Aromatase excess syndrome

Summary

Aromatase excess syndrome (MONDO:0007690) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 17
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000771	Gynecomastia	Very frequent (80-99%)
HP:0025139	Increased serum estrone	Very frequent (80-99%)
HP:0034699	Elevated aromatase activity	Very frequent (80-99%)
HP:0000044	Hypogonadotropic hypogonadism	Frequent (30-79%)
HP:0005616	Accelerated skeletal maturation	Frequent (30-79%)
HP:0007464	Sparse facial hair	Frequent (30-79%)
HP:0025134	Increased serum estradiol	Frequent (30-79%)
HP:0030341	Decreased circulating follicle stimulating hormone concentration	Frequent (30-79%)
HP:0000026	Male hypogonadism	Occasional (5-29%)
HP:0000858	Irregular menstruation	Occasional (5-29%)
HP:0001620	Abnormally high-pitched voice	Occasional (5-29%)
HP:0003502	Mild short stature	Occasional (5-29%)
HP:0008734	Decreased testicular size	Occasional (5-29%)
HP:0010313	Breast hypertrophy	Occasional (5-29%)
HP:0010314	Premature thelarche	Occasional (5-29%)
HP:0010465	Precocious puberty in females	Occasional (5-29%)
HP:0040171	Decreased serum testosterone concentration	Occasional (5-29%)
HP:0100878	Enlarged uterus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	aromatase excess syndrome
Mondo ID	MONDO:0007690
MeSH	C000591739
OMIM	139300
Orphanet	178345
DOID	DOID:0090122
ICD-11	191989744
SNOMED CT	709075008
UMLS	C1970109
MedGen	409989
GARD	0012494
Is cancer (heuristic)	no

Also known as: AEXS · aromatase excess syndrome · familial hyperestrogenism · gynecomastia, familial, due to increased aromatase activity · gynecomastia, hereditary · hereditary prepubertal gynecomastia

Data availability: 17 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › aromatase excess syndrome

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, 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, 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

17 retrieved; paginated sample, class counts are floors:

8 likely pathogenic, 3 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 2 benign, 1 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2780299	NM_000103.4(CYP19A1):c.1263+1G>A	CYP19A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
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
859794	NM_000103.4(CYP19A1):c.297-1G>C	CYP19A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3577358	NM_000103.4(CYP19A1):c.145+2T>A	PIRC66	Likely pathogenic	criteria provided, single submitter
887527	NM_000103.4(CYP19A1):c.242A>G (p.Tyr81Cys)	CYP19A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2503834	NM_000103.4(CYP19A1):c.1232A>G (p.Asn411Ser)	MIR4713HG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316473	NM_000103.4(CYP19A1):c.953T>C (p.Met318Thr)	CYP19A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
316469	NM_000103.4(CYP19A1):c.*19C>T	MIR4713HG	Benign	criteria provided, multiple submitters, no conflicts
316477	NM_000103.4(CYP19A1):c.240A>G (p.Val80=)	PIRC66	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
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

Cohort genes → proteins

3 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYP19A1	HGNC:2594	ENSG00000137869	P11511	Aromatase	gencc,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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

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
PIRC66	Other/Unknown	no
MIR4713HG	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

1 cohort gene 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)	2
unknown	1

Top tissues across cohort

Tissue	Cohort genes
left testis	1
placenta	1
right testis	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
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
PIRC66	0
MIR4713HG	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYP19A1	P11511	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of estradiol secretion	1	8426.0×	9e-04	CYP19A1
negative regulation of chronic inflammatory response	1	5617.3×	9e-04	CYP19A1
obsolete syncytium formation	1	4213.0×	9e-04	CYP19A1
androgen catabolic process	1	3370.4×	9e-04	CYP19A1
testosterone biosynthetic process	1	2808.7×	9e-04	CYP19A1
negative regulation of macrophage chemotaxis	1	2407.4×	9e-04	CYP19A1
female genitalia development	1	2407.4×	9e-04	CYP19A1
prostate gland growth	1	2106.5×	9e-04	CYP19A1
estrogen biosynthetic process	1	1532.0×	0.001	CYP19A1
sterol metabolic process	1	842.6×	0.002	CYP19A1
female gonad development	1	802.5×	0.002	CYP19A1
uterus development	1	802.5×	0.002	CYP19A1
mammary gland development	1	648.1×	0.002	CYP19A1
steroid biosynthetic process	1	601.9×	0.002	CYP19A1
response to estradiol	1	198.3×	0.005	CYP19A1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
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: 2; 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	2	PIRC66, MIR4713HG

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.