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.

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

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.

Artifacts

• Edison artifact artifact-00