Apparent mineralocorticoid excess is a rare autosomal recessive form of monogenic low-renin hypertension caused by biallelic loss-of-function variants in HSD11B2. Deficiency of renal 11-beta-hydroxysteroid dehydrogenase type 2 allows cortisol to escape inactivation to cortisone and illicitly activate the mineralocorticoid receptor, producing severe early-onset hypertension, hypokalemic metabolic alkalosis, suppressed renin and aldosterone, and an elevated urinary cortisol-to-cortisone metabolite ratio.
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name: apparent mineralocorticoid excess
creation_date: "2026-07-24T00:00:00Z"
description: >-
Apparent mineralocorticoid excess is a rare autosomal recessive form of
monogenic low-renin hypertension caused by biallelic loss-of-function variants
in HSD11B2. Deficiency of renal 11-beta-hydroxysteroid dehydrogenase type 2
allows cortisol to escape inactivation to cortisone and illicitly activate the
mineralocorticoid receptor, producing severe early-onset hypertension,
hypokalemic metabolic alkalosis, suppressed renin and aldosterone, and an
elevated urinary cortisol-to-cortisone metabolite ratio.
category: Mendelian
parents:
- hereditary disease
disease_term:
preferred_term: apparent mineralocorticoid excess
term:
id: MONDO:0009025
label: apparent mineralocorticoid excess
synonyms:
- AME
- apparent mineralocorticoid excess syndrome
- 11-beta-hydroxysteroid dehydrogenase type 2 deficiency
- cortisol 11-beta-ketoreductase deficiency
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Classic apparent mineralocorticoid excess is caused by biallelic
loss-of-function variants in HSD11B2 and is inherited in an autosomal
recessive manner.
evidence:
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites.
explanation: >-
This molecular-genetics review states that AME is an autosomal recessive
monogenic disease.
- reference: PMID:39931437
reference_title: "Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic analysis revealed biallelic recessive variations in the HSD11B2 gene in all three patients.
explanation: >-
Pediatric case series confirms biallelic (recessive) HSD11B2 variants in
affected children.
pathophysiology:
- name: 11-beta-HSD2 deficiency and impaired cortisol inactivation
description: >-
Loss of renal 11-beta-hydroxysteroid dehydrogenase type 2 activity, encoded
by HSD11B2, fails to convert active cortisol to inactive cortisone in
mineralocorticoid target tissues, allowing cortisol to accumulate at the
mineralocorticoid receptor.
genes:
- preferred_term: HSD11B2
term:
id: hgnc:5209
label: HSD11B2
biological_processes:
- preferred_term: cortisol metabolic process
term:
id: GO:0034650
label: cortisol metabolic process
modifier: DECREASED
- preferred_term: glucocorticoid metabolic process
term:
id: GO:0008211
label: glucocorticoid metabolic process
modifier: DECREASED
molecular_functions:
- preferred_term: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity
term:
id: GO:0070523
label: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity
modifier: DECREASED
chemical_entities:
- preferred_term: cortisol
term:
id: CHEBI:17650
label: cortisol
modifier: INCREASED
- preferred_term: cortisone
term:
id: CHEBI:16962
label: cortisone
modifier: DECREASED
evidence:
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It is caused by defects in the HSD11B2 gene, encoding the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is primarily involved in the peripheral conversion of cortisol to cortisone.
explanation: >-
Directly supports HSD11B2/11-beta-HSD2 as the deficient enzyme catalyzing
cortisol-to-cortisone conversion.
- reference: PMID:15761540
reference_title: "Apparent mineralocorticoid excess syndrome: an overview."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This enzyme is co-expressed with the mineralocorticoid receptor (MR) in the kidney and converts cortisol (F) to its inactive metabolite cortisone (E).
explanation: >-
Confirms renal co-expression of 11-beta-HSD2 with the mineralocorticoid
receptor and its role converting cortisol to cortisone.
downstream:
- target: Cortisol-mediated mineralocorticoid receptor activation
description: >-
Accumulating cortisol binds and illicitly activates the mineralocorticoid
receptor in the distal nephron.
causal_link_type: DIRECT
evidence:
- reference: PMID:15761540
reference_title: "Apparent mineralocorticoid excess syndrome: an overview."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension.
explanation: >-
Directly links loss of 11-beta-HSD2 to cortisol binding the
mineralocorticoid receptor.
- name: Cortisol-mediated mineralocorticoid receptor activation
description: >-
Because the mineralocorticoid receptor binds cortisol and aldosterone with
similar affinity, unmetabolized cortisol illicitly activates the receptor,
reproducing a mineralocorticoid-excess state despite suppressed aldosterone.
evidence:
- reference: PMID:31909799
reference_title: "Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Subtypes of essential hypertension characterized by low renin levels allowed the identification of 2 different clinical entities: aldosterone-mediated mineralocorticoid receptor (MR) activation and cortisol-mediated MR activation.
explanation: >-
Identifies cortisol-mediated mineralocorticoid receptor activation as the
mechanism distinguishing AME from aldosterone-driven hypertension.
downstream:
- target: Distal nephron sodium retention and volume expansion
description: >-
Mineralocorticoid receptor activation drives sodium reabsorption and
volume expansion in the distal nephron.
causal_link_type: DIRECT
evidence:
- reference: PMID:15761540
reference_title: "Apparent mineralocorticoid excess syndrome: an overview."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension.
explanation: >-
Directly supports sodium retention as a consequence of cortisol-driven
MR activation.
- name: Distal nephron sodium retention and volume expansion
description: >-
Illicit mineralocorticoid receptor activation increases sodium reabsorption
in distal nephron principal cells, expanding extracellular volume and
promoting renal potassium and hydrogen ion loss and suppression of the
renin-angiotensin-aldosterone axis.
cell_types:
- preferred_term: kidney collecting duct principal cell
term:
id: CL:1001431
label: kidney collecting duct principal cell
biological_processes:
- preferred_term: sodium ion transport
term:
id: GO:0006814
label: sodium ion transport
modifier: INCREASED
chemical_entities:
- preferred_term: sodium(1+)
term:
id: CHEBI:29101
label: sodium(1+)
modifier: INCREASED
evidence:
- reference: PMID:15761540
reference_title: "Apparent mineralocorticoid excess syndrome: an overview."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension.
explanation: >-
Supports sodium retention with secondary hypokalemia, renin suppression,
and hypertension.
downstream:
- target: Hypertension
description: Volume expansion from sodium retention causes hypertension.
causal_link_type: DIRECT
evidence:
- reference: PMID:15761540
reference_title: "Apparent mineralocorticoid excess syndrome: an overview."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension.
explanation: >-
Places hypertension downstream of MR-driven sodium retention.
- target: Hypokalemia
description: Enhanced distal potassium secretion causes hypokalemia.
causal_link_type: DIRECT
evidence:
- reference: PMID:15761540
reference_title: "Apparent mineralocorticoid excess syndrome: an overview."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension.
explanation: >-
Places hypokalemia downstream of MR-driven distal tubular transport.
- target: Decreased circulating renin
description: >-
Volume expansion and hypertension suppress plasma renin activity.
causal_link_type: DIRECT
evidence:
- reference: PMID:15761540
reference_title: "Apparent mineralocorticoid excess syndrome: an overview."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension.
explanation: >-
Supports suppression of plasma renin activity (PRA) as a downstream
consequence.
- name: Reduced placental 11-beta-HSD2 barrier
description: >-
Reduced placental 11-beta-HSD2 activity weakens the feto-placental
glucocorticoid barrier, a proposed contributor to reduced birth weight in
affected infants.
evidence:
- reference: PMID:15761540
reference_title: "Apparent mineralocorticoid excess syndrome: an overview."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Reduced placental 11beta-HSD2 expression might explain the link between reduced birth weight and adult hypertension.
explanation: >-
Supports reduced placental 11-beta-HSD2 as a mechanism linking the enzyme
defect to low birth weight.
downstream:
- target: Small for gestational age
description: Impaired placental glucocorticoid barrier is associated with reduced birth weight.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:15761540
reference_title: "Apparent mineralocorticoid excess syndrome: an overview."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Reduced placental 11beta-HSD2 expression might explain the link between reduced birth weight and adult hypertension.
explanation: >-
Links reduced placental enzyme expression to reduced birth weight.
phenotypes:
- name: Hypertension
category: Cardiovascular
description: >-
Severe, often resistant low-renin hypertension is the cardinal feature,
typically beginning in infancy or childhood in classic AME.
phenotype_term:
preferred_term: Hypertension
term:
id: HP:0000822
label: Hypertension
evidence:
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites.
explanation: >-
Review identifies juvenile resistant low-renin hypertension as a defining
feature.
- reference: PMID:39931437
reference_title: "Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria.
explanation: >-
Pediatric series documents hypertension in all affected children.
- name: Hypokalemia
category: Metabolic
description: >-
Renal potassium wasting from mineralocorticoid receptor overactivation
causes marked, often chronic hypokalemia.
phenotype_term:
preferred_term: Hypokalemia
term:
id: HP:0002900
label: Hypokalemia
evidence:
- reference: PMID:15761540
reference_title: "Apparent mineralocorticoid excess syndrome: an overview."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension.
explanation: >-
Lists hypokalemia among the direct consequences of the enzyme deficiency.
- reference: PMID:39931437
reference_title: "Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria.
explanation: >-
Documents severe hypokalemia in all affected children.
- reference: PMID:42503627
reference_title: "A rare genetically confirmed case of apparent mineralocorticoid excess syndrome due to a homozygous HSD11B2 variant in a 2-year-old child with severe hypertension: response to targeted therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
On the second day of admission, the nephrology team was consulted due to persistent hypokalemia requiring repeated potassium chloride (KCl) supplementation.
explanation: >-
Documents persistent hypokalemia requiring repeated KCl supplementation in a
2-year-old patient with a homozygous HSD11B2 variant.
- name: Metabolic alkalosis
category: Metabolic
description: >-
Enhanced distal hydrogen ion secretion produces hypokalemic metabolic
alkalosis.
phenotype_term:
preferred_term: Metabolic alkalosis
term:
id: HP:0200114
label: Metabolic alkalosis
evidence:
- reference: PMID:39931437
reference_title: "Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria.
explanation: >-
Documents metabolic alkalosis in all affected children.
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites.
explanation: >-
Review identifies marked hypokalemic alkalosis as a defining feature.
- reference: PMID:42503627
reference_title: "A rare genetically confirmed case of apparent mineralocorticoid excess syndrome due to a homozygous HSD11B2 variant in a 2-year-old child with severe hypertension: response to targeted therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
persistent hypokalemia, metabolic alkalosis, and hypertension, were highly suggestive of AME syndrome.
explanation: >-
Pediatric case documents metabolic alkalosis as part of the classic AME
phenotype in a 2-year-old with a homozygous HSD11B2 variant.
- name: Decreased circulating renin
category: Endocrine
description: >-
Plasma renin activity is suppressed by chronic volume expansion and
hypertension.
phenotype_term:
preferred_term: Decreased circulating renin concentration
term:
id: HP:0003351
label: Decreased circulating renin concentration
evidence:
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites.
explanation: >-
Review characterizes AME as a low-renin hypertension.
- reference: PMID:15761540
reference_title: "Apparent mineralocorticoid excess syndrome: an overview."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension.
explanation: >-
Describes suppression of plasma renin activity (PRA).
- name: Decreased circulating aldosterone
category: Endocrine
description: >-
Aldosterone is suppressed despite the mineralocorticoid-excess phenotype,
the paradox for which the disorder is named.
phenotype_term:
preferred_term: Decreased circulating aldosterone concentration
term:
id: HP:0004319
label: Decreased circulating aldosterone concentration
evidence:
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites.
explanation: >-
Review identifies low aldosterone levels as a defining feature.
- name: Small for gestational age
category: Growth
description: >-
Affected neonates are frequently small for gestational age with low birth
weight, linked to reduced placental 11-beta-HSD2 activity.
phenotype_term:
preferred_term: Small for gestational age
term:
id: HP:0001518
label: Small for gestational age
evidence:
- reference: PMID:39931437
reference_title: "Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria.
explanation: >-
Documents small-for-gestational-age birth in all affected children.
- name: Nephrocalcinosis
category: Renal
description: >-
Hypercalciuria associated with the disorder predisposes to nephrocalcinosis,
which may persist despite treatment.
phenotype_term:
preferred_term: Nephrocalcinosis
term:
id: HP:0000121
label: Nephrocalcinosis
evidence:
- reference: PMID:39931437
reference_title: "Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria.
explanation: >-
Documents nephrocalcinosis in all affected children.
- name: Hypercalciuria
category: Renal
description: >-
Increased urinary calcium excretion accompanies the renal phenotype and
underlies nephrocalcinosis.
phenotype_term:
preferred_term: Hypercalciuria
term:
id: HP:0002150
label: Hypercalciuria
evidence:
- reference: PMID:39931437
reference_title: "Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria.
explanation: >-
Documents hypercalciuria in all affected children.
- name: Polyuria
category: Renal
description: >-
Chronic hypokalemia impairs renal concentrating ability, causing polyuria
and polydipsia.
phenotype_term:
preferred_term: Polyuria
term:
id: HP:0000103
label: Polyuria
evidence:
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
refractory hypertension, delayed growth, polyuria and
explanation: >-
Review lists polyuria among the clinical manifestations of AME.
- name: Failure to thrive
category: Growth
description: >-
Poor postnatal growth and failure to thrive are common in infancy and often
improve with disease control.
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
polydipsia, failure to thrive
explanation: >-
Review lists failure to thrive among the clinical manifestations of AME.
biochemical:
- name: Urinary cortisol-to-cortisone metabolite ratio
presence: INCREASED
context: >-
An elevated ratio of cortisol to cortisone metabolites is the biochemical
hallmark of AME, reflecting impaired 11-beta-HSD2 conversion of cortisol to
cortisone.
biomarker_term:
preferred_term: cortisol
term:
id: CHEBI:17650
label: cortisol
readouts:
- target: 11-beta-HSD2 deficiency and impaired cortisol inactivation
relationship: READOUT_OF
direction: POSITIVE
endpoint_context: DIAGNOSTIC
interpretation: >-
A high urinary cortisol-to-cortisone metabolite ratio directly reports
deficient 11-beta-HSD2 activity.
evidence:
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites.
explanation: >-
Identifies high ratios of cortisol to cortisone metabolites as a defining
biochemical feature.
genetic:
- name: HSD11B2
association: Loss of function mutation
gene_term:
preferred_term: HSD11B2
term:
id: hgnc:5209
label: HSD11B2
evidence:
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It is caused by defects in the HSD11B2 gene, encoding the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is primarily involved in the peripheral conversion of cortisol to cortisone.
explanation: >-
Directly identifies HSD11B2 defects as the cause of AME.
- reference: PMID:39931437
reference_title: "Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic analysis revealed biallelic recessive variations in the HSD11B2 gene in all three patients.
explanation: >-
Confirms biallelic recessive HSD11B2 variants in affected patients.
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
To date, over 50 deleterious HSD11B2 mutations have been identified worldwide.
explanation: >-
Documents the allelic heterogeneity of HSD11B2, with over 50 deleterious
mutations reported worldwide.
- reference: PMID:42503627
reference_title: "A rare genetically confirmed case of apparent mineralocorticoid excess syndrome due to a homozygous HSD11B2 variant in a 2-year-old child with severe hypertension: response to targeted therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
identified a homozygous pathogenic HSD11B2 variant (c.622C>T; p.Arg208Cys), confirming AME syndrome.
explanation: >-
Pediatric case documents pathogenic homozygous HSD11B2 p.Arg208Cys variant
(c.622C>T) confirmed by whole exome sequencing in a 2-year-old with severe
AME phenotype.
diagnosis:
- name: HSD11B2 molecular genetic testing
description: >-
Sequence and deletion/duplication analysis of HSD11B2 confirms the diagnosis;
a precise molecular diagnosis enables early, specific management.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C19770
label: Molecular Analysis
qualifiers:
- predicate:
preferred_term: has participant
term:
id: RO:0000057
label: has participant
value:
preferred_term: HSD11B2
term:
id: hgnc:5209
label: HSD11B2
results: Biallelic pathogenic HSD11B2 variants in a patient with low-renin hypertension, hypokalemic alkalosis, and an elevated cortisol-to-cortisone ratio.
evidence:
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A precise diagnosis depends on genetic testing, which allows for early and specific management to avoid the morbidity and mortality from target organ damage.
explanation: >-
Supports molecular genetic testing as the basis for a precise AME
diagnosis.
treatments:
- name: Mineralocorticoid receptor antagonists
description: >-
Mineralocorticoid receptor antagonists (spironolactone or eplerenone)
directly oppose inappropriate cortisol-driven receptor activation, lowering
blood pressure and correcting hypokalemia.
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_phenotypes:
- preferred_term: Hypertension
term:
id: HP:0000822
label: Hypertension
target_mechanisms:
- target: Cortisol-mediated mineralocorticoid receptor activation
treatment_effect: INHIBITS
description: >-
MR antagonists block the mineralocorticoid receptor that cortisol illicitly
activates.
evidence:
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mineralocorticoid receptor blocker, spironolactone, could block the hyperactivation of mineralocorticoid receptors while amiloride blocks EnaC
explanation: >-
Supports spironolactone blocking mineralocorticoid receptor
hyperactivation.
evidence:
- reference: PMID:31909799
reference_title: "Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
NC-AME subjects are candidates to be treated with MR antagonists aimed to improve blood pressure, end-organ damage, and modulate the renin levels.
explanation: >-
Supports MR antagonists to improve blood pressure and end-organ damage.
- reference: PMID:39931437
reference_title: "Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Treatment with oral spironolactone and potassium chloride resulted in the normalization of both blood pressure and serum potassium levels in all patients.
explanation: >-
Documents spironolactone normalizing blood pressure in affected children.
- reference: PMID:42503627
reference_title: "A rare genetically confirmed case of apparent mineralocorticoid excess syndrome due to a homozygous HSD11B2 variant in a 2-year-old child with severe hypertension: response to targeted therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
As spironolactone was gradually increased to 8 mg/kg/day, potassium improved to 3.1 mmol/L
explanation: >-
Ties the mineralocorticoid receptor antagonist specifically to correction of
hypokalemia: escalating spironolactone dose produced a graded rise in serum
potassium sufficient to withdraw intravenous supplementation, in a 2-year-old
with a homozygous HSD11B2 p.Arg208Cys variant.
- name: Epithelial sodium channel blockade
description: >-
Amiloride blocks the downstream epithelial sodium channel (ENaC) and can be
used alone or with mineralocorticoid receptor blockade.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: amiloride
term:
id: CHEBI:2639
label: amiloride
target_phenotypes:
- preferred_term: Hypertension
term:
id: HP:0000822
label: Hypertension
target_mechanisms:
- target: Distal nephron sodium retention and volume expansion
treatment_effect: INHIBITS
description: >-
Amiloride blocks ENaC-mediated sodium reabsorption downstream of the
mineralocorticoid receptor.
evidence:
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mineralocorticoid receptor blocker, spironolactone, could block the hyperactivation of mineralocorticoid receptors while amiloride blocks EnaC
explanation: >-
Supports amiloride blocking the epithelial sodium channel (ENaC).
evidence:
- reference: PMID:36329487
reference_title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mineralocorticoid receptor blocker, spironolactone, could block the hyperactivation of mineralocorticoid receptors while amiloride blocks EnaC
explanation: >-
Supports amiloride as an ENaC-directed therapy in AME.
- name: Dietary sodium restriction and potassium replacement
description: >-
Low-sodium diet reduces the salt-sensitive component of hypertension, and
potassium replacement corrects hypokalemia.
treatment_term:
preferred_term: dietary intervention
term:
id: NCIT:C15447
label: Dietary Intervention
target_phenotypes:
- preferred_term: Hypokalemia
term:
id: HP:0002900
label: Hypokalemia
target_mechanisms:
- target: Distal nephron sodium retention and volume expansion
treatment_effect: INHIBITS
description: >-
Sodium restriction reduces the substrate for MR-driven sodium retention.
evidence:
- reference: PMID:31909799
reference_title: "Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
NC-AME condition should benefit from low-sodium and potassium diet recommendations and monotherapy with MR antagonists.
explanation: >-
Supports low-sodium and potassium diet recommendations in AME.
evidence:
- reference: PMID:31909799
reference_title: "Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
NC-AME condition should benefit from low-sodium and potassium diet recommendations and monotherapy with MR antagonists.
explanation: >-
Supports dietary low-sodium and potassium recommendations.
- reference: PMID:39931437
reference_title: "Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Treatment with oral spironolactone and potassium chloride resulted in the normalization of both blood pressure and serum potassium levels in all patients.
explanation: >-
Documents potassium chloride replacement normalizing serum potassium.
references:
- reference: PMID:36329487
title: "Apparent mineralocorticoid excess: comprehensive overview of molecular genetics."
- reference: PMID:31909799
title: "Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome."
- reference: PMID:15761540
title: "Apparent mineralocorticoid excess syndrome: an overview."
- reference: PMID:39931437
title: "Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series."
- reference: PMID:42503627
title: "A rare genetically confirmed case of apparent mineralocorticoid excess syndrome due to a homozygous HSD11B2 variant in a 2-year-old child with severe hypertension: response to targeted therapy."
- reference: clinicaltrials:NCT00474942
title: "Apparent Mineralocorticoid Excess Syndrome Natural History Clinical Protocol"
differential_diagnoses: []
clinical_trials: []
Apparent mineralocorticoid excess (AME) is a rare, usually autosomal-recessive monogenic hypertension syndrome caused by deficient 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). The enzyme normally converts cortisol to cortisone in mineralocorticoid-sensitive tissues. Its loss allows abundant cortisol to activate the mineralocorticoid receptor (MR), producing renal sodium retention, potassium and hydrogen loss, volume expansion, suppressed renin and aldosterone, and often severe childhood hypertension. The classic disorder is caused by biallelic germline HSD11B2 variants; partial genetic, epigenetic, and environmental impairment produces a broader, less firmly delimited “nonclassic AME” phenotype. (carvajal2020classicandnonclassic pages 6-7, lu2022apparentmineralocorticoidexcess pages 1-3)
The following table provides a curated overview.
| Core fact | Summary | Key details / ontology suggestions | Evidence |
|---|---|---|---|
| Identifiers | Apparent mineralocorticoid excess (AME) is a rare monogenic mineralocorticoid-hypertension disorder caused by impaired cortisol inactivation. | MONDO:0009025; OMIM: 218030; MeSH: D043204 (“Mineralocorticoid Excess Syndrome, Apparent”); category: Mendelian / autosomal recessive low-renin hypertension. Synonyms: AME, apparent mineralocorticoid excess syndrome, mineralocorticoid excess syndrome apparent. | (OpenTargets Search: apparent mineralocorticoid excess-HSD11B2, lu2022apparentmineralocorticoidexcess pages 1-3, NCT00474942 chunk 1) |
| Cause / inheritance | Classic AME is caused by biallelic germline pathogenic variants in HSD11B2, encoding 11β-HSD2; inheritance is autosomal recessive. | Causal gene: HSD11B2; protein: hydroxysteroid 11-beta dehydrogenase 2; mechanism is usually loss of function. Founder effects and consanguinity are recurrent in reported families. Nonclassic AME reflects partial deficiency with genetic/epigenetic contribution. | (carvajal2020classicandnonclassic pages 6-7, lu2022apparentmineralocorticoidexcess pages 1-3, palermo2004apparentmineralocorticoidexcess pages 2-4, carvajal2020classicandnonclassic pages 28-29) |
| Hallmark phenotype | Core phenotype is childhood-onset low-renin, low-aldosterone hypertension with hypokalemic metabolic alkalosis due to cortisol-mediated mineralocorticoid receptor activation. | Suggested HPO: Hypertension, Hypokalemia, Metabolic alkalosis, Low renin hypertension, Failure to thrive, Polyuria, Polydipsia, Nephrocalcinosis, Left ventricular hypertrophy, Low birth weight. Classic AME usually presents from infancy/childhood; nonclassic AME often in adolescents/adults and may be normotensive or mildly hypertensive. | (carvajal2020classicandnonclassic pages 6-7, NCT00474942 chunk 1, lu2022apparentmineralocorticoidexcess pages 16-16, lu2022apparentmineralocorticoidexcess pages 3-4) |
| Diagnostic signature | Biochemical hallmark is impaired cortisol-to-cortisone conversion with suppressed renin and aldosterone plus elevated cortisol/cortisone metabolite ratios; confirmation is by genetic testing. | Typical tests: plasma renin activity or concentration low/suppressed; aldosterone low; urinary steroid profile with elevated (THF + 5αTHF)/THE and/or serum/urine cortisol:cortisone ratio; classic AME often has 11βHSD2 activity ~1–6%, nonclassic ~40–60%. ClinicalTrials.gov eligibility required low renin, low aldosterone, elevated urinary cortisol/cortisone metabolite ratio, and two HSD11B2 mutations. | (carvajal2020classicandnonclassic pages 28-29, lu2022apparentmineralocorticoidexcess pages 1-3, NCT00474942 chunk 1) |
| Mechanism / pathophysiology | Loss of renal 11β-HSD2 prevents conversion of cortisol to cortisone, allowing cortisol to activate mineralocorticoid receptor despite low aldosterone, driving sodium retention and potassium wasting. | Upstream defect: HSD11B2 loss/partial loss. Downstream pathway: MR activation → ENaC and Na+/K+-ATPase upregulation → sodium and water retention, hypokalemia, low renin, hypertension. Primary anatomy: kidney distal nephron/collecting duct; additional expression in placenta, colon, brain. Suggested GO/UBERON/CL concepts: cortisol catabolic process, mineralocorticoid receptor signaling pathway, kidney, placenta, colon, renal tubular epithelial cell. | (lu2022apparentmineralocorticoidexcess pages 1-3, palermo2004apparentmineralocorticoidexcess pages 1-2) |
| Treatment / real-world management | Mainstays are salt restriction, mineralocorticoid receptor blockade, potassium-sparing approaches, potassium replacement, and selected glucocorticoid suppression therapy; renal transplant can cure the endocrine-renal defect in advanced kidney failure. | Reported regimens: spironolactone or eplerenone for classic and nonclassic AME; low-dose nonclassic examples include spironolactone 12.5–25 mg/day or eplerenone 25–50 mg/day; classic AME may need higher weight-based MR antagonist dosing plus potassium; amiloride blocks ENaC mechanistically; glucocorticoids may suppress ACTH-driven cortisol production in selected classic cases; kidney transplantation reported as curative. Suggested MAXO: low sodium diet, mineralocorticoid receptor antagonist therapy, potassium supplementation, renal transplantation. | (carvajal2020classicandnonclassic pages 17-19, lu2022apparentmineralocorticoidexcess pages 3-4, ding2025casereportclinical pages 6-7) |
| Prognosis / statistics | Prognosis depends strongly on early diagnosis and treatment; untreated disease can cause severe target-organ injury. | Long-term data cited in review: cardiovascular mortality 19%, persistent nephrocalcinosis 89%, kidney failure 15% in a 36-patient classic AME series; one long-term family follow-up found worst outcomes in the sibling with longest diagnostic delay. Natural-history study NCT00474942 enrolled 130 participants and notes some patients progress despite spironolactone. | (lu2022apparentmineralocorticoidexcess pages 3-4, NCT00474942 chunk 1) |
| Evidence limitations | Evidence base is dominated by case reports, small family series, reviews, and observational natural-history data; randomized trials and population prevalence estimates for classic AME are lacking. | Classic AME prevalence remains unclear; nonclassic AME estimate of 7.1% comes from one Chilean primary-care cohort and should not be generalized. Recent 2023–2024 literature mainly provides reviews, low-renin hypertension synthesis, epigenetic discussion, and case-series updates rather than interventional trials or gene therapy. | (carvajal2020classicandnonclassic pages 3-3, carvajal2020classicandnonclassic pages 9-9, NCT00474942 chunk 1, lu2022apparentmineralocorticoidexcess pages 1-3) |
Table: This table summarizes the most important knowledge-base facts for apparent mineralocorticoid excess, including identifiers, etiology, phenotype, diagnosis, mechanism, treatment, prognosis, and major evidence gaps. It is designed as a compact reference for disease curation and clinical interpretation.
Definition. Classic AME is an inborn error of cortisol metabolism and a form of low-renin monogenic hypertension. Its characteristic combination is juvenile resistant hypertension, hypokalemic metabolic alkalosis, low renin, low aldosterone, and an elevated cortisol-to-cortisone metabolite ratio. It is “apparent” mineralocorticoid excess because the phenotype resembles excess aldosterone even though aldosterone is suppressed. (carvajal2020classicandnonclassic pages 6-7, lu2022apparentmineralocorticoidexcess pages 1-3)
Identifiers and synonyms
The evidence is primarily aggregated disease-level literature, family studies, case series, and a prospective natural-history protocol—not routine EHR-derived population evidence. The completed multicenter natural-history study NCT00474942 enrolled 130 affected individuals and family members. (NCT00474942 chunk 1)
Classic AME results from biallelic germline loss-of-function variants in HSD11B2, inherited in an autosomal-recessive manner. More than 50 deleterious variants had been reported worldwide by 2022. They reduce enzyme function through protein instability, impaired substrate or NAD⁺-cofactor affinity, disrupted folding, altered catalytic activity, or disruption of the dimer interface. (lu2022apparentmineralocorticoidexcess pages 1-3)
Licorice or glycyrrhizin/glycyrrhetinic acid, carbenoxolone, certain bioflavonoids, grapefruit-associated compounds, and some azole antifungals can inhibit 11β-HSD2 and produce an acquired AME-like state. Cortisol substrate excess in Cushing syndrome or ectopic ACTH production can overwhelm residual enzyme capacity. High sodium intake magnifies volume expansion and hypertension. (palermo2004apparentmineralocorticoidexcess pages 1-2, carvajal2020classicandnonclassic pages 11-12)
The proposed two-hit model for nonclassic AME comprises a first hit—partial genetic or epigenetic impairment of HSD11B2—and a second hit such as high salt intake, age-related change, or an endogenous/exogenous 11β-HSD2 inhibitor. (carvajal2020classicandnonclassic pages 3-3, carvajal2020classicandnonclassic pages 28-29)
No validated protective allele is established. Avoidance of licorice and other inhibitors, sodium restriction, early diagnosis, adherence to MR/ENaC-directed treatment, and correction of hypokalemia reduce expression or complications but do not prevent inherited genotype formation. (lu2022apparentmineralocorticoidexcess pages 3-4, palermo2004apparentmineralocorticoidexcess pages 1-2)
| Phenotype | Type and usual characteristics | Suggested HPO term |
|---|---|---|
| Hypertension | Clinical sign; often severe, resistant, and beginning in infancy or childhood in classic AME; normal to mildly/severely elevated in nonclassic disease | Hypertension; Early-onset hypertension |
| Suppressed renin and aldosterone | Laboratory abnormality; persistent unless treatment restores volume homeostasis | Low-renin hypertension; Decreased circulating renin; Hypoaldosteronism |
| Hypokalemia | Laboratory abnormality; often marked and chronic; may cause weakness, paralysis, tetany, or arrhythmia | Hypokalemia |
| Metabolic alkalosis | Laboratory abnormality secondary to renal hydrogen and potassium loss | Metabolic alkalosis |
| Low birth weight/IUGR | Prenatal manifestation related partly to loss of placental glucocorticoid protection | Low birth weight; Intrauterine growth retardation |
| Failure to thrive/growth retardation | Pediatric physical manifestation; variable and often improved with disease control | Failure to thrive; Short stature/Growth delay |
| Polyuria and polydipsia | Symptoms, partly related to chronic hypokalemia and renal concentrating impairment | Polyuria; Polydipsia |
| Muscle weakness or hypokalemic paralysis | Symptom; episodic or persistent according to potassium level | Muscle weakness; Hypokalemic paralysis |
| Nephrocalcinosis, hypercalciuria, renal calculi/cysts | Renal manifestations; nephrocalcinosis may persist despite treatment | Nephrocalcinosis; Hypercalciuria; Nephrolithiasis; Renal cyst |
| LV hypertrophy/cardiac dysfunction | Target-organ manifestations of severe hypertension | Left ventricular hypertrophy; Cardiomyopathy |
| Hypertensive retinopathy/stroke | Advanced vascular complications, especially after delayed control | Hypertensive retinopathy; Stroke |
| Delayed puberty | Reported in severe pediatric disease | Delayed puberty |
Classic AME generally starts in infancy or childhood with low birth weight, growth delay, severe hypertension, polyuria/polydipsia, hypokalemia, alkalosis, and failure to thrive. Nephrocalcinosis and renal cysts are repeatedly reported. Nonclassic AME usually presents in adolescence or adulthood with subtler steroid abnormalities and normal or moderately increased blood pressure. (NCT00474942 chunk 1, lu2022apparentmineralocorticoidexcess pages 3-4)
Phenotype frequencies are poorly quantified because most evidence consists of small families and case series. In a 36-patient long-term classic AME series summarized in the 2022 review, persistent nephrocalcinosis occurred in 89%, kidney failure in 15%, and cardiovascular mortality in 19%. These estimates should not be treated as population-wide rates. (lu2022apparentmineralocorticoidexcess pages 3-4)
No disease-specific EQ-5D, SF-36, or PROMIS dataset was identified. Expected quality-of-life burdens include medication and dietary demands, weakness or arrhythmia from hypokalemia, polyuria, growth and pubertal effects, and disability from renal, cardiac, retinal, or cerebrovascular injury.
Reported classes include missense, nonsense, frameshift, and splice-disrupting variants. One review catalogued more than 260 HSD11B2 SNPs, including 66 coding variants, 35 missense changes, 10 frameshifts, and two variants causing severe splicing impairment; these totals mix disease-causing mutations and polymorphisms and therefore must not be interpreted as counts of pathogenic variants. (carvajal2020classicandnonclassic pages 12-13)
Examples include:
Variant-specific gnomAD/TOPMed frequencies were not supplied in the retrieved literature and should be obtained directly from the current database release and transcript before curation. Most classic-AME pathogenic alleles are expected to be individually very rare. Copy-number changes or large chromosomal abnormalities are not established as a common mechanism; CMA, karyotyping, and FISH are therefore not first-line tests.
Glucocorticoid receptor signaling, RAC1-GTPase, SUMOylation at 11β-HSD2 residue K266, and Hedgehog signaling can alter HSD11B2 expression or function. Promoter/first-exon CpG methylation, histone regulation, and microRNAs have been implicated in tissue-specific expression and nonclassic or salt-sensitive phenotypes, but none is a validated routine diagnostic biomarker. (carvajal2020classicandnonclassic pages 13-14, carvajal2020classicandnonclassic pages 11-12)
The environmental component is principally chemical and dietary rather than infectious:
A detailed medication, supplement, confectionery, herbal-product, and dietary history is essential before diagnosing genetic AME. (lu2022apparentmineralocorticoidexcess pages 3-4, palermo2004apparentmineralocorticoidexcess pages 1-2)
Urinary tetrahydrocortisol and allo-tetrahydrocortisol increase relative to tetrahydrocortisone, creating the elevated (THF + 5αTHF)/THE ratio. Serum cortisol can remain normal because intact hypothalamic-pituitary-adrenal feedback reduces secretion while cortisol clearance is prolonged; historical measurements found a cortisol half-life of 120–190 minutes versus 70–90 minutes in controls. (lu2022apparentmineralocorticoidexcess pages 1-3, palermo2004apparentmineralocorticoidexcess pages 2-4)
Suggested ontology annotations include cortisol catabolic process, steroid metabolic process, mineralocorticoid receptor signaling, renal sodium-ion transport, potassium-ion homeostasis, and regulation of blood pressure. Relevant cell types are renal tubular epithelial cells, particularly distal-nephron/collecting-duct principal cells; placental trophoblasts; colonic epithelial cells; and selected neurons. No AME-specific single-cell, spatial-transcriptomic, proteomic, lipidomic, or validated multi-omic clinical classifier was identified.
Suggested UBERON concepts are kidney, renal collecting duct, distal convoluted tubule, placenta, colon, heart, blood vessel, retina, and brain. Suggested Cell Ontology concepts are kidney collecting-duct principal cell, distal-tubule epithelial cell, trophoblast, colonic epithelial cell, vascular endothelial cell, vascular smooth-muscle cell, and cardiomyocyte. At the subcellular level, 11β-HSD2 is associated mainly with the endoplasmic-reticulum membrane, while MR acts through cytoplasmic/nuclear receptor trafficking and nuclear transcription. Disease is systemic and has no meaningful lateralization.
Classic AME commonly begins prenatally with growth restriction or low birth weight and becomes clinically evident during infancy or childhood. Onset is chronic rather than acute, although hypokalemic paralysis, arrhythmia, stroke, or hypertensive crisis can be episodic acute presentations. Nonclassic disease generally appears in adolescence or adulthood and may remain subtle. (NCT00474942 chunk 1, lu2022apparentmineralocorticoidexcess pages 3-4)
The untreated course is chronic and potentially progressive: persistent hypertension and electrolyte disturbance lead to cardiac, vascular, retinal, and renal injury. Early biochemical and genetic diagnosis is the principal window for preventing irreversible damage. Treatment can normalize blood pressure and potassium, but nephrocalcinosis or established organ injury may persist. The natural-history protocol explicitly notes that some individuals progress or die within years despite spironolactone, although it does not provide a controlled treatment comparison. (NCT00474942 chunk 1)
Classic AME is autosomal recessive. Penetrance for severe biallelic loss-of-function genotypes appears high, but expressivity varies with residual activity, genotype, salt exposure, treatment, and diagnostic delay. Anticipation is not expected. Germline mosaicism has not emerged as an important recurrent mechanism. Each sibling of an affected individual born to two confirmed carriers has the standard recessive risks: 25% affected, 50% carrier, and 25% inheriting neither familial allele.
True prevalence and incidence of classic AME remain unknown. Fewer than 100 cases were noted in a recent pediatric case-series discussion, but case counts are subject to publication and ascertainment bias. Cases occur worldwide, with clustering in consanguineous, endogamous, or founder populations; no reliable global sex, incidence, or carrier-frequency estimate was established in the evidence reviewed. (lu2022apparentmineralocorticoidexcess pages 3-4, ding2025casereportclinical pages 4-5)
A Chilean primary-care study found biochemical evidence interpreted as partial 11β-HSD2 deficiency in 7.1% of its cohort. This is a proposed nonclassic phenotype estimate, not the prevalence of biallelic classic AME and not necessarily generalizable to other populations. (carvajal2020classicandnonclassic pages 3-3, lu2022apparentmineralocorticoidexcess pages 3-4)
Suspect AME in a child, adolescent, or young adult with severe or resistant hypertension plus hypokalemia, metabolic alkalosis, suppressed renin, and unexpectedly low aldosterone—especially with low birth weight, growth failure, polyuria/polydipsia, nephrocalcinosis, consanguinity, or similarly affected siblings. (carvajal2020classicandnonclassic pages 6-7, NCT00474942 chunk 1)
Classic AME was summarized as having 11β-HSD2 activity of roughly 1–6%, versus an inferred 40–60% in nonclassic AME. Proposed biochemical definitions use cortisol/cortisone ratios above the 97.5th percentile for classic and above the 75th percentile for nonclassic disease, but these percentile criteria are research-oriented and assay/population dependent. (carvajal2020classicandnonclassic pages 28-29)
CMA, karyotyping, FISH, mitochondrial testing, repeat-expansion testing, biopsy, and liquid biopsy are not routinely indicated. Renal ultrasound evaluates nephrocalcinosis; echocardiography, retinal examination, urine albumin, and renal-function assessment identify target-organ damage.
The completed natural-history study required low renin and aldosterone, an elevated urinary metabolite ratio, and two HSD11B2 mutations for affected-participant enrollment. (NCT00474942 chunk 1)
Early diagnosis and sustained control of blood pressure and potassium can produce substantial clinical improvement and prevent target-organ injury. Delayed diagnosis predicts worse renal and cardiac outcomes: in one 20-year family follow-up, the sibling with the longest diagnostic delay developed left-ventricular dysfunction and renal failure requiring transplantation, whereas the two earlier-managed siblings avoided comparable end-organ damage. (lu2022apparentmineralocorticoidexcess pages 3-4)
The best available long-term statistics are small-series estimates rather than survival curves: cardiovascular mortality 19%, persistent nephrocalcinosis 89%, and kidney failure 15% among 36 classic-AME patients summarized in the 2022 review. No reliable five- or ten-year survival rate, population mortality rate, or validated prognostic calculator exists. (lu2022apparentmineralocorticoidexcess pages 3-4)
Adverse prognostic features include very low residual enzyme activity, very early/severe hypertension, profound chronic hypokalemia, delayed diagnosis, poor medication adherence, high sodium intake, albuminuria/nephrocalcinosis, left-ventricular hypertrophy, and declining eGFR.
Monitoring should include blood pressure, renin as a marker of adequate reversal of volume suppression, potassium, bicarbonate, creatinine/eGFR, urine albumin and calcium, growth/puberty, ECG where indicated, renal imaging, and cardiac assessment. Spironolactone can cause gynecomastia and sex-steroid adverse effects; eplerenone is more selective but often more costly and may require divided dosing. MR antagonists, amiloride, and potassium all create hyperkalemia risk as renal function changes.
No approved gene therapy, cell therapy, RNA therapy, immunotherapy, or AME-specific pharmacogenomic dosing guideline was identified. NCT00474942 was observational, not a therapeutic trial. (NCT00474942 chunk 1)
Primary prevention of inherited disease requires reproductive rather than lifestyle intervention: genetic counseling, carrier testing for adult relatives, partner testing when relevant, and discussion of prenatal or preimplantation genetic testing once familial variants are known. Population-wide newborn screening is not established.
Secondary prevention consists of cascade testing, blood-pressure and electrolyte assessment of siblings, and early steroid profiling/genetic testing in high-risk relatives. Family members carrying one variant may merit blood-pressure review, especially under high-salt or 11β-HSD2-inhibiting exposures. (NCT00474942 chunk 1)
Tertiary prevention includes lifelong sodium restriction, avoidance of licorice and interacting products, treatment adherence, correction of potassium, and surveillance for renal, retinal, cardiac, and cerebrovascular injury. There is no vaccine or infectious prophylaxis relevant to AME.
11β-HSD2 is evolutionarily conserved across mammals, and orthologous Hsd11b2 genes regulate glucocorticoid access to MR. No well-established, naturally occurring veterinary counterpart with a defined breed association was identified in the retrieved evidence. AME is noninfectious and has no zoonotic or cross-species transmission potential.
Suggested comparative taxa are Mus musculus (NCBI Taxon 10090) and Rattus norvegicus (Taxon 10116). Veterinary breed-ontology mapping is not applicable without a documented natural breed disorder.
Genetic Hsd11b2-null and haploinsufficient mouse/rat models are the principal mammalian systems. They reproduce key mechanistic features—salt-sensitive hypertension, suppressed renin, altered electrolyte handling, renal/cardiac injury, and dependence on dietary sodium—and are used to dissect kidney-specific versus extra-renal 11β-HSD2 functions and test MR/ENaC-directed treatment. Their limitations include species differences in the predominant glucocorticoid (corticosterone rather than cortisol), developmental severity, diet dependence, and incomplete replication of human allelic heterogeneity.
Cell-based expression systems are used to measure cortisol-to-cortisone conversion, protein abundance/stability, cofactor or substrate affinity, and effects of individual variants. Placental and renal epithelial models are biologically relevant. No validated patient-derived organoid, iPSC, CRISPR-screen, or advanced spatial/single-cell AME platform was identified as a clinical implementation in the retrieved evidence.
Recent work has shifted emphasis from AME as a binary ultra-rare syndrome toward a continuum of cortisol-mediated MR activation, including nonclassic, epigenetically modified, and environmentally unmasked phenotypes. However, classic AME remains a genetically defined recessive disease, whereas nonclassic AME criteria and prevalence require external validation. The 7.1% Chilean estimate should therefore be regarded as hypothesis-generating rather than a global disease-frequency estimate. (carvajal2020classicandnonclassic pages 3-3, carvajal2020classicandnonclassic pages 9-9)
The strongest contemporary expert message is that molecular testing should occur early in young patients with low-renin/low-aldosterone hypertension because “a precise diagnosis depends on genetic testing, which allows for early and specific management to avoid the morbidity and mortality from target organ damage.” This is a direct quotation from the November 2022 open-access molecular-genetics review (DOI: https://doi.org/10.1186/s12967-022-03698-9). (lu2022apparentmineralocorticoidexcess pages 1-3)
The available 2023–2024 literature is dominated by expert reviews of low-renin hypertension, HSD11B2 epigenetic regulation, and case-based diagnosis rather than randomized AME trials. A recent Chinese pediatric series, published online under DOI https://doi.org/10.3389/fendo.2024.1491825, expanded the allelic spectrum and reported normalization of blood pressure and potassium with spironolactone plus potassium in three children, but its size and case-report design preclude response-rate estimation. (ding2025casereportclinical pages 4-5, ding2025casereportclinical pages 6-7)
Mechanistic certainty is high for biallelic HSD11B2 deficiency, impaired cortisol inactivation, and cortisol-driven MR activation. Clinical-management evidence is much weaker: it is derived mostly from biochemical physiology, family studies, case reports, small series, and one 130-participant observational natural-history protocol. No randomized AME-specific drug trial, validated population screening program, robust quality-of-life dataset, or approved molecular therapy was identified. Exact phenotype frequencies, variant penetrance, carrier frequency, and long-term survival therefore remain incompletely defined. (NCT00474942 chunk 1, lu2022apparentmineralocorticoidexcess pages 3-4, lu2022apparentmineralocorticoidexcess pages 1-3)
References
(carvajal2020classicandnonclassic pages 6-7): Cristian A Carvajal, Alejandra Tapia-Castillo, Andrea Vecchiola, Rene Baudrand, and Carlos E Fardella. Classic and nonclassic apparent mineralocorticoid excess syndrome. The Journal of clinical endocrinology and metabolism, 105:e924-e936, Dec 2020. URL: https://doi.org/10.1210/clinem/dgz315, doi:10.1210/clinem/dgz315. This article has 55 citations.
(lu2022apparentmineralocorticoidexcess pages 1-3): Yi-ting Lu, Di Zhang, Qiong-yu Zhang, Ze-ming Zhou, Kun-qi Yang, Xian-liang Zhou, and Fan Peng. Apparent mineralocorticoid excess: comprehensive overview of molecular genetics. Journal of Translational Medicine, Nov 2022. URL: https://doi.org/10.1186/s12967-022-03698-9, doi:10.1186/s12967-022-03698-9. This article has 44 citations and is from a peer-reviewed journal.
(OpenTargets Search: apparent mineralocorticoid excess-HSD11B2): Open Targets Query (apparent mineralocorticoid excess-HSD11B2, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(NCT00474942 chunk 1): Natural History of Apparent Mineralocorticoid Excess Syndrome. Icahn School of Medicine at Mount Sinai. 2007. ClinicalTrials.gov Identifier: NCT00474942
(palermo2004apparentmineralocorticoidexcess pages 2-4): Mario Palermo, Marcus Quinkler, and Paul M. Stewart. Apparent mineralocorticoid excess syndrome: an overview. Arquivos brasileiros de endocrinologia e metabologia, 48 5:687-96, Oct 2004. URL: https://doi.org/10.1590/s0004-27302004000500015, doi:10.1590/s0004-27302004000500015. This article has 128 citations and is from a peer-reviewed journal.
(carvajal2020classicandnonclassic pages 28-29): Cristian A Carvajal, Alejandra Tapia-Castillo, Andrea Vecchiola, Rene Baudrand, and Carlos E Fardella. Classic and nonclassic apparent mineralocorticoid excess syndrome. The Journal of clinical endocrinology and metabolism, 105:e924-e936, Dec 2020. URL: https://doi.org/10.1210/clinem/dgz315, doi:10.1210/clinem/dgz315. This article has 55 citations.
(lu2022apparentmineralocorticoidexcess pages 16-16): Yi-ting Lu, Di Zhang, Qiong-yu Zhang, Ze-ming Zhou, Kun-qi Yang, Xian-liang Zhou, and Fan Peng. Apparent mineralocorticoid excess: comprehensive overview of molecular genetics. Journal of Translational Medicine, Nov 2022. URL: https://doi.org/10.1186/s12967-022-03698-9, doi:10.1186/s12967-022-03698-9. This article has 44 citations and is from a peer-reviewed journal.
(lu2022apparentmineralocorticoidexcess pages 3-4): Yi-ting Lu, Di Zhang, Qiong-yu Zhang, Ze-ming Zhou, Kun-qi Yang, Xian-liang Zhou, and Fan Peng. Apparent mineralocorticoid excess: comprehensive overview of molecular genetics. Journal of Translational Medicine, Nov 2022. URL: https://doi.org/10.1186/s12967-022-03698-9, doi:10.1186/s12967-022-03698-9. This article has 44 citations and is from a peer-reviewed journal.
(palermo2004apparentmineralocorticoidexcess pages 1-2): Mario Palermo, Marcus Quinkler, and Paul M. Stewart. Apparent mineralocorticoid excess syndrome: an overview. Arquivos brasileiros de endocrinologia e metabologia, 48 5:687-96, Oct 2004. URL: https://doi.org/10.1590/s0004-27302004000500015, doi:10.1590/s0004-27302004000500015. This article has 128 citations and is from a peer-reviewed journal.
(carvajal2020classicandnonclassic pages 17-19): Cristian A Carvajal, Alejandra Tapia-Castillo, Andrea Vecchiola, Rene Baudrand, and Carlos E Fardella. Classic and nonclassic apparent mineralocorticoid excess syndrome. The Journal of clinical endocrinology and metabolism, 105:e924-e936, Dec 2020. URL: https://doi.org/10.1210/clinem/dgz315, doi:10.1210/clinem/dgz315. This article has 55 citations.
(ding2025casereportclinical pages 6-7): Yuan Ding, Ming Cheng, Bingyan Cao, Min Liu, Xuyun Hu, and Di Wu. Case report: clinical characteristics and genetical analysis of hsd11b2 in three chinese children with apparent mineralocorticoid excess: a case series. Frontiers in Endocrinology, Jan 2025. URL: https://doi.org/10.3389/fendo.2024.1491825, doi:10.3389/fendo.2024.1491825. This article has 3 citations.
(carvajal2020classicandnonclassic pages 3-3): Cristian A Carvajal, Alejandra Tapia-Castillo, Andrea Vecchiola, Rene Baudrand, and Carlos E Fardella. Classic and nonclassic apparent mineralocorticoid excess syndrome. The Journal of clinical endocrinology and metabolism, 105:e924-e936, Dec 2020. URL: https://doi.org/10.1210/clinem/dgz315, doi:10.1210/clinem/dgz315. This article has 55 citations.
(carvajal2020classicandnonclassic pages 9-9): Cristian A Carvajal, Alejandra Tapia-Castillo, Andrea Vecchiola, Rene Baudrand, and Carlos E Fardella. Classic and nonclassic apparent mineralocorticoid excess syndrome. The Journal of clinical endocrinology and metabolism, 105:e924-e936, Dec 2020. URL: https://doi.org/10.1210/clinem/dgz315, doi:10.1210/clinem/dgz315. This article has 55 citations.
(carvajal2020classicandnonclassic pages 11-12): Cristian A Carvajal, Alejandra Tapia-Castillo, Andrea Vecchiola, Rene Baudrand, and Carlos E Fardella. Classic and nonclassic apparent mineralocorticoid excess syndrome. The Journal of clinical endocrinology and metabolism, 105:e924-e936, Dec 2020. URL: https://doi.org/10.1210/clinem/dgz315, doi:10.1210/clinem/dgz315. This article has 55 citations.
(carvajal2020classicandnonclassic pages 12-13): Cristian A Carvajal, Alejandra Tapia-Castillo, Andrea Vecchiola, Rene Baudrand, and Carlos E Fardella. Classic and nonclassic apparent mineralocorticoid excess syndrome. The Journal of clinical endocrinology and metabolism, 105:e924-e936, Dec 2020. URL: https://doi.org/10.1210/clinem/dgz315, doi:10.1210/clinem/dgz315. This article has 55 citations.
(carvajal2020classicandnonclassic pages 13-14): Cristian A Carvajal, Alejandra Tapia-Castillo, Andrea Vecchiola, Rene Baudrand, and Carlos E Fardella. Classic and nonclassic apparent mineralocorticoid excess syndrome. The Journal of clinical endocrinology and metabolism, 105:e924-e936, Dec 2020. URL: https://doi.org/10.1210/clinem/dgz315, doi:10.1210/clinem/dgz315. This article has 55 citations.
(ding2025casereportclinical pages 4-5): Yuan Ding, Ming Cheng, Bingyan Cao, Min Liu, Xuyun Hu, and Di Wu. Case report: clinical characteristics and genetical analysis of hsd11b2 in three chinese children with apparent mineralocorticoid excess: a case series. Frontiers in Endocrinology, Jan 2025. URL: https://doi.org/10.3389/fendo.2024.1491825, doi:10.3389/fendo.2024.1491825. This article has 3 citations.