Familial hyperaldosteronism type I

Mendelian MONDO:0007080 Pathograph 11 familial hyperaldosteronism primary aldosteronism low-renin hypertension

Familial hyperaldosteronism type I is an autosomal dominant form of primary aldosteronism caused by unequal crossover between CYP11B1 and CYP11B2. The resulting chimeric CYP11B1/CYP11B2 gene places aldosterone synthase coding sequence under ACTH-responsive regulatory control, so aldosterone and hybrid steroid production become glucocorticoid-suppressible rather than normally angiotensin II-regulated. The endocrine consequence is early-onset hypertension with hyperaldosteronism, low plasma renin activity, variable hypokalemia, and elevated 18-oxocortisol and 18-hydroxycortisol.

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1
Mappings
1
Definitions
1
Inheritance
4
Pathophys.
13
Phenotypes
11
Pathograph
2
Genes
2
Treatments
1
Deep Research
🔗

Mappings

MONDO
MONDO:0007080 glucocorticoid-remediable aldosteronism
skos:exactMatch Orphanet ORPHA:403
Orphanet ORPHA:403 lists MONDO:0007080 as an exact cross-reference for familial hyperaldosteronism type I.
📘

Definitions

1
Orphanet familial hyperaldosteronism type I definition
A rare glucocorticoid-remediable primary aldosteronism with early-onset hypertension, hyperaldosteronism, variable hypokalemia, low renin, and abnormal hybrid steroid production.
OTHER
Show evidence (1 reference)
ORPHA:403 SUPPORT Other
"A rare heritable, glucocorticoid remediable form of primary aldosteronism (PA) characterized by early-onset hypertension, hyperaldosteronism, variable hypokalemia, low plasma renin activity (PRA), and abnormal production of 18-oxocortisol and 18-hydroxycortisol."
Orphanet defines the core endocrine and clinical pattern of FH-I.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Familial hyperaldosteronism type I is inherited in an autosomal dominant pattern.
Autosomal dominant inheritance
Show evidence (2 references)
ORPHA:403 SUPPORT Other
"Autosomal dominant"
Orphanet records autosomal dominant inheritance.
PMID:1731223 SUPPORT Human Clinical
"Glucocorticoid-remediable aldosteronism (GRA), an autosomal dominant disorder"
The original linkage study describes GRA as autosomal dominant.
⚙

Pathophysiology

4
CYP11B1-CYP11B2 chimeric gene formation
Unequal crossover between the adjacent, highly similar CYP11B1 and CYP11B2 genes creates a chimeric gene in which CYP11B1 regulatory sequence controls CYP11B2 aldosterone synthase coding sequence.
CYP11B1 link CYP11B2 link
adrenal cortex link
Downstream
ACTH-regulated aldosterone synthase expression
Show evidence (2 references)
PMID:1731223 SUPPORT Human Clinical
"a gene duplication arising from unequal crossing over"
The original study identifies unequal crossover as the causal genomic event.
PMID:35012455 SUPPORT Human Clinical
"Glucocorticoid-remediable aldosteronism (GRA) is a form of heritable hypertension caused by a chimeric fusion"
The diagnostic sequencing paper confirms the chimeric fusion in affected patients.
ACTH-regulated aldosterone synthase expression
The CYP11B1 promoter drives aldosterone synthase activity under ACTH control rather than normal angiotensin II regulation, producing glucocorticoid- suppressible aldosterone excess.
adrenocortical cell link
CYP11B1 link CYP11B2 link
aldosterone biosynthetic process link ↑ INCREASED
zona fasciculata link
Downstream
Aldosterone and hybrid steroid excess
Show evidence (2 references)
PMID:1731223 SUPPORT Human Clinical
"under control of adrenocorticotropic hormone and suppressible by glucocorticoids"
The original study links the endocrine phenotype to ACTH control and glucocorticoid suppression.
PMID:35778363 SUPPORT Human Clinical
"the synthesis of aldosterone becomes to be regulated by ACTH instead of by angiotensin II"
The review summarizes the altered regulatory control of aldosterone synthesis.
Aldosterone and hybrid steroid excess
ACTH-regulated aldosterone synthase activity increases aldosterone and the hybrid steroids 18-oxocortisol and 18-hydroxycortisol, producing primary aldosteronism with suppressed plasma renin activity.
aldosterone biosynthetic process link ↑ INCREASED
adrenal cortex link
Downstream
Low-renin mineralocorticoid hypertension
Show evidence (2 references)
ORPHA:403 SUPPORT Other
"hyperaldosteronism, variable hypokalemia, low plasma renin activity (PRA), and abnormal production of 18-oxocortisol and 18-hydroxycortisol"
Orphanet records aldosterone excess, low PRA, and hybrid steroid production.
PMID:1731223 SUPPORT Human Clinical
"high levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol"
The original study identifies abnormal hybrid steroid excess.
Low-renin mineralocorticoid hypertension
Aldosterone excess drives a primary aldosteronism phenotype with hypertension, suppressed renin, and variable potassium depletion.
Show evidence (2 references)
ORPHA:403 SUPPORT Other
"early-onset hypertension, hyperaldosteronism, variable hypokalemia, low plasma renin activity (PRA)"
Orphanet records the low-renin hypertension and potassium phenotype.
PMID:35778363 SUPPORT Human Clinical
"Primary hyperaldosteronism (PAH) is the most frequent cause of secondary arterial hypertension."
Review context links primary aldosteronism to secondary hypertension.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Familial hyperaldosteronism type I Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

13
Blood 1
Epistaxis OCCASIONAL Epistaxis (HP:0000421)
Show evidence (1 reference)
ORPHA:403 SUPPORT Other
"HP:0000421 | Epistaxis | Occasional (29-5%)"
Orphanet records epistaxis as occasional.
Cardiovascular 1
Hypertension OBLIGATE Hypertension (HP:0000822)
Show evidence (2 references)
ORPHA:403 SUPPORT Other
"HP:0000822 | Hypertension | Obligate (100%)"
Orphanet records hypertension as obligate.
PMID:1731223 SUPPORT Human Clinical
"hypertension with variable hyperaldosteronism"
The original study describes hypertension as part of GRA.
Metabolism 1
Hypokalemia OCCASIONAL Hypokalemia (HP:0002900)
Show evidence (2 references)
ORPHA:403 SUPPORT Other
"HP:0002900 | Hypokalemia | Occasional (29-5%)"
Orphanet records hypokalemia as occasional.
ORPHA:403 SUPPORT Other
"variable hypokalemia"
Orphanet definition records variable hypokalemia.
Musculoskeletal 1
Muscle weakness OCCASIONAL Muscle weakness (HP:0001324)
Show evidence (1 reference)
ORPHA:403 SUPPORT Other
"HP:0001324 | Muscle weakness | Occasional (29-5%)"
Orphanet records muscle weakness as occasional.
Nervous System 2
Headache OCCASIONAL Headache (HP:0002315)
Show evidence (1 reference)
ORPHA:403 SUPPORT Other
"HP:0002315 | Headache | Occasional (29-5%)"
Orphanet records headache as occasional.
Polydipsia OCCASIONAL Polydipsia (HP:0001959)
Show evidence (1 reference)
ORPHA:403 SUPPORT Other
"HP:0001959 | Polydipsia | Occasional (29-5%)"
Orphanet records polydipsia as occasional.
Other 7
Dexamethasone-suppressible primary hyperaldosteronism OBLIGATE Dexamethasone-suppressible primary hyperaldosteronism (HP:0011739)
Show evidence (2 references)
ORPHA:403 SUPPORT Other
"HP:0011739 | Dexamethasone-suppresible primary hyperaldosteronism | Obligate (100%)"
Orphanet records dexamethasone-suppressible primary hyperaldosteronism as obligate.
PMID:1731223 SUPPORT Human Clinical
"under control of adrenocorticotropic hormone and suppressible by glucocorticoids"
The original study supports glucocorticoid suppression of the endocrine phenotype.
Low plasma renin activity VERY_FREQUENT Abnormal circulating renin concentration (HP:0040084)
Show evidence (2 references)
ORPHA:403 SUPPORT Other
"HP:0040084 | Abnormal circulating renin | Very frequent (99-80%)"
Orphanet records abnormal circulating renin as very frequent.
ORPHA:403 SUPPORT Other
"low plasma renin activity (PRA)"
Orphanet definition specifies low plasma renin activity.
Adrenal hyperplasia VERY_FREQUENT Adrenal hyperplasia (HP:0008221)
Show evidence (1 reference)
ORPHA:403 SUPPORT Other
"HP:0008221 | Adrenal hyperplasia | Very frequent (99-80%)"
Orphanet records adrenal hyperplasia as very frequent.
Secretory adrenocortical adenoma OCCASIONAL Secretory adrenocortical adenoma (HP:0011746)
Show evidence (1 reference)
ORPHA:403 SUPPORT Other
"HP:0011746 | Secretory adrenocortical adenoma | Occasional (29-5%)"
Orphanet records secretory adrenocortical adenoma as occasional.
Preeclampsia OCCASIONAL
Show evidence (1 reference)
ORPHA:403 SUPPORT Other
"HP:0100602 | Preeclampsia | Occasional (29-5%)"
Orphanet records preeclampsia as occasional.
Intracranial hemorrhage OCCASIONAL Intracranial hemorrhage (HP:0002170)
Show evidence (1 reference)
ORPHA:403 SUPPORT Other
"HP:0002170 | Intracranial hemorrhage | Occasional (29-5%)"
Orphanet records intracranial hemorrhage as occasional.
Caesarean section OCCASIONAL Caesarean section (HP:0011410)
Show evidence (1 reference)
ORPHA:403 SUPPORT Other
"section | Occasional (29-5%)"
Orphanet records caesarean section as occasional.
🧬

Genetic Associations

2
CYP11B1 (Fusion gene component)
Show evidence (2 references)
ORPHA:403 SUPPORT Other
"CYP11B1 | cytochrome P450 family 11 subfamily B member 1 | hgnc:2591 | Part of a fusion gene in"
Orphanet lists CYP11B1 as part of the FH-I fusion gene.
PMID:1731223 SUPPORT Human Clinical
"fusing the 5' regulatory region of 11 beta-hydroxylase to the coding sequences of aldosterone synthase"
The original linkage study identifies the CYP11B1 regulatory contribution to the fusion.
CYP11B2 (Fusion gene component)
Show evidence (2 references)
ORPHA:403 SUPPORT Other
"CYP11B2 | cytochrome P450 family 11 subfamily B member 2 | hgnc:2592 | Part of a fusion gene in"
Orphanet lists CYP11B2 as part of the FH-I fusion gene.
PMID:35778363 SUPPORT Human Clinical
"Type I familial PAH is produced by a fusion of the CYP11B2 and CYP11B1 genes"
The review confirms CYP11B2 and CYP11B1 fusion as the molecular cause.
💊

Treatments

2
Glucocorticoid suppression
Action: Pharmacotherapy NCIT:C15986
Agent: dexamethasone ↗
Low-dose glucocorticoid therapy suppresses ACTH drive to the chimeric gene, reducing aldosterone excess in glucocorticoid-remediable aldosteronism.
Mechanism Target:
INHIBITS ACTH-regulated aldosterone synthase expression — Glucocorticoids suppress ACTH-regulated chimeric aldosterone synthase expression.
Target Phenotypes: Hypertension ↗ Dexamethasone-suppressible primary hyperaldosteronism ↗
Show evidence (2 references)
PMID:1731223 SUPPORT Human Clinical
"under control of adrenocorticotropic hormone and suppressible by glucocorticoids"
The original study supports glucocorticoid suppression as mechanism-directed therapy.
ORPHA:403 SUPPORT Other
"glucocorticoid remediable form of primary aldosteronism"
Orphanet describes FH-I as glucocorticoid remediable.
Mineralocorticoid receptor antagonist therapy
Action: Pharmacotherapy NCIT:C15986
Agent: spironolactone ↗ eplerenone ↗
Mineralocorticoid receptor antagonists such as spironolactone and eplerenone can be used to control mineralocorticoid-mediated hypertension, particularly when glucocorticoid therapy is limited by corticosteroid side effects or additional blood pressure control is needed.
Mechanism Target:
INHIBITS Low-renin mineralocorticoid hypertension — Mineralocorticoid receptor antagonism reduces aldosterone-driven blood pressure effects.
Target Phenotypes: Hypertension ↗ Hypokalemia ↗
Show evidence (2 references)
PMID:10618671 SUPPORT Human Clinical
"A change of therapy from dexamethasone to spironolactone was necessary due to the side effects of corticosteroids after 3 months. Spironolactone alone (0.8-2 mg/kg/day) was able to control the BP sufficiently."
A genetically proven GRA case supports spironolactone as an alternative when corticosteroid side effects limit dexamethasone.
PMID:21451421 SUPPORT Human Clinical
"We compared the efficacy, safety and tolerability of eplerenone versus spironolactone in patients with hypertension associated with primary aldosteronism."
A randomized primary-aldosteronism trial supports the mineralocorticoid receptor antagonist treatment class that includes spironolactone and eplerenone.
🔬

Biochemical Markers

4
Plasma renin activity (DECREASED)
Show evidence (1 reference)
ORPHA:403 SUPPORT Other
"low plasma renin activity (PRA)"
Orphanet definition specifies low plasma renin activity.
Serum aldosterone (INCREASED)
Show evidence (1 reference)
ORPHA:403 SUPPORT Other
"hyperaldosteronism, variable hypokalemia"
Orphanet definition records hyperaldosteronism.
18-oxocortisol and 18-hydroxycortisol (INCREASED)
Show evidence (2 references)
ORPHA:403 SUPPORT Other
"abnormal production of 18-oxocortisol and 18-hydroxycortisol"
Orphanet records abnormal hybrid steroid production.
PMID:1731223 SUPPORT Human Clinical
"high levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol"
The original study identifies high hybrid steroid levels.
Serum potassium (DECREASED)
Show evidence (1 reference)
ORPHA:403 SUPPORT Other
"HP:0002900 | Hypokalemia | Occasional (29-5%)"
Orphanet records hypokalemia as occasional.
{ }

Source YAML

click to show 
name: Familial hyperaldosteronism type I
category: Mendelian
creation_date: '2026-05-03T23:51:12Z'
updated_date: '2026-05-04T00:42:11Z'
synonyms:
- Glucocorticoid-remediable aldosteronism
- Glucocorticoid-suppressible hyperaldosteronism
- Dexamethasone-sensitive hypertension
- FH-I
- FH1
- GRA
description: >
  Familial hyperaldosteronism type I is an autosomal dominant form of primary
  aldosteronism caused by unequal crossover between CYP11B1 and CYP11B2. The
  resulting chimeric CYP11B1/CYP11B2 gene places aldosterone synthase coding
  sequence under ACTH-responsive regulatory control, so aldosterone and hybrid
  steroid production become glucocorticoid-suppressible rather than normally
  angiotensin II-regulated. The endocrine consequence is early-onset
  hypertension with hyperaldosteronism, low plasma renin activity, variable
  hypokalemia, and elevated 18-oxocortisol and 18-hydroxycortisol.
disease_term:
  preferred_term: Familial hyperaldosteronism type I
  term:
    id: MONDO:0007080
    label: glucocorticoid-remediable aldosteronism
parents:
- familial hyperaldosteronism
- primary aldosteronism
- low-renin hypertension
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0007080
      label: glucocorticoid-remediable aldosteronism
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:403
    mapping_justification: >
      Orphanet ORPHA:403 lists MONDO:0007080 as an exact cross-reference for
      familial hyperaldosteronism type I.
external_assertions:
- name: Orphanet familial hyperaldosteronism type I record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:403
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=403
  description: >
    Orphanet's ORPHA:403 structured record provides the exact MONDO and OMIM
    mappings, autosomal dominant inheritance, definition, fusion-gene component
    assertions for CYP11B1 and CYP11B2, epidemiology, and HPO annotations used
    in this curation.
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0007080 | Exact"
    explanation: Orphanet maps ORPHA:403 exactly to the MONDO identifier used here.
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:103900 | Exact"
    explanation: Orphanet maps ORPHA:403 exactly to OMIM:103900.
definitions:
- name: Orphanet familial hyperaldosteronism type I definition
  definition_type: OTHER
  description: >
    A rare glucocorticoid-remediable primary aldosteronism with early-onset
    hypertension, hyperaldosteronism, variable hypokalemia, low renin, and
    abnormal hybrid steroid production.
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare heritable, glucocorticoid remediable form of primary aldosteronism (PA) characterized by early-onset hypertension, hyperaldosteronism, variable hypokalemia, low plasma renin activity (PRA), and abnormal production of 18-oxocortisol and 18-hydroxycortisol."
    explanation: Orphanet defines the core endocrine and clinical pattern of FH-I.
inheritance:
- name: Autosomal dominant inheritance
  description: Familial hyperaldosteronism type I is inherited in an autosomal dominant pattern.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance.
  - reference: PMID:1731223
    reference_title: "A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glucocorticoid-remediable aldosteronism (GRA), an autosomal dominant disorder"
    explanation: The original linkage study describes GRA as autosomal dominant.
prevalence:
- population: Worldwide
  notes: Orphanet records worldwide point prevalence as unknown.
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unknown | Worldwide | Point prevalence | PMID:23610123"
    explanation: Orphanet records unknown worldwide point prevalence.
progression:
- phase: Recognition and variable presentation
  age_range: Childhood to adulthood
  notes: >
    Orphanet records childhood, adolescent, and adult onset. Presentation is
    driven by early-onset hypertension, suppressed renin, variable hypokalemia,
    and glucocorticoid-suppressible aldosterone excess.
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Childhood"
    explanation: Orphanet records childhood onset.
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Adolescent"
    explanation: Orphanet records adolescent onset.
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Adult"
    explanation: Orphanet records adult onset.
  - reference: PMID:35778363
    reference_title: "Familial forms and molecular profile of primary hyperaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four forms of familial PAH have been described."
    explanation: Review context supports the subtype framing among familial primary hyperaldosteronism forms.
genetic:
- name: CYP11B1
  association: Fusion gene component
  gene_term:
    preferred_term: CYP11B1
    term:
      id: hgnc:2591
      label: CYP11B1
  notes: >
    The CYP11B1 regulatory region is fused to CYP11B2 coding sequence in the
    pathogenic chimeric gene, creating ACTH-responsive aldosterone synthase
    expression.
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CYP11B1 | cytochrome P450 family 11 subfamily B member 1 | hgnc:2591 | Part of a fusion gene in"
    explanation: Orphanet lists CYP11B1 as part of the FH-I fusion gene.
  - reference: PMID:1731223
    reference_title: "A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fusing the 5' regulatory region of 11 beta-hydroxylase to the coding sequences of aldosterone synthase"
    explanation: The original linkage study identifies the CYP11B1 regulatory contribution to the fusion.
- name: CYP11B2
  association: Fusion gene component
  gene_term:
    preferred_term: CYP11B2
    term:
      id: hgnc:2592
      label: CYP11B2
  notes: >
    CYP11B2 contributes the aldosterone synthase coding sequence to the chimeric
    gene, allowing ectopic ACTH-regulated aldosterone synthase activity.
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CYP11B2 | cytochrome P450 family 11 subfamily B member 2 | hgnc:2592 | Part of a fusion gene in"
    explanation: Orphanet lists CYP11B2 as part of the FH-I fusion gene.
  - reference: PMID:35778363
    reference_title: "Familial forms and molecular profile of primary hyperaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Type I familial PAH is produced by a fusion of the CYP11B2 and CYP11B1 genes"
    explanation: The review confirms CYP11B2 and CYP11B1 fusion as the molecular cause.
pathophysiology:
- name: CYP11B1-CYP11B2 chimeric gene formation
  description: >
    Unequal crossover between the adjacent, highly similar CYP11B1 and CYP11B2
    genes creates a chimeric gene in which CYP11B1 regulatory sequence controls
    CYP11B2 aldosterone synthase coding sequence.
  genes:
  - preferred_term: CYP11B1
    term:
      id: hgnc:2591
      label: CYP11B1
  - preferred_term: CYP11B2
    term:
      id: hgnc:2592
      label: CYP11B2
  locations:
  - preferred_term: adrenal cortex
    term:
      id: UBERON:0001235
      label: adrenal cortex
  evidence:
  - reference: PMID:1731223
    reference_title: "A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a gene duplication arising from unequal crossing over"
    explanation: The original study identifies unequal crossover as the causal genomic event.
  - reference: PMID:35012455
    reference_title: "GRAde: a long-read sequencing approach to efficiently identifying the CYP11B1/CYP11B2 chimeric form in patients with glucocorticoid-remediable aldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glucocorticoid-remediable aldosteronism (GRA) is a form of heritable hypertension caused by a chimeric fusion"
    explanation: The diagnostic sequencing paper confirms the chimeric fusion in affected patients.
  downstream:
  - target: ACTH-regulated aldosterone synthase expression
    causal_link_type: DIRECT
- name: ACTH-regulated aldosterone synthase expression
  description: >
    The CYP11B1 promoter drives aldosterone synthase activity under ACTH control
    rather than normal angiotensin II regulation, producing glucocorticoid-
    suppressible aldosterone excess.
  genes:
  - preferred_term: CYP11B1
    term:
      id: hgnc:2591
      label: CYP11B1
  - preferred_term: CYP11B2
    term:
      id: hgnc:2592
      label: CYP11B2
  cell_types:
  - preferred_term: adrenocortical cell
    term:
      id: CL:0002097
      label: cortical cell of adrenal gland
  locations:
  - preferred_term: zona fasciculata
    term:
      id: UBERON:0002054
      label: zona fasciculata of adrenal gland
  biological_processes:
  - preferred_term: aldosterone biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0032342
      label: aldosterone biosynthetic process
  evidence:
  - reference: PMID:1731223
    reference_title: "A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "under control of adrenocorticotropic hormone and suppressible by glucocorticoids"
    explanation: The original study links the endocrine phenotype to ACTH control and glucocorticoid suppression.
  - reference: PMID:35778363
    reference_title: "Familial forms and molecular profile of primary hyperaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the synthesis of aldosterone becomes to be regulated by ACTH instead of by angiotensin II"
    explanation: The review summarizes the altered regulatory control of aldosterone synthesis.
  downstream:
  - target: Aldosterone and hybrid steroid excess
    causal_link_type: DIRECT
- name: Aldosterone and hybrid steroid excess
  description: >
    ACTH-regulated aldosterone synthase activity increases aldosterone and the
    hybrid steroids 18-oxocortisol and 18-hydroxycortisol, producing primary
    aldosteronism with suppressed plasma renin activity.
  locations:
  - preferred_term: adrenal cortex
    term:
      id: UBERON:0001235
      label: adrenal cortex
  biological_processes:
  - preferred_term: aldosterone biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0032342
      label: aldosterone biosynthetic process
  chemical_entities:
  - preferred_term: aldosterone
    term:
      id: CHEBI:27584
      label: aldosterone
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "hyperaldosteronism, variable hypokalemia, low plasma renin activity (PRA), and abnormal production of 18-oxocortisol and 18-hydroxycortisol"
    explanation: Orphanet records aldosterone excess, low PRA, and hybrid steroid production.
  - reference: PMID:1731223
    reference_title: "A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol"
    explanation: The original study identifies abnormal hybrid steroid excess.
  downstream:
  - target: Low-renin mineralocorticoid hypertension
    causal_link_type: DIRECT
- name: Low-renin mineralocorticoid hypertension
  description: >
    Aldosterone excess drives a primary aldosteronism phenotype with
    hypertension, suppressed renin, and variable potassium depletion.
  chemical_entities:
  - preferred_term: aldosterone
    term:
      id: CHEBI:27584
      label: aldosterone
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "early-onset hypertension, hyperaldosteronism, variable hypokalemia, low plasma renin activity (PRA)"
    explanation: Orphanet records the low-renin hypertension and potassium phenotype.
  - reference: PMID:35778363
    reference_title: "Familial forms and molecular profile of primary hyperaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary hyperaldosteronism (PAH) is the most frequent cause of secondary arterial hypertension."
    explanation: Review context links primary aldosteronism to secondary hypertension.
phenotypes:
- category: Cardiovascular
  name: Hypertension
  description: >
    Chronic systemic hypertension is an obligate feature of FH-I and can present
    early in life.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000822 | Hypertension | Obligate (100%)"
    explanation: Orphanet records hypertension as obligate.
  - reference: PMID:1731223
    reference_title: "A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypertension with variable hyperaldosteronism"
    explanation: The original study describes hypertension as part of GRA.
- category: Endocrine
  name: Dexamethasone-suppressible primary hyperaldosteronism
  description: >
    Aldosterone overproduction suppresses with glucocorticoids because the
    chimeric gene is regulated by ACTH.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Dexamethasone-suppressible primary hyperaldosteronism
    term:
      id: HP:0011739
      label: Dexamethasone-suppressible primary hyperaldosteronism
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011739 | Dexamethasone-suppresible primary hyperaldosteronism | Obligate (100%)"
    explanation: Orphanet records dexamethasone-suppressible primary hyperaldosteronism as obligate.
  - reference: PMID:1731223
    reference_title: "A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "under control of adrenocorticotropic hormone and suppressible by glucocorticoids"
    explanation: The original study supports glucocorticoid suppression of the endocrine phenotype.
- category: Biochemical
  name: Low plasma renin activity
  description: >
    Suppressed plasma renin activity reflects primary aldosteronism physiology.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Low plasma renin activity
    term:
      id: HP:0040084
      label: Abnormal circulating renin concentration
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0040084 | Abnormal circulating renin | Very frequent (99-80%)"
    explanation: Orphanet records abnormal circulating renin as very frequent.
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "low plasma renin activity (PRA)"
    explanation: Orphanet definition specifies low plasma renin activity.
- category: Biochemical
  name: Hypokalemia
  description: Variable hypokalemia can occur from mineralocorticoid excess.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002900 | Hypokalemia | Occasional (29-5%)"
    explanation: Orphanet records hypokalemia as occasional.
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "variable hypokalemia"
    explanation: Orphanet definition records variable hypokalemia.
- category: Endocrine
  name: Adrenal hyperplasia
  description: Adrenal hyperplasia is recorded as a very frequent endocrine morphology finding.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Adrenal hyperplasia
    term:
      id: HP:0008221
      label: Adrenal hyperplasia
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008221 | Adrenal hyperplasia | Very frequent (99-80%)"
    explanation: Orphanet records adrenal hyperplasia as very frequent.
- category: Endocrine
  name: Secretory adrenocortical adenoma
  description: Secretory adrenocortical adenoma is recorded as an occasional endocrine morphology finding.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Secretory adrenocortical adenoma
    term:
      id: HP:0011746
      label: Secretory adrenocortical adenoma
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011746 | Secretory adrenocortical adenoma | Occasional (29-5%)"
    explanation: Orphanet records secretory adrenocortical adenoma as occasional.
- category: Obstetric
  name: Preeclampsia
  description: >
    Preeclampsia is recorded as an occasional pregnancy-related complication.
    Orphanet supplies the HPO row for HP:0100602, but that term is outside the
    current dismech PhenotypeTerm dynamic enum and is therefore cited in
    evidence rather than bound in phenotype_term.
  frequency: OCCASIONAL
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100602 | Preeclampsia | Occasional (29-5%)"
    explanation: Orphanet records preeclampsia as occasional.
- category: Neurological
  name: Headache
  description: Headache is an occasional symptom in the Orphanet HPO profile.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002315 | Headache | Occasional (29-5%)"
    explanation: Orphanet records headache as occasional.
- category: Musculoskeletal
  name: Muscle weakness
  description: Muscle weakness can occur in the setting of hypokalemia.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001324 | Muscle weakness | Occasional (29-5%)"
    explanation: Orphanet records muscle weakness as occasional.
- category: Neurological
  name: Intracranial hemorrhage
  description: Intracranial hemorrhage is recorded as an occasional complication.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002170 | Intracranial hemorrhage | Occasional (29-5%)"
    explanation: Orphanet records intracranial hemorrhage as occasional.
- category: Hematologic
  name: Epistaxis
  description: Epistaxis is recorded as an occasional bleeding manifestation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000421 | Epistaxis | Occasional (29-5%)"
    explanation: Orphanet records epistaxis as occasional.
- category: Obstetric
  name: Caesarean section
  description: Caesarean section is recorded as an occasional abnormal delivery association.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Caesarean section
    term:
      id: HP:0011410
      label: Caesarean section
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "section | Occasional (29-5%)"
    explanation: Orphanet records caesarean section as occasional.
- category: Behavioral
  name: Polydipsia
  description: Polydipsia is recorded as an occasional symptom.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Polydipsia
    term:
      id: HP:0001959
      label: Polydipsia
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001959 | Polydipsia | Occasional (29-5%)"
    explanation: Orphanet records polydipsia as occasional.
biochemical:
- name: Plasma renin activity
  presence: DECREASED
  notes: Low plasma renin activity reflects primary aldosteronism physiology.
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "low plasma renin activity (PRA)"
    explanation: Orphanet definition specifies low plasma renin activity.
- name: Serum aldosterone
  presence: INCREASED
  notes: Hyperaldosteronism is the primary endocrine abnormality.
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "hyperaldosteronism, variable hypokalemia"
    explanation: Orphanet definition records hyperaldosteronism.
- name: 18-oxocortisol and 18-hydroxycortisol
  presence: INCREASED
  notes: Hybrid steroid excess is characteristic of the chimeric enzyme.
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "abnormal production of 18-oxocortisol and 18-hydroxycortisol"
    explanation: Orphanet records abnormal hybrid steroid production.
  - reference: PMID:1731223
    reference_title: "A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol"
    explanation: The original study identifies high hybrid steroid levels.
- name: Serum potassium
  presence: DECREASED
  notes: Hypokalemia is variable and recorded as occasional in Orphanet.
  evidence:
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002900 | Hypokalemia | Occasional (29-5%)"
    explanation: Orphanet records hypokalemia as occasional.
treatments:
- name: Glucocorticoid suppression
  description: >
    Low-dose glucocorticoid therapy suppresses ACTH drive to the chimeric gene,
    reducing aldosterone excess in glucocorticoid-remediable aldosteronism.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dexamethasone
      term:
        id: CHEBI:41879
        label: dexamethasone
  target_mechanisms:
  - target: ACTH-regulated aldosterone synthase expression
    treatment_effect: INHIBITS
    description: Glucocorticoids suppress ACTH-regulated chimeric aldosterone synthase expression.
  target_phenotypes:
  - preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  - preferred_term: Dexamethasone-suppressible primary hyperaldosteronism
    term:
      id: HP:0011739
      label: Dexamethasone-suppressible primary hyperaldosteronism
  evidence:
  - reference: PMID:1731223
    reference_title: "A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "under control of adrenocorticotropic hormone and suppressible by glucocorticoids"
    explanation: The original study supports glucocorticoid suppression as mechanism-directed therapy.
  - reference: ORPHA:403
    reference_title: "Familial hyperaldosteronism type I (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "glucocorticoid remediable form of primary aldosteronism"
    explanation: Orphanet describes FH-I as glucocorticoid remediable.
- name: Mineralocorticoid receptor antagonist therapy
  description: >
    Mineralocorticoid receptor antagonists such as spironolactone and
    eplerenone can be used to control mineralocorticoid-mediated hypertension,
    particularly when glucocorticoid therapy is limited by corticosteroid side
    effects or additional blood pressure control is needed.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: spironolactone
      term:
        id: CHEBI:9241
        label: spironolactone
    - preferred_term: eplerenone
      term:
        id: CHEBI:31547
        label: eplerenone
  target_mechanisms:
  - target: Low-renin mineralocorticoid hypertension
    treatment_effect: INHIBITS
    description: Mineralocorticoid receptor antagonism reduces aldosterone-driven blood pressure effects.
  target_phenotypes:
  - preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  - preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:10618671
    reference_title: "Abolished nocturnal blood pressure fall in a boy with glucocorticoid-remediable aldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A change of therapy from dexamethasone to spironolactone was necessary due to the side effects of corticosteroids after 3 months. Spironolactone alone (0.8-2 mg/kg/day) was able to control the BP sufficiently."
    explanation: A genetically proven GRA case supports spironolactone as an alternative when corticosteroid side effects limit dexamethasone.
  - reference: PMID:21451421
    reference_title: "A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We compared the efficacy, safety and tolerability of eplerenone versus spironolactone in patients with hypertension associated with primary aldosteronism."
    explanation: A randomized primary-aldosteronism trial supports the mineralocorticoid receptor antagonist treatment class that includes spironolactone and eplerenone.
diagnosis:
- name: CYP11B1/CYP11B2 chimeric gene testing
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  description: >
    Molecular testing for the CYP11B1/CYP11B2 chimeric gene confirms the
    glucocorticoid-remediable aldosteronism genotype.
  evidence:
  - reference: PMID:35012455
    reference_title: "GRAde: a long-read sequencing approach to efficiently identifying the CYP11B1/CYP11B2 chimeric form in patients with glucocorticoid-remediable aldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PCR-based target enrichment followed by long-read sequencing is an efficient and precise approach to dissecting complex genomic regions"
    explanation: The sequencing paper supports molecular testing for the chimeric CYP11B1/CYP11B2 region.
notes: >-
  This entry focuses on the ORPHA:403 leaf disorder. The broader Orphanet
  familial hyperaldosteronism group is not emitted by the structured Orphanet
  cache because the repo's source currently serializes leaf disorder records.
  Deep-research provider attempts with falcon and openai stalled without
  producing output and were terminated; final curation used the structured
  Orphanet cache and fetched PubMed abstracts.
📚

References & Deep Research

Deep Research

1
Manual Fallback ▸
Familial Hyperaldosteronism Type I Research Fallback

Familial Hyperaldosteronism Type I Research Fallback

Deep-research provider attempts were made after the ORPHA:403 leaf disorder was selected:

  • timeout 240 just research-disorder falcon Familial_Hyperaldosteronism_Type_I
  • timeout 180 just research-disorder openai Familial_Hyperaldosteronism_Type_I

Both commands stalled without producing a research output file and were terminated. The curation therefore used the structured Orphanet cache plus fetched PubMed abstracts as the auditable evidence base.

Literature Scope Checked

  • references_cache/ORPHA_403.md: direct Orphanet leaf record for familial hyperaldosteronism type I, including definition, autosomal dominant inheritance, exact MONDO and OMIM mappings, CYP11B1/CYP11B2 fusion-gene assertions, and HPO phenotype rows.
  • references_cache/PMID_1731223.md: seminal human study identifying unequal crossover producing a chimeric CYP11B1/CYP11B2 gene under ACTH control.
  • references_cache/PMID_35778363.md: clinical review summarizing familial primary hyperaldosteronism forms and confirming that type I results from CYP11B2/CYP11B1 fusion with ACTH-regulated aldosterone synthesis.
  • references_cache/PMID_35012455.md: human diagnostic sequencing paper supporting molecular testing for the CYP11B1/CYP11B2 chimeric form.
  • references_cache/PMID_10618671.md: genetically proven GRA case in which spironolactone replaced dexamethasone after corticosteroid side effects and controlled blood pressure.
  • references_cache/PMID_21451421.md: randomized primary-aldosteronism trial comparing spironolactone and eplerenone, supporting the mineralocorticoid receptor antagonist treatment class.

Curation Conclusions

  • Disease identity is the leaf disorder ORPHA:403, exact to MONDO:0007080 and OMIM:103900. The broader familial hyperaldosteronism group ORPHA:235936 was checked but is not emitted by the repository's structured Orphanet source.
  • The primary mechanism is a CYP11B1/CYP11B2 chimeric gene from unequal crossover, causing ACTH-regulated aldosterone synthase expression, aldosterone and hybrid steroid excess, suppressed renin, variable hypokalemia, and hypertension.
  • Orphanet directly supports the added phenotype profile, including hypertension, dexamethasone-suppressible primary hyperaldosteronism, low renin, hypokalemia, adrenal hyperplasia, secretory adrenocortical adenoma, preeclampsia, epistaxis, caesarean section, intracranial hemorrhage, headache, muscle weakness, and polydipsia.
  • Mechanism-directed treatment includes low-dose glucocorticoid suppression and mineralocorticoid receptor antagonist therapy when corticosteroid side effects or additional blood pressure control make receptor blockade clinically relevant.