Glucocorticoid-remediable aldosteronism

Summary

Glucocorticoid-remediable aldosteronism (MONDO:0007080) is a disease caused by CYP11B1 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: CYP11B1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 374
• Phenotypes (HPO): 15

Clinical features

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0000822	Hypertension	Obligate (100%)
HP:0011739	Dexamethasone-suppresible primary hyperaldosteronism	Obligate (100%)
HP:0008221	Adrenal hyperplasia	Very frequent (80-99%)
HP:0040084	Abnormal circulating renin	Very frequent (80-99%)
HP:0000360	Tinnitus	Occasional (5-29%)
HP:0000421	Epistaxis	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001959	Polydipsia	Occasional (5-29%)
HP:0002018	Nausea	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002900	Hypokalemia	Occasional (5-29%)
HP:0011410	Caesarian section	Occasional (5-29%)
HP:0011746	Secretory adrenocortical adenoma	Occasional (5-29%)
HP:0100602	Preeclampsia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glucocorticoid-remediable aldosteronism
Mondo ID	MONDO:0007080
MeSH	C563177
OMIM	103900
Orphanet	403
DOID	DOID:14080
ICD-10-CM	E26.02
UMLS	C3838731
MedGen	824577
GARD	0002790
Is cancer (heuristic)	no

Also known as: aldosteronism, glucocorticoid-remediable · dexamethasone sensitive hypertension · dexamethasone-sensitive hypertension · familial hyperaldosteronism type 1 · FH-I · FH1 · glucocorticoid sensitive hypertension · glucocorticoid-remediable aldosteronism · glucocorticoid-sensitive hypertension · GRA · HALD1 · hyperaldosteronism, familial type 1

Data availability: 374 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › adrenal gland disorder › adrenal cortex disorder › adrenal gland hyperfunction › hyperaldosteronism › primary aldosteronism › familial hyperaldosteronism › glucocorticoid-remediable aldosteronism

Related subtypes (4): familial hyperaldosteronism type II, familial hyperaldosteronism type III, aldosterone-producing adenoma with seizures and neurological abnormalities, hyperaldosteronism, familial, type IV

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

374 retrieved; paginated sample, class counts are floors:

168 uncertain significance, 61 conflicting classifications of pathogenicity, 42 benign, 31 benign/likely benign, 25 likely benign, 20 pathogenic/likely pathogenic, 16 likely pathogenic, 11 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030831	NM_000497.4(CYP11B1):c.1343G>C (p.Arg448Pro)	CYP11B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1171	NM_000497.4(CYP11B1):c.1343G>A (p.Arg448His)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172	NC_000008.11:g.(142876886_142877022)_(142914909_142915045)dup	CYP11B1	Pathogenic	no assertion criteria provided
1173	NM_000497.4(CYP11B1):c.953C>T (p.Thr318Met)	CYP11B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1179	NM_000497.4(CYP11B1):c.124C>T (p.Pro42Ser)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1186	NM_000497.4(CYP11B1):c.281C>T (p.Pro94Leu)	CYP11B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1403418	NM_000497.4(CYP11B1):c.1179_1180dup (p.Asn394fs)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2112958	NM_000497.4(CYP11B1):c.706C>T (p.Gln236Ter)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2735226	NM_000497.4(CYP11B1):c.1150C>T (p.Arg384Ter)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551876	NM_000497.4(CYP11B1):c.317_344del (p.Leu106fs)	CYP11B1	Pathogenic	criteria provided, multiple submitters, no conflicts
552238	NM_000497.4(CYP11B1):c.1151G>A (p.Arg384Gln)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
556405	NM_000497.4(CYP11B1):c.1361G>A (p.Arg454His)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56830	NM_000497.4(CYP11B1):c.1066C>T (p.Gln356Ter)	CYP11B1	Pathogenic	criteria provided, multiple submitters, no conflicts
56831	NM_000497.4(CYP11B1):c.427C>T (p.Arg143Trp)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56832	NM_000497.4(CYP11B1):c.896T>C (p.Leu299Pro)	CYP11B1	Pathogenic	criteria provided, multiple submitters, no conflicts
56835	NM_000497.4(CYP11B1):c.995G>A (p.Arg332Gln)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
857403	NM_000497.4(CYP11B1):c.1358G>A (p.Arg453Gln)	CYP11B1	Pathogenic	criteria provided, multiple submitters, no conflicts
951304	NM_000497.4(CYP11B1):c.546_552del (p.Ser183fs)	CYP11B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072465	NM_000497.4(CYP11B1):c.726del (p.Ser243fs)	LOC106799833	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1178	NM_000497.4(CYP11B1):c.956C>T (p.Thr319Met)	LOC106799833	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1185	NM_000497.4(CYP11B1):c.1269T>G (p.Tyr423Ter)	LOC106799833	Pathogenic	criteria provided, multiple submitters, no conflicts
1683257	NM_000497.4(CYP11B1):c.1359dup (p.Arg454fs)	LOC106799833	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685685	NM_000497.4(CYP11B1):c.799G>A (p.Gly267Ser)	LOC106799833	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136710	NM_000497.4(CYP11B1):c.396-1G>A	LOC106799833	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235678	NM_000497.4(CYP11B1):c.1331G>A (p.Gly444Asp)	LOC106799833	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447222	NM_000497.4(CYP11B1):c.1181del (p.Asn394fs)	LOC106799833	Pathogenic	criteria provided, multiple submitters, no conflicts
552598	NM_000497.4(CYP11B1):c.992C>T (p.Ala331Val)	LOC106799833	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
555319	NM_000497.4(CYP11B1):c.1128C>A (p.Tyr376Ter)	LOC106799833	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
940650	NM_000497.4(CYP11B1):c.1012C>T (p.Gln338Ter)	LOC106799833	Pathogenic	criteria provided, multiple submitters, no conflicts
995869	NM_000497.4(CYP11B1):c.946G>A (p.Val316Met)	LOC106799833	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 7 · 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
CYP11B1	Strong	Autosomal dominant	glucocorticoid-remediable aldosteronism	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP11B1	Orphanet:403	Familial hyperaldosteronism type I
CYP11B1	Orphanet:90795	Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency
CYP11B2	Orphanet:403	Familial hyperaldosteronism type I
CYP11B2	Orphanet:556030	Early-onset familial hypoaldosteronism
HBD	Orphanet:231237	Delta-beta-thalassemia
HBD	Orphanet:330032	Hemoglobin Lepore-beta-thalassemia syndrome
HBD	Orphanet:699822	Sickle cell S-Lepore disease

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
CYP11B1	HGNC:2591	ENSG00000160882	P15538	Cytochrome P450 11B1, mitochondrial	gencc,clinvar
CYP11B2	HGNC:2592	ENSG00000179142	P19099	Cytochrome P450 11B2, mitochondrial	clinvar
HBD	HGNC:4829	ENSG00000223609	P02042	Hemoglobin subunit delta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP11B1	Cytochrome P450 11B1, mitochondrial	A cytochrome P450 monooxygenase involved in the biosynthesis of adrenal corticoids.
CYP11B2	Cytochrome P450 11B2, mitochondrial	A cytochrome P450 monooxygenase that catalyzes the biosynthesis of aldosterone, the main mineralocorticoid in the human body responsible for salt and water homeostasis, thus involved in blood pressure regulation, arterial hypertension, and…
HBD	Hemoglobin subunit delta	Involved in oxygen transport from the lung to the various peripheral tissues.

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)
CYP11B1	Enzyme (other)	yes	1.14.15.4	Cyt_P450, Cyt_P450_mitochondrial, Cyt_P450_CS
CYP11B2	Enzyme (other)	yes	1.14.15.4	Cyt_P450, Cyt_P450_mitochondrial, Cyt_P450_CS
HBD	Other/Unknown	no		Globin, Hemoglobin_b, Globin-like_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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	2
right adrenal gland	2
right adrenal gland cortex	2
bone marrow	1
bone marrow cell	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYP11B1	137		yes	right adrenal gland cortex, right adrenal gland, left adrenal gland
CYP11B2	30		yes	right adrenal gland cortex, right adrenal gland, left adrenal gland
HBD	170	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYP11B2	1,718
CYP11B1	1,596
HBD	1,206

Intra-cohort edges

A	B	Sources
CYP11B1	HBD	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYP11B2	P19099	7
CYP11B1	P15538	2
HBD	P02042	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glucocorticoid biosynthesis	2	585.6×	3e-05	CYP11B1, CYP11B2
Metabolic disorders of biological oxidation enzymes	2	585.6×	3e-05	CYP11B1, CYP11B2
Cytochrome P450 - arranged by substrate type	2	475.8×	3e-05	CYP11B1, CYP11B2
Metabolism of steroid hormones	2	346.1×	4e-05	CYP11B1, CYP11B2
Endogenous sterols	2	262.5×	6e-05	CYP11B1, CYP11B2
Phase I - Functionalization of compounds	2	146.4×	2e-04	CYP11B1, CYP11B2
Metabolism of steroids	2	91.7×	4e-04	CYP11B1, CYP11B2
Biological oxidations	2	86.5×	4e-04	CYP11B1, CYP11B2
Defective CYP11B2 causes CMO-1 deficiency	1	1903.3×	8e-04	CYP11B2
Defective CYP11B1 causes AH4	1	1903.3×	8e-04	CYP11B1
Diseases of metabolism	2	53.6×	8e-04	CYP11B1, CYP11B2
Mineralocorticoid biosynthesis	1	475.8×	0.003	CYP11B2
Metabolism of lipids	2	21.0×	0.004	CYP11B1, CYP11B2
Disease	2	8.7×	0.019	CYP11B1, CYP11B2
Metabolism	2	7.7×	0.022	CYP11B1, CYP11B2
Factors involved in megakaryocyte development and platelet production	1	22.1×	0.045	HBD

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
aldosterone biosynthetic process	2	2246.9×	3e-06	CYP11B1, CYP11B2
cortisol metabolic process	2	1872.4×	3e-06	CYP11B1, CYP11B2
cortisol biosynthetic process	2	1404.3×	4e-06	CYP11B1, CYP11B2
C21-steroid hormone biosynthetic process	2	1248.3×	4e-06	CYP11B1, CYP11B2
glucocorticoid biosynthetic process	2	1021.3×	5e-06	CYP11B1, CYP11B2
cellular response to potassium ion	2	702.2×	9e-06	CYP11B1, CYP11B2
sterol metabolic process	2	561.7×	1e-05	CYP11B1, CYP11B2
cellular response to peptide hormone stimulus	2	561.7×	1e-05	CYP11B1, CYP11B2
cellular response to hormone stimulus	2	255.3×	5e-05	CYP11B1, CYP11B2
cholesterol metabolic process	2	130.6×	2e-04	CYP11B1, CYP11B2
regulation of blood volume by renal aldosterone	1	1872.4×	0.001	CYP11B2
mineralocorticoid biosynthetic process	1	1404.3×	0.001	CYP11B2
carbon dioxide transport	1	432.1×	0.004	HBD
oxygen transport	1	351.1×	0.004	HBD
sodium ion homeostasis	1	312.1×	0.004	CYP11B2
potassium ion homeostasis	1	255.3×	0.005	CYP11B2
erythrocyte development	1	175.5×	0.007	HBD
renal water homeostasis	1	170.2×	0.007	CYP11B2
regulation of blood pressure	1	73.9×	0.015	CYP11B1
glucose homeostasis	1	43.5×	0.024	CYP11B1
immune response	1	15.7×	0.062	CYP11B1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
CYP11B1	FLUCONAZOLE
CYP11B2	FLUCONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP11B1	13	4
CYP11B2	12	4
HBD	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FLUCONAZOLE	4	CYP11B1, CYP11B2
POSACONAZOLE	4	CYP11B1, CYP11B2
LETROZOLE	4	CYP11B1, CYP11B2
KETOCONAZOLE	4	CYP11B1, CYP11B2
ABIRATERONE	4	CYP11B1, CYP11B2
OSILODROSTAT	4	CYP11B1, CYP11B2
ETOMIDATE	4	CYP11B1, CYP11B2
METYRAPONE	4	CYP11B1, CYP11B2
BAXDROSTAT	3	CYP11B1, CYP11B2
LORUNDROSTAT	3	CYP11B2
VOROZOLE	2	CYP11B1
DEXFADROSTAT	2	CYP11B1, CYP11B2
AZALANSTAT	2	CYP11B1
FADROZOLE	2	CYP11B1, CYP11B2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CYP11B2	147	Binding:135, ADMET:12
CYP11B1	113	Binding:95, ADMET:16, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP11B1	1.14.15.4	steroid 11beta-monooxygenase
CYP11B2	1.14.15.4, 1.14.15.5	steroid 11beta-monooxygenase, corticosterone 18-monooxygenase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CYP11B1	113
CYP11B2	147

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

14 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)
FLUCONAZOLE	4	CYP11B1, CYP11B2
POSACONAZOLE	4	CYP11B1, CYP11B2
LETROZOLE	4	CYP11B1, CYP11B2
KETOCONAZOLE	4	CYP11B1, CYP11B2
ABIRATERONE	4	CYP11B1, CYP11B2
OSILODROSTAT	4	CYP11B1, CYP11B2
ETOMIDATE	4	CYP11B1, CYP11B2
METYRAPONE	4	CYP11B1, CYP11B2
BAXDROSTAT	3	CYP11B1, CYP11B2
LORUNDROSTAT	3	CYP11B2
VOROZOLE	2	CYP11B1
DEXFADROSTAT	2	CYP11B1, CYP11B2
AZALANSTAT	2	CYP11B1
FADROZOLE	2	CYP11B1, CYP11B2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CYP11B1, CYP11B2
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	1	HBD

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)
HBD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.