Familial hyperaldosteronism is the inherited subset of primary aldosteronism, characterized by autonomous aldosterone production, suppressed renin, hypertension, and variable hypokalemia. Recognized subtypes converge on increased adrenal CYP11B2/aldosterone synthase activity through either an ACTH-regulated CYP11B1/CYP11B2 chimeric gene or germline ion-channel variants that depolarize adrenal glomerulosa cells and increase calcium signaling.
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name: familial hyperaldosteronism
category: Mendelian
creation_date: '2026-05-07T18:59:42Z'
updated_date: '2026-05-07T19:54:41Z'
synonyms:
- FH
- familial primary aldosteronism
- genetic hyperaldosteronism
- hereditary hyperaldosteronism
description: >
Familial hyperaldosteronism is the inherited subset of primary aldosteronism,
characterized by autonomous aldosterone production, suppressed renin,
hypertension, and variable hypokalemia. Recognized subtypes converge on
increased adrenal CYP11B2/aldosterone synthase activity through either an
ACTH-regulated CYP11B1/CYP11B2 chimeric gene or germline ion-channel variants
that depolarize adrenal glomerulosa cells and increase calcium signaling.
disease_term:
preferred_term: familial hyperaldosteronism
term:
id: MONDO:0016525
label: familial hyperaldosteronism
parents:
- primary aldosteronism
- hereditary disease
definitions:
- name: Familial primary aldosteronism group
definition_type: OTHER
description: >
Familial hyperaldosteronism comprises inherited forms of primary
aldosteronism, historically grouped as types I through IV, with shared
aldosterone excess and low-renin hypertension physiology.
evidence:
- reference: PMID:35778363
reference_title: "Familial forms and molecular profile of primary hyperaldosteronism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Most PAHs occur sporadically, but 5% of cases have a hereditary origin (familial PAH)."
explanation: The review defines familial primary hyperaldosteronism as the hereditary subset of primary aldosteronism.
- reference: PMID:21876069
reference_title: "Prevalence and characteristics of familial hyperaldosteronism: the PATOGEN study (Primary Aldosteronism in TOrino-GENetic forms)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "To date, 3 familial forms of PA have been described and termed familial hyperaldosteronism types I, II, and III"
explanation: The PATOGEN cohort supports the recognized familial hyperaldosteronism grouping.
has_subtypes:
- name: Type I
display_name: Familial hyperaldosteronism type I
subtype_term:
preferred_term: glucocorticoid-remediable aldosteronism
term:
id: MONDO:0007080
label: glucocorticoid-remediable aldosteronism
description: >
Glucocorticoid-remediable aldosteronism caused by a CYP11B1/CYP11B2
chimeric gene that places aldosterone synthase under ACTH regulation.
genes:
- preferred_term: CYP11B1
term:
id: hgnc:2591
label: CYP11B1
- preferred_term: CYP11B2
term:
id: hgnc:2592
label: CYP11B2
evidence:
- 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 identifies the causal fusion for type I familial hyperaldosteronism.
- name: Type II
display_name: Familial hyperaldosteronism type II
subtype_term:
preferred_term: familial hyperaldosteronism type II
term:
id: MONDO:0011576
label: familial hyperaldosteronism type II
description: >
Familial primary aldosteronism associated with germline gain-of-function
CLCN2 variants, typically not glucocorticoid-remediable.
genes:
- preferred_term: CLCN2
term:
id: hgnc:2020
label: CLCN2
evidence:
- reference: PMID:29403011
reference_title: "CLCN2 chloride channel mutations in familial hyperaldosteronism type II."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II) 2 and 80 additional probands with unsolved early-onset primary aldosteronism."
explanation: The CLCN2 discovery study directly analyzed FH-II and early-onset primary aldosteronism probands.
- name: Type III
display_name: Familial hyperaldosteronism type III
subtype_term:
preferred_term: familial hyperaldosteronism type III
term:
id: MONDO:0013359
label: familial hyperaldosteronism type III
description: >
Familial primary aldosteronism caused by inherited KCNJ5 variants affecting
potassium-channel selectivity, with severity ranging from controlled
hypertension to severe childhood aldosteronism with adrenal hyperplasia.
genes:
- preferred_term: KCNJ5
term:
id: hgnc:6266
label: KCNJ5
evidence:
- reference: PMID:22308486
reference_title: "Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "affected members of two kindreds had KCNJ5(G151R) mutations"
explanation: The KCNJ5 study identifies inherited KCNJ5 variants in affected kindreds.
- name: Type IV
display_name: Familial hyperaldosteronism type IV
subtype_term:
preferred_term: hyperaldosteronism, familial, type IV
term:
id: MONDO:0014875
label: hyperaldosteronism, familial, type IV
description: >
Familial or early-onset primary aldosteronism associated with germline
gain-of-function CACNA1H variants affecting the CaV3.2 T-type calcium
channel.
genes:
- preferred_term: CACNA1H
term:
id: hgnc:1395
label: CACNA1H
evidence:
- reference: PMID:25907736
reference_title: "Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1H(M1549V) mutation."
explanation: The CACNA1H study identifies a recurrent heterozygous CACNA1H mutation in early-onset primary aldosteronism.
progression:
- phase: Young-onset or familial primary aldosteronism recognition
age_range: Childhood to adulthood
notes: >
FH should be considered when primary aldosteronism occurs at young age or in
multiple relatives. Subtype severity is variable: FH-I and FH-III have
distinctive profiles, while FH-II and FH-IV may resemble sporadic primary
aldosteronism apart from younger presentation.
evidence:
- reference: PMID:38495792
reference_title: "Differences in the clinical and hormonal presentation of patients with familial and sporadic primary aldosteronism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A total of 360 FH (246 FH type I, 73 type II, 29 type III, and 12 type IV) cases and 830 sporadic PA patients were included."
explanation: The comparative synthesis provides the subtype case distribution used for broad FH clinical framing.
- reference: PMID:38495792
reference_title: "Differences in the clinical and hormonal presentation of patients with familial and sporadic primary aldosteronism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "clinical and hormonal phenotype of type II and IV is similar to the sporadic cases."
explanation: The study supports the note that FH-II and FH-IV can resemble sporadic PA.
genetic:
- name: CYP11B1/CYP11B2 chimeric gene
association: Causal fusion gene for type I familial hyperaldosteronism
subtype: Type I
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: CYP11B2
term:
id: hgnc:2592
label: CYP11B2
notes: >
Unequal crossover between CYP11B1 regulatory sequence and CYP11B2 coding
sequence creates an ACTH-regulated aldosterone synthase fusion gene.
CYP11B1 is recorded in this entry's subtype genes because this Genetic
object can bind only one primary gene term.
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: "fusing the 5' regulatory region of 11 beta-hydroxylase to the coding sequences of aldosterone synthase"
explanation: The original study supports the causal CYP11B1/CYP11B2 chimeric gene structure.
- name: CLCN2
association: Causal gain-of-function variant for type II familial hyperaldosteronism
subtype: Type II
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: CLCN2
term:
id: hgnc:2020
label: CLCN2
notes: >
CLCN2 gain-of-function variants affect the ClC-2 chloride channel in
adrenal glomerulosa cells, increasing membrane depolarization and aldosterone
synthase expression.
evidence:
- reference: PMID:29403011
reference_title: "CLCN2 chloride channel mutations in familial hyperaldosteronism type II."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations"
explanation: The discovery study identifies heterozygous and de novo CLCN2 variants in FH-II/early-onset PA.
- name: KCNJ5
association: Causal gain-of-function variant for type III familial hyperaldosteronism
subtype: Type III
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: KCNJ5
term:
id: hgnc:6266
label: KCNJ5
notes: >
Inherited KCNJ5 variants alter channel selectivity and produce different
clinical severities depending on the allele.
evidence:
- reference: PMID:22308486
reference_title: "Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These individuals had severe progressive aldosteronism and hyperplasia requiring bilateral adrenalectomy in childhood for blood pressure control."
explanation: The KCNJ5 kindred study supports the severe FH-III phenotype for G151R carriers.
- name: CACNA1H
association: Causal gain-of-function variant for type IV familial hyperaldosteronism
subtype: Type IV
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: CACNA1H
term:
id: hgnc:1395
label: CACNA1H
notes: >
CACNA1H encodes the CaV3.2 T-type calcium channel. Germline variants can
increase calcium entry and aldosterone production in early-onset or familial
primary aldosteronism.
evidence:
- reference: PMID:27729216
reference_title: "CACNA1H Mutations Are Associated With Different Forms of Primary Aldosteronism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified four germline variations in CACNA1H which affect the electrophysiological and functional properties of the channel"
explanation: The study supports germline CACNA1H variation as a primary aldosteronism mechanism.
pathophysiology:
- name: ACTH-regulated aldosterone synthase expression
description: >
In FH-I, the CYP11B1/CYP11B2 chimeric gene causes aldosterone synthase to be
regulated by ACTH rather than angiotensin II, producing glucocorticoid-
suppressible aldosterone excess.
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
- 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: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 supports the altered hormonal regulation in FH-I.
downstream:
- target: Aldosterone excess with suppressed renin
causal_link_type: DIRECT
- name: CLCN2 gain-of-function channel opening
description: >
In FH-II, gain-of-function CLCN2 variants increase ClC-2 chloride-channel
activity in adrenal glomerulosa cells, causing membrane depolarization and
increased CYP11B2 expression.
genes:
- preferred_term: CLCN2
term:
id: hgnc:2020
label: CLCN2
subtypes:
- Type II
cell_types:
- preferred_term: adrenal glomerulosa cell
term:
id: CL:0002097
label: cortical cell of adrenal gland
locations:
- preferred_term: zona glomerulosa
term:
id: UBERON:0002053
label: zona glomerulosa of adrenal gland
evidence:
- reference: PMID:29403011
reference_title: "CLCN2 chloride channel mutations in familial hyperaldosteronism type II."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "mutations cause gain of function, producing membrane depolarization and increasing CYP11B2 expression"
explanation: The CLCN2 paper supports gain-of-function channel activity as an upstream depolarizing mechanism in FH-II.
downstream:
- target: Adrenal glomerulosa depolarization and calcium signaling
causal_link_type: DIRECT
- name: KCNJ5 selectivity filter loss and sodium conductance
description: >
In FH-III, inherited KCNJ5 variants alter the potassium-channel selectivity
filter so the channel conducts sodium, depolarizing adrenal glomerulosa
cells.
genes:
- preferred_term: KCNJ5
term:
id: hgnc:6266
label: KCNJ5
subtypes:
- Type III
cell_types:
- preferred_term: adrenal glomerulosa cell
term:
id: CL:0002097
label: cortical cell of adrenal gland
locations:
- preferred_term: zona glomerulosa
term:
id: UBERON:0002053
label: zona glomerulosa of adrenal gland
evidence:
- reference: PMID:22308486
reference_title: "Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "producing increased Na(+) conductance and membrane depolarization, the signal for aldosterone production"
explanation: The KCNJ5 study supports altered selectivity, sodium conductance, and depolarization in FH-III.
downstream:
- target: Adrenal glomerulosa depolarization and calcium signaling
causal_link_type: DIRECT
- name: CACNA1H gain-of-function calcium influx
description: >
In FH-IV, gain-of-function CACNA1H variants affect the CaV3.2 T-type
calcium channel, increasing calcium influx and calcium signaling in adrenal
cells.
genes:
- preferred_term: CACNA1H
term:
id: hgnc:1395
label: CACNA1H
subtypes:
- Type IV
cell_types:
- preferred_term: adrenal glomerulosa cell
term:
id: CL:0002097
label: cortical cell of adrenal gland
locations:
- preferred_term: zona glomerulosa
term:
id: UBERON:0002053
label: zona glomerulosa of adrenal gland
evidence:
- reference: PMID:25907736
reference_title: "Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "producing increased intracellular Ca(2+), the signal for aldosterone production"
explanation: The CACNA1H study supports gain-of-function calcium influx as the upstream FH-IV mechanism.
downstream:
- target: Adrenal glomerulosa depolarization and calcium signaling
causal_link_type: DIRECT
- name: Adrenal glomerulosa depolarization and calcium signaling
description: >
Ion-channel defects in FH-II, FH-III, and FH-IV converge on adrenal
glomerulosa membrane depolarization and calcium signaling, which induce
aldosterone synthase and aldosterone biosynthesis.
cell_types:
- preferred_term: adrenal glomerulosa cell
term:
id: CL:0002097
label: cortical cell of adrenal gland
locations:
- preferred_term: zona glomerulosa
term:
id: UBERON:0002053
label: zona glomerulosa of adrenal gland
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: PMID:29403011
reference_title: "CLCN2 chloride channel mutations in familial hyperaldosteronism type II."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "glomerulosa cell membrane depolarization activates voltage-gated Ca2+ channels, which induces the rate-limiting enzyme for aldosterone biosynthesis, aldosterone synthase (CYP11B2)"
explanation: The CLCN2 paper states the shared depolarization-calcium-CYP11B2 pathway for monogenic and sporadic PA.
downstream:
- target: Aldosterone excess with suppressed renin
causal_link_type: DIRECT
- name: Aldosterone excess with suppressed renin
description: >
Autonomous aldosterone excess suppresses renin and drives mineralocorticoid
hypertension, with variable potassium wasting and hypokalemia.
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: PMID:40658480
reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Primary aldosteronism (PA), a primary adrenal disorder leading to excessive aldosterone production by one or both adrenal glands, is a common cause of hypertension."
explanation: The guideline supports aldosterone excess as a cause of hypertension in PA.
- reference: PMID:29403011
reference_title: "CLCN2 chloride channel mutations in familial hyperaldosteronism type II."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The plasma aldosterone level in primary aldosteronism is constitutively elevated despite low levels of the normal upstream regulator renin; hypokalemia is variable."
explanation: The CLCN2 paper states the core aldosterone, renin, and potassium pattern.
phenotypes:
- category: Cardiovascular
name: Hypertension
description: >
Hypertension is the central clinical presentation of familial
hyperaldosteronism and may occur early in life, especially in severe
channelopathy subtypes.
phenotype_term:
preferred_term: Hypertension
term:
id: HP:0000822
label: Hypertension
evidence:
- reference: PMID:21876069
reference_title: "Prevalence and characteristics of familial hyperaldosteronism: the PATOGEN study (Primary Aldosteronism in TOrino-GENetic forms)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Primary aldosteronism (PA) is the most frequent cause of secondary hypertension"
explanation: The PATOGEN study supports hypertension as a core PA/FH context.
- reference: PMID:25907736
reference_title: "Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10."
explanation: The CACNA1H study supports early-onset hypertension in familial/monogenic PA.
- category: Endocrine
name: Increased circulating aldosterone concentration
description: >
Autonomous aldosterone excess is the defining endocrine abnormality across
familial hyperaldosteronism subtypes.
phenotype_term:
preferred_term: Increased circulating aldosterone concentration
term:
id: HP:0000859
label: Increased circulating aldosterone concentration
evidence:
- reference: PMID:40658480
reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a primary adrenal disorder leading to excessive aldosterone production by one or both adrenal glands"
explanation: The guideline supports excess aldosterone production as the defining PA abnormality.
- category: Biochemical
name: Low renin
description: >
Suppressed renin is part of the primary aldosteronism biochemical pattern.
phenotype_term:
preferred_term: Low renin
term:
id: HP:0040084
label: Abnormal circulating renin concentration
evidence:
- reference: PMID:29403011
reference_title: "CLCN2 chloride channel mutations in familial hyperaldosteronism type II."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "constitutively elevated despite low levels of the normal upstream regulator renin"
explanation: The CLCN2 paper supports low renin in primary aldosteronism physiology.
- category: Biochemical
name: Hypokalemia
description: >
Hypokalemia is variable across familial hyperaldosteronism. It is uncommon
in many FH-I cases but prominent in severe FH-III.
phenotype_term:
preferred_term: Hypokalemia
term:
id: HP:0002900
label: Hypokalemia
evidence:
- reference: PMID:38495792
reference_title: "Differences in the clinical and hormonal presentation of patients with familial and sporadic primary aldosteronism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "FH-I is characterized by a low prevalence of hypokalemia and FH-III by a severe aldosterone excess causing hypokalemia in more than 85% of patients."
explanation: The 2024 synthesis supports subtype variation in hypokalemia frequency.
- category: Biochemical
name: Metabolic alkalosis
description: >
Aldosterone excess can produce metabolic alkalosis as part of the primary
aldosteronism biochemical phenotype.
phenotype_term:
preferred_term: Metabolic alkalosis
term:
id: HP:0001948
label: Alkalosis
evidence:
- reference: PMID:28844072
reference_title: "Update in diagnosis and management of primary aldosteronism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These disorders can lead to hypertension, hypokalemia, hypervolemia and metabolic alkalosis."
explanation: The PA review supports metabolic alkalosis as a biochemical consequence of aldosterone excess.
- category: Endocrine
name: Adrenal hyperplasia
description: >
Adrenal hyperplasia is especially associated with severe KCNJ5-related FH-III.
phenotype_term:
preferred_term: Adrenal hyperplasia
term:
id: HP:0008221
label: Adrenal hyperplasia
evidence:
- reference: PMID:22308486
reference_title: "Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "severe progressive aldosteronism and hyperplasia requiring bilateral adrenalectomy in childhood"
explanation: The KCNJ5 study supports adrenal hyperplasia in severe FH-III.
- category: Neurological
name: Cerebral hemorrhage
description: >
Cerebrovascular hemorrhage is a recognized complication of
glucocorticoid-remediable aldosteronism and is treated here as subtype-
scoped rather than a universal FH phenotype.
subtype: Type I
phenotype_term:
preferred_term: Hemorrhagic stroke
term:
id: HP:0001342
label: Cerebral hemorrhage
evidence:
- reference: PMID:9453343
reference_title: "Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There are anecdotal reports of early cerebrovascular complications occurring in patients with glucocorticoid-remediable aldosteronism (GRA)."
explanation: The paper is specific to GRA/FH-I, supporting subtype scoping.
- reference: PMID:9453343
reference_title: "Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GRA is associated with high morbidity and mortality from early onset of hemorrhagic stroke and ruptured intracranial aneurysms."
explanation: The study supports hemorrhagic stroke as a major FH-I complication.
- category: Neurological
name: Intracranial aneurysm
description: >
Intracranial aneurysm and ruptured aneurysm are reported complications of
glucocorticoid-remediable aldosteronism, so this phenotype is scoped to
FH-I rather than generalized across all FH subtypes.
subtype: Type I
phenotype_term:
preferred_term: Intracranial aneurysm
term:
id: HP:0004944
label: Dilatation of the cerebral artery
evidence:
- reference: PMID:9453343
reference_title: "Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GRA is associated with high morbidity and mortality from early onset of hemorrhagic stroke and ruptured intracranial aneurysms."
explanation: The GRA/FH-I cerebrovascular study supports intracranial aneurysm as a distinct subtype-scoped phenotype.
biochemical:
- name: Serum aldosterone
presence: INCREASED
notes: Autonomous aldosterone excess is the core biochemical abnormality.
evidence:
- reference: PMID:40658480
reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "excessive aldosterone production by one or both adrenal glands"
explanation: The guideline supports increased aldosterone in PA.
- name: Renin
presence: DECREASED
notes: Renin is suppressed by autonomous aldosterone excess.
evidence:
- reference: PMID:29403011
reference_title: "CLCN2 chloride channel mutations in familial hyperaldosteronism type II."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "low levels of the normal upstream regulator renin"
explanation: The CLCN2 paper supports low renin in primary aldosteronism.
- name: Serum potassium
presence: DECREASED
notes: Hypokalemia is variable and subtype-dependent.
evidence:
- reference: PMID:29403011
reference_title: "CLCN2 chloride channel mutations in familial hyperaldosteronism type II."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypokalemia is variable"
explanation: The CLCN2 paper supports variable hypokalemia in primary aldosteronism.
treatments:
- name: Mineralocorticoid receptor antagonist therapy
description: >
Mineralocorticoid receptor antagonists are PA-specific medical therapy for
aldosterone-mediated hypertension and are relevant across FH subtypes when
medical management is selected.
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: Aldosterone excess with suppressed renin
treatment_effect: INHIBITS
description: Mineralocorticoid receptor antagonism reduces aldosterone-mediated hypertension.
target_phenotypes:
- preferred_term: Hypertension
term:
id: HP:0000822
label: Hypertension
- preferred_term: Hypokalemia
term:
id: HP:0002900
label: Hypokalemia
evidence:
- reference: PMID:40658480
reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We suggest the use of mineralocorticoid receptor antagonists (MRAs) over epithelial sodium-channel (ENaC) inhibitors in the medical treatment of PA."
explanation: The Endocrine Society guideline supports MRA therapy for PA.
- 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: "The antihypertensive effect of spironolactone was significantly greater than that of eplerenone in hypertension associated with primary aldosteronism."
explanation: The randomized trial supports spironolactone and eplerenone as PA antihypertensive therapies.
- name: Glucocorticoid suppression for type I disease
description: >
Low-dose glucocorticoid therapy can suppress ACTH-regulated aldosterone
production 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-driven aldosterone synthase activity in FH-I.
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 GRA study supports mechanism-directed glucocorticoid suppression.
- name: Adrenalectomy for severe or lateralizing disease
description: >
Surgery is considered for lateralizing PA and may be required in severe
KCNJ5-related FH-III with adrenal hyperplasia.
treatment_term:
preferred_term: adrenalectomy
term:
id: MAXO:0001030
label: adrenalectomy
target_mechanisms:
- target: Aldosterone excess with suppressed renin
treatment_effect: INHIBITS
description: Removing aldosterone-producing adrenal tissue reduces aldosterone excess.
evidence:
- reference: PMID:22308486
reference_title: "Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "requiring bilateral adrenalectomy in childhood for blood pressure control"
explanation: The KCNJ5 FH-III study supports adrenalectomy in severe childhood disease.
diagnosis:
- name: Aldosterone-renin screening
diagnosis_term:
preferred_term: clinical laboratory test
term:
id: MAXO:0000003
label: diagnostic procedure
description: >
Screening for primary aldosteronism uses aldosterone and renin measurements
with aldosterone-to-renin ratio interpretation.
evidence:
- reference: PMID:40658480
reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "all individuals with hypertension be screened for PA by measuring aldosterone and renin and determining the aldosterone to renin ratio"
explanation: The guideline supports aldosterone-renin screening.
- name: Familial hyperaldosteronism genetic testing
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: MAXO:0000533
label: molecular genetic testing
description: >
Genetic testing is used for young-onset PA, familial case finding, and
subtype-specific diagnosis, including CYP11B1/CYP11B2 fusion testing and
sequencing of early-onset PA genes such as CLCN2, KCNJ5, and CACNA1H.
evidence:
- reference: PMID:29403011
reference_title: "CLCN2 chloride channel mutations in familial hyperaldosteronism type II."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Genetic testing for germline mutations in CLCN2 and other early primary aldosteronism genes can be useful for establishing diagnosis"
explanation: The CLCN2 study supports genetic testing in early/familial PA.
- reference: PMID:21876069
reference_title: "Prevalence and characteristics of familial hyperaldosteronism: the PATOGEN study (Primary Aldosteronism in TOrino-GENetic forms)."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "reinforces the recommendation of the Endocrine Society Guidelines to screen all first-degree hypertensive relatives of PA patients."
explanation: The PATOGEN study supports family screening among relatives of PA patients.
- name: Adrenal venous sampling
diagnosis_term:
preferred_term: adrenal venous sampling
term:
id: MAXO:0000003
label: diagnostic procedure
description: >
Adrenal venous sampling is used with adrenal imaging to establish whether
aldosterone excess lateralizes before choosing surgical versus medical
treatment.
evidence:
- reference: PMID:40658480
reference_title: "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we suggest adrenal lateralization with computed tomography scanning and adrenal venous sampling prior to deciding the treatment approach"
explanation: The 2025 Endocrine Society guideline supports AVS for lateralization before treatment selection.
notes: >
Falcon research identified recent reviews and a 2025 primary-aldosteronism
guideline, plus several DOI-only sources. This initial generic parent page
uses PubMed/cache-backed snippets for the core assertions and leaves
Orphanet/OMIM subgroup crosswalks, founder effects, and FH-specific
quality-of-life data for later expansion.
Familial hyperaldosteronism (FH) is a group of inherited (typically autosomal-dominant) forms of primary aldosteronism (PA) characterized by inappropriate aldosterone production, suppressed renin, and hypertension; hypokalemia may be present depending on subtype and severity. (okorafor2024lowreninforms pages 2-3, araujocastro2024differencesinthe pages 3-5)
A practical clinical definition used in recent endocrine genetics reviews is that FH is suspected/identified when a person has PA and ≥1 first-degree relative is also affected. (kim2024molecularandgenetics pages 11-12)
ICD-10/ICD-11 and MeSH identifiers were not retrievable from the current tool-accessible corpus and should be added from OMIM/Orphanet/MeSH lookups in a follow-on curation step.
The information summarized here is derived from aggregated disease-level resources (guidelines, cohort studies, systematic reviews) and primary research studies (genetic discovery, registry cohorts, and a complication study in FH-I). (adler2025primaryaldosteronisman pages 5-6, araujocastro2024differencesinthe pages 3-5, mulatero2011prevalenceandcharacteristics pages 1-2, aldosteronism1998intracranialaneurysmand pages 1-2)
FH comprises multiple genetic subtypes defined by germline alterations that increase aldosterone biosynthesis: - FH-I (GRA): CYP11B1/CYP11B2 chimeric fusion gene created by unequal/asymmetric crossover. (kim2024molecularandgenetics pages 11-12, ekman2024whatweknow pages 2-4) - FH-II: germline CLCN2 gain-of-function variants (chloride channel). (kim2024molecularandgenetics pages 11-12, okorafor2024lowreninforms pages 2-3) - FH-III: germline KCNJ5 variants affecting a potassium channel (Kir3.4/GIRK4). Primary evidence shows distinct phenotypes for different variants at the same residue (G151R vs G151E). (scholl2012hypertensionwithor pages 1-2) - FH-IV: germline CACNA1H variants (T-type Ca2+ channel, CaV3.2); the original report identified heterozygous variants in familial and early-onset PA and demonstrated functional effects. (daniil2016cacna1hmutationsare pages 1-2)
OpenTargets disease–gene association evidence (supporting MONDO mapping) lists strong associations for KCNJ5, CLCN2, CACNA1H, CYP11B2/CYP11B1 (via GRA), and other linked entities. (OpenTargets Search: familial hyperaldosteronism)
Primary risk is family history of PA/FH and young onset hypertension/PA. A 2025 Endocrine Society guideline emphasizes genetic screening for familial forms and young-onset PA (see Diagnostics). (adler2025primaryaldosteronisman pages 5-6)
Specific protective variants or gene–environment interactions were not identified in the retrieved corpus.
A large 2024 comparative analysis compiled 360 FH cases (systematic review) vs 830 sporadic PA patients (SPAIN-ALDO registry). (araujocastro2024differencesinthe pages 3-5)
FH-I (GRA) - Younger age at diagnosis: 33.6 ± 18.07 vs 56.5 ± 4.76 years (FH-I vs sporadic). (araujocastro2024differencesinthe pages 3-5) - Hypokalemia prevalence: 11.6% vs 59.6% (FH-I vs sporadic). (araujocastro2024differencesinthe pages 3-5) - PAC: 29.5 ± 15.03 vs 44.4 ± 78.85 ng/dL (FH-I vs sporadic). (araujocastro2024differencesinthe pages 3-5) - PRA: 1.3 ± 6.81 vs 0.4 ± 0.86 ng/mL/h (FH-I vs sporadic). (araujocastro2024differencesinthe pages 3-5) - A synthesis within the same paper notes many FH-I patients may be normotensive (reported ~40%) and hypokalemia can be <12%. (araujocastro2024differencesinthe pages 5-6)
FH-II (CLCN2-related) - Phenotype often resembles sporadic PA except younger age and higher diastolic BP; in the same cohort, mean age is markedly younger than sporadic (example values reported for FH-II: 33.6 ± 19.7 vs 56.5 ± 4.8 years). (araujocastro2024differencesinthe pages 5-6)
FH-III (KCNJ5-related) - Severe early-onset phenotype with hypokalemia ~89.3% and mean serum potassium ~2.6 mEq/L in the cohort. (araujocastro2024differencesinthe pages 3-5) - High need for bilateral adrenalectomy in severe cases: 17/29 underwent bilateral adrenalectomy for BP control in the 2024 synthesis. (araujocastro2024differencesinthe pages 3-5)
FH-IV (CACNA1H-related) - In the 2024 synthesis, phenotype was largely similar to sporadic PA, but with younger age, lower serum potassium and higher PRA. (araujocastro2024differencesinthe pages 5-6, araujocastro2024differencesinthe pages 3-5)
A landmark 1998 study of 27 GRA pedigrees reported major cerebrovascular morbidity: - In genetically proven GRA subjects (n=167), 18 cerebrovascular events occurred in 15 patients vs 0 events in GRA-negative relatives (P<0.001). (aldosteronism1998intracranialaneurysmand pages 1-2) - 70% of events were hemorrhagic; overall case fatality 61%. (aldosteronism1998intracranialaneurysmand pages 1-2) - The authors conclude GRA “is associated with high morbidity and mortality from early onset of hemorrhage stroke and ruptured intracranial aneurysms” and recommend aneurysm screening by MRA in genetically proven GRA. (aldosteronism1998intracranialaneurysmand pages 1-2) - Hemorrhagic stroke incidence rates in proven GRA were markedly higher than Framingham (Framingham 0.020% vs proven GRA 0.28% in patient-years comparisons). (aldosteronism1998intracranialaneurysmand pages 4-5)
The retrieved sources did not supply explicit HPO mappings; suggested terms for knowledge-base curation: - Hypertension: HP:0000822 - Hyperaldosteronism: HP:0000859 - Hypokalemia: HP:0002900 - Low renin (as a lab phenotype; may map to “decreased renin”): HP:0020031 (check exact HPO label in current HPO) - Metabolic alkalosis: HP:0001948 (not universal; more typical in mineralocorticoid excess syndromes) (okorafor2024lowreninforms pages 2-3) - Intracranial aneurysm: HP:0004944; Hemorrhagic stroke: HP:0001342 (FH-I/GRA complication) (aldosteronism1998intracranialaneurysmand pages 1-2)
No FH-specific validated QoL instruments or quantified QoL outcomes were identified in the retrieved corpus.
See subtype summary table below and genetic discovery evidence: - FH-I: CYP11B1/CYP11B2 chimeric fusion (OMIM #103900). (carvajal2012anewpresentation pages 1-3) - FH-II: CLCN2. (kim2024molecularandgenetics pages 11-12, okorafor2024lowreninforms pages 2-3) - FH-III: KCNJ5. (scholl2012hypertensionwithor pages 1-2) - FH-IV: CACNA1H. (daniil2016cacna1hmutationsare pages 1-2)
FH is defined by germline changes, but there is mechanistic overlap with somatic driver mutations in sporadic aldosterone-producing adenomas (APAs) (e.g., KCNJ5, CACNA1D), which converge on Ca2+ signaling and CYP11B2 upregulation. (ekman2024whatweknow pages 2-4, kim2024molecularandgenetics pages 11-12)
No FH-specific modifier genes, epigenetic signatures, or chromosomal abnormalities were identified in the retrieved corpus.
No specific non-genetic environmental triggers for FH onset were identified; however, aldosterone excess phenotypes interact with salt intake and antihypertensive medications via ARR interpretation and downstream cardiovascular risk (primarily addressed in PA guidelines rather than FH-specific evidence). (adler2025primaryaldosteronisman pages 5-6, ylanenUnknownyeardiagnosticsofprimary pages 49-52)
Across most FH subtypes, causal variants affect ion channels or transport in adrenal zona glomerulosa (ZG) cells, leading to membrane depolarization, increased intracellular Ca2+ signaling, increased CYP11B2 (aldosterone synthase) expression, and aldosterone overproduction. (ekman2024whatweknow pages 2-4, kim2024molecularandgenetics pages 11-12)
A CYP11B1/CYP11B2 chimeric gene results in aldosterone synthase activity being controlled by ACTH rather than angiotensin II/potassium, explaining dexamethasone suppressibility. (ekman2024whatweknow pages 2-4, kim2024molecularandgenetics pages 11-12)
A 2024 review summarizes FH-II mechanism as a mutant chloride channel with increased permeability that causes depolarization and “influx of calcium intracellularly, resulting in the activation of aldosterone synthesis.” (okorafor2024lowreninforms pages 2-3)
Primary evidence shows KCNJ5 mutations disrupt the selectivity filter so channels conduct Na+, leading to depolarization and Ca2+ channel activation, which increases aldosterone production and can drive hyperplasia; phenotype differs by allele (G151R severe vs G151E mild). (scholl2012hypertensionwithor pages 1-2)
CACNA1H variants alter Ca2+ current properties in electrophysiology studies and increase aldosterone production and steroidogenic enzyme expression in cell models, supporting a calcium-driven aldosteronism mechanism. (daniil2016cacna1hmutationsare pages 1-2)
The 1998 GRA complication study proposes multiple plausible contributors, including longstanding congenital hypertension, aldosterone-related vascular remodeling/fibrosis, or developmental effects of mineralocorticoid excess on cerebrovascular development; it draws a parallel to intracranial aneurysm risk in autosomal dominant polycystic kidney disease. (aldosteronism1998intracranialaneurysmand pages 4-5)
FH subtypes are generally described as autosomal dominant with variable expressivity; FH-II and FH-IV are often noted to have incomplete penetrance in reviews. (okorafor2024lowreninforms pages 2-3, santana2022pathogenesisofprimary pages 4-5)
Founder mutations, geographic clustering, and carrier frequencies were not extractable from the current corpus.
The 2025 Endocrine Society guideline emphasizes screening using aldosterone, renin (PRA or DRC), and potassium, with ARR interpretation in the context of pretest probability and medication effects; it provides guidance on repeating testing and medication washout where feasible. (adler2025primaryaldosteronisman pages 5-6)
The 2025 guideline describes an individualized algorithm: patients likely to have PA who do not desire surgery can be treated with MRA without extensive confirmatory/subtyping; those pursuing surgery may proceed via probabilistic shared decision-making and consider aldosterone suppression testing, CT imaging, and AVS depending on likelihood of lateralizing disease. (adler2025primaryaldosteronisman pages 6-7)
Figure: Endocrine Society 2025 algorithm for likely PA management (includes pathways to MRA therapy vs CT/AVS workup). (adler2025primaryaldosteronisman media 47196b32)
The 2025 Endocrine Society guideline states: - “Aldosterone suppression testing is unnecessary in individuals from families with germline mutations associated with familial hyperaldosteronism.” (adler2025primaryaldosteronisman pages 5-6) - “Genetic screening is recommended for all first-degree relatives of individuals with familial hyperaldosteronism and for individuals with young-onset PA (<20 years) to enable early diagnosis and treatment.” (adler2025primaryaldosteronisman pages 5-6)
Real-world implementation considerations: In Aotearoa/New Zealand, FH-I testing cost (NZD$127.91) was far lower than AVS (NZD$6663), supporting cost-effectiveness of early FH-I testing in young-onset PA without adrenal adenoma on imaging. (elston2024genetictestingfor pages 5-6)
The corpus included broader reviews of monogenic low-renin hypertension syndromes, emphasizing that multiple Mendelian disorders can present with low renin and hypertension (e.g., Liddle, apparent mineralocorticoid excess). FH is differentiated by aldosterone excess and genetic subtype testing. (okorafor2024lowreninforms pages 2-3)
The 1998 pedigree study reported high morbidity and mortality: - 18% of genetically proven GRA patients had cerebrovascular complications. - 61% case fatality across events. - Strong enrichment for hemorrhagic stroke and intracranial aneurysm. (aldosteronism1998intracranialaneurysmand pages 1-2)
FH-II families had clinically relevant complications: the cohort reported stroke (3 patients) and severe kidney damage in one patient among FH-II affected individuals (descriptive). (mulatero2011prevalenceandcharacteristics pages 3-4)
PATOGEN reports that very low-dose dexamethasone and/or MRAs controlled BP satisfactorily in FH-I families; FH-II cases more often had hypertension and higher complication burden. (mulatero2011prevalenceandcharacteristics pages 3-4)
Primary prevention is not applicable (genetic). Secondary/tertiary prevention focuses on: - Cascade genetic screening of relatives per 2025 Endocrine Society guideline to enable early diagnosis and treatment. (adler2025primaryaldosteronisman pages 5-6) - In FH-I/GRA, intracranial aneurysm screening by MRA in genetically proven cases is recommended in the 1998 study (beginning at puberty and repeated approximately every five years per the paper’s recommendations). (aldosteronism1998intracranialaneurysmand pages 4-5, aldosteronism1998intracranialaneurysmand pages 1-2)
No naturally occurring FH analogs in non-human species were identified in the retrieved corpus.
FH subtype-relevant models were not systematically retrieved, but mechanistic animal/cellular models exist for channelopathies and are referenced in broader PA genetics literature; specific model details require additional targeted retrieval beyond the present corpus.
| FH subtype | Alternative names / synonyms | Causal gene(s) and variant mechanism | Inheritance / penetrance | Key distinguishing clinical / biochemical features | Key citations (year) |
|---|---|---|---|---|---|
| FH-I | Glucocorticoid-remediable aldosteronism (GRA); glucocorticoid-suppressible hyperaldosteronism | CYP11B1/CYP11B2 chimeric fusion gene from unequal/asymmetric crossover; ACTH-regulated aldosterone synthase expression; functional gain-of-function of aldosterone production in zona fasciculata and glomerulosa (kim2024molecularandgenetics pages 11-12, ekman2024whatweknow pages 2-4, okorafor2024lowreninforms pages 2-3) | Autosomal dominant; marked variable expressivity/phenotypic heterogeneity; some affected individuals may be normotensive (okorafor2024lowreninforms pages 2-3, mulatero2011prevalenceandcharacteristics pages 1-2, monticone2018geneticsinendocrinology pages 1-5) | Earlier onset; often younger than sporadic PA; more common in women; lower PAC, higher PRA, less frequent hypokalemia than sporadic PA; hypokalemia reported in <12% in one synthesis and 40.3% may be normotensive in one cohort; ACTH-dependent and dexamethasone suppressible; dexamethasone suppression / long-PCR useful diagnostically (araujocastro2024differencesinthe pages 2-3, araujocastro2024differencesinthe pages 5-6, kim2024molecularandgenetics pages 11-12, santana2022pathogenesisofprimary pages 2-4, adler2025primaryaldosteronisman pages 5-6) | Araujo-Castro et al. 2024, DOI:10.3389/fendo.2024.1336306; Kim et al. 2024, DOI:10.3390/ijms252111341; Ekman et al. 2024, DOI:10.3390/ijms25020900; PATOGEN 2011, DOI:10.1161/HYPERTENSIONAHA.111.175083; Endocrine Society guideline 2025, DOI:10.1210/clinem/dgaf284 (araujocastro2024differencesinthe pages 2-3, kim2024molecularandgenetics pages 11-12, ekman2024whatweknow pages 2-4, mulatero2011prevalenceandcharacteristics pages 1-2, adler2025primaryaldosteronisman pages 5-6) |
| FH-II | Familial hyperaldosteronism type II; nonglucocorticoid-remediable familial hyperaldosteronism | CLCN2 (ClC-2 chloride channel) gain-of-function variants causing increased chloride permeability/efflux, depolarization, calcium influx, and aldosterone synthesis; variant examples include p.Arg172Gln, p.Met22Lys, p.Tyr26Asn, p.Lys362del, p.Ser865Arg, and p.Gly24Asp (kim2024molecularandgenetics pages 11-12, okorafor2024lowreninforms pages 2-3, santana2022pathogenesisofprimary pages 4-5) | Usually autosomal dominant with incomplete penetrance and variable expressivity (okorafor2024lowreninforms pages 2-3, santana2022pathogenesisofprimary pages 2-4) | Clinical and hormonal profile often similar to sporadic PA; younger age at presentation and somewhat higher diastolic BP in one cohort; PRA may be slightly higher than sporadic PA; not dexamethasone-remediable (araujocastro2024differencesinthe pages 2-3, araujocastro2024differencesinthe pages 5-6, kim2024molecularandgenetics pages 11-12) | Araujo-Castro et al. 2024, DOI:10.3389/fendo.2024.1336306; Kim et al. 2024, DOI:10.3390/ijms252111341; Okorafor 2024, DOI:10.23950/jcmk/14269; Santana 2022, DOI:10.3389/fendo.2022.927669 (araujocastro2024differencesinthe pages 2-3, kim2024molecularandgenetics pages 11-12, okorafor2024lowreninforms pages 2-3, santana2022pathogenesisofprimary pages 2-4, santana2022pathogenesisofprimary pages 4-5) |
| FH-III | Familial hyperaldosteronism type III | KCNJ5 (GIRK4 / Kir3.4 potassium channel) germline variants causing loss of K+ selectivity, abnormal Na+ influx, membrane depolarization, and increased intracellular Ca2+; examples include p.Gly151Arg, p.Gly151Glu, p.Tyr152Cys, p.Ile157Ser, p.Thr158Ala; mechanism is pathogenic gain-of-function for aldosterone production (kim2024molecularandgenetics pages 11-12, ekman2024whatweknow pages 2-4, scholl2012hypertensionwithor pages 1-2, santana2022pathogenesisofprimary pages 4-5) | Autosomal dominant; marked genotype-phenotype variability; some variants cause massive hyperplasia and severe childhood disease, others milder controllable hypertension (scholl2012hypertensionwithor pages 1-2, santana2022pathogenesisofprimary pages 4-5) | Most severe classic FH subtype: very early onset (often infancy/childhood), marked aldosterone excess, high PAC, low PRA, hypokalemia >85% / nearing 90%, extensive adrenocortical hyperplasia, hybrid steroid synthesis; over 60% required bilateral adrenalectomy in one synthesis; many cases resistant to pharmacotherapy (araujocastro2024differencesinthe pages 5-6, araujocastro2024differencesinthe pages 3-5, okorafor2024lowreninforms pages 2-3, scholl2012hypertensionwithor pages 1-2) | Scholl et al. 2012 PNAS, DOI:10.1073/pnas.1121407109; Araujo-Castro et al. 2024, DOI:10.3389/fendo.2024.1336306; Ekman et al. 2024, DOI:10.3390/ijms25020900; Santana 2022, DOI:10.3389/fendo.2022.927669 (scholl2012hypertensionwithor pages 1-2, araujocastro2024differencesinthe pages 2-3, araujocastro2024differencesinthe pages 5-6, ekman2024whatweknow pages 2-4, santana2022pathogenesisofprimary pages 4-5) |
| FH-IV | Familial hyperaldosteronism type IV | CACNA1H (CaV3.2 T-type calcium channel) germline gain-of-function variants increasing calcium influx and aldosterone biosynthesis; recurrent example p.Met1549Val / p.Met1549Ile and other heterozygous variants reported (okorafor2024lowreninforms pages 2-3, ekman2024whatweknow pages 2-4, daniil2016cacna1hmutationsare pages 1-2, santana2022pathogenesisofprimary pages 4-5) | Autosomal dominant; incomplete / late penetrance with variable expressivity (okorafor2024lowreninforms pages 2-3, santana2022pathogenesisofprimary pages 2-4, santana2022pathogenesisofprimary pages 4-5) | Often early-onset hypertension, but phenotype in 2024 comparative cohort was otherwise similar to sporadic PA, with younger age and lower serum potassium; not dexamethasone-remediable; no specific targeted therapy established in cited reviews (araujocastro2024differencesinthe pages 2-3, araujocastro2024differencesinthe pages 5-6, okorafor2024lowreninforms pages 2-3, daniil2016cacna1hmutationsare pages 1-2) | Daniil et al. 2016, DOI:10.1016/j.ebiom.2016.10.002; Araujo-Castro et al. 2024, DOI:10.3389/fendo.2024.1336306; Ekman et al. 2024, DOI:10.3390/ijms25020900; Santana 2022, DOI:10.3389/fendo.2022.927669 (daniil2016cacna1hmutationsare pages 1-2, araujocastro2024differencesinthe pages 2-3, ekman2024whatweknow pages 2-4, santana2022pathogenesisofprimary pages 4-5) |
Table: This table summarizes the currently recognized Familial Hyperaldosteronism subtypes FH-I through FH-IV, including synonyms, causal genes and mechanisms, inheritance patterns, and distinguishing clinical features. It is useful for quickly comparing subtype-specific genetics and phenotype patterns using only the cited context sources.
2025 Endocrine Society PA guideline: moves toward broader screening and explicitly recommends genetic screening of all first-degree relatives of FH cases and those with young-onset PA (<20 years); also supports streamlined pathways where empirical MRA therapy can be initiated without extensive confirmatory testing in appropriate contexts. Publication date: July 2025. URL: https://doi.org/10.1210/clinem/dgaf284 (adler2025primaryaldosteronisman pages 5-6, adler2025primaryaldosteronisman pages 6-7)
2024 phenotype synthesis (familial vs sporadic PA): largest compiled comparison in the retrieved corpus (360 FH cases) quantifies subtype-specific differences (e.g., very low hypokalemia in FH-I vs extreme hypokalemia and early onset in FH-III). Publication date: March 2024. URL: https://doi.org/10.3389/fendo.2024.1336306 (araujocastro2024differencesinthe pages 3-5)
2024 real-world implementation work (New Zealand): highlights practical cost advantages of FH-I genetic testing compared with AVS and ethical/insurance considerations for testing. Publication date: Aug 2024. URL: https://doi.org/10.1111/imj.16511 (elston2024genetictestingfor pages 5-6)
Large-scale implementation gap quantified (Taiwan, 7.8 million hypertensives): only 4.4% ever screened for PA, despite high-risk features; annual screening only 0.75% by 2022. Preprint date: Nov 2025. URL: https://doi.org/10.1101/2025.11.13.25340212 (tsai2025screeninganddiagnosis pages 1-6)
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(ekman2024whatweknow pages 2-4): Natalia Ekman, Ashley B. Grossman, and Dorota Dworakowska. What we know about and what is new in primary aldosteronism. International Journal of Molecular Sciences, 25:900, Jan 2024. URL: https://doi.org/10.3390/ijms25020900, doi:10.3390/ijms25020900. This article has 21 citations.
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(tsai2025screeninganddiagnosis pages 1-6): Cheng-Hsuan Tsai, Yu-Ching Chang, Zheng-Wei Chen, Stefanie Parisien-La Salle, Jenifer M Brown, Anand Vaidya, Vin-Cent Wu, and Yen-Hung Lin. Screening and diagnosis trends for primary aldosteronism: a longitudinal nationwide cohort study of 7.8 million people. MedRxiv, Nov 2025. URL: https://doi.org/10.1101/2025.11.13.25340212, doi:10.1101/2025.11.13.25340212. This article has 0 citations.