apparent mineralocorticoid excess

Mendelian MONDO:0009025 Pathograph 33 Show in embeddings browser hereditary disease

Apparent mineralocorticoid excess (AME) is an autosomal recessive disorder caused by biallelic pathogenic HSD11B2 variants. Reduced 11-beta-HSD2 activity impairs cortisol inactivation at renal mineralocorticoid receptors, producing salt-sensitive low-renin hypertension with variably severe hypokalemic alkalosis and low aldosterone. Circulating cortisol can remain normal. Early growth impairment, nephrocalcinosis and cardiovascular or renal complications characterize many severe cases; residual-function alleles can cause milder, later presentations.

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1
Inheritance
13
Pathophys.
27
Phenotypes
3
Gaps
33
Pathograph
1
Genes
8
Medical Actions
2
Differentials
1
Trials
3
Models
13
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Inherited AME is autosomal recessive. Consanguinity is common in selected reported cohorts but is not required; confirmed compound-heterozygous cases occur in unrelated parents. Clinical severity varies with residual function and other influences.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Human Clinical
"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."
This molecular-genetics review states that AME is an autosomal recessive monogenic disease.
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Discussions and Knowledge Gaps

3
Which mechanisms produce nephrocalcinosis and chronic renal injury in AME?
KNOWLEDGE GAP OPEN ame_renal_calcification_mechanism
Attached to
phenotypes#Nephrocalcinosis phenotypes#Renal insufficiency pathophysiology#Renal Potassium Wasting
Chronic hypokalemia, urinary calcium handling and renal injury are proposed contributors, but nephrocalcinosis can occur without documented hypercalciuria and may persist after potassium correction. The Chinese case series speculates about fibrosis without biopsy evidence. No necessary hypercalciuria-to-fibrosis-to-calcification chain is established.
Show evidence (2 references)
PMID:38652803 SUPPORT PRIMARY RESULT Human Clinical
"While all patients developed nephrocalcinosis, only 1 showed hypercalciuria."
Observed discordance limits a universal hypercalciuria-mediated route.
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"Another notable clinical feature was nephrocalcinosis, which persisted in eight of nine patients at 4.1–14.5 y follow-up, despite treatment of hypokalemia."
Persistence limits inference that potassium normalization necessarily reverses calcification.
How do residual enzyme function and clinical context predict long-term treatment response?
KNOWLEDGE GAP OPEN ame_variable_genotype_and_treatment_outcomes
Attached to
genetic#HSD11B2 pathophysiology#Reduced 11-Beta-HSD2 Activity treatments#Mineralocorticoid receptor antagonists
Milder residual-function alleles, delayed recognition, different co-treatments and treatment-associated hyperkalemia complicate prediction from genotype or initial blood-pressure response. Computational structural interpretation is not a validated prognostic assay. Prospective natural-history data with standardized measurements are needed.
Show evidence (2 references)
PMID:38652803 SUPPORT PRIMARY RESULT Human Clinical
"Nevertheless, despite early diagnosis and management, AME is commonly associated with serious complications of the disease or its treatment."
Longitudinal observations show remaining outcome uncertainty.
PMID:29229831 SUPPORT PRIMARY RESULT Computational
"Here, we report the successful identification, by computational modeling, of structural changes in silico that are induced by HSD11B2 mutations."
The structural analysis is computational, separate from the clinical cohort.
How does the proposed nonclassic AME construct overlap with milder biallelic HSD11B2 disease?
KNOWLEDGE GAP OPEN ame_nonclassic_construct_scope
Attached to
genetic#HSD11B2 pathophysiology#Reduced 11-Beta-HSD2 Activity
The 2020 review describes a broader partial-enzyme-deficiency construct involving genetic, epigenetic, environmental and inhibitor effects. This should not automatically be equated with genetically confirmed mild recessive AME. Its 7.1% estimate comes from a particular screening population and is not the prevalence of biallelic HSD11B2 disease. The screening construct used high serum cortisol/cortisone together with low cortisone in a selected Chilean population including normotensive and hypertensive people. Renin-guided outcome benefit is extrapolated from primary aldosteronism, not demonstrated prospectively in nonclassic AME.
Show evidence (3 references)
PMID:31909799 SUPPORT REVIEW SYNTHESIS Human Clinical
"Nonclassic AME (NC-AME) is mainly related to partial 11βHSD2 deficiency associated with genetic variations and epigenetic modifications (first hit) and potential additive actions of endogenous or exogenous inhibitors (ie, glycyrrhetinic acid-like factors [GALFS]) and other factors (ie, age, high..."
The review defines a broader proposed multifactorial construct, distinct from a confirmed biallelic genotype series.
url:https://oup.silverchair-cdn.com/article-minimal/5691192 SUPPORT REVIEW SYNTHESIS Human Clinical
"identified 9 subjects with suggestive NC-AME phenotype, of whom 2 had the previously described heterozygous pathogenic variant R213C (p.Arg213Cys), which impairs the activity and stability of 11βHSD2"
The screened phenotype is suggestive and does not constitute nine molecularly confirmed recessive cases.
url:https://oup.silverchair-cdn.com/article-minimal/5691192 SUPPORT REVIEW SYNTHESIS Other
"Despite that there is no prospective data in NC-AME, inference from PA studies support the concept of improved renin levels as a proxy of MR inactivation"
The review explicitly identifies absent prospective evidence and extrapolation from primary aldosteronism.
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Pathophysiology

13
Biallelic HSD11B2 Dysfunction
Inherited pathogenic variants in both HSD11B2 alleles impair enzyme function. Missense, truncating and other variants can differ in their residual function; a reported variant of uncertain significance does not become established pathogenic merely because a patient has a compatible phenotype.
HSD11B2 hgnc:5209 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HSD11B2 (hgnc:5209). hgnc:5209 is a gene from the HUGO Gene Nomenclature Committee.
Computational models
HSD11B2 homology and molecular-dynamics variant analysis STRUCTURAL PREDICTION Introduces sequence changes into a modeled protein to predict structural consequences.
Downstream
Reduced 11-Beta-HSD2 Activity Pathogenic alleles reduce the effective enzyme activity through allele-dependent effects on catalysis, substrate/cofactor interactions or abundance.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"It is caused by defects in the HSD11B2 gene, encoding the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)"
The review identifies the causal gene and encoded enzyme.
Reduced 11-Beta-HSD2 Activity
Cortisol-oxidizing 11-beta-HSD2 activity is reduced, sometimes severely, in inherited AME. Residual activity can persist. Variant-specific catalytic impairment and protein instability are alternative molecular explanations, not interchangeable measurements or universal defects.
cortisol metabolic process GO:0034650 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cortisol metabolic process (GO:0034650). GO:0034650 is a biological process from the Gene Ontology.
11-beta-hydroxysteroid dehydrogenase (NAD+) activity GO:0070523 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased 11-beta-hydroxysteroid dehydrogenase (NAD+) activity (GO:0070523). GO:0070523 is a molecular function from the Gene Ontology.
Experimental models
R279C HSD11B2 heterologous expression OTHER Measures catalytic parameters for the tested mutant versus wild type.
Downstream
Increased Cortisol Access to Renal Mineralocorticoid Receptors Reduced oxidation of active cortisol to inactive cortisone weakens the renal metabolic barrier to receptor occupancy.
Reduced Placental Cortisol Inactivation Loss of enzyme activity in the placental compartment reduces cortisol inactivation; the compartmental extension is a mechanistic synthesis.
Show evidence (1 reference)
PMID:9683587 SUPPORT PRIMARY RESULT In Vitro
"Expression of the 11beta-HSD2 mutant cDNA resulted in an enzyme with reduced maximum velocity, but similar substrate affinity, compared with activity of the wild-type cDNA."
The R279C expression experiment supports reduced catalytic capacity with preserved apparent substrate affinity; this cache is abstract-limited.
Increased Cortisol Access to Renal Mineralocorticoid Receptors
Impaired conversion to cortisone increases the availability of active cortisol at renal mineralocorticoid receptors. This local ligand-access defect does not require elevated serum cortisol: intact hypothalamic-pituitary-adrenal feedback can maintain normal circulating concentrations.
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cortisol-Mediated Mineralocorticoid Receptor Activation The available cortisol binds the receptor and produces mineralocorticoid signaling.
Show evidence (2 references)
PMID:15761540 SUPPORT REVIEW SYNTHESIS Other
"Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension."
The review describes failure of local metabolic protection.
PMID:36329487 SUPPORT REVIEW SYNTHESIS Human Clinical
"patients with AME have normal serum cortisol concentration and don’t present with clin- ical features of Cushing’s syndrome or Addison’s disease"
Normal circulating cortisol is compatible with the local receptor-access defect.
Cortisol-Mediated Mineralocorticoid Receptor Activation
Cortisol occupies and activates the mineralocorticoid receptor despite low aldosterone. Human suppression and cortisol add-back physiology supports cortisol-dependent mineralocorticoid activity, while the receptor specificity explanation is informed by receptor and enzyme biology.
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Increased Distal Nephron Sodium Transport Nuclear receptor signaling induces sodium-transport machinery through transcriptional intermediates.
Metabolic alkalosis Excess distal mineralocorticoid action alters potassium and acid-base handling, producing hypokalemic alkalosis; intermediate tubular acid-secretory steps are not resolved by these clinical sources.
Show evidence (2 references)
PMID:3164727 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"These results suggest that cortisol acts as a potent mineralocorticoid in 11 beta-OHSD deficiency."
The single-patient metabolic intervention supports cortisol-driven mineralocorticoid physiology, rather than measuring receptor occupancy directly.
PMID:15761540 SUPPORT REVIEW SYNTHESIS Other
"Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension."
The synthesis supplies the receptor-level explanation.
Increased Distal Nephron Sodium Transport
Mineralocorticoid signaling increases epithelial sodium-channel and sodium-potassium-pump activity in the distal nephron. Kidney-specific Hsd11b2 deletion supports an ENaC-associated transport phenotype; secondary potassium-sensitive NCC activation is an additional model observation, not a measured universal human abnormality.
kidney collecting duct principal cell CL:1001431 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney collecting duct principal cell (CL:1001431). CL:1001431 is a cell type from the Cell Ontology.
sodium ion transport GO:0006814 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased sodium ion transport (GO:0006814). GO:0006814 is a biological process from the Gene Ontology.
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Kidney-specific Hsd11b2 knockout mouse Mouse measures Transporter cleavage/phosphorylation and natriuretic drug responses inform distal sodium handling.
Downstream
Renal Sodium Retention Increased distal tubular reabsorption reduces urinary sodium elimination.
Renal Potassium Wasting Enhanced electrogenic sodium transport favors distal potassium secretion through coupled electrochemical and channel mechanisms.
Show evidence (2 references)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"Physically, aldosterone and cortisol are both ligands of mineralocorticoid receptors, which results in binding to nuclear hormone response elements, leading to transcription of Na +/K+ ATPase and EnaC channels."
The figure legend describes receptor-dependent transcription of transport machinery.
PMID:28559392 SUPPORT PRIMARY RESULT Model Organism
"we detected an increase in renal membrane expressions of cleaved epithelial sodium channel-α and T53-phosphorylated Na+-Cl- cotransporter in the knockout mice."
The kidney-specific mouse model provides transporter readouts.
Renal Sodium Retention
Renal sodium conservation produces positive sodium balance. In one adult with AME, cortisol suppression caused natriuresis and hydrocortisone add-back restored sodium retention on a fixed electrolyte intake.
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Extracellular Volume Expansion Positive sodium balance retains water and expands extracellular volume.
Show evidence (2 references)
PMID:3164727 SUPPORT PRIMARY RESULT Human Clinical
"When hydrocortisone (10 mg daily s.c. for 4 d) was added, there was marked Na+ retention, a kaliuresis (urinary Na+/K+ falling from 1.2 to 0.15), with suppression of plasma renin activity and an increase in blood pressure."
The controlled within-patient intervention documents sodium retention and its associated systemic responses.
url:https://oup.silverchair-cdn.com/article-minimal/5691192 SUPPORT REVIEW SYNTHESIS Other
"since both can increase sodium transport in renal collecting ducts, increasing water uptake, blood volume, and secondary raising of blood pressure (BP)."
The full review supplies the physiological sodium-water-volume-pressure connection.
Extracellular Volume Expansion
Sodium retention expands extracellular and plasma volume, contributing to salt-sensitive hypertension. This physiological consequence is not synonymous with clinically visible edema.
Downstream
Hypertension Expanded effective circulating volume contributes to hypertension through renal and cardiovascular intermediates; vascular resistance and chronic remodeling can also contribute.
Suppressed Renin Release Salt and volume expansion suppress renin through renal feedback mechanisms.
Show evidence (2 references)
PMID:15761540 SUPPORT REVIEW SYNTHESIS Human Clinical
"hypertension, plasma volume expansion, hypokalemic alkalosis and a suppressed renin-angiotensin-aldosterone system"
The clinical synthesis describes volume expansion in the mineralocorticoid-excess state.
url:https://oup.silverchair-cdn.com/article-minimal/5691192 SUPPORT REVIEW SYNTHESIS Other
"since both can increase sodium transport in renal collecting ducts, increasing water uptake, blood volume, and secondary raising of blood pressure (BP)."
The full review supplies the physiological sodium-water-volume-pressure connection.
Suppressed Renin Release
Feedback suppression of renin is characteristic of untreated salt-retaining AME. Renin measurements can vary with treatment and are not invariably low at every observation.
Downstream
Decreased circulating renin Reduced release produces the low circulating renin phenotype.
Reduced Aldosterone Secretion Reduced angiotensin signaling lowers adrenal aldosterone production; this is a physiological feedback interpretation of the suppressed axis.
Show evidence (1 reference)
PMID:3164727 SUPPORT PRIMARY RESULT Human Clinical
"Plasma renin activity became detectable. When hydrocortisone (10 mg daily s.c. for 4 d) was added, there was marked Na+ retention, a kaliuresis (urinary Na+/K+ falling from 1.2 to 0.15), with suppression of plasma renin activity"
Cortisol add-back restores renin suppression following dexamethasone-associated natriuresis.
Reduced Aldosterone Secretion
Suppressed renin-angiotensin signaling reduces aldosterone secretion. Potassium status, chronic zona-glomerulosa suppression and treatment can modify the measured level; a value within a laboratory interval does not exclude an otherwise supported diagnosis.
Downstream
Decreased circulating aldosterone Lower secretion produces the characteristic low circulating aldosterone phenotype, with treatment-related variability.
Show evidence (2 references)
PMID:15761540 SUPPORT REVIEW SYNTHESIS Human Clinical
"Biochemical abnormalities comprise suppressed PRA, undetectable serum aldosterone levels and hypokalemia."
The review describes the characteristic untreated hormonal pattern.
PMID:3164727 SUPPORT PRIMARY RESULT Human Clinical
"Plasma aldosterone over this short period oftime remained low as expected following prolonged suppression of the zona glomerulosa."
The intervention illustrates delayed aldosterone recovery despite initially detectable renin.
Renal Potassium Wasting
Distal-nephron mineralocorticoid activity promotes urinary potassium loss. The electrical and transport consequences of enhanced sodium reabsorption connect this renal process to hypokalemia.
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hypokalemia Urinary potassium loss lowers the circulating potassium concentration unless intake and treatment compensate.
Impaired Renal Urine Concentration Sustained potassium depletion can produce hypokalemic tubular injury and loss of concentrating ability.
Show evidence (1 reference)
PMID:3164727 SUPPORT PRIMARY RESULT Human Clinical
"When hydrocortisone (10 mg daily s.c. for 4 d) was added, there was marked Na+ retention, a kaliuresis"
The metabolic balance experiment documents urinary potassium loss during cortisol exposure.
Impaired Renal Urine Concentration
Chronic hypokalemic nephropathy can impair urinary concentration and produce nephrogenic diabetes insipidus in a subset of patients. This is not required for all AME or for every episode of polyuria.
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Polyuria Impaired concentration causes urinary water loss and compensatory thirst.
Polydipsia Impaired concentration causes urinary water loss and compensatory thirst.
Show evidence (1 reference)
PMID:15761540 SUPPORT REVIEW SYNTHESIS Human Clinical
"Hypokalemic nephropathy some- times causes nephrocalcinosis, polycystic kidney and nephrogenic diabetes insipidus manifesting as thirst and polyuria."
The review describes a subset-specific renal concentrating complication.
Reduced Placental Cortisol Inactivation
Placental 11-beta-HSD2 normally limits fetal exposure to maternal cortisol. Loss of this metabolic barrier is a proposed contributor to prenatal growth restriction in AME, rather than a directly measured placental defect in every affected pregnancy.
placenta UBERON:0001987 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in placenta (UBERON:0001987). UBERON:0001987 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Increased Fetal Glucocorticoid Exposure A weaker placental metabolic barrier permits more active maternal glucocorticoid to reach the fetus.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"Feto-placental 11β-HSD2 is regarded as a ‘glucocorticoid barrier’ which ensures most maternal cor- tisol inactivated strictly determining the fetal homeosta - sis of cortisol [ 18]."
The review describes the placental metabolic barrier.
Increased Fetal Glucocorticoid Exposure
Reduced placental inactivation can increase fetal exposure to maternal glucocorticoids. The proposed growth effect involves fetal glucocorticoid-receptor signaling; source clinical birth-weight observations do not themselves measure fetal hormone exposure.
Downstream
Small for gestational age Increased fetal glucocorticoid signaling is a proposed contributor to restricted prenatal growth; individual pregnancies were not assayed for this mediator.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"Abolished 11β-HSD2 in the placenta causes the fetus to be over-exposed to maternal glucocor- ticoids, leading to the phenotype of intrauterine growth restriction associated to glucocorticoid receptor [19, 20]."
The review proposes the fetal exposure and receptor-mediated growth route.
⬡

Pathograph

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

27
Cardiovascular 5
Hypertension HP:0000822 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertension (HP:0000822). HP:0000822 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Human Clinical
"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."
Review identifies juvenile resistant low-renin hypertension as a defining feature.
PMID:39931437 SUPPORT PRIMARY RESULT Human Clinical
"All three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria."
Pediatric series documents hypertension in all affected children.
Left ventricular hypertrophy HP:0001712 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular hypertrophy (HP:0001712). HP:0001712 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"For the 13 surviving patients with available follow-up echocardiograms, 12 had persistent left ventricular hypertrophy, 3 showed aortic root dilation, and 2 had aortic insufficiency."
Defines the imaging subset and concurrent structural observations.
Aortic regurgitation HP:0001659 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aortic regurgitation (HP:0001659). HP:0001659 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"For the 13 surviving patients with available follow-up echocardiograms, 12 had persistent left ventricular hypertrophy, 3 showed aortic root dilation, and 2 had aortic insufficiency."
Two observations in the imaged survivor subset.
Hypertensive retinopathy HP:0001095 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertensive retinopathy (HP:0001095). HP:0001095 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"Severe hypertension, left ventricular hypertrophy (12 of 16), and hypertensive retinopathy (10 of 16) were prominent clinical features."
The source uses the 16-person historical subgroup denominator.
Cardiac arrest HP:0001695 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiac arrest (HP:0001695). HP:0001695 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"Cardiovascular complications were prominent, with three patients dying from cardiac arrest at 16, 16, and 17 y of age."
Reports three events without assigning a general mortality rate.
PMID:38652803 SUPPORT PRIMARY RESULT Human Clinical
"One patient survived cardiac arrest secondary to severe hyperkalemia."
Demonstrates a serious potassium-related treatment hazard.
Endocrine 2
Decreased circulating renin Decreased circulating renin concentration HP:0003351 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating renin concentration (HP:0003351). HP:0003351 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Human Clinical
"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."
Review characterizes AME as a low-renin hypertension.
PMID:15761540 SUPPORT REVIEW SYNTHESIS Other
"Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension."
Describes suppression of plasma renin activity (PRA).
Decreased circulating aldosterone Decreased circulating aldosterone concentration HP:0004319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating aldosterone concentration (HP:0004319). HP:0004319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Human Clinical
"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."
Review identifies low aldosterone levels as a defining feature.
Genitourinary 6
Nephrocalcinosis HP:0000121 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrocalcinosis (HP:0000121). HP:0000121 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:39931437 SUPPORT PRIMARY RESULT Human Clinical
"All three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria."
Documents nephrocalcinosis in all affected children.
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"medullary nephrocalcinosis, and multiple small bilateral cysts."
Genetically confirmed case with imaging documentation of bilateral medullary nephrocalcinosis associated with homozygous HSD11B2 variant.
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"Of note is that 27 of 36 (75%) patients also presented with nephrocalcinosis."
Selected international cohort at presentation.
Hypercalciuria HP:0002150 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypercalciuria (HP:0002150). HP:0002150 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39931437 SUPPORT PRIMARY RESULT Human Clinical
"All three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria."
Documents hypercalciuria in all affected children.
PMID:38652803 SUPPORT PRIMARY RESULT Human Clinical
"While all patients developed nephrocalcinosis, only 1 showed hypercalciuria."
Nephrocalcinosis in seven patients was not contingent on recorded hypercalciuria.
Polyuria HP:0000103 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polyuria (HP:0000103). HP:0000103 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Human Clinical
"Classic AME usually starts in infancy to juvenile and typically manifests as low birth weight, refractory hypertension, delayed growth, polyuria and polydipsia, failure to thrive [ 32]."
The review describes infantile growth and urinary manifestations without a disease-wide numerical frequency.
Renal cysts HP:0000107 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal cyst (HP:0000107). HP:0000107 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"medullary nephrocalcinosis, and multiple small bilateral cysts."
Direct ultrasound finding in one child.
Enlarged kidneys HP:0000105 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enlarged kidney (HP:0000105). HP:0000105 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"Kidney ultrasound revealed bilaterally enlarged echogenic kidneys with preserved corticome- dullary differentiation, medullary nephrocalcinosis, and multiple small bilateral cysts."
Ultrasound documents enlargement and cystic/calcific findings in one child.
Renal insufficiency HP:0000083 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal insufficiency (HP:0000083). HP:0000083 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"Four patients developed renal insufficiency more than 10 y after diagnosis, with two progressing to renal failure and received renal transplantation (30)."
Counts belong to the described longitudinal subset, not a 36-person risk denominator.
PMID:38652803 SUPPORT PRIMARY RESULT Human Clinical
"The 2 patients who presented with CKD progressed to end-stage kidney disease (ESKD) necessitating dialysis and kidney transplantation."
Two initially impaired patients in a seven-person cohort progressed to kidney failure.
Head and Neck 3
Depressed nasal bridge HP:0005280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flat nasal bridge, annotated with Depressed nasal bridge (HP:0005280). HP:0005280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"Dysmorphic features included brittle hair, flat nasal bridge, large forehead, frontal bossing, long eyelashes, and ear tag."
Single-patient case report listing a flat nasal bridge among the dysmorphic features observed in a genetically confirmed AME patient.
Frontal bossing HP:0002007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frontal bossing (HP:0002007). HP:0002007 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"Dysmorphic features included brittle hair, flat nasal bridge, large forehead, frontal bossing, long eyelashes, and ear tag."
Single-patient case report listing a large forehead with frontal bossing among the dysmorphic features observed in a genetically confirmed AME patient.
Long eyelashes HP:0000527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long eyelashes (HP:0000527). HP:0000527 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"Dysmorphic features included brittle hair, flat nasal bridge, large forehead, frontal bossing, long eyelashes, and ear tag."
Single-patient case report listing long eyelashes among the dysmorphic features observed in a genetically confirmed AME patient.
Integument 1
Brittle hair HP:0002299 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brittle hair (HP:0002299). HP:0002299 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"Dysmorphic features included brittle hair, flat nasal bridge, large forehead, frontal bossing, long eyelashes, and ear tag."
Single-patient case report listing brittle hair among the dysmorphic features observed in a genetically confirmed AME patient.
Metabolism 2
Hypokalemia HP:0002900 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypokalemia (HP:0002900). HP:0002900 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:15761540 SUPPORT REVIEW SYNTHESIS Other
"Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension."
Lists hypokalemia among the direct consequences of the enzyme deficiency.
PMID:39931437 SUPPORT PRIMARY RESULT Human Clinical
"All three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria."
Documents severe hypokalemia in all affected children.
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"On the second day of admission, the nephrology team was consulted due to persistent hypokalemia requiring repeated potassium chloride (KCl) supplementation."
Documents persistent hypokalemia requiring repeated KCl supplementation in a 2-year-old patient with a homozygous HSD11B2 variant.
Metabolic alkalosis HP:0200114 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic alkalosis (HP:0200114). HP:0200114 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:39931437 SUPPORT PRIMARY RESULT Human Clinical
"All three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria."
Documents metabolic alkalosis in all affected children.
PMID:36329487 SUPPORT REVIEW SYNTHESIS Human Clinical
"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."
Review identifies marked hypokalemic alkalosis as a defining feature.
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"persistent hypokalemia, metabolic alkalosis, and hypertension, were highly suggestive of AME syndrome."
Pediatric case documents metabolic alkalosis as part of the classic AME phenotype in a 2-year-old with a homozygous HSD11B2 variant.
Musculoskeletal 1
Muscle weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15761540 SUPPORT REVIEW SYNTHESIS Human Clinical
"Usually patients are children with low birth weight, failure to thrive, short stature, and severe, often fatal, hypertension with hypokalemic metabolic alkalosis and muscle weakness."
The historical review explicitly describes short stature and weakness in the severe clinical presentation.
Nervous System 3
Polydipsia HP:0001959 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polydipsia (HP:0001959). HP:0001959 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Human Clinical
"Classic AME usually starts in infancy to juvenile and typically manifests as low birth weight, refractory hypertension, delayed growth, polyuria and polydipsia, failure to thrive [ 32]."
The review describes the clinical presentation of classic AME.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39931437 SUPPORT PRIMARY RESULT Human Clinical
"Previously, the patient was diagnosed with epilepsy at an outside hospital after experiencing one seizure (speci fic details of diagnosis and treatment are unspeci fied). No antiepileptic drugs were given, and there have been no subsequent seizures."
The full clinical narrative limits the abstract/background epilepsy wording.
Cerebral atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059). HP:0002059 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39931437 SUPPORT PRIMARY RESULT Human Clinical
"Head MRI indicated localized cerebral atrophy and cystic changes in the left parietal lobe"
Single imaging observation, without demonstrated mechanism or longitudinal progression.
Growth 3
Small for gestational age HP:0001518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small for gestational age (HP:0001518). HP:0001518 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39931437 SUPPORT PRIMARY RESULT Human Clinical
"All three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria."
Documents small-for-gestational-age birth in all affected children.
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"and was small for gestational age at 1.97 kg."
Genetically confirmed AME case documents low birth weight (1.97 kg) and small-for-gestational-age status in neonate with homozygous HSD11B2 variant.
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Human Clinical
"Classic AME usually starts in infancy to juvenile and typically manifests as low birth weight, refractory hypertension, delayed growth, polyuria and polydipsia, failure to thrive [ 32]."
The review describes infantile growth and urinary manifestations without a disease-wide numerical frequency.
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15761540 SUPPORT REVIEW SYNTHESIS Human Clinical
"Usually patients are children with low birth weight, failure to thrive, short stature, and severe, often fatal, hypertension with hypokalemic metabolic alkalosis and muscle weakness."
The historical review explicitly describes short stature and weakness in the severe clinical presentation.
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"Like CAH, height of the patients improved, but fell below the target height (height SDS: −1.1 ± 0.6)."
Longitudinal growth observation in the previously reported follow-up subset, not all 36 cases.
Other 1
Ear tag
The source states ear tag without specifying preauricular location; a more specific anatomical HPO binding is not assigned.
Show evidence (1 reference)
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"Dysmorphic features included brittle hair, flat nasal bridge, large forehead, frontal bossing, long eyelashes, and ear tag."
Single-patient case report listing an ear tag among the dysmorphic features observed in a genetically confirmed AME patient.
🧬

Genetic Associations

1
HSD11B2
Gene: HSD11B2 hgnc:5209 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HSD11B2 (hgnc:5209). hgnc:5209 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (4 references)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"It is caused by defects in the HSD11B2 gene, encoding the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)"
The review identifies the gene and enzyme.
PMID:39931437 SUPPORT PRIMARY RESULT Human Clinical
"The p.V217A variant, although rated as “uncertain” by ACMG"
The paper explicitly retains uncertain classification; a compatible phenotype is not an enzyme functional test.
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"identified a homozygous pathogenic HSD11B2 variant (c.622C>T; p.Arg208Cys), confirming AME syndrome."
Molecular diagnosis in the reported child.
+ 1 more reference
💊

Medical Actions

8
Mineralocorticoid receptor antagonists
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: spironolactone CHEBI:9241 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses spironolactone (CHEBI:9241). CHEBI:9241 is a therapeutic agent from Chemical Entities of Biological Interest. eplerenone CHEBI:31547 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses eplerenone (CHEBI:31547). CHEBI:31547 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Spironolactone or eplerenone opposes inappropriate cortisol-driven MR signaling. Response varies and additional potassium replacement or antihypertensives may be needed. The three-child report does not show universal spironolactone success: its first patient had persistent abnormalities and was switched to eplerenone. Monitor blood pressure, potassium and kidney function; doses from individual reports are not a universal regimen.
Mechanism Target:
INHIBITS Cortisol-Mediated Mineralocorticoid Receptor Activation — MR antagonism opposes cortisol-driven receptor signaling; clinical response and treatment tolerance vary.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"Mineralocorticoid receptor blocker, spironolactone, could block the hyperactivation of mineralocorticoid receptors while amiloride blocks EnaC"
The review distinguishes receptor antagonism from channel blockade.
Show evidence (4 references)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"Mineralocorticoid receptor blocker, spironolactone, could block the hyperactivation of mineralocorticoid receptors while amiloride blocks EnaC"
The review distinguishes receptor antagonism from channel blockade.
PMID:39931437 SUPPORT PRIMARY RESULT Human Clinical
"Despite the dosage of spironolactone being increased to 6.8 mg/kg/day, serum potassium levels could not be stabilized within normal range."
The detailed first-case narrative contradicts the abstract statement of uniform normalization.
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"Management included spironolactone 5 mg orally once daily with continued oral and intravenous (IV) KCl."
Potassium improvement occurred with combined therapy, not isolated spironolactone exposure.
+ 1 more reference
Epithelial sodium-channel blockade
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: amiloride CHEBI:2639 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses amiloride (CHEBI:2639). CHEBI:2639 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Amiloride blocks distal ENaC downstream of receptor activation. It may be used alone or with MR antagonism under electrolyte and renal monitoring. A kidney-specific mouse knockout supports transport effects but does not determine the effective human dose or comparative regimen.
Mechanism Target:
INHIBITS Increased Distal Nephron Sodium Transport — Amiloride reduces ENaC-mediated sodium entry without repairing HSD11B2.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"Mineralocorticoid receptor blocker, spironolactone, could block the hyperactivation of mineralocorticoid receptors while amiloride blocks EnaC"
The review distinguishes receptor antagonism from channel blockade.
Show evidence (2 references)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"Mineralocorticoid receptor blocker, spironolactone, could block the hyperactivation of mineralocorticoid receptors while amiloride blocks EnaC"
The review distinguishes receptor antagonism from channel blockade.
PMID:15761540 SUPPORT REVIEW SYNTHESIS Human Clinical
"Patients have been successfully treated with the potassium sparing diuretics tri- amterene and/or amiloride."
Historical clinical experience supports the channel-blocking approach.
Potassium replacement
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: potassium chloride CHEBI:32588 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses potassium chloride (CHEBI:32588). CHEBI:32588 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Individualized oral or intravenous potassium replacement corrects clinically significant hypokalemia while disease-directed therapy takes effect. Reduce or stop supplementation as potassium stabilizes; combination treatment can cause severe hyperkalemia.
Mechanism Target:
BYPASSES Hypokalemia — Replacement supplies potassium despite ongoing renal loss; response requires monitoring.
Show evidence (1 reference)
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"Management included spironolactone 5 mg orally once daily with continued oral and intravenous (IV) KCl."
Potassium improvement occurred with combined therapy, not isolated spironolactone exposure.
Show evidence (3 references)
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"Management included spironolactone 5 mg orally once daily with continued oral and intravenous (IV) KCl."
Potassium improvement occurred with combined therapy, not isolated spironolactone exposure.
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"Oral KCl was gradually tapered and stopped once serum potassium stabilized at 3.7–4.1 mmol/L."
The case shows tapering after correction rather than indefinite fixed supplementation.
PMID:38652803 SUPPORT PRIMARY RESULT Human Clinical
"One patient survived cardiac arrest secondary to severe hyperkalemia."
Requires monitoring for overcorrection and impaired excretion.
Dietary sodium restriction
Action: Dietary InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. NCIT:C15447
Reduce dietary sodium to address salt-sensitive hypertension, with age-appropriate nutritional planning. This is a physiologically targeted adjunct rather than proof that diet alone prevents all renal or cardiac complications.
Mechanism Target:
INHIBITS Renal Sodium Retention — Lower intake reduces the sodium load available for retention.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"For the nature of AME is a kind of salt-sensitive hyper - tension, salt-limited diet is necessary"
The recommendation follows the salt-sensitive physiology.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"salt-limited diet is necessary for both classic and non-classic AME patients"
The review recommends sodium restriction in both clinical settings.
Selected glucocorticoid suppression
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: dexamethasone CHEBI:41879 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dexamethasone (CHEBI:41879). CHEBI:41879 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Dexamethasone has been used to suppress endogenous cortisol production in selected adults. In a historical single-patient fixed-intake study, suppression caused natriuresis and potassium retention and cortisol add-back reversed these changes. This is proof of physiological responsiveness in one patient, not a comparative pediatric treatment guideline or universal first-line regimen.
Mechanism Target:
INHIBITS Increased Cortisol Access to Renal Mineralocorticoid Receptors — Suppressing endogenous cortisol secretion reduces ligand availability; it does not restore the enzyme.
Show evidence (1 reference)
PMID:3164727 SUPPORT PRIMARY RESULT Human Clinical
"When established on a fixed Na+/K+ intake, dexamethasone, given orally, produced a natriuresis and potassium retention."
Within-patient metabolic intervention supports cortisol-suppression physiology.
Show evidence (2 references)
PMID:3164727 SUPPORT PRIMARY RESULT Human Clinical
"When established on a fixed Na+/K+ intake, dexamethasone, given orally, produced a natriuresis and potassium retention."
Within-patient metabolic intervention supports cortisol-suppression physiology.
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"Glucocorticoids also have been administrated for suppressing the secre - tion of endogenous adrenocorticotropic hormone-medi - ated corticosteroid in adult classic AME patients"
The newer review restricts this historical option to selected adult reports.
Adjunct antihypertensive treatment
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: hydralazine CHEBI:5775 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses hydralazine (CHEBI:5775). CHEBI:5775 is a therapeutic agent from Chemical Entities of Biological Interest. atenolol CHEBI:2904 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses atenolol (CHEBI:2904). CHEBI:2904 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Additional antihypertensives may be needed when targeted therapy does not adequately control pressure. Hydralazine and atenolol accompanied spironolactone in the 2026 child. A short hydrochlorothiazide trial worsened hypokalemia without BP benefit in that child; this single outcome does not establish a universal class contraindication.
Mechanism Target:
INHIBITS Hypertension — Adjunct agents lower pressure without correcting the cortisol-inactivation defect.
Show evidence (1 reference)
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"Additional BP medications, including hy- dralazine and atenolol, were also needed."
Adjunctive treatment was part of the reported combination regimen.
Show evidence (2 references)
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"Additional BP medications, including hy- dralazine and atenolol, were also needed."
Adjunctive treatment was part of the reported combination regimen.
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"Hydrochlorothiazide was briefly in troduced but discontinued after 5 days due to worsening hypokalemia and no significant BP improvement."
One patient-specific unsuccessful exposure, rather than evidence against every thiazide use.
Kidney transplantation for advanced renal disease
Action: Kidney TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Kidney Transplantation (NCIT:C15265). NCIT:C15265 is a clinical intervention from the NCI Thesaurus. NCIT:C15265
Kidney transplantation may be required for end-stage renal disease. Selected transplanted patients had remission of low-renin hypertension and hypokalemic alkalosis after spironolactone withdrawal, consistent with restored renal cortisol inactivation. This does not demonstrate correction of every extra-renal genotype effect or justify routine transplantation for medically manageable disease.
Mechanism Target:
RESTORES Reduced 11-Beta-HSD2 Activity — A functioning donor kidney can restore renal enzyme capacity; whole-body correction is not established.
Show evidence (1 reference)
PMID:29229831 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"Interestingly, following transplant, these patients no longer showed clinical signs of AME, with a remission of the low-renin hypertension and hypokalemic alkalosis when medical treatment with spironolactone was discontinued."
Clinical remission supports renal functional replacement; enzyme activity was not directly assayed in this passage.
Show evidence (1 reference)
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"Interestingly, following transplant, these patients no longer showed clinical signs of AME, with a remission of the low-renin hypertension and hypokalemic alkalosis when medical treatment with spironolactone was discontinued."
Two severe cases had a reported post-transplant phenotype remission.
Genetic counseling and family evaluation
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Offer counseling and testing to relevant relatives once familial pathogenic variants are defined. Discuss recessive inheritance, variable severity and reproductive options using variant-specific interpretation. Mild biochemical changes in some heterozygotes do not convert the established recessive disorder into a uniformly dominant disease.
Show evidence (2 references)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"with an increasing number of asymptomatic cases detected among individuals with a positive family history, it is necessary to conduct genetic counseling in affected families to clarify genetic involvement [ 56]."
The review supports family counseling and ascertainment.
PMID:9683587 SUPPORT PRIMARY RESULT Human Clinical
"The heterozygote state was phenotypically normal but was associated with subtle defects in cortisol metabolism."
Thirteen heterozygotes in one family did not show the affected phenotype despite subtle biochemical findings.
🔬

Biochemical Markers

3
Urinary cortisol-metabolite to cortisone-metabolite ratio (INCREASED)
Context: Urinary (THF + allo-THF)/THE is often elevated. In 29 members of the selected 36-person cohort, the mean was 19 (range 3–55; source normal approximately 1). The reduced metabolites reflect hepatic as well as renal steroid handling, so this is not a direct quantitative assay of kidney 11-beta-HSD2 or a universal diagnostic cutoff.
Show evidence (2 references)
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"In a subset of 29 patients, the average (THF + alloTHF)/THE ratio, representing the major urinary metabolites of cortisol and cortisone, was significantly elevated at 19 (range: 3–55, normal: 1.0) (Fig. 1G)."
Reports the measured subset and source comparator.
PMID:15761540 SUPPORT REVIEW SYNTHESIS Human Clinical
"whereas the reduced fraction THF, allo-THF and THE are products of the hepatic metabolism of F (38)."
Reduced urinary steroid metabolites include hepatic metabolism, so their ratio is not a kidney-specific enzyme activity assay.
Urinary free cortisol to free cortisone ratio (INCREASED)
Context: The UFF/UFE ratio more closely reflects renal cortisol inactivation than the reduced-metabolite ratio, but it is also altered by acquired enzyme inhibition and extreme cortisol exposure. A ratio is not the concentration of cortisol alone, and no single-metabolite ontology binding is assigned.
Pathograph Readouts
Readout Of Reduced 11-Beta-HSD2 Activity Negative Diagnostic
A higher ratio is consistent with reduced inactivation, interpreted with exposure history and molecular findings.
Show evidence (1 reference)
PMID:15761540 SUPPORT REVIEW SYNTHESIS Human Clinical
"In AME, however, UFE excretion is virtually undetectable (16) resulting in a high UFF/UFE ratio."
Historical clinical synthesis of the free-steroid pattern, without modern assay sensitivity or specificity.
Circulating cortisol
Context: Serum cortisol can remain normal because feedback reduces secretion as clearance slows. The disease mechanism is impaired local ligand inactivation, not obligatory systemic hypercortisolism.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Human Clinical
"patients with AME have normal serum cortisol concentration and don’t present with clin- ical features of Cushing’s syndrome or Addison’s disease"
Normal circulating cortisol is compatible with inherited AME.
🔬

Diagnosis

4
HSD11B2 molecular genetic testing
Identify biallelic pathogenic or likely pathogenic HSD11B2 variants in the clinical and steroid-metabolic context, using sequencing and appropriate copy-number/segregation assessment. A VUS alone does not establish a molecular diagnosis; apparent homozygosity and phenotype discordance require interpretation.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"Identifying specific causative mutations utilizing genetic testing is a confirmatory tool in the diagnosis of AME."
The AME review recommends molecular confirmation.
PMID:39931437 SUPPORT PRIMARY RESULT Human Clinical
"The p.V217A variant, although rated as “uncertain” by ACMG"
The source itself distinguishes uncertain classification from confirmed pathogenic alleles.
Urinary steroid profile
Measure urinary cortisol/cortisone and reduced steroid metabolites with a suitable specialist assay. Interpret free and reduced-metabolite ratios separately and alongside medicines, licorice exposure, cortisol excess and genotype. Neither ratio is an isolated molecular diagnosis.
Urinalysis NCIT:C17241 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"We suggest that patients with clinical symptoms resembling AME should undergo 24-h urinary steroid quantification to determine the profile of cortisol and cortisol metabolites."
The review recommends steroid profiling in a compatible presentation.
PMID:15761540 SUPPORT REVIEW SYNTHESIS Human Clinical
"whereas the reduced fraction THF, allo-THF and THE are products of the hepatic metabolism of F (38)."
Reduced urinary steroid metabolites include hepatic metabolism, so their ratio is not a kidney-specific enzyme activity assay.
Blood pressure and electrolyte assessment
Repeated age-appropriate blood-pressure measurements, serum potassium/bicarbonate and renin/aldosterone characterize the mineralocorticoid phenotype. Initially normal pressure, potassium or a nonzero aldosterone result does not exclude milder or treated AME.
Blood Pressure Measurement NCIT:C167233 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"Serum aldosterone levels were expectedly low (Fig. 1F), with two patients with elevated levels due to unclear reasons."
The cohort includes exceptions to the typical hormone pattern.
PMID:42503627 SUPPORT PRIMARY RESULT Human Clinical
"BP progressively increased during hospitalization, re- aching 136/97 mmHg, exceeding the 95th percentile for age.6)"
A child developed hypertension during hospitalization after an initially normal measurement.
Target-organ and treatment surveillance
Follow blood pressure, growth, potassium, renal function and urine findings; assess renal imaging, cardiac structure/function and retinal injury according to clinical status. Monitor potassium particularly when changing supplements, MR antagonists or potassium-sparing diuretics. Severe hyperkalemia has caused cardiac arrest during treatment.
Show evidence (3 references)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"Patients with high-risk pathogenic mutations require close monitoring to ensure that the disease is well controlled"
The review supports ongoing monitoring rather than a validated universal schedule.
PMID:38652803 SUPPORT PRIMARY RESULT Human Clinical
"One patient survived cardiac arrest secondary to severe hyperkalemia."
The primary series documents a serious treatment-associated potassium complication.
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"For the 13 surviving patients with available follow-up echocardiograms, 12 had persistent left ventricular hypertrophy, 3 showed aortic root dilation, and 2 had aortic insufficiency."
Persistent cardiac findings support organ-specific follow-up.
📈

Progression

3
Early severe or later milder presentation
Classic disease often presents in infancy or childhood with growth impairment and low-renin hypertension. In the selected 36-person cohort, median diagnosis age was 4.6 years, with range 0.1–15. Residual-function biallelic disease can be recognized in adulthood. This clinical continuum should not be conflated with every proposed multifactorial nonclassic low-renin hypertensive phenotype.
Show evidence (2 references)
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"The median age of AME diagnosis was 4.6 y (range: 0.1–15) and the cohort was distributed equally for either sex."
Selected cohort age at diagnosis, not a universal onset interval.
PMID:9683587 SUPPORT PRIMARY RESULT Human Clinical
"AME represents a spectrum of mineralocorticoid hypertension with severity reflecting the underlying genetic defect in the 11beta-HSD2 gene; classification into distinct subtypes is inappropriate."
The family study argues for variable severity within inherited AME.
Long-term target-organ complications
The 2017 report follows a previously published severe subgroup rather than all 36 patients uniformly. It describes three cardiac deaths, persistent hypertrophy in 12/13 imaged survivors, persistent nephrocalcinosis in 8/9 assessed patients and four cases of renal insufficiency more than ten years after diagnosis. Treatment response and prognosis vary; a later seven-patient series also records serious disease and treatment complications despite early diagnosis.
Show evidence (3 references)
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"Of the 16 patients we have reported preliminarily (6, 8, 27–29), follow-up data were available on 8 males and 6 females (6–26 y of age)."
Defines the available follow-up population.
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"Another notable clinical feature was nephrocalcinosis, which persisted in eight of nine patients at 4.1–14.5 y follow-up, despite treatment of hypokalemia."
Persistence is reported in a selected imaging subset.
PMID:38652803 SUPPORT PRIMARY RESULT Human Clinical
"Nevertheless, despite early diagnosis and management, AME is commonly associated with serious complications of the disease or its treatment."
The cohort does not support guaranteed prevention by early care.
Pregnancy in affected adults
Three women conceived spontaneously in the historical cohort; outcomes ranged from term deliveries to severe hypertension, renal deterioration or early preeclampsia with a nonviable fetus. This small series supports individualized specialist planning and monitoring, without estimating pregnancy risk or proving comparative safety of a drug regimen.
Show evidence (2 references)
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"On follow-up, three females conceived spontaneously."
Defines the small pregnancy series.
PMID:29229831 SUPPORT PRIMARY RESULT Human Clinical
"she had severe hypertension (BP: 217/91) associated with preeclampsia at 24 wk of gestation and delivered a nonviable fetus."
Reports one severe pregnancy outcome, not a population risk.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from apparent mineralocorticoid excess:

Acquired impairment of cortisol inactivation
Overlapping Features Licorice and some azole antifungals can inhibit 11-beta-HSD2 and cause an AME-like low-renin phenotype without biallelic inherited HSD11B2 disease. Review exposures before attributing an abnormal steroid profile to a Mendelian disorder.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Other
"HSD2 inhibitors such as licorice and azole antifun - gals results in MR induced hypertension; thus, taking a detailed personal and pharmacological history is benefi - cial when identifying acquired forms of AME [21–23]."
The review describes acquired inhibitors producing a similar phenotype.
Other monogenic low-renin hypertensive disorders
Overlapping Features Liddle syndrome and glucocorticoid-resistance syndromes can overlap clinically. Hormone and steroid profiles, exposure history and gene-specific findings distinguish the cause; low renin alone is not specific for AME.
Show evidence (1 reference)
PMID:36329487 SUPPORT REVIEW SYNTHESIS Human Clinical
"Traditional laboratory evalua - tion findings have been shown to be ambiguous in terms of ruling out other monogenic disorders with similar clinical and hormonal patterns, such as Liddle syndrome, Batter syndrome and primary glucocorticoid resistance [10, 74, 75]."
The review explicitly notes overlapping clinical and hormonal patterns.
🔬

Clinical Trials

1
NCT00474942 NOT_APPLICABLE COMPLETED
Completed observational natural-history and genetics protocol for AME and family members, rather than an interventional drug trial. The official registry lists 130 total enrolled participants including relatives; it does not establish 130 affected patients or treatment efficacy.
Show evidence (1 reference)
clinicaltrials:NCT00474942 SUPPORT BACKGROUND Other
"This study will focus on the genetic basis, natural history, disease progression, and survival of people with AME."
Defines the observational research purpose.
🧫

Experimental Models

1
R279C HSD11B2 heterologous expression OTHER
Wild-type and R279C mutant cDNA expression was compared for enzyme kinetics in the study of a milder AME pedigree. The mutant retained activity with lower maximum velocity and similar substrate affinity.
Publication
PMID:9683587
Pathograph links
Reduced 11-Beta-HSD2 Activity measures fidelity: moderate observes: molecular Measures catalytic parameters for the tested mutant versus wild type.
Limitations: Allele-specific heterologous expression; no universal genotype-to-severity calibration.
Show evidence (1 reference)
PMID:9683587 SUPPORT PRIMARY RESULT In Vitro
"Expression of the 11beta-HSD2 mutant cDNA resulted in an enzyme with reduced maximum velocity, but similar substrate affinity, compared with activity of the wild-type cDNA."
Expression of R279C demonstrates reduced apparent catalytic capacity.
The available primary abstract does not identify the expression-host system, so a specific cell-line class is not inferred. Four homozygous adults and 13 heterozygous relatives informed the human pedigree, but the kinetic readout is an in-vitro experiment. This allele does not define residual activity for all variants; full-body recovery attempts were blocked.
Show evidence (1 reference)
PMID:9683587 SUPPORT PRIMARY RESULT In Vitro
"Expression of the 11beta-HSD2 mutant cDNA resulted in an enzyme with reduced maximum velocity, but similar substrate affinity, compared with activity of the wild-type cDNA."
Expression of R279C demonstrates reduced apparent catalytic capacity.
🐁

Animal Models

1
Kidney-specific Hsd11b2 knockout mouse
Kidney-specific knockout caused salt-dependent hypertension with increased cleaved ENaC-alpha and phosphorylated NCC. Amiloride, high-potassium diet, hydrochlorothiazide and spironolactone interventions modified selected pressure and transporter readouts.
Species
Mouse
Genotype
Kidney-specific Hsd11b2 deletion
Publication
PMID:28559392
Pathograph links
Increased Distal Nephron Sodium Transport measures fidelity: moderate observes: tissue Transporter cleavage/phosphorylation and natriuretic drug responses inform distal sodium handling.
Limitations: Protein abundance/phosphorylation are not a complete quantitative transport-flux assay.
Show evidence (2 references)
PMID:28559392 SUPPORT PRIMARY RESULT Model Organism
"we detected an increase in renal membrane expressions of cleaved epithelial sodium channel-α and T53-phosphorylated Na+-Cl- cotransporter in the knockout mice."
Direct transporter-associated protein readouts in the model.
+ 1 more reference
Notes
The primary cache contains the complete abstract; full-body retrieval was unsuccessful. The renal genetic compartment is explicit, but strain, sex, sample sizes and dosing schedules are not supplied here. This establishes a renal contribution, not exclusion of extra-renal pathways or validated human treatment ranking. A negative brief thiazide exposure in one child is not a refutation of this mouse experiment.
Show evidence (2 references)
PMID:28559392 SUPPORT PRIMARY RESULT Model Organism
"The knockout mice exhibited systemic hypertension, which was abolished by reducing salt intake, suggesting its salt-dependency."
Kidney-specific deletion produces a salt-dependent pressure phenotype.
PMID:28559392 SUPPORT PRIMARY RESULT Model Organism
"we detected an increase in renal membrane expressions of cleaved epithelial sodium channel-α and T53-phosphorylated Na+-Cl- cotransporter in the knockout mice."
Direct transporter-associated protein readouts in the model.
🧮

Computational Models

1
HSD11B2 homology and molecular-dynamics variant analysis STRUCTURAL_PREDICTION
HSD17B1 templates were used to model HSD11B2 residues 81–369, with cortisol docking and 500-ns monomer/dimer simulations. The authors proposed allele-specific effects on cofactor/substrate interactions, dimerization and structural stability. Template homology was limited and previously published activity data informed interpretation; the study did not newly assay all variants or validate an individual prenatal prognostic test.
PMID:29229831 Base model: HSD17B1 structural templates 1IOL, 1JTV and 1FDV
Pathograph links
Biallelic HSD11B2 Dysfunction perturbs fidelity: low observes: molecular Introduces sequence changes into a modeled protein to predict structural consequences.
Limitations: In-silico single-mutation effects do not establish compound-genotype function or clinical severity.
Show evidence (1 reference)
PMID:29229831 SUPPORT PRIMARY RESULT Computational
"Here, we report the successful identification, by computational modeling, of structural changes in silico that are induced by HSD11B2 mutations."
The structural analysis is computational, separate from the clinical cohort.
Findings
Structural hypotheses are distinct from measured enzyme activity; the reported fetal cell-free-DNA diagnostic example concerns congenital adrenal hyperplasia, not a validated AME application.
Show evidence (1 reference)
PMID:29229831 SUPPORT PRIMARY RESULT Computational
"Here, we report the successful identification, by computational modeling, of structural changes in silico that are induced by HSD11B2 mutations."
The structural analysis is computational, separate from the clinical cohort.
{ }

Source YAML

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name: apparent mineralocorticoid excess
creation_date: '2026-07-24T00:00:00Z'
description: Apparent mineralocorticoid excess (AME) is an autosomal recessive disorder caused by biallelic pathogenic HSD11B2 variants. Reduced 11-beta-HSD2 activity impairs cortisol inactivation at renal mineralocorticoid receptors, producing salt-sensitive low-renin hypertension with variably severe hypokalemic alkalosis and low aldosterone. Circulating cortisol can remain normal. Early growth impairment, nephrocalcinosis and cardiovascular or renal complications characterize many severe cases; residual-function alleles can cause milder, later presentations.
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: Inherited AME is autosomal recessive. Consanguinity is common in selected reported cohorts but is not required; confirmed compound-heterozygous cases occur in unrelated parents. Clinical severity varies with residual function and other influences.
  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.
    quote_role: REVIEW_SYNTHESIS
pathophysiology:
- name: Biallelic HSD11B2 Dysfunction
  biological_scale: MOLECULAR
  description: Inherited pathogenic variants in both HSD11B2 alleles impair enzyme function. Missense, truncating and other variants can differ in their residual function; a reported variant of uncertain significance does not become established pathogenic merely because a patient has a compatible phenotype.
  evidence:
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: It is caused by defects in the HSD11B2 gene, encoding the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)
    explanation: The review identifies the causal gene and encoded enzyme.
  genes:
  - preferred_term: HSD11B2
    term:
      id: hgnc:5209
      label: HSD11B2
  role: trigger
  downstream:
  - target: Reduced 11-Beta-HSD2 Activity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Pathogenic alleles reduce the effective enzyme activity through allele-dependent effects on catalysis, substrate/cofactor interactions or abundance.
    evidence: &id001
    - reference: PMID:9683587
      reference_title: Molecular basis for hypertension in the "type II variant" of apparent mineralocorticoid excess.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Expression of the 11beta-HSD2 mutant cDNA resulted in an enzyme with reduced maximum velocity, but similar substrate affinity, compared with activity of the wild-type cDNA.
      explanation: The R279C expression experiment supports reduced catalytic capacity with preserved apparent substrate affinity; this cache is abstract-limited.
- name: Reduced 11-Beta-HSD2 Activity
  biological_scale: MOLECULAR
  description: Cortisol-oxidizing 11-beta-HSD2 activity is reduced, sometimes severely, in inherited AME. Residual activity can persist. Variant-specific catalytic impairment and protein instability are alternative molecular explanations, not interchangeable measurements or universal defects.
  evidence: *id001
  molecular_functions:
  - preferred_term: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity
    term:
      id: GO:0070523
      label: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity
    modifier: DECREASED
  downstream:
  - target: Increased Cortisol Access to Renal Mineralocorticoid Receptors
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Reduced oxidation of active cortisol to inactive cortisone weakens the renal metabolic barrier to receptor occupancy.
    evidence:
    - reference: PMID:15761540
      reference_title: 'Apparent mineralocorticoid excess syndrome: an overview.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      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: The enzyme acts on the ligand before receptor binding.
  - target: Reduced Placental Cortisol Inactivation
    causal_link_type: DIRECT
    description: Loss of enzyme activity in the placental compartment reduces cortisol inactivation; the compartmental extension is a mechanistic synthesis.
    evidence:
    - reference: PMID:36329487
      reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Feto-placental 11β-HSD2 is regarded as a ‘glucocorticoid barrier’ which ensures most maternal cor- tisol inactivated strictly determining the fetal homeosta - sis of cortisol [ 18].
      explanation: The review describes the placental metabolic barrier.
      directness: INDIRECT
  biological_processes:
  - preferred_term: cortisol metabolic process
    term:
      id: GO:0034650
      label: cortisol metabolic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: cortisol
    term:
      id: CHEBI:17650
      label: cortisol
  - preferred_term: cortisone
    term:
      id: CHEBI:16962
      label: cortisone
- name: Increased Cortisol Access to Renal Mineralocorticoid Receptors
  biological_scale: MOLECULAR
  description: 'Impaired conversion to cortisone increases the availability of active cortisol at renal mineralocorticoid receptors. This local ligand-access defect does not require elevated serum cortisol: intact hypothalamic-pituitary-adrenal feedback can maintain normal circulating concentrations.'
  evidence:
  - reference: PMID:15761540
    reference_title: 'Apparent mineralocorticoid excess syndrome: an overview.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension.
    explanation: The review describes failure of local metabolic protection.
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: patients with AME have normal serum cortisol concentration and don’t present with clin- ical features of Cushing’s syndrome or Addison’s disease
    explanation: Normal circulating cortisol is compatible with the local receptor-access defect.
  locations: &id003
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  downstream:
  - target: Cortisol-Mediated Mineralocorticoid Receptor Activation
    causal_link_type: DIRECT
    description: The available cortisol binds the receptor and produces mineralocorticoid signaling.
    evidence:
    - &id002
      reference: PMID:15761540
      reference_title: 'Apparent mineralocorticoid excess syndrome: an overview.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension.
      explanation: The synthesis supplies the receptor-level explanation.
- name: Cortisol-Mediated Mineralocorticoid Receptor Activation
  biological_scale: MOLECULAR
  description: Cortisol occupies and activates the mineralocorticoid receptor despite low aldosterone. Human suppression and cortisol add-back physiology supports cortisol-dependent mineralocorticoid activity, while the receptor specificity explanation is informed by receptor and enzyme biology.
  evidence:
  - reference: PMID:3164727
    reference_title: Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: These results suggest that cortisol acts as a potent mineralocorticoid in 11 beta-OHSD deficiency.
    explanation: The single-patient metabolic intervention supports cortisol-driven mineralocorticoid physiology, rather than measuring receptor occupancy directly.
    directness: INDIRECT
  - *id002
  locations: *id003
  downstream:
  - target: Increased Distal Nephron Sodium Transport
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Nuclear receptor signaling induces sodium-transport machinery through transcriptional intermediates.
    evidence:
    - &id004
      reference: PMID:36329487
      reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Physically, aldosterone and cortisol are both ligands of mineralocorticoid receptors, which results in binding to nuclear hormone response elements, leading to transcription of Na +/K+ ATPase and EnaC channels.
      explanation: The figure legend describes receptor-dependent transcription of transport machinery.
  - target: Metabolic alkalosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Excess distal mineralocorticoid action alters potassium and acid-base handling, producing hypokalemic alkalosis; intermediate tubular acid-secretory steps are not resolved by these clinical sources.
    evidence:
    - reference: PMID:36329487
      reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Marked hypokalemia, metabolic alkalosis, suppressed plasma renin activity, low levels of aldosterone
      explanation: The review identifies the characteristic biochemical syndrome, with the renal acid-base route represented as physiological inference.
- name: Increased Distal Nephron Sodium Transport
  biological_scale: CELLULAR
  description: Mineralocorticoid signaling increases epithelial sodium-channel and sodium-potassium-pump activity in the distal nephron. Kidney-specific Hsd11b2 deletion supports an ENaC-associated transport phenotype; secondary potassium-sensitive NCC activation is an additional model observation, not a measured universal human abnormality.
  evidence:
  - *id004
  - reference: PMID:28559392
    reference_title: Renal Dysfunction Induced by Kidney-Specific Gene Deletion of Hsd11b2 as a Primary Cause of Salt-Dependent Hypertension.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: we detected an increase in renal membrane expressions of cleaved epithelial sodium channel-α and T53-phosphorylated Na+-Cl- cotransporter in the knockout mice.
    explanation: The kidney-specific mouse model provides transporter readouts.
  locations: *id003
  downstream:
  - target: Renal Sodium Retention
    causal_link_type: DIRECT
    description: Increased distal tubular reabsorption reduces urinary sodium elimination.
    evidence:
    - reference: PMID:28559392
      reference_title: Renal Dysfunction Induced by Kidney-Specific Gene Deletion of Hsd11b2 as a Primary Cause of Salt-Dependent Hypertension.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Acute intraperitoneal administration of amiloride-induced natriuresis and increased urinary sodium/potassium ratio more in the knockout mice compared with those in the wild-type control mice.
      explanation: ENaC blockade produces a greater natriuretic response in kidney-specific knockout mice.
  - target: Renal Potassium Wasting
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Enhanced electrogenic sodium transport favors distal potassium secretion through coupled electrochemical and channel mechanisms.
    evidence:
    - reference: PMID:36329487
      reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: MR overstimulation following the upregulation of sodium reabsorption, increased potassium loss, and low-level renin
      explanation: The review links the sodium-retaining state to increased potassium loss.
  biological_processes:
  - preferred_term: sodium ion transport
    term:
      id: GO:0006814
      label: sodium ion transport
    modifier: INCREASED
  cell_types:
  - preferred_term: kidney collecting duct principal cell
    term:
      id: CL:1001431
      label: kidney collecting duct principal cell
  chemical_entities:
  - preferred_term: sodium(1+)
    term:
      id: CHEBI:29101
      label: sodium(1+)
- name: Renal Sodium Retention
  biological_scale: TISSUE
  description: Renal sodium conservation produces positive sodium balance. In one adult with AME, cortisol suppression caused natriuresis and hydrocortisone add-back restored sodium retention on a fixed electrolyte intake.
  evidence: &id005
  - reference: PMID:3164727
    reference_title: Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: When hydrocortisone (10 mg daily s.c. for 4 d) was added, there was marked Na+ retention, a kaliuresis (urinary Na+/K+ falling from 1.2 to 0.15), with suppression of plasma renin activity and an increase in blood pressure.
    explanation: The controlled within-patient intervention documents sodium retention and its associated systemic responses.
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/5691192
    reference_title: https://oup.silverchair-cdn.com/article-minimal/5691192
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: since both can increase sodium transport in renal collecting ducts, increasing water uptake, blood volume, and secondary raising of blood pressure (BP).
    explanation: The full review supplies the physiological sodium-water-volume-pressure connection.
  locations: *id003
  downstream:
  - target: Extracellular Volume Expansion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Positive sodium balance retains water and expands extracellular volume.
    evidence:
    - reference: PMID:3164727
      reference_title: Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Asexpected there wasweight gain and suppres- sion of PRA and plasma aldosterone (Table III).
      explanation: Weight gain accompanies sodium retention during the single-patient cortisol add-back experiment; volume expansion is the physiological interpretation.
      directness: INDIRECT
    - reference: url:https://oup.silverchair-cdn.com/article-minimal/5691192
      reference_title: https://oup.silverchair-cdn.com/article-minimal/5691192
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: since both can increase sodium transport in renal collecting ducts, increasing water uptake, blood volume, and secondary raising of blood pressure (BP).
      explanation: The full review supplies the physiological sodium-water-volume-pressure connection.
- name: Extracellular Volume Expansion
  biological_scale: ORGANISM
  description: Sodium retention expands extracellular and plasma volume, contributing to salt-sensitive hypertension. This physiological consequence is not synonymous with clinically visible edema.
  evidence: &id007
  - reference: PMID:15761540
    reference_title: 'Apparent mineralocorticoid excess syndrome: an overview.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: hypertension, plasma volume expansion, hypokalemic alkalosis and a suppressed renin-angiotensin-aldosterone system
    explanation: The clinical synthesis describes volume expansion in the mineralocorticoid-excess state.
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/5691192
    reference_title: https://oup.silverchair-cdn.com/article-minimal/5691192
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: since both can increase sodium transport in renal collecting ducts, increasing water uptake, blood volume, and secondary raising of blood pressure (BP).
    explanation: The full review supplies the physiological sodium-water-volume-pressure connection.
  downstream:
  - target: Hypertension
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Expanded effective circulating volume contributes to hypertension through renal and cardiovascular intermediates; vascular resistance and chronic remodeling can also contribute.
    evidence: *id005
  - target: Suppressed Renin Release
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Salt and volume expansion suppress renin through renal feedback mechanisms.
    evidence: &id006
    - reference: PMID:3164727
      reference_title: Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Plasma renin activity became detectable. When hydrocortisone (10 mg daily s.c. for 4 d) was added, there was marked Na+ retention, a kaliuresis (urinary Na+/K+ falling from 1.2 to 0.15), with suppression of plasma renin activity
      explanation: Cortisol add-back restores renin suppression following dexamethasone-associated natriuresis.
- name: Suppressed Renin Release
  biological_scale: MOLECULAR
  description: Feedback suppression of renin is characteristic of untreated salt-retaining AME. Renin measurements can vary with treatment and are not invariably low at every observation.
  evidence: *id006
  downstream:
  - target: Decreased circulating renin
    causal_link_type: DIRECT
    description: Reduced release produces the low circulating renin phenotype.
    evidence: *id006
  - target: Reduced Aldosterone Secretion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Reduced angiotensin signaling lowers adrenal aldosterone production; this is a physiological feedback interpretation of the suppressed axis.
    evidence: *id007
- name: Reduced Aldosterone Secretion
  biological_scale: MOLECULAR
  description: Suppressed renin-angiotensin signaling reduces aldosterone secretion. Potassium status, chronic zona-glomerulosa suppression and treatment can modify the measured level; a value within a laboratory interval does not exclude an otherwise supported diagnosis.
  evidence:
  - &id008
    reference: PMID:15761540
    reference_title: 'Apparent mineralocorticoid excess syndrome: an overview.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Biochemical abnormalities comprise suppressed PRA, undetectable serum aldosterone levels and hypokalemia.
    explanation: The review describes the characteristic untreated hormonal pattern.
  - reference: PMID:3164727
    reference_title: Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Plasma aldosterone over this short period oftime remained low as expected following prolonged suppression of the zona glomerulosa.
    explanation: The intervention illustrates delayed aldosterone recovery despite initially detectable renin.
  downstream:
  - target: Decreased circulating aldosterone
    causal_link_type: DIRECT
    description: Lower secretion produces the characteristic low circulating aldosterone phenotype, with treatment-related variability.
    evidence:
    - *id008
- name: Renal Potassium Wasting
  biological_scale: TISSUE
  description: Distal-nephron mineralocorticoid activity promotes urinary potassium loss. The electrical and transport consequences of enhanced sodium reabsorption connect this renal process to hypokalemia.
  evidence:
  - reference: PMID:3164727
    reference_title: Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: When hydrocortisone (10 mg daily s.c. for 4 d) was added, there was marked Na+ retention, a kaliuresis
    explanation: The metabolic balance experiment documents urinary potassium loss during cortisol exposure.
  locations: *id003
  downstream:
  - target: Hypokalemia
    causal_link_type: DIRECT
    description: Urinary potassium loss lowers the circulating potassium concentration unless intake and treatment compensate.
    evidence:
    - reference: PMID:3164727
      reference_title: Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: As shown in Fig. 2 this caused marked Na+ retention and a kaliuresis with a fall in urinary Na+/K+ ratio from 1.2 to 0.15. Plasma electrolytes showed corresponding changes, Na+ rising from 136 to 145 mmol - liter-', K+ falling from 4.5 to 3.3 mmol. liter-'.
      explanation: Hydrocortisone-associated kaliuresis is followed by an explicitly identified fall in plasma potassium.
  - target: Impaired Renal Urine Concentration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Sustained potassium depletion can produce hypokalemic tubular injury and loss of concentrating ability.
    evidence: &id009
    - reference: PMID:15761540
      reference_title: 'Apparent mineralocorticoid excess syndrome: an overview.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Hypokalemic nephropathy some- times causes nephrocalcinosis, polycystic kidney and nephrogenic diabetes insipidus manifesting as thirst and polyuria.
      explanation: The review describes a subset-specific renal concentrating complication.
- name: Impaired Renal Urine Concentration
  biological_scale: TISSUE
  description: Chronic hypokalemic nephropathy can impair urinary concentration and produce nephrogenic diabetes insipidus in a subset of patients. This is not required for all AME or for every episode of polyuria.
  evidence: *id009
  locations: *id003
  downstream:
  - target: Polyuria
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired concentration causes urinary water loss and compensatory thirst.
    evidence: *id009
  - target: Polydipsia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired concentration causes urinary water loss and compensatory thirst.
    evidence: *id009
- name: Reduced Placental Cortisol Inactivation
  biological_scale: TISSUE
  description: Placental 11-beta-HSD2 normally limits fetal exposure to maternal cortisol. Loss of this metabolic barrier is a proposed contributor to prenatal growth restriction in AME, rather than a directly measured placental defect in every affected pregnancy.
  evidence:
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Feto-placental 11β-HSD2 is regarded as a ‘glucocorticoid barrier’ which ensures most maternal cor- tisol inactivated strictly determining the fetal homeosta - sis of cortisol [ 18].
    explanation: The review describes the placental metabolic barrier.
  locations:
  - preferred_term: placenta
    term:
      id: UBERON:0001987
      label: placenta
  downstream:
  - target: Increased Fetal Glucocorticoid Exposure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: A weaker placental metabolic barrier permits more active maternal glucocorticoid to reach the fetus.
    evidence: &id010
    - reference: PMID:36329487
      reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Abolished 11β-HSD2 in the placenta causes the fetus to be over-exposed to maternal glucocor- ticoids, leading to the phenotype of intrauterine growth restriction associated to glucocorticoid receptor [19, 20].
      explanation: The review proposes the fetal exposure and receptor-mediated growth route.
- name: Increased Fetal Glucocorticoid Exposure
  biological_scale: ORGANISM
  description: Reduced placental inactivation can increase fetal exposure to maternal glucocorticoids. The proposed growth effect involves fetal glucocorticoid-receptor signaling; source clinical birth-weight observations do not themselves measure fetal hormone exposure.
  evidence: *id010
  downstream:
  - target: Small for gestational age
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Increased fetal glucocorticoid signaling is a proposed contributor to restricted prenatal growth; individual pregnancies were not assayed for this mediator.
    evidence: *id010
phenotypes:
- name: Hypertension
  category: Cardiovascular
  description: Hypertension is often severe and salt sensitive in classic AME. Mild inherited disease can present later, and an initially normal blood-pressure reading does not exclude later hypertension.
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: PRIMARY_RESULT
- name: Hypokalemia
  category: Metabolic
  description: Renal potassium loss commonly causes hypokalemia in severe AME, but normal potassium occurs in some milder cases. Treatment can instead cause dangerous hyperkalemia.
  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: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: PRIMARY_RESULT
  - 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.
    quote_role: PRIMARY_RESULT
- 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.
    quote_role: PRIMARY_RESULT
  - 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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: PRIMARY_RESULT
- 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.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:15761540
    reference_title: 'Apparent mineralocorticoid excess syndrome: an overview.'
    supports: SUPPORT
    evidence_source: OTHER
    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).
    quote_role: REVIEW_SYNTHESIS
- name: Decreased circulating aldosterone
  category: Endocrine
  description: 'Low aldosterone is characteristic despite mineralocorticoid effects. Values are not universally undetectable: the 36-person cohort included two unexplained elevated results, and the three Chinese children had values within their reported laboratory interval.'
  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.
    quote_role: REVIEW_SYNTHESIS
- name: Small for gestational age
  category: Growth
  description: Reduced birth size occurs in many severe cases. A 36-person selected cohort reported 76% small for gestational age. Reduced placental cortisol inactivation is a proposed contributor, rather than a placental measurement in those infants.
  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.
    quote_role: PRIMARY_RESULT
  - 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: and was small for gestational age at 1.97 kg.
    explanation: Genetically confirmed AME case documents low birth weight (1.97 kg) and small-for-gestational-age status in neonate with homozygous HSD11B2 variant.
    quote_role: PRIMARY_RESULT
- name: Nephrocalcinosis
  category: Renal
  description: Nephrocalcinosis occurred in 27/36 patients in one selected cohort and can persist despite correction of hypokalemia. Its mechanism is incompletely resolved; it can occur without documented hypercalciuria.
  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.
    quote_role: PRIMARY_RESULT
  - 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: medullary nephrocalcinosis, and multiple small bilateral cysts.
    explanation: Genetically confirmed case with imaging documentation of bilateral medullary nephrocalcinosis associated with homozygous HSD11B2 variant.
    quote_role: PRIMARY_RESULT
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Of note is that 27 of 36 (75%) patients also presented with nephrocalcinosis.
    explanation: Selected international cohort at presentation.
- name: Hypercalciuria
  category: Renal
  description: 'Hypercalciuria was reported in the three Chinese cases. It is not obligatory: all seven Israeli patients had nephrocalcinosis but only one had hypercalciuria.'
  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.
    quote_role: PRIMARY_RESULT
  - reference: PMID:38652803
    reference_title: 'Apparent mineralocorticoid excess in Israel: a case series and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: While all patients developed nephrocalcinosis, only 1 showed hypercalciuria.
    explanation: Nephrocalcinosis in seven patients was not contingent on recorded hypercalciuria.
- name: Polyuria
  category: Renal
  description: Polyuria is a recognized presentation; chronic hypokalemia can impair urinary concentration. Additional causes and treatment effects require clinical assessment.
  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
    quote_role: REVIEW_SYNTHESIS
    snippet: Classic AME usually starts in infancy to juvenile and typically manifests as low birth weight, refractory hypertension, delayed growth, polyuria and polydipsia, failure to thrive [ 32].
    explanation: The review describes infantile growth and urinary manifestations without a disease-wide numerical frequency.
- name: Failure to thrive
  category: Growth
  description: Poor postnatal weight gain and growth occur in severe AME. Control of disease may improve growth, but catch-up is not guaranteed and was not demonstrated by discharge-only follow-up in the 2026 child report.
  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
    quote_role: REVIEW_SYNTHESIS
    snippet: Classic AME usually starts in infancy to juvenile and typically manifests as low birth weight, refractory hypertension, delayed growth, polyuria and polydipsia, failure to thrive [ 32].
    explanation: The review describes infantile growth and urinary manifestations without a disease-wide numerical frequency.
- name: Brittle hair
  category: Dermatologic
  description: Observed in the single 2-year-old child reported in 2026. Its relationship to HSD11B2 deficiency is unresolved; this isolated observation does not establish a frequency or a characteristic dysmorphic syndrome.
  phenotype_term:
    preferred_term: Brittle hair
    term:
      id: HP:0002299
      label: Brittle hair
  evidence:
  - 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: Dysmorphic features included brittle hair, flat nasal bridge, large forehead, frontal bossing, long eyelashes, and ear tag.
    explanation: Single-patient case report listing brittle hair among the dysmorphic features observed in a genetically confirmed AME patient.
    quote_role: PRIMARY_RESULT
- name: Depressed nasal bridge
  category: Craniofacial
  description: Observed in the single 2-year-old child reported in 2026. Its relationship to HSD11B2 deficiency is unresolved; this isolated observation does not establish a frequency or a characteristic dysmorphic syndrome.
  phenotype_term:
    preferred_term: Flat nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - 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: Dysmorphic features included brittle hair, flat nasal bridge, large forehead, frontal bossing, long eyelashes, and ear tag.
    explanation: Single-patient case report listing a flat nasal bridge among the dysmorphic features observed in a genetically confirmed AME patient.
    quote_role: PRIMARY_RESULT
- name: Frontal bossing
  category: Craniofacial
  description: Observed in the single 2-year-old child reported in 2026. Its relationship to HSD11B2 deficiency is unresolved; this isolated observation does not establish a frequency or a characteristic dysmorphic syndrome.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - 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: Dysmorphic features included brittle hair, flat nasal bridge, large forehead, frontal bossing, long eyelashes, and ear tag.
    explanation: Single-patient case report listing a large forehead with frontal bossing among the dysmorphic features observed in a genetically confirmed AME patient.
    quote_role: PRIMARY_RESULT
- name: Long eyelashes
  category: Craniofacial
  description: Observed in the single 2-year-old child reported in 2026. Its relationship to HSD11B2 deficiency is unresolved; this isolated observation does not establish a frequency or a characteristic dysmorphic syndrome.
  phenotype_term:
    preferred_term: Long eyelashes
    term:
      id: HP:0000527
      label: Long eyelashes
  evidence:
  - 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: Dysmorphic features included brittle hair, flat nasal bridge, large forehead, frontal bossing, long eyelashes, and ear tag.
    explanation: Single-patient case report listing long eyelashes among the dysmorphic features observed in a genetically confirmed AME patient.
    quote_role: PRIMARY_RESULT
- name: Ear tag
  category: Craniofacial
  description: Observed in the single 2-year-old child reported in 2026. Its relationship to HSD11B2 deficiency is unresolved; this isolated observation does not establish a frequency or a characteristic dysmorphic syndrome.
  evidence:
  - 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: Dysmorphic features included brittle hair, flat nasal bridge, large forehead, frontal bossing, long eyelashes, and ear tag.
    explanation: Single-patient case report listing an ear tag among the dysmorphic features observed in a genetically confirmed AME patient.
    quote_role: PRIMARY_RESULT
  notes: The source states ear tag without specifying preauricular location; a more specific anatomical HPO binding is not assigned.
- name: Polydipsia
  category: Renal
  description: Excess thirst accompanies the urinary-concentrating phenotype in reported severe AME.
  phenotype_term:
    preferred_term: Polydipsia
    term:
      id: HP:0001959
      label: Polydipsia
  evidence:
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Classic AME usually starts in infancy to juvenile and typically manifests as low birth weight, refractory hypertension, delayed growth, polyuria and polydipsia, failure to thrive [ 32].
    explanation: The review describes the clinical presentation of classic AME.
- name: Short stature
  category: Growth
  description: Linear growth can remain below familial target despite treatment. This is separate from cognitive or motor development; the three Chinese children had normal intellectual and motor development.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - &id011
    reference: PMID:15761540
    reference_title: 'Apparent mineralocorticoid excess syndrome: an overview.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Usually patients are children with low birth weight, failure to thrive, short stature, and severe, often fatal, hypertension with hypokalemic metabolic alkalosis and muscle weakness.
    explanation: The historical review explicitly describes short stature and weakness in the severe clinical presentation.
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'Like CAH, height of the patients improved, but fell below the target height (height SDS: −1.1 ± 0.6).'
    explanation: Longitudinal growth observation in the previously reported follow-up subset, not all 36 cases.
- name: Renal cysts
  category: Renal
  description: Renal cysts accompany nephrocalcinosis in some reports; their mechanism is not established by these observations.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - 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
    quote_role: PRIMARY_RESULT
    snippet: medullary nephrocalcinosis, and multiple small bilateral cysts.
    explanation: Direct ultrasound finding in one child.
- name: Enlarged kidneys
  category: Renal
  description: Bilateral enlargement was reported in the 2026 child; no population frequency is known.
  phenotype_term:
    preferred_term: Enlarged kidney
    term:
      id: HP:0000105
      label: Enlarged kidney
  evidence:
  - 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
    quote_role: PRIMARY_RESULT
    snippet: Kidney ultrasound revealed bilaterally enlarged echogenic kidneys with preserved corticome- dullary differentiation, medullary nephrocalcinosis, and multiple small bilateral cysts.
    explanation: Ultrasound documents enlargement and cystic/calcific findings in one child.
- name: Renal insufficiency
  category: Renal
  description: Chronic renal impairment and progression to end-stage disease occur in some severe cases. Early treatment does not guarantee prevention; observational timing comparisons are confounded by initial disease severity.
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Four patients developed renal insufficiency more than 10 y after diagnosis, with two progressing to renal failure and received renal transplantation (30).
    explanation: Counts belong to the described longitudinal subset, not a 36-person risk denominator.
  - reference: PMID:38652803
    reference_title: 'Apparent mineralocorticoid excess in Israel: a case series and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The 2 patients who presented with CKD progressed to end-stage kidney disease (ESKD) necessitating dialysis and kidney transplantation.
    explanation: Two initially impaired patients in a seven-person cohort progressed to kidney failure.
- name: Left ventricular hypertrophy
  category: Cardiovascular
  description: Longstanding severe hypertension can accompany marked ventricular hypertrophy. Twelve of 13 surviving patients with follow-up echocardiograms in the older series had persistent hypertrophy; this survivor subset is not a disease-wide prevalence.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: For the 13 surviving patients with available follow-up echocardiograms, 12 had persistent left ventricular hypertrophy, 3 showed aortic root dilation, and 2 had aortic insufficiency.
    explanation: Defines the imaging subset and concurrent structural observations.
- name: Aortic regurgitation
  category: Cardiovascular
  description: Aortic insufficiency was observed in two of 13 surviving patients with follow-up echocardiograms. It is a reported complication, not an obligatory feature.
  phenotype_term:
    preferred_term: Aortic regurgitation
    term:
      id: HP:0001659
      label: Aortic regurgitation
  evidence:
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: For the 13 surviving patients with available follow-up echocardiograms, 12 had persistent left ventricular hypertrophy, 3 showed aortic root dilation, and 2 had aortic insufficiency.
    explanation: Two observations in the imaged survivor subset.
- name: Hypertensive retinopathy
  category: Ophthalmic
  description: Retinal complications of hypertension were prominent in the historical severe-case series; the report describes ten among the 16 previously reported patients.
  phenotype_term:
    preferred_term: Hypertensive retinopathy
    term:
      id: HP:0001095
      label: Hypertensive retinopathy
  evidence:
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Severe hypertension, left ventricular hypertrophy (12 of 16), and hypertensive retinopathy (10 of 16) were prominent clinical features.
    explanation: The source uses the 16-person historical subgroup denominator.
- name: Cardiac arrest
  category: Cardiovascular
  description: Fatal cardiac arrest occurred in three patients in the older longitudinal cohort. A later report also documented survival after treatment-associated severe hyperkalemia; these events have different immediate contexts.
  phenotype_term:
    preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
  evidence:
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Cardiovascular complications were prominent, with three patients dying from cardiac arrest at 16, 16, and 17 y of age.
    explanation: Reports three events without assigning a general mortality rate.
  - reference: PMID:38652803
    reference_title: 'Apparent mineralocorticoid excess in Israel: a case series and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: One patient survived cardiac arrest secondary to severe hyperkalemia.
    explanation: Demonstrates a serious potassium-related treatment hazard.
- name: Seizure
  category: Neurological
  description: One Chinese child had a single outside-hospital seizure, without specified diagnostic details, antiseizure treatment or recurrence. The report does not establish chronic epilepsy or its cause.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  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
    quote_role: PRIMARY_RESULT
    snippet: Previously, the patient was diagnosed with epilepsy at an outside hospital after experiencing one seizure (speci fic details of diagnosis and treatment are unspeci fied). No antiepileptic drugs were given, and there have been no subsequent seizures.
    explanation: The full clinical narrative limits the abstract/background epilepsy wording.
- name: Cerebral atrophy
  category: Neurological
  description: Localized cerebral atrophy and cystic changes were reported in the same child with severe hypertension. A direct HSD11B2-mediated neurodegenerative route is not established.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  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
    quote_role: PRIMARY_RESULT
    snippet: Head MRI indicated localized cerebral atrophy and cystic changes in the left parietal lobe
    explanation: Single imaging observation, without demonstrated mechanism or longitudinal progression.
- name: Muscle weakness
  category: Musculoskeletal
  description: Muscle weakness accompanies hypokalemic alkalosis in some severe presentations. It is not equivalent to a primary developmental or degenerative myopathy.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - *id011
biochemical:
- name: Urinary cortisol-metabolite to cortisone-metabolite ratio
  presence: INCREASED
  context: Urinary (THF + allo-THF)/THE is often elevated. In 29 members of the selected 36-person cohort, the mean was 19 (range 3–55; source normal approximately 1). The reduced metabolites reflect hepatic as well as renal steroid handling, so this is not a direct quantitative assay of kidney 11-beta-HSD2 or a universal diagnostic cutoff.
  evidence:
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'In a subset of 29 patients, the average (THF + alloTHF)/THE ratio, representing the major urinary metabolites of cortisol and cortisone, was significantly elevated at 19 (range: 3–55, normal: 1.0) (Fig. 1G).'
    explanation: Reports the measured subset and source comparator.
  - &id012
    reference: PMID:15761540
    reference_title: 'Apparent mineralocorticoid excess syndrome: an overview.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: whereas the reduced fraction THF, allo-THF and THE are products of the hepatic metabolism of F (38).
    explanation: Reduced urinary steroid metabolites include hepatic metabolism, so their ratio is not a kidney-specific enzyme activity assay.
- name: Urinary free cortisol to free cortisone ratio
  presence: INCREASED
  context: The UFF/UFE ratio more closely reflects renal cortisol inactivation than the reduced-metabolite ratio, but it is also altered by acquired enzyme inhibition and extreme cortisol exposure. A ratio is not the concentration of cortisol alone, and no single-metabolite ontology binding is assigned.
  evidence:
  - reference: PMID:15761540
    reference_title: 'Apparent mineralocorticoid excess syndrome: an overview.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: In AME, however, UFE excretion is virtually undetectable (16) resulting in a high UFF/UFE ratio.
    explanation: Historical clinical synthesis of the free-steroid pattern, without modern assay sensitivity or specificity.
  readouts:
  - target: Reduced 11-Beta-HSD2 Activity
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: A higher ratio is consistent with reduced inactivation, interpreted with exposure history and molecular findings.
- name: Circulating cortisol
  context: Serum cortisol can remain normal because feedback reduces secretion as clearance slows. The disease mechanism is impaired local ligand inactivation, not obligatory systemic hypercortisolism.
  biomarker_term:
    preferred_term: cortisol
    term:
      id: CHEBI:17650
      label: cortisol
  evidence:
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: patients with AME have normal serum cortisol concentration and don’t present with clin- ical features of Cushing’s syndrome or Addison’s disease
    explanation: Normal circulating cortisol is compatible with inherited AME.
genetic:
- name: HSD11B2
  gene_term:
    preferred_term: HSD11B2
    term:
      id: hgnc:5209
      label: HSD11B2
  relationship_type: CAUSATIVE
  notes: Biallelic pathogenic variants include missense, truncating, splice and insertion/deletion alleles. Homozygous and compound-heterozygous genotypes occur; residual-function variants can produce milder disease. In the 2025 three-child series, p.Val217Ala remained a VUS with no new enzyme assay, while the other two children carried variants classified likely pathogenic. The 2026 child carried homozygous p.Arg208Cys; a single heterozygous UBE3B variant was incidental. Structural proposals in the 2017 study derive from homology modeling and molecular dynamics, not direct measurements of each patient variant. Genotype alone does not provide a validated individual severity prediction.
  evidence:
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: It is caused by defects in the HSD11B2 gene, encoding the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)
    explanation: The review identifies the gene and enzyme.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: The p.V217A variant, although rated as “uncertain” by ACMG
    explanation: The paper explicitly retains uncertain classification; a compatible phenotype is not an enzyme functional test.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: identified a homozygous pathogenic HSD11B2 variant (c.622C>T; p.Arg208Cys), confirming AME syndrome.
    explanation: Molecular diagnosis in the reported child.
  - reference: PMID:9683587
    reference_title: Molecular basis for hypertension in the "type II variant" of apparent mineralocorticoid excess.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Expression of the 11beta-HSD2 mutant cDNA resulted in an enzyme with reduced maximum velocity, but similar substrate affinity, compared with activity of the wild-type cDNA.
    explanation: The R279C study demonstrates residual catalytic impairment in a transfected expression experiment.
diagnosis:
- name: HSD11B2 molecular genetic testing
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: Identify biallelic pathogenic or likely pathogenic HSD11B2 variants in the clinical and steroid-metabolic context, using sequencing and appropriate copy-number/segregation assessment. A VUS alone does not establish a molecular diagnosis; apparent homozygosity and phenotype discordance require interpretation.
  evidence:
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Identifying specific causative mutations utilizing genetic testing is a confirmatory tool in the diagnosis of AME.
    explanation: The AME review recommends molecular confirmation.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: The p.V217A variant, although rated as “uncertain” by ACMG
    explanation: The source itself distinguishes uncertain classification from confirmed pathogenic alleles.
- name: Urinary steroid profile
  diagnosis_term:
    preferred_term: Urinalysis
    term:
      id: NCIT:C17241
      label: Urinalysis
  description: Measure urinary cortisol/cortisone and reduced steroid metabolites with a suitable specialist assay. Interpret free and reduced-metabolite ratios separately and alongside medicines, licorice exposure, cortisol excess and genotype. Neither ratio is an isolated molecular diagnosis.
  evidence:
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: We suggest that patients with clinical symptoms resembling AME should undergo 24-h urinary steroid quantification to determine the profile of cortisol and cortisol metabolites.
    explanation: The review recommends steroid profiling in a compatible presentation.
  - *id012
- name: Blood pressure and electrolyte assessment
  diagnosis_term:
    preferred_term: Blood Pressure Measurement
    term:
      id: NCIT:C167233
      label: Blood Pressure Measurement
  description: Repeated age-appropriate blood-pressure measurements, serum potassium/bicarbonate and renin/aldosterone characterize the mineralocorticoid phenotype. Initially normal pressure, potassium or a nonzero aldosterone result does not exclude milder or treated AME.
  evidence:
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Serum aldosterone levels were expectedly low (Fig. 1F), with two patients with elevated levels due to unclear reasons.
    explanation: The cohort includes exceptions to the typical hormone pattern.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: BP progressively increased during hospitalization, re- aching 136/97 mmHg, exceeding the 95th percentile for age.6)
    explanation: A child developed hypertension during hospitalization after an initially normal measurement.
- name: Target-organ and treatment surveillance
  description: Follow blood pressure, growth, potassium, renal function and urine findings; assess renal imaging, cardiac structure/function and retinal injury according to clinical status. Monitor potassium particularly when changing supplements, MR antagonists or potassium-sparing diuretics. Severe hyperkalemia has caused cardiac arrest during treatment.
  evidence:
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Patients with high-risk pathogenic mutations require close monitoring to ensure that the disease is well controlled
    explanation: The review supports ongoing monitoring rather than a validated universal schedule.
  - reference: PMID:38652803
    reference_title: 'Apparent mineralocorticoid excess in Israel: a case series and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: One patient survived cardiac arrest secondary to severe hyperkalemia.
    explanation: The primary series documents a serious treatment-associated potassium complication.
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: For the 13 surviving patients with available follow-up echocardiograms, 12 had persistent left ventricular hypertrophy, 3 showed aortic root dilation, and 2 had aortic insufficiency.
    explanation: Persistent cardiac findings support organ-specific follow-up.
treatments:
- name: Mineralocorticoid receptor antagonists
  description: 'Spironolactone or eplerenone opposes inappropriate cortisol-driven MR signaling. Response varies and additional potassium replacement or antihypertensives may be needed. The three-child report does not show universal spironolactone success: its first patient had persistent abnormalities and was switched to eplerenone. Monitor blood pressure, potassium and kidney function; doses from individual reports are not a universal regimen.'
  therapeutic_modality: SMALL_MOLECULE
  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
  evidence:
  - &id013
    reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Mineralocorticoid receptor blocker, spironolactone, could block the hyperactivation of mineralocorticoid receptors while amiloride blocks EnaC
    explanation: The review distinguishes receptor antagonism from channel blockade.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: Despite the dosage of spironolactone being increased to 6.8 mg/kg/day, serum potassium levels could not be stabilized within normal range.
    explanation: The detailed first-case narrative contradicts the abstract statement of uniform normalization.
  - &id014
    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
    quote_role: PRIMARY_RESULT
    snippet: Management included spironolactone 5 mg orally once daily with continued oral and intravenous (IV) KCl.
    explanation: Potassium improvement occurred with combined therapy, not isolated spironolactone exposure.
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/5691192
    reference_title: https://oup.silverchair-cdn.com/article-minimal/5691192
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: 'Treatment for AME must be started at diagnosis, and sustained and monitored. Mineralocorticoid receptor antagonists at age-appropriate doses are mandatory: relatively low doses are sufficient, given the side effects (spironolactone) or cost (eplerenone), with amiloride and calcium channel blockers occasionally required to normalize BP.'
    explanation: The 2020 review recommends MR antagonism and monitoring; its expectation of dose adequacy is qualified here by variable responses in later case reports.
  target_mechanisms:
  - target: Cortisol-Mediated Mineralocorticoid Receptor Activation
    treatment_effect: INHIBITS
    description: MR antagonism opposes cortisol-driven receptor signaling; clinical response and treatment tolerance vary.
    evidence:
    - *id013
- name: Epithelial sodium-channel blockade
  description: Amiloride blocks distal ENaC downstream of receptor activation. It may be used alone or with MR antagonism under electrolyte and renal monitoring. A kidney-specific mouse knockout supports transport effects but does not determine the effective human dose or comparative regimen.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: amiloride
      term:
        id: CHEBI:2639
        label: amiloride
  evidence:
  - *id013
  - reference: PMID:15761540
    reference_title: 'Apparent mineralocorticoid excess syndrome: an overview.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Patients have been successfully treated with the potassium sparing diuretics tri- amterene and/or amiloride.
    explanation: Historical clinical experience supports the channel-blocking approach.
  target_mechanisms:
  - target: Increased Distal Nephron Sodium Transport
    treatment_effect: INHIBITS
    description: Amiloride reduces ENaC-mediated sodium entry without repairing HSD11B2.
    evidence:
    - *id013
- name: Potassium replacement
  description: Individualized oral or intravenous potassium replacement corrects clinically significant hypokalemia while disease-directed therapy takes effect. Reduce or stop supplementation as potassium stabilizes; combination treatment can cause severe hyperkalemia.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: potassium chloride
      term:
        id: CHEBI:32588
        label: potassium chloride
  evidence:
  - *id014
  - 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
    quote_role: PRIMARY_RESULT
    snippet: Oral KCl was gradually tapered and stopped once serum potassium stabilized at 3.7–4.1 mmol/L.
    explanation: The case shows tapering after correction rather than indefinite fixed supplementation.
  - reference: PMID:38652803
    reference_title: 'Apparent mineralocorticoid excess in Israel: a case series and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: One patient survived cardiac arrest secondary to severe hyperkalemia.
    explanation: Requires monitoring for overcorrection and impaired excretion.
  target_mechanisms:
  - target: Hypokalemia
    treatment_effect: BYPASSES
    description: Replacement supplies potassium despite ongoing renal loss; response requires monitoring.
    evidence:
    - *id014
- name: Dietary sodium restriction
  description: Reduce dietary sodium to address salt-sensitive hypertension, with age-appropriate nutritional planning. This is a physiologically targeted adjunct rather than proof that diet alone prevents all renal or cardiac complications.
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: salt-limited diet is necessary for both classic and non-classic AME patients
    explanation: The review recommends sodium restriction in both clinical settings.
  target_mechanisms:
  - target: Renal Sodium Retention
    treatment_effect: INHIBITS
    description: Lower intake reduces the sodium load available for retention.
    evidence:
    - reference: PMID:36329487
      reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: For the nature of AME is a kind of salt-sensitive hyper - tension, salt-limited diet is necessary
      explanation: The recommendation follows the salt-sensitive physiology.
- name: Selected glucocorticoid suppression
  description: Dexamethasone has been used to suppress endogenous cortisol production in selected adults. In a historical single-patient fixed-intake study, suppression caused natriuresis and potassium retention and cortisol add-back reversed these changes. This is proof of physiological responsiveness in one patient, not a comparative pediatric treatment guideline or universal first-line regimen.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dexamethasone
      term:
        id: CHEBI:41879
        label: dexamethasone
  evidence:
  - &id015
    reference: PMID:3164727
    reference_title: Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: When established on a fixed Na+/K+ intake, dexamethasone, given orally, produced a natriuresis and potassium retention.
    explanation: Within-patient metabolic intervention supports cortisol-suppression physiology.
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Glucocorticoids also have been administrated for suppressing the secre - tion of endogenous adrenocorticotropic hormone-medi - ated corticosteroid in adult classic AME patients
    explanation: The newer review restricts this historical option to selected adult reports.
  target_mechanisms:
  - target: Increased Cortisol Access to Renal Mineralocorticoid Receptors
    treatment_effect: INHIBITS
    description: Suppressing endogenous cortisol secretion reduces ligand availability; it does not restore the enzyme.
    evidence:
    - *id015
- name: Adjunct antihypertensive treatment
  description: Additional antihypertensives may be needed when targeted therapy does not adequately control pressure. Hydralazine and atenolol accompanied spironolactone in the 2026 child. A short hydrochlorothiazide trial worsened hypokalemia without BP benefit in that child; this single outcome does not establish a universal class contraindication.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydralazine
      term:
        id: CHEBI:5775
        label: hydralazine
    - preferred_term: atenolol
      term:
        id: CHEBI:2904
        label: atenolol
  evidence:
  - &id016
    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
    quote_role: PRIMARY_RESULT
    snippet: Additional BP medications, including hy- dralazine and atenolol, were also needed.
    explanation: Adjunctive treatment was part of the reported combination regimen.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: Hydrochlorothiazide was briefly in troduced but discontinued after 5 days due to worsening hypokalemia and no significant BP improvement.
    explanation: One patient-specific unsuccessful exposure, rather than evidence against every thiazide use.
  target_mechanisms:
  - target: Hypertension
    treatment_effect: INHIBITS
    description: Adjunct agents lower pressure without correcting the cortisol-inactivation defect.
    evidence:
    - *id016
- name: Kidney transplantation for advanced renal disease
  description: Kidney transplantation may be required for end-stage renal disease. Selected transplanted patients had remission of low-renin hypertension and hypokalemic alkalosis after spironolactone withdrawal, consistent with restored renal cortisol inactivation. This does not demonstrate correction of every extra-renal genotype effect or justify routine transplantation for medically manageable disease.
  treatment_term:
    preferred_term: Kidney Transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  evidence:
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Interestingly, following transplant, these patients no longer showed clinical signs of AME, with a remission of the low-renin hypertension and hypokalemic alkalosis when medical treatment with spironolactone was discontinued.
    explanation: Two severe cases had a reported post-transplant phenotype remission.
  target_mechanisms:
  - target: Reduced 11-Beta-HSD2 Activity
    treatment_effect: RESTORES
    description: A functioning donor kidney can restore renal enzyme capacity; whole-body correction is not established.
    evidence:
    - reference: PMID:29229831
      reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Interestingly, following transplant, these patients no longer showed clinical signs of AME, with a remission of the low-renin hypertension and hypokalemic alkalosis when medical treatment with spironolactone was discontinued.
      explanation: Clinical remission supports renal functional replacement; enzyme activity was not directly assayed in this passage.
      directness: INDIRECT
- name: Genetic counseling and family evaluation
  description: Offer counseling and testing to relevant relatives once familial pathogenic variants are defined. Discuss recessive inheritance, variable severity and reproductive options using variant-specific interpretation. Mild biochemical changes in some heterozygotes do not convert the established recessive disorder into a uniformly dominant disease.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: with an increasing number of asymptomatic cases detected among individuals with a positive family history, it is necessary to conduct genetic counseling in affected families to clarify genetic involvement [ 56].
    explanation: The review supports family counseling and ascertainment.
  - reference: PMID:9683587
    reference_title: Molecular basis for hypertension in the "type II variant" of apparent mineralocorticoid excess.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The heterozygote state was phenotypically normal but was associated with subtle defects in cortisol metabolism.
    explanation: Thirteen heterozygotes in one family did not show the affected phenotype despite subtle biochemical findings.
differential_diagnoses:
- name: Acquired impairment of cortisol inactivation
  description: Licorice and some azole antifungals can inhibit 11-beta-HSD2 and cause an AME-like low-renin phenotype without biallelic inherited HSD11B2 disease. Review exposures before attributing an abnormal steroid profile to a Mendelian disorder.
  evidence:
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: HSD2 inhibitors such as licorice and azole antifun - gals results in MR induced hypertension; thus, taking a detailed personal and pharmacological history is benefi - cial when identifying acquired forms of AME [21–23].
    explanation: The review describes acquired inhibitors producing a similar phenotype.
- name: Other monogenic low-renin hypertensive disorders
  description: Liddle syndrome and glucocorticoid-resistance syndromes can overlap clinically. Hormone and steroid profiles, exposure history and gene-specific findings distinguish the cause; low renin alone is not specific for AME.
  evidence:
  - reference: PMID:36329487
    reference_title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Traditional laboratory evalua - tion findings have been shown to be ambiguous in terms of ruling out other monogenic disorders with similar clinical and hormonal patterns, such as Liddle syndrome, Batter syndrome and primary glucocorticoid resistance [10, 74, 75].
    explanation: The review explicitly notes overlapping clinical and hormonal patterns.
clinical_trials:
- name: NCT00474942
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: Completed observational natural-history and genetics protocol for AME and family members, rather than an interventional drug trial. The official registry lists 130 total enrolled participants including relatives; it does not establish 130 affected patients or treatment efficacy.
  notes: Official full registry JSON was read on 2026-09-21. Actual completion was in November 2013, with a December 2015 last update and no posted results. Prospective observational, nonprobability sampling limits generalization.
  evidence:
  - reference: clinicaltrials:NCT00474942
    reference_title: Apparent Mineralocorticoid Excess Syndrome Natural History Clinical Protocol
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: This study will focus on the genetic basis, natural history, disease progression, and survival of people with AME.
    explanation: Defines the observational research purpose.
review_notes: The original references, genuine deep-research narrative, available full scientific bodies and tables were reviewed. Primary long-term follow-up denominators replace percentages misattributed to all 36 patients by a later review. Detailed Chinese case narratives take precedence over contradictory abstract claims of universal spironolactone success. One reported Val217Ala genotype remains a VUS, and single-case dysmorphic findings have no inferred disease-wide frequency or demonstrated causal route. The 2026 child report ends at discharge and does not demonstrate growth catch-up or long-term renal protection. The 2004 review is historical care context; newer AME reviews and primary clinical observations qualify its dexamethasone-first framing. No dedicated AME GeneReviews chapter was identified; applicable clinical, diagnostic, management and counseling domains are supplied by AME-specific sources. The recovered full 2020 review was read through the scientific body, tables and figure legends. Its proposed nonclassic construct, screening denominator and primary-aldosteronism extrapolations remain distinct from confirmed recessive AME and AME-specific outcome evidence. Chemical
  annotations identify cortisol/cortisone substrates and sodium without asserting a universal circulating concentration change; increased transport is annotated separately.
updated_date: '2026-09-21T11:20:00Z'
progression:
- phase: Early severe or later milder presentation
  notes: Classic disease often presents in infancy or childhood with growth impairment and low-renin hypertension. In the selected 36-person cohort, median diagnosis age was 4.6 years, with range 0.1–15. Residual-function biallelic disease can be recognized in adulthood. This clinical continuum should not be conflated with every proposed multifactorial nonclassic low-renin hypertensive phenotype.
  evidence:
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'The median age of AME diagnosis was 4.6 y (range: 0.1–15) and the cohort was distributed equally for either sex.'
    explanation: Selected cohort age at diagnosis, not a universal onset interval.
  - reference: PMID:9683587
    reference_title: Molecular basis for hypertension in the "type II variant" of apparent mineralocorticoid excess.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: AME represents a spectrum of mineralocorticoid hypertension with severity reflecting the underlying genetic defect in the 11beta-HSD2 gene; classification into distinct subtypes is inappropriate.
    explanation: The family study argues for variable severity within inherited AME.
- phase: Long-term target-organ complications
  notes: The 2017 report follows a previously published severe subgroup rather than all 36 patients uniformly. It describes three cardiac deaths, persistent hypertrophy in 12/13 imaged survivors, persistent nephrocalcinosis in 8/9 assessed patients and four cases of renal insufficiency more than ten years after diagnosis. Treatment response and prognosis vary; a later seven-patient series also records serious disease and treatment complications despite early diagnosis.
  evidence:
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Of the 16 patients we have reported preliminarily (6, 8, 27–29), follow-up data were available on 8 males and 6 females (6–26 y of age).
    explanation: Defines the available follow-up population.
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Another notable clinical feature was nephrocalcinosis, which persisted in eight of nine patients at 4.1–14.5 y follow-up, despite treatment of hypokalemia.
    explanation: Persistence is reported in a selected imaging subset.
  - reference: PMID:38652803
    reference_title: 'Apparent mineralocorticoid excess in Israel: a case series and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Nevertheless, despite early diagnosis and management, AME is commonly associated with serious complications of the disease or its treatment.
    explanation: The cohort does not support guaranteed prevention by early care.
- phase: Pregnancy in affected adults
  notes: Three women conceived spontaneously in the historical cohort; outcomes ranged from term deliveries to severe hypertension, renal deterioration or early preeclampsia with a nonviable fetus. This small series supports individualized specialist planning and monitoring, without estimating pregnancy risk or proving comparative safety of a drug regimen.
  evidence:
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: On follow-up, three females conceived spontaneously.
    explanation: Defines the small pregnancy series.
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'she had severe hypertension (BP: 217/91) associated with preeclampsia at 24 wk of gestation and delivered a nonviable fetus.'
    explanation: Reports one severe pregnancy outcome, not a population risk.
experimental_models:
- name: R279C HSD11B2 heterologous expression
  experimental_model_type: OTHER
  publication: PMID:9683587
  description: Wild-type and R279C mutant cDNA expression was compared for enzyme kinetics in the study of a milder AME pedigree. The mutant retained activity with lower maximum velocity and similar substrate affinity.
  notes: The available primary abstract does not identify the expression-host system, so a specific cell-line class is not inferred. Four homozygous adults and 13 heterozygous relatives informed the human pedigree, but the kinetic readout is an in-vitro experiment. This allele does not define residual activity for all variants; full-body recovery attempts were blocked.
  evidence:
  - &id017
    reference: PMID:9683587
    reference_title: Molecular basis for hypertension in the "type II variant" of apparent mineralocorticoid excess.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Expression of the 11beta-HSD2 mutant cDNA resulted in an enzyme with reduced maximum velocity, but similar substrate affinity, compared with activity of the wild-type cDNA.
    explanation: Expression of R279C demonstrates reduced apparent catalytic capacity.
  modeled_mechanisms:
  - target: Reduced 11-Beta-HSD2 Activity
    relationship: MEASURES
    model_scale: MOLECULAR
    fidelity: MODERATE
    description: Measures catalytic parameters for the tested mutant versus wild type.
    limitations: Allele-specific heterologous expression; no universal genotype-to-severity calibration.
    evidence:
    - *id017
animal_models:
- name: Kidney-specific Hsd11b2 knockout mouse
  species: Mouse
  genotype: Kidney-specific Hsd11b2 deletion
  publication: PMID:28559392
  description: Kidney-specific knockout caused salt-dependent hypertension with increased cleaved ENaC-alpha and phosphorylated NCC. Amiloride, high-potassium diet, hydrochlorothiazide and spironolactone interventions modified selected pressure and transporter readouts.
  notes: The primary cache contains the complete abstract; full-body retrieval was unsuccessful. The renal genetic compartment is explicit, but strain, sex, sample sizes and dosing schedules are not supplied here. This establishes a renal contribution, not exclusion of extra-renal pathways or validated human treatment ranking. A negative brief thiazide exposure in one child is not a refutation of this mouse experiment.
  evidence:
  - &id018
    reference: PMID:28559392
    reference_title: Renal Dysfunction Induced by Kidney-Specific Gene Deletion of Hsd11b2 as a Primary Cause of Salt-Dependent Hypertension.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: The knockout mice exhibited systemic hypertension, which was abolished by reducing salt intake, suggesting its salt-dependency.
    explanation: Kidney-specific deletion produces a salt-dependent pressure phenotype.
  - &id019
    reference: PMID:28559392
    reference_title: Renal Dysfunction Induced by Kidney-Specific Gene Deletion of Hsd11b2 as a Primary Cause of Salt-Dependent Hypertension.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: we detected an increase in renal membrane expressions of cleaved epithelial sodium channel-α and T53-phosphorylated Na+-Cl- cotransporter in the knockout mice.
    explanation: Direct transporter-associated protein readouts in the model.
  modeled_mechanisms:
  - target: Hypertension
    relationship: PARTIALLY_RECAPITULATES
    model_scale: ORGANISM
    fidelity: MODERATE
    description: The knockout reproduces a salt-dependent pressure phenotype.
    limitations: Mouse kidney-specific deletion does not reproduce every human allele or tissue effect.
    evidence:
    - *id018
  - target: Increased Distal Nephron Sodium Transport
    relationship: MEASURES
    model_scale: TISSUE
    fidelity: MODERATE
    description: Transporter cleavage/phosphorylation and natriuretic drug responses inform distal sodium handling.
    limitations: Protein abundance/phosphorylation are not a complete quantitative transport-flux assay.
    evidence:
    - *id019
    - reference: PMID:28559392
      reference_title: Renal Dysfunction Induced by Kidney-Specific Gene Deletion of Hsd11b2 as a Primary Cause of Salt-Dependent Hypertension.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Acute intraperitoneal administration of amiloride-induced natriuresis and increased urinary sodium/potassium ratio more in the knockout mice compared with those in the wild-type control mice.
      explanation: A greater natriuretic response supports ENaC-associated sodium handling.
computational_models:
- name: HSD11B2 homology and molecular-dynamics variant analysis
  model_type: STRUCTURAL_PREDICTION
  publication: PMID:29229831
  description: HSD17B1 templates were used to model HSD11B2 residues 81–369, with cortisol docking and 500-ns monomer/dimer simulations. The authors proposed allele-specific effects on cofactor/substrate interactions, dimerization and structural stability. Template homology was limited and previously published activity data informed interpretation; the study did not newly assay all variants or validate an individual prenatal prognostic test.
  base_model: HSD17B1 structural templates 1IOL, 1JTV and 1FDV
  findings:
  - statement: Structural hypotheses are distinct from measured enzyme activity; the reported fetal cell-free-DNA diagnostic example concerns congenital adrenal hyperplasia, not a validated AME application.
    evidence:
    - &id020
      reference: PMID:29229831
      reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      quote_role: PRIMARY_RESULT
      snippet: Here, we report the successful identification, by computational modeling, of structural changes in silico that are induced by HSD11B2 mutations.
      explanation: The structural analysis is computational, separate from the clinical cohort.
  modeled_mechanisms:
  - target: Biallelic HSD11B2 Dysfunction
    relationship: PERTURBS
    model_scale: MOLECULAR
    fidelity: LOW
    description: Introduces sequence changes into a modeled protein to predict structural consequences.
    limitations: In-silico single-mutation effects do not establish compound-genotype function or clinical severity.
    evidence:
    - *id020
discussions:
- discussion_id: ame_renal_calcification_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which mechanisms produce nephrocalcinosis and chronic renal injury in AME?
  attaches_to:
  - phenotypes#Nephrocalcinosis
  - phenotypes#Renal insufficiency
  - pathophysiology#Renal Potassium Wasting
  rationale: Chronic hypokalemia, urinary calcium handling and renal injury are proposed contributors, but nephrocalcinosis can occur without documented hypercalciuria and may persist after potassium correction. The Chinese case series speculates about fibrosis without biopsy evidence. No necessary hypercalciuria-to-fibrosis-to-calcification chain is established.
  evidence:
  - reference: PMID:38652803
    reference_title: 'Apparent mineralocorticoid excess in Israel: a case series and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: While all patients developed nephrocalcinosis, only 1 showed hypercalciuria.
    explanation: Observed discordance limits a universal hypercalciuria-mediated route.
  - reference: PMID:29229831
    reference_title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Another notable clinical feature was nephrocalcinosis, which persisted in eight of nine patients at 4.1–14.5 y follow-up, despite treatment of hypokalemia.
    explanation: Persistence limits inference that potassium normalization necessarily reverses calcification.
- discussion_id: ame_variable_genotype_and_treatment_outcomes
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How do residual enzyme function and clinical context predict long-term treatment response?
  attaches_to:
  - genetic#HSD11B2
  - pathophysiology#Reduced 11-Beta-HSD2 Activity
  - treatments#Mineralocorticoid receptor antagonists
  rationale: Milder residual-function alleles, delayed recognition, different co-treatments and treatment-associated hyperkalemia complicate prediction from genotype or initial blood-pressure response. Computational structural interpretation is not a validated prognostic assay. Prospective natural-history data with standardized measurements are needed.
  evidence:
  - reference: PMID:38652803
    reference_title: 'Apparent mineralocorticoid excess in Israel: a case series and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Nevertheless, despite early diagnosis and management, AME is commonly associated with serious complications of the disease or its treatment.
    explanation: Longitudinal observations show remaining outcome uncertainty.
  - *id020
- discussion_id: ame_nonclassic_construct_scope
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How does the proposed nonclassic AME construct overlap with milder biallelic HSD11B2 disease?
  attaches_to:
  - genetic#HSD11B2
  - pathophysiology#Reduced 11-Beta-HSD2 Activity
  rationale: The 2020 review describes a broader partial-enzyme-deficiency construct involving genetic, epigenetic, environmental and inhibitor effects. This should not automatically be equated with genetically confirmed mild recessive AME. Its 7.1% estimate comes from a particular screening population and is not the prevalence of biallelic HSD11B2 disease. The screening construct used high serum cortisol/cortisone together with low cortisone in a selected Chilean population including normotensive and hypertensive people. Renin-guided outcome benefit is extrapolated from primary aldosteronism, not demonstrated prospectively in nonclassic AME.
  evidence:
  - reference: PMID:31909799
    reference_title: Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Nonclassic AME (NC-AME) is mainly related to partial 11βHSD2 deficiency associated with genetic variations and epigenetic modifications (first hit) and potential additive actions of endogenous or exogenous inhibitors (ie, glycyrrhetinic acid-like factors [GALFS]) and other factors (ie, age, high sodium intake) (second hit).
    explanation: The review defines a broader proposed multifactorial construct, distinct from a confirmed biallelic genotype series.
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/5691192
    reference_title: https://oup.silverchair-cdn.com/article-minimal/5691192
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: identified 9 subjects with suggestive NC-AME phenotype, of whom 2 had the previously described heterozygous pathogenic variant R213C (p.Arg213Cys), which impairs the activity and stability of 11βHSD2
    explanation: The screened phenotype is suggestive and does not constitute nine molecularly confirmed recessive cases.
  - reference: url:https://oup.silverchair-cdn.com/article-minimal/5691192
    reference_title: https://oup.silverchair-cdn.com/article-minimal/5691192
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Despite that there is no prospective data in NC-AME, inference from PA studies support the concept of improved renin levels as a proxy of MR inactivation
    explanation: The review explicitly identifies absent prospective evidence and extrapolation from primary aldosteronism.
references:
- reference: PMID:36329487
  title: 'Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.'
  findings:
  - statement: Complete 2022 review PDF read, including clinical and molecular tables. Long-term percentages were checked against the primary cohort and are not assigned a universal denominator.
- reference: PMID:9683587
  title: Molecular basis for hypertension in the "type II variant" of apparent mineralocorticoid excess.
  findings:
  - statement: Complete primary abstract read; official full-text routes returned access challenges. Host-specific assay details are not inferred.
- reference: PMID:15761540
  title: 'Apparent mineralocorticoid excess syndrome: an overview.'
  findings:
  - statement: Complete historical review read. Older treatment hierarchy and assay-sensitivity wording are qualified using newer sources; PDF extraction contains corrupted beta characters, which are not silently repaired in quotations.
- reference: PMID:3164727
  title: Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.
  findings:
  - statement: Complete original physiological paper read, including fixed-intake protocol, suppression/add-back results and co-treatment hyperkalemia. The experiment is one adult, not a universal dosing guideline.
- reference: PMID:28559392
  title: Renal Dysfunction Induced by Kidney-Specific Gene Deletion of Hsd11b2 as a Primary Cause of Salt-Dependent Hypertension.
  findings:
  - statement: Complete primary abstract read; full-text retrieval was unsuccessful. Animal dose, sex and sample-size details are not supplied by this cache.
- reference: PMID:39931437
  title: 'Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series.'
  findings:
  - statement: Complete case narratives and tables read. Abstract and final Discussion claims of universal spironolactone success conflict with case 1; report-specific unit, birthweight, blood-pressure and calciuria inconsistencies are not propagated. Val217Ala remains a VUS.
- 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.'
  findings:
  - statement: Complete case report read. Hospital-discharge outcomes do not establish long-term growth or kidney benefit. The Discussion mentions a steroid ratio without reporting numerical values or assay methods.
- reference: PMID:29229831
  title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
  findings:
  - statement: Complete clinical cohort and structural-model Methods/Results/Discussion read. Follow-up uses distinct historical and available-survivor denominators; structural predictions are not newly measured functional assays. Linked separate supplementary material was not available in the generated body.
- reference: PMID:38652803
  title: 'Apparent mineralocorticoid excess in Israel: a case series and literature review.'
  findings:
  - statement: Complete primary abstract read; seven patients from two families provide observational outcome and treatment-harm evidence, not comparative effectiveness.
- reference: clinicaltrials:NCT00474942
  title: Apparent Mineralocorticoid Excess Syndrome Natural History Clinical Protocol
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT00474942
  title: https://clinicaltrials.gov/api/v2/studies/NCT00474942
  findings:
  - statement: 'Full official registry JSON read on 2026-09-21: completed observational study, 130 affected people plus family members in total, no posted results. The denominator is not 130 confirmed AME cases.'
- reference: PMID:31909799
  title: Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome.
  findings:
  - statement: Canonical abstract and genuine complete publisher body were read, including tables, genetic/epigenetic hypotheses and care. The companion publisher URL is the full-text view of this same review, not independent evidence. Its nonclassic screening construct and selected-population frequency are not generalized to inherited biallelic AME; proposed renin-guided benefit draws on primary aldosteronism rather than prospective nonclassic-AME outcomes.
- reference: url:https://oup.silverchair-cdn.com/article-minimal/5691192
  title: https://oup.silverchair-cdn.com/article-minimal/5691192
  findings:
  - statement: Full publisher text of Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome (PMID:31909799; DOI:10.1210/clinem/dgz315), read through all scientific sections, tables and figure legends. The generated URL cache retains its URL title; canonical bibliographic identity is recorded separately. The subsequent erratum (DOI:10.1210/clinem/dgaa272) corrects reference numbering after citation 58, not clinical results.
📚

References & Deep Research

References

13
PMID:36329487
Apparent mineralocorticoid excess: comprehensive overview of molecular genetics.
1 finding
Complete 2022 review PDF read, including clinical and molecular tables. Long-term percentages were checked against the primary cohort and are not assigned a universal denominator.
PMID:9683587
Molecular basis for hypertension in the "type II variant" of apparent mineralocorticoid excess.
1 finding
Complete primary abstract read; official full-text routes returned access challenges. Host-specific assay details are not inferred.
PMID:15761540
Apparent mineralocorticoid excess syndrome: an overview.
1 finding
Complete historical review read. Older treatment hierarchy and assay-sensitivity wording are qualified using newer sources; PDF extraction contains corrupted beta characters, which are not silently repaired in quotations.
PMID:3164727
Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.
1 finding
Complete original physiological paper read, including fixed-intake protocol, suppression/add-back results and co-treatment hyperkalemia. The experiment is one adult, not a universal dosing guideline.
PMID:28559392
Renal Dysfunction Induced by Kidney-Specific Gene Deletion of Hsd11b2 as a Primary Cause of Salt-Dependent Hypertension.
1 finding
Complete primary abstract read; full-text retrieval was unsuccessful. Animal dose, sex and sample-size details are not supplied by this cache.
PMID:39931437
Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series.
1 finding
Complete case narratives and tables read. Abstract and final Discussion claims of universal spironolactone success conflict with case 1; report-specific unit, birthweight, blood-pressure and calciuria inconsistencies are not propagated. Val217Ala remains a VUS.
PMID:42503627
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.
1 finding
Complete case report read. Hospital-discharge outcomes do not establish long-term growth or kidney benefit. The Discussion mentions a steroid ratio without reporting numerical values or assay methods.
PMID:29229831
Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency.
1 finding
Complete clinical cohort and structural-model Methods/Results/Discussion read. Follow-up uses distinct historical and available-survivor denominators; structural predictions are not newly measured functional assays. Linked separate supplementary material was not available in the generated body.
PMID:38652803
Apparent mineralocorticoid excess in Israel: a case series and literature review.
1 finding
Complete primary abstract read; seven patients from two families provide observational outcome and treatment-harm evidence, not comparative effectiveness.
clinicaltrials:NCT00474942
Apparent Mineralocorticoid Excess Syndrome Natural History Clinical Protocol
No top-level findings curated for this source.
url:https://clinicaltrials.gov/api/v2/studies/NCT00474942
https://clinicaltrials.gov/api/v2/studies/NCT00474942
1 finding
Full official registry JSON read on 2026-09-21: completed observational study, 130 affected people plus family members in total, no posted results. The denominator is not 130 confirmed AME cases.
PMID:31909799
Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome.
1 finding
Canonical abstract and genuine complete publisher body were read, including tables, genetic/epigenetic hypotheses and care. The companion publisher URL is the full-text view of this same review, not independent evidence. Its nonclassic screening construct and selected-population frequency are not generalized to inherited biallelic AME; proposed renin-guided benefit draws on primary aldosteronism rather than prospective nonclassic-AME outcomes.
url:https://oup.silverchair-cdn.com/article-minimal/5691192
https://oup.silverchair-cdn.com/article-minimal/5691192
1 finding
Full publisher text of Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome (PMID:31909799; DOI:10.1210/clinem/dgz315), read through all scientific sections, tables and figure legends. The generated URL cache retains its URL title; canonical bibliographic identity is recorded separately. The subsequent erratum (DOI:10.1210/clinem/dgaa272) corrects reference numbering after citation 58, not clinical results.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record review notes

The original references, genuine deep-research narrative, available full scientific bodies and tables were reviewed. Primary long-term follow-up denominators replace percentages misattributed to all 36 patients by a later review. Detailed Chinese case narratives take precedence over contradictory abstract claims of universal spironolactone success. One reported Val217Ala genotype remains a VUS, and single-case dysmorphic findings have no inferred disease-wide frequency or demonstrated causal route. The 2026 child report ends at discharge and does not demonstrate growth catch-up or long-term renal protection. The 2004 review is historical care context; newer AME reviews and primary clinical observations qualify its dexamethasone-first framing. No dedicated AME GeneReviews chapter was identified; applicable clinical, diagnostic, management and counseling domains are supplied by AME-specific sources. The recovered full 2020 review was read through the scientific body, tables and figure legends. Its proposed nonclassic construct, screening denominator and primary-aldosteronism extrapolations remain distinct from confirmed recessive AME and AME-specific outcome evidence. Chemical annotations identify cortisol/cortisone substrates and sodium without asserting a universal circulating concentration change; increased transport is annotated separately.

Review AME mechanisms, clinical spectrum, steroid diagnostics and longitudinal care evidence · 2026-09-21T11:23:56Z · View source

Comprehensive review of all original cited references and genuine matching deep-research content, using complete cached scientific bodies and tables where available. New full primary physiological and 36-patient/structural-model papers resolve local cortisol access, renal sodium/potassium balance, selected follow-up denominators and prediction-versus-experiment boundaries. Thirteen atomic events distinguish enzyme activity, receptor access/activation, renal transport, volume and hormonal feedback, with a separately qualified placental route. Expanded 27 clinical findings preserve isolated dysmorphism without frequency claims, normal neurodevelopment in the Chinese series, and cohort-specific renal/cardiac outcomes. Corrected metabolite-versus-free-steroid ratios and normal serum cortisol. Replaced the contradicted universal spironolactone-response claim with case-specific combination treatment and monitoring; added selected cortisol suppression, transplantation and family care. Added kidney-specific mouse, residual-function expression and computational structural models with explicit limitations. The completed natural-history registry includes relatives and is not a treatment trial. Independent peers checked the graph and both recent clinical bodies; final care and diagnostic integration also passed independent review. Recovered and read the full 2020 review, retaining the proposed nonclassic screening construct and primary-aldosteronism treatment extrapolation as explicit limitations. No dedicated AME GeneReviews chapter was found. Some primary studies remain abstract-limited after sanctioned retrieval attempts; failed access-challenge bodies were excluded. Cache files were generated only with just fetch-reference.

Create: Apparent_Mineralocorticoid_Excess · 2026-07-25T00:00:49Z · View source

Created AME MONDO:0009025 HSD11B2 via parametric draft then Edison/falcon deep research; evidence from PMID:36329487 Lu 2022, PMID:31909799 Carvajal 2020, PMID:15761540 Palermo 2004, PMID:39931437 Ding 2025, and clinicaltrials:NCT00474942; validated with schema, terms, and references gates.

Falcon ▸
Apparent Mineralocorticoid Excess: Disease Characteristics Report
Edison Scientific Literature 25 citations 2026-07-24T16:48:58.372401

Apparent Mineralocorticoid Excess: Disease Characteristics Report

Executive summary

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.

1. Disease information

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

  • MONDO: MONDO:0009025.
  • OMIM: 218030.
  • MeSH: D043204, Mineralocorticoid Excess Syndrome, Apparent.
  • Open Targets disease–gene association: HSD11B2, Ensembl ENSG00000176387; association score 0.835 based on five evidence records. (OpenTargets Search: apparent mineralocorticoid excess-HSD11B2)
  • Common names: apparent mineralocorticoid excess; apparent mineralocorticoid excess syndrome; AME; syndrome of apparent mineralocorticoid excess; 11β-HSD2 deficiency; inherited cortisol-cortisone shuttle defect. “AME type II” has historically described a milder phenotype, now often termed nonclassic AME.
  • ICD: No uniquely disease-specific ICD-10 code was established in the retrieved evidence. Cases are commonly represented through hypertension, hypokalemia, endocrine/metabolic, or rare-disease codes. Mapping to a unique ICD code should therefore not be inferred without jurisdiction-specific verification.

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)

2. Etiology, risk, protection, and gene–environment interaction

Primary cause

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)

Genetic and demographic risk factors

  • Having two pathogenic HSD11B2 alleles is the principal risk factor.
  • Consanguinity, endogamy, and founder effects increase the probability of biallelic disease in particular families and populations. (lu2022apparentmineralocorticoidexcess pages 3-4, palermo2004apparentmineralocorticoidexcess pages 2-4)
  • Some heterozygotes have normal findings, whereas others show mild or moderate biochemical or blood-pressure phenotypes. Proposed explanations include haploinsufficiency, dominant-negative effects of particular proteins, and environmental “second hits”; this is not equivalent to established dominant inheritance of classic AME. (lu2022apparentmineralocorticoidexcess pages 3-4)
  • No consistent sex predominance has been reported. (lu2022apparentmineralocorticoidexcess pages 3-4)

Environmental and acquired causes

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)

Protective factors

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)

3. Phenotypes

Core clinical and laboratory phenotype

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.

4. Genetic and molecular information

Causal gene

  • Gene: HSD11B2, hydroxysteroid 11-beta dehydrogenase 2.
  • Location: chromosome 16q22; the historically described gene spans approximately 6.2 kb and contains five exons. (palermo2004apparentmineralocorticoidexcess pages 2-4)
  • Origin: constitutional/germline, not somatic.
  • Mechanism: loss or marked reduction of 11β-HSD2 enzymatic activity.

Variant spectrum and examples

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:

  • p.Arg213Cys (R213C): pathogenic in recessive AME; disrupts hydrogen bonding in the central β-sheet, protein folding, stability, and catalytic activity. It has also been reported in subjects with nonclassic phenotypes. (carvajal2020classicandnonclassic pages 13-14)
  • c.650T>C, p.Val217Ala: reported as an ACMG VUS in a homozygous child, with multiple computational predictions suggesting damage; computational evidence alone does not establish pathogenicity.
  • c.763dup, p.Val255GlyfsTer102; c.204_226del, p.Leu69AlafsTer15; c.1017C>A, p.Tyr339Ter: truncating variants reported in compound-heterozygous pediatric cases.
  • c.662C>T, p.Ala221Val: missense variant reported with p.Tyr339Ter. (ding2025casereportclinical pages 4-5)
  • rs5479, c.468C>A, p.Thr156=, and rs45483293, c.534G>A, p.Glu178= are synonymous variants associated in some cohorts with hypertension-related phenotypes, but they are not equivalent to highly penetrant classic-AME alleles. (carvajal2020classicandnonclassic pages 13-14, carvajal2020classicandnonclassic pages 12-13)

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.

Modifiers and epigenetics

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)

5. Environmental information

The environmental component is principally chemical and dietary rather than infectious:

  • Licorice/glycyrrhizin and related herbal medicines: direct 11β-HSD2 inhibition.
  • Carbenoxolone, selected azoles, grapefruit/bioflavonoid compounds: reported or proposed enzyme inhibition.
  • High sodium intake: amplifies sodium retention and salt-sensitive blood pressure.
  • Cushing syndrome/ectopic ACTH: endogenous cortisol overload can saturate the enzyme.
  • Infectious agents, smoking, radiation, pollution, and occupational exposures: no established causal role in inherited AME.

A detailed medication, supplement, confectionery, herbal-product, and dietary history is essential before diagnosing genetic AME. (lu2022apparentmineralocorticoidexcess pages 3-4, palermo2004apparentmineralocorticoidexcess pages 1-2)

6. Mechanism and pathophysiology

Causal chain

  1. Upstream trigger: biallelic HSD11B2 loss, partial genetic/epigenetic suppression, or pharmacological enzyme inhibition.
  2. Biochemical defect: reduced NAD⁺-dependent conversion of active cortisol to inactive cortisone.
  3. Receptor-level effect: cortisol reaches and activates MR in epithelial target cells. MR binds cortisol and aldosterone with similar affinity in vitro, while circulating cortisol is vastly more abundant.
  4. Renal effector response: MR-dependent transcription increases epithelial sodium channel (ENaC) and Na⁺/K⁺-ATPase activity in the distal nephron.
  5. Physiological effects: sodium/water retention, potassium and hydrogen loss, extracellular-volume expansion, hypokalemic alkalosis, and suppression of renin and aldosterone.
  6. Downstream injury: sustained hypertension and MR signaling promote endothelial oxidative stress, inflammation, vascular remodeling, cardiac hypertrophy, retinopathy, stroke, nephrocalcinosis, albuminuria, and progressive kidney damage. (carvajal2020classicandnonclassic pages 6-7, lu2022apparentmineralocorticoidexcess pages 1-3, 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.

7. Anatomical structures affected

  • Primary organ: kidney, especially distal tubule and collecting duct epithelium where 11β-HSD2 and MR are coexpressed.
  • Developmental organ: placenta, where 11β-HSD2 forms a glucocorticoid barrier protecting the fetus.
  • Other expressing tissues: distal colon, salivary gland, and restricted brain regions.
  • Secondary target organs: heart and vasculature, retina, brain, and kidneys themselves through hypertensive injury. (lu2022apparentmineralocorticoidexcess pages 1-3, palermo2004apparentmineralocorticoidexcess pages 1-2)

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.

8. Temporal development and natural history

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)

9. Inheritance and population characteristics

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)

10. Diagnostics

When to suspect AME

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)

Recommended sequence

  1. Confirm blood pressure using age-appropriate repeated or ambulatory measurements.
  2. Measure serum electrolytes, bicarbonate, creatinine/eGFR, magnesium, calcium, and urine potassium/calcium; obtain ECG when hypokalemia is substantial.
  3. Measure plasma renin activity or direct renin and plasma/serum aldosterone under interpretable medication, posture, sodium, and potassium conditions.
  4. Obtain serum or urine cortisol/cortisone and preferably urinary steroid profiling. The characteristic ratio is elevated (THF + 5αTHF)/THE.
  5. Exclude licorice, herbal products, carbenoxolone, azoles, Cushing syndrome, and exogenous glucocorticoids.
  6. Confirm with sequence and deletion/duplication analysis of HSD11B2; parental testing establishes phase. A multigene monogenic-hypertension panel or WES/WGS is appropriate when the phenotype overlaps other disorders or single-gene testing is negative. (NCT00474942 chunk 1, lu2022apparentmineralocorticoidexcess pages 1-3)

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.

Differential diagnosis

  • Primary aldosteronism: low renin but aldosterone elevated/inappropriately normal, unlike AME.
  • Liddle syndrome: low renin/aldosterone and ENaC activation, but normal cortisol–cortisone metabolism; caused by SCNN1B/SCNN1G gain-of-function.
  • 11β-hydroxylase or 17α-hydroxylase deficiency: excess deoxycorticosterone with characteristic adrenal/sex-steroid abnormalities.
  • Glucocorticoid-remediable aldosteronism: aldosterone-mediated and genetically distinct.
  • Gordon syndrome: usually hyperkalemia and metabolic acidosis rather than hypokalemic alkalosis.
  • Cushing syndrome/ectopic ACTH, licorice-induced pseudoaldosteronism, renal artery disease, and other causes of secondary hypertension.

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)

11. Outcome and prognosis

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.

12. Treatment

Core management

  • Dietary sodium restriction: reduces the salt-sensitive component; suggested MAXO concept: therapeutic low-sodium diet.
  • MR antagonists: spironolactone or eplerenone directly oppose inappropriate cortisol-driven MR activation. Reviews cite classic-AME spironolactone-equivalent dosing in the approximate range of 2–10 mg/kg/day, individualized carefully, and lower nonclassic doses such as spironolactone 12.5–25 mg/day or eplerenone 25–50 mg/day. Suggested MAXO: mineralocorticoid-receptor antagonist therapy. (lu2022apparentmineralocorticoidexcess pages 3-4, carvajal2020classicandnonclassic pages 17-19)
  • ENaC blockade: amiloride targets the downstream epithelial sodium channel and can be used alone or with MR blockade; suggested MAXO: potassium-sparing diuretic therapy.
  • Potassium replacement: oral potassium chloride for active depletion; suggested MAXO: potassium supplementation.
  • Glucocorticoid suppression: dexamethasone or related therapy has sometimes been used to suppress ACTH-driven endogenous cortisol production, but long-term glucocorticoid toxicity and incomplete response limit routine use.
  • Additional antihypertensives: used when MR/ENaC blockade and sodium restriction do not adequately control pressure.
  • Kidney transplantation: reported to resolve the renal enzymatic defect in patients with end-stage kidney disease, permitting discontinuation of spironolactone in reported cases; suggested MAXO: renal transplantation. (lu2022apparentmineralocorticoidexcess pages 3-4, ding2025casereportclinical pages 6-7)

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)

13. Prevention

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.

14. Other species and natural disease

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.

15. Model organisms and experimental systems

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 developments and expert assessment

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)

Evidence-quality statement

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)

Key source links and dates

  • Lu et al., Journal of Translational Medicine, November 2022, “Apparent mineralocorticoid excess: comprehensive overview of molecular genetics,” DOI: https://doi.org/10.1186/s12967-022-03698-9. (lu2022apparentmineralocorticoidexcess pages 1-3)
  • Carvajal et al., Journal of Clinical Endocrinology & Metabolism, 2020, “Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome,” DOI: https://doi.org/10.1210/clinem/dgz315. (carvajal2020classicandnonclassic pages 6-7)
  • Palermo et al., Arquivos Brasileiros de Endocrinologia & Metabologia, October 2004, PMID 15761540, DOI: https://doi.org/10.1590/S0004-27302004000500015. (NCT00474942 chunk 1, palermo2004apparentmineralocorticoidexcess pages 1-2)
  • Natural History of Apparent Mineralocorticoid Excess Syndrome, NCT00474942, posted May 17, 2007; completed November 2013: https://clinicaltrials.gov/study/NCT00474942. (NCT00474942 chunk 1)
  • Ding et al., Frontiers in Endocrinology, article DOI year 2024, published January 2025, DOI: https://doi.org/10.3389/fendo.2024.1491825. (ding2025casereportclinical pages 4-5)

References

  1. (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.

  2. (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.

  3. (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.

  4. (NCT00474942 chunk 1): Natural History of Apparent Mineralocorticoid Excess Syndrome. Icahn School of Medicine at Mount Sinai. 2007. ClinicalTrials.gov Identifier: NCT00474942

  5. (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.

  6. (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.

  7. (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.

  8. (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.

  9. (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.

  10. (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.

  11. (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.

  12. (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.

  13. (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.

  14. (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.

  15. (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.

  16. (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.

  17. (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.

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