4(CYP19A1):c.1263+1G>T	CYP19A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1212857	NM_000103.4(CYP19A1):c.343C>T (p.Arg115Ter)	MIR4713HG	Pathogenic	criteria provided, multiple submitters, no conflicts
17822	NM_000103.4(CYP19A1):c.469del (p.Val158fs)	MIR4713HG	Pathogenic	no assertion criteria provided
17823	NM_000103.4(CYP19A1):c.629-3C>A	MIR4713HG	Pathogenic	no assertion criteria provided
3776041	NM_000103.4(CYP19A1):c.367C>T (p.Gln123Ter)	MIR4713HG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4816278	NM_000103.4(CYP19A1):c.744-3_747del	MIR4713HG	Pathogenic	criteria provided, single submitter
1448719	NM_000103.4(CYP19A1):c.200G>A (p.Trp67Ter)	PIRC66	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17815	NM_000103.4(CYP19A1):c.1303C>T (p.Arg435Cys)	PIRC66	Pathogenic	criteria provided, multiple submitters, no conflicts
17817	NM_000103.4(CYP19A1):c.743+2T>C	PIRC66	Pathogenic	no assertion criteria provided
17819	NM_000103.4(CYP19A1):c.1224del (p.Lys409fs)	PIRC66	Pathogenic	no assertion criteria provided
17820	NM_000103.4(CYP19A1):c.296+1G>A	PIRC66	Pathogenic	criteria provided, single submitter
17826	NM_000103.4(CYP19A1):c.628G>A (p.Glu210Lys)	PIRC66	Pathogenic	criteria provided, multiple submitters, no conflicts
2744294	NM_000103.4(CYP19A1):c.1024G>T (p.Glu342Ter)	PIRC66	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
653853	NM_000103.4(CYP19A1):c.1058dup (p.Leu353fs)	PIRC66	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17818	NM_000103.4(CYP19A1):c.1123C>T (p.Arg375Cys)	CYP19A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
17821	NM_000103.4(CYP19A1):c.1094G>A (p.Arg365Gln)	CYP19A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2012702	NM_000103.4(CYP19A1):c.146-2A>G	CYP19A1	Likely pathogenic	criteria provided, single submitter
3577353	NM_000103.4(CYP19A1):c.1369C>T (p.Arg457Ter)	CYP19A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3577354	NM_000103.4(CYP19A1):c.1022-2A>G	CYP19A1	Likely pathogenic	criteria provided, single submitter
3577355	NM_000103.4(CYP19A1):c.724A>T (p.Lys242Ter)	CYP19A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3577356	NM_000103.4(CYP19A1):c.316del (p.His105_Ile106insTer)	CYP19A1	Likely pathogenic	criteria provided, single submitter
3577357	NM_031226.3(CYP19A1):c.297del	CYP19A1	Likely pathogenic	criteria provided, single submitter
4065721	NM_000103.4(CYP19A1):c.451+2T>C	CYP19A1	Likely pathogenic	criteria provided, single submitter
4816264	NM_000103.4(CYP19A1):c.1001_1002insT (p.Lys334fs)	CYP19A1	Likely pathogenic	criteria provided, single submitter
4816268	NM_000103.4(CYP19A1):c.1232del (p.Asn411fs)	CYP19A1	Likely pathogenic	criteria provided, single submitter
4816273	NM_000103.4(CYP19A1):c.575G>A (p.Arg192His)	CYP19A1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
CYP19A1	Definitive	Autosomal recessive	aromatase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP19A1	Orphanet:178345	Aromatase excess syndrome
CYP19A1	Orphanet:91	Aromatase deficiency
GLDN	Orphanet:994	Fetal akinesia deformation sequence

Cohort genes → proteins

4 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYP19A1	HGNC:2594	ENSG00000137869	P11511	Aromatase	gencc,clinvar
GLDN	HGNC:29514	ENSG00000186417	Q6ZMI3	Gliomedin	clinvar
PIRC66	HGNC:37570			piwi-interacting RNA cluster 66	clinvar
MIR4713HG	HGNC:53124	ENSG00000259240		MIR4713 host gene	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP19A1	Aromatase	A cytochrome P450 monooxygenase that catalyzes the conversion of C19 androgens, androst-4-ene-3,17-dione (androstenedione) and testosterone to the C18 estrogens, estrone and estradiol, respectively.
GLDN	Gliomedin	Ligand for NRCAM and NFASC/neurofascin that plays a role in the formation and maintenance of the nodes of Ranvier on myelinated axons.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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	3.0×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYP19A1	Enzyme (other)	yes	1.14.14.14	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
GLDN	Other/Unknown	no		Olfac-like_dom, Collagen, Olfactomedin-like_domain
PIRC66	Other/Unknown	no
MIR4713HG	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

2 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	1

Top tissues across cohort

Tissue	Cohort genes
left testis	1
placenta	1
right testis	1
inferior vagus X ganglion	1
pons	1
trigeminal ganglion	1
hindlimb stylopod muscle	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYP19A1	159	tissue_specific	marker	placenta, right testis, left testis
GLDN	226	broad	marker	inferior vagus X ganglion, trigeminal ganglion, pons
PIRC66
MIR4713HG	104		yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYP19A1	3,732
GLDN	866
PIRC66	0
MIR4713HG	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYP19A1	P11511	11
GLDN	Q6ZMI3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 4 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 CYP19A1 causes AEXS	1	11420.0×	3e-04	CYP19A1
Estrogen biosynthesis	1	1903.3×	8e-04	CYP19A1
Endogenous sterols	1	393.8×	0.003	CYP19A1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
microvillus organization	1	4213.0×	0.002	GLDN
positive regulation of estradiol secretion	1	4213.0×	0.002	CYP19A1
negative regulation of chronic inflammatory response	1	2808.7×	0.002	CYP19A1
obsolete syncytium formation	1	2106.5×	0.002	CYP19A1
androgen catabolic process	1	1685.2×	0.002	CYP19A1
testosterone biosynthetic process	1	1404.3×	0.002	CYP19A1
negative regulation of macrophage chemotaxis	1	1203.7×	0.002	CYP19A1
female genitalia development	1	1203.7×	0.002	CYP19A1
clustering of voltage-gated sodium channels	1	1203.7×	0.002	GLDN
prostate gland growth	1	1053.2×	0.002	CYP19A1
estrogen biosynthetic process	1	766.0×	0.002	CYP19A1
sterol metabolic process	1	421.3×	0.003	CYP19A1
female gonad development	1	401.2×	0.003	CYP19A1
uterus development	1	401.2×	0.003	CYP19A1
mammary gland development	1	324.1×	0.004	CYP19A1
steroid biosynthetic process	1	300.9×	0.004	CYP19A1
response to estradiol	1	99.1×	0.011	CYP19A1
signal transduction	1	8.0×	0.121	GLDN

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
CYP19A1	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP19A1	40	4
GLDN	0	0
PIRC66	0	0
MIR4713HG	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	CYP19A1
FLUCONAZOLE	4	CYP19A1
EXEMESTANE	4	CYP19A1
POSACONAZOLE	4	CYP19A1
ANASTROZOLE	4	CYP19A1
ESTRONE	4	CYP19A1
LETROZOLE	4	CYP19A1
TESTOLACTONE	4	CYP19A1
KETOCONAZOLE	4	CYP19A1
FLUOROURACIL	4	CYP19A1
OSILODROSTAT	4	CYP19A1
TESTOSTERONE	4	CYP19A1
AMINOGLUTETHIMIDE	4	CYP19A1
NIMESULIDE	4	CYP19A1
MICONAZOLE	4	CYP19A1
ENDOXIFEN	3	CYP19A1
RESVERATROL	3	CYP19A1
DOCONEXENT	3	CYP19A1
ICOSAPENT	3	CYP19A1
QUERCETIN	3	CYP19A1
FORMESTANE	2	CYP19A1
LUTEOLIN	2	CYP19A1
URSOLIC ACID	2	CYP19A1
PLOMESTANE	2	CYP19A1
VOROZOLE	2	CYP19A1
LINOLEIC ACID	2	CYP19A1
FLAVONE	2	CYP19A1
STANOLONE	2	CYP19A1
IROSUSTAT	2	CYP19A1
DEXFADROSTAT	2	CYP19A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CYP19A1	728	Binding:698, ADMET:17, Functional:13

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP19A1	1.14.14.14	aromatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CYP19A1	728

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

30 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	CYP19A1
FLUCONAZOLE	4	CYP19A1
EXEMESTANE	4	CYP19A1
POSACONAZOLE	4	CYP19A1
ANASTROZOLE	4	CYP19A1
ESTRONE	4	CYP19A1
LETROZOLE	4	CYP19A1
TESTOLACTONE	4	CYP19A1
KETOCONAZOLE	4	CYP19A1
FLUOROURACIL	4	CYP19A1
OSILODROSTAT	4	CYP19A1
TESTOSTERONE	4	CYP19A1
AMINOGLUTETHIMIDE	4	CYP19A1
NIMESULIDE	4	CYP19A1
MICONAZOLE	4	CYP19A1
ENDOXIFEN	3	CYP19A1
RESVERATROL	3	CYP19A1
DOCONEXENT	3	CYP19A1
ICOSAPENT	3	CYP19A1
QUERCETIN	3	CYP19A1
FORMESTANE	2	CYP19A1
LUTEOLIN	2	CYP19A1
URSOLIC ACID	2	CYP19A1
PLOMESTANE	2	CYP19A1
VOROZOLE	2	CYP19A1
LINOLEIC ACID	2	CYP19A1
FLAVONE	2	CYP19A1
STANOLONE	2	CYP19A1
IROSUSTAT	2	CYP19A1
DEXFADROSTAT	2	CYP19A1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYP19A1
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	3	GLDN, PIRC66, MIR4713HG

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GLDN	0	—
PIRC66	0	—
MIR4713HG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.