Apparent mineralocorticoid excess

Summary

Apparent mineralocorticoid excess (MONDO:0009025) is a disease caused by HSD11B2 (GenCC Strong), with 1 cohort gene and 4 clinical trials. Top therapeutic interventions include enoxolone.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: HSD11B2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 93
• Phenotypes (HPO): 17
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000822	Hypertension	Very frequent (80-99%)
HP:0002900	Hypokalemia	Very frequent (80-99%)
HP:0003351	Decreased circulating renin concentration	Very frequent (80-99%)
HP:0000121	Nephrocalcinosis	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001959	Polydipsia	Frequent (30-79%)
HP:0001960	Hypokalemic metabolic alkalosis	Frequent (30-79%)
HP:0004319	Decreased circulating aldosterone level	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0011731	Abnormality of circulating cortisol level	Frequent (30-79%)
HP:0012603	Abnormal urine sodium concentration	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0001095	Hypertensive retinopathy	Occasional (5-29%)
HP:0001297	Stroke	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001712	Left ventricular hypertrophy	Occasional (5-29%)
HP:0012606	Renal sodium wasting	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	apparent mineralocorticoid excess
Mondo ID	MONDO:0009025
MeSH	C537422, D043204
OMIM	218030
Orphanet	320
DOID	DOID:0090121, DOID:4367
ICD-11	1737310323
NCIT	C123231, C131083
SNOMED CT	237770005, 703256004
UMLS	C0342488
MedGen	90983
GARD	0000433
Is cancer (heuristic)	no

Also known as: 11 Beta-hydroxysteroid dehydrogenase type 2 deficiency · 11-beta-hydroxysteroid dehydrogenase deficiency type 2 · AME · AME 1 · APE · apparent mineralocorticoid excess · apparent mineralocorticoid excess syndrome · cortisol 11-beta-ketoreductase deficiency · syndrome of apparent mineralocorticoid Excess · Ulick syndrome

Data availability: 93 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › adrenal gland disorder › apparent mineralocorticoid excess

Related subtypes (17): medulloadrenal hyperfunction, adrenal cortex disorder, adrenal medullary hyperplasia, pituitary dwarfism, pseudoleprechaunism syndrome, Patterson type, autoimmune polyendocrine syndrome type 1, adrenomyodystrophy, corticosteroid-binding globulin deficiency, Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, adrenogenital syndrome, hypoaldosteronism disease, primary pigmented nodular adrenocortical disease, adrenoleukodystrophy, adrenal gland neoplasm, ectopic ACTH secretion syndrome, endogenous Cushing syndrome, isolated micronodular adrenocortical disease

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

93 retrieved; paginated sample, class counts are floors:

65 uncertain significance, 7 pathogenic, 7 likely pathogenic, 5 conflicting classifications of pathogenicity, 3 benign/likely benign, 2 pathogenic/likely pathogenic, 2 benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12093	NM_000196.4(HSD11B2):c.622C>T (p.Arg208Cys)	HSD11B2	Pathogenic	criteria provided, single submitter
12094	NM_000196.4(HSD11B2):c.637C>T (p.Arg213Cys)	HSD11B2	Pathogenic	criteria provided, single submitter
12095	NM_000196.4(HSD11B2):c.1009C>T (p.Arg337Cys)	HSD11B2	Pathogenic	no assertion criteria provided
12096	NM_000196.4(HSD11B2):c.623G>A (p.Arg208His)	HSD11B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12097	NM_000196.4(HSD11B2):c.1010_1012del (p.Arg337_Tyr338delinsHis)	HSD11B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12098	NM_000196.4(HSD11B2):c.835C>T (p.Arg279Cys)	HSD11B2	Pathogenic	no assertion criteria provided
31131	NM_000196.4(HSD11B2):c.1012T>C (p.Tyr338His)	HSD11B2	Pathogenic	no assertion criteria provided
31132	NM_000196.4(HSD11B2):c.77_78del (p.Arg25_Ser26insTer)	HSD11B2	Pathogenic	no assertion criteria provided
974390	NM_000196.4(HSD11B2):c.1020del (p.Gly341fs)	HSD11B2	Pathogenic	criteria provided, single submitter
3581148	NM_000196.4(HSD11B2):c.433dup (p.Ile145fs)	HSD11B2	Likely pathogenic	criteria provided, single submitter
3581156	NM_000196.4(HSD11B2):c.662C>T (p.Ala221Val)	HSD11B2	Likely pathogenic	criteria provided, single submitter
3581157	NM_000196.4(HSD11B2):c.665-1G>A	HSD11B2	Likely pathogenic	criteria provided, single submitter
3581159	NM_000196.4(HSD11B2):c.665-1G>C	HSD11B2	Likely pathogenic	criteria provided, single submitter
3581160	NM_000196.4(HSD11B2):c.695_703del (p.Tyr232_Thr234del)	HSD11B2	Likely pathogenic	criteria provided, single submitter
3581165	NM_000196.4(HSD11B2):c.917_927del (p.Gln306fs)	HSD11B2	Likely pathogenic	criteria provided, single submitter
974391	NM_000196.4(HSD11B2):c.983C>T (p.Ala328Val)	HSD11B2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
12100	NM_000196.4(HSD11B2):c.343_348del (p.Glu115_Leu116del)	HSD11B2	Conflicting classifications of pathogenicity	no assertion criteria provided
12101	NM_000196.4(HSD11B2):c.667G>A (p.Asp223Asn)	HSD11B2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2035909	NM_000196.4(HSD11B2):c.1184T>C (p.Leu395Pro)	HSD11B2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3581151	NM_000196.4(HSD11B2):c.501C>T (p.Asn167=)	HSD11B2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
447525	NM_000196.4(HSD11B2):c.266G>A (p.Gly89Asp)	HSD11B2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028126	NM_000196.4(HSD11B2):c.1010G>T (p.Arg337Leu)	HSD11B2	Uncertain significance	criteria provided, multiple submitters, no conflicts
12102	NM_000196.4(HSD11B2):c.895_897del (p.Tyr299del)	HSD11B2	Uncertain significance	criteria provided, single submitter
1311586	NM_000196.4(HSD11B2):c.1007G>A (p.Arg336His)	HSD11B2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1486263	NM_000196.4(HSD11B2):c.935G>A (p.Arg312His)	HSD11B2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2081334	NM_000196.4(HSD11B2):c.865C>A (p.Gln289Lys)	HSD11B2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2183074	NM_000196.4(HSD11B2):c.478G>A (p.Gly160Ser)	HSD11B2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2366657	NM_000196.4(HSD11B2):c.947C>T (p.Ser316Phe)	HSD11B2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432534	NM_000196.4(HSD11B2):c.512A>G (p.Asn171Ser)	HSD11B2	Uncertain significance	criteria provided, single submitter
2432535	NM_000196.4(HSD11B2):c.586G>A (p.Ala196Thr)	HSD11B2	Uncertain significance	criteria provided, multiple submitters, no conflicts

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
HSD11B2	Strong	Autosomal recessive	apparent mineralocorticoid excess	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HSD11B2	Orphanet:320	Apparent mineralocorticoid excess

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
HSD11B2	HGNC:5209	ENSG00000176387	P80365	11-beta-hydroxysteroid dehydrogenase type 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HSD11B2	11-beta-hydroxysteroid dehydrogenase type 2	Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids (11beta-hydroxysteroid) such as cortisol, to inactive 11-ketoglucocorticoids (11-oxosteroid) such as cortisone, in the presence of NAD(+).

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)
HSD11B2	Enzyme (other)	yes	1.1.1.146	SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf

Expression context

Cohort genes with no expression data: 0.

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	1
rectum	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HSD11B2	174	broad	marker	mucosa of transverse colon, renal medulla, rectum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSD11B2	1,300

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HSD11B2	P80365	87.49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Prednisone ADME	1	1268.9×	0.001	HSD11B2
Glucocorticoid biosynthesis	1	878.5×	0.001	HSD11B2

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
regulation of blood volume by renal aldosterone	1	5617.3×	0.001	HSD11B2
glucocorticoid metabolic process	1	2808.7×	0.001	HSD11B2
cortisol metabolic process	1	2808.7×	0.001	HSD11B2
response to food	1	495.6×	0.005	HSD11B2
response to glucocorticoid	1	324.1×	0.006	HSD11B2
response to insulin	1	230.8×	0.006	HSD11B2
female pregnancy	1	210.7×	0.006	HSD11B2
response to hypoxia	1	95.8×	0.012	HSD11B2
response to xenobiotic stimulus	1	69.1×	0.014	HSD11B2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
HSD11B2	CARBENOXOLONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HSD11B2	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CARBENOXOLONE	4	HSD11B2
CURCUMIN	3	HSD11B2
EPIGALOCATECHIN GALLATE	3	HSD11B2
ENOXOLONE	2	HSD11B2
GLYCYRRHIZIN	2	HSD11B2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HSD11B2	125	Binding:120, ADMET:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HSD11B2	1.1.1.146, 1.1.1.B40	11beta-hydroxysteroid dehydrogenase,

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
HSD11B2	125

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

4 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)
CARBENOXOLONE	4	HSD11B2
CURCUMIN	3	HSD11B2
EPIGALOCATECHIN GALLATE	3	HSD11B2
GLYCYRRHIZIN	2	HSD11B2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HSD11B2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00759525	PHASE2/PHASE3	COMPLETED	The Role of Mineralocorticoid Receptors in Vascular Function
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT00474942	Not specified	COMPLETED	Natural History of Apparent Mineralocorticoid Excess Syndrome
NCT02939144	Not specified	COMPLETED	An Investigation Into the Effect of Liquorice Ingestion on the Salivary Cortisol to Cortisone Molar Ratio

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ENOXOLONE	2	1