ACTH-Independent Macronodular Adrenal Hyperplasia 3

Mendelian MONDO:0700299 Pathograph 12 Show in embeddings browser hereditary disease Endocrine Disease Adrenal Gland Disorder

ACTH-independent macronodular adrenal hyperplasia 3 (AIMAH3) is the KDM1A-driven form of primary bilateral macronodular adrenal hyperplasia (PBMAH), and it is the molecular explanation for a clinical curiosity that had been described for three decades before its cause was known: food-dependent Cushing syndrome (FDCS), in which cortisol is low in the fasting morning state and rises after meals, inverting the normal diurnal rhythm. The mechanism is a two-hit inactivation of KDM1A (lysine demethylase 1A, LSD1), a chromatin-modifying enzyme that removes methyl marks from histone H3 lysine 4 and thereby represses transcription. Patients carry a germline heterozygous truncating variant; the adrenal nodules additionally lose the wild-type allele through a recurrent somatic deletion of chromosome 1p, where KDM1A sits. In the resulting KDM1A-null adrenocortical cells the gene encoding the receptor for glucose-dependent insulinotropic polypeptide (GIP) is derepressed and expressed ectopically. GIP is an incretin released by the gut after eating, so a receptor that should not be on adrenocortical cells at all now couples every meal to adenylate-cyclase activation and cortisol synthesis. Chronic stimulation drives bilateral macronodular hyperplasia; the resulting hypercortisolism suppresses pituitary ACTH, which is what makes the syndrome ACTH-independent. Two features make this entity worth modelling separately from PBMAH at large. First, the genotype-phenotype link is unusually tight in both directions: food-dependence was present in every KDM1A-variant patient and in no other patient in a 301-case series, and KDM1A inactivation accounts for roughly 90% of FDCS. Second, the mechanism predicts its own diagnostic test - a morning/midnight plasma cortisol ratio below 0.65 - which is a rare case of a pathophysiological model yielding a directly computable clinical discriminator. The disease is nonetheless rare in absolute terms, at about 3% of PBMAH index cases, and the reported cohorts are strikingly and unexplainedly female.

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1
Inheritance
9
Pathophys.
10
Phenotypes
5
Gaps
12
Pathograph
2
Genes
3
Medical Actions
8
References
1
Deep Research
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Inheritance

1
Autosomal Dominant HP:0000006
Transmission of the germline truncating KDM1A allele is autosomal dominant with incomplete penetrance for overt Cushing syndrome. The disease in the adrenal cortex is nonetheless recessive at the cellular level: a somatic second hit removing the wild-type allele is required for a nodule to lose KDM1A expression, which is the classic two-hit tumour-suppressor configuration.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:34655521 SUPPORT Human Clinical
"We propose that GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome results from a two-hit inactivation of KDM1A, consistent with the tumour suppressor gene model of tumorigenesis."
States the germline-plus-somatic two-hit architecture that this inheritance block describes.
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Discussions and Knowledge Gaps

5
Is adrenal-sparing surgery preferable to bilateral adrenalectomy specifically in KDM1A-related PBMAH?
KNOWLEDGE GAP aimah3_adrenal_sparing_surgery_in_kdm1a
Attached to
treatments#Adrenalectomy
The only comparative surgical outcome data in bilateral macronodular adrenal disease come from a cohort in which no KDM1A pathogenic variants were found. KDM1A patients differ from that cohort in ways that could plausibly change the answer - notably a higher integrated cortisol burden and a secretory stimulus (meals) that does not go away after partial resection. Treatment guidance for this entity is therefore currently extrapolated from a group it was measured to be absent from.
Does the morning/midnight plasma cortisol ratio below 0.65 retain its reported perfect sensitivity and specificity in an independent cohort?
KNOWLEDGE GAP aimah3_cortisol_ratio_external_validation
Attached to
biochemical#Morning to Midnight Plasma Cortisol Ratio
100% sensitivity and specificity reported in the cohort that derived a threshold is the classic setting for optimistic bias, and the KDM1A group in that series was ten patients. The figure is quoted here because it is the published one, but a discriminator with no independent validation should not be treated as settled.
Why were all reported KDM1A-variant patients female?
OPEN QUESTION aimah3_female_predominance
Attached to
genetic#KDM1A
Female predominance is near-total in the KDM1A group (all carriers) against roughly two-thirds in both comparison groups, and it reached statistical significance. No mechanism has been proposed. Candidate explanations - an effect of sex on penetrance, an ascertainment effect, or chance in a ten-patient group - have not been distinguished, and the cohorts are too small to distinguish them.
Has the cAMP/PKA step been measured in KDM1A-null adrenocortical tissue, or is it inferred from GIPR's canonical coupling?
KNOWLEDGE GAP aimah3_camp_pka_step_unmeasured
Attached to
pathophysiology#Meal-Triggered Adenylate Cyclase Activation and Cortisol Synthesis
The entry models GIPR signalling through adenylate cyclase because that is GIPR's established coupling and no other route would produce the observed postprandial cortisol rise. But the disease-specific measurements stop at GIPR transcript and protein on one side and at plasma cortisol on the other. The intervening second-messenger step is the least directly evidenced link in the chain and is flagged rather than smoothed over.
Is the reported association between KDM1A-related PBMAH and plasma-cell disorders causal, and should carriers have haematological surveillance?
OPEN QUESTION aimah3_plasma_cell_neoplasia_association
Attached to
phenotypes#Associated Extra-Adrenal Neoplasia
An expert review records adrenal myelolipoma, MGUS and multiple myeloma as associations of KDM1A-related PBMAH. If real and causal it would be clinically consequential - a germline tumour-suppressor carrier state with a second, non-adrenal neoplastic risk changes what surveillance a carrier should be offered. But the association is reported without a denominator or an incidence, the KDM1A cohorts are small, and no mechanism connecting KDM1A loss to plasma-cell biology has been proposed. The entry records the association and explicitly declines to assert a frequency.
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Pathophysiology

9
Germline Truncating KDM1A Variant
The initiating lesion is a germline heterozygous truncating variant in KDM1A at chromosome 1p36.12. The allelic series reported to date is dominated by nonsense and frameshift alleles rather than missense, which is what would be expected if the disease mechanism is loss of the protein rather than alteration of its activity. Heterozygosity alone is not sufficient to produce a nodule; it establishes the predisposed background on which the somatic second hit acts.
KDM1A hgnc:29079 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KDM1A (hgnc:29079). hgnc:29079 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Somatic Loss of the KDM1A Wild-Type Allele on 1p The germline allele is the first hit; the nodule arises where a somatic deletion removes the remaining wild-type copy.
Show evidence (2 references)
PMID:34655521 SUPPORT Human Clinical
"We identified germline heterozygous pathogenic or most likely pathogenic variants in the KDM1A gene in all 17 patients."
Establishes the germline heterozygous KDM1A variant as the constant genetic finding in this disease.
PMID:34906447 SUPPORT Human Clinical
"Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels"
Independently identifies the same germline truncating allele class in a separate multiomics cohort, and names the truncating variant type specifically.
Somatic Loss of the KDM1A Wild-Type Allele on 1p
Within adrenal lesions, a recurrent somatic deletion of the short arm of chromosome 1 removes the wild-type KDM1A allele. This is the second hit, and it is what converts a heterozygous carrier into a locally KDM1A-null tissue. Its presence in lesions and absence in control adrenal tissue is the specific observation that places KDM1A in the tumour-suppressor category rather than treating the germline variant as a simple dominant.
KDM1A hgnc:29079 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KDM1A (hgnc:29079). hgnc:29079 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Loss of KDM1A H3K4 Demethylase Activity in Adrenocortical Cells Biallelic inactivation abolishes KDM1A expression in the lesion, so the enzyme's repressive chromatin activity is lost locally.
Show evidence (2 references)
PMID:34655521 SUPPORT Human Clinical
"We also identified a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in adrenal lesions of these patients."
Documents the somatic second hit as a recurrent 1p deletion in the lesions themselves.
PMID:34655521 SUPPORT Human Clinical
"None of the 29 patients in the control groups had KDM1A germline or somatic alterations."
The control-group negative result that makes the two-hit finding specific to this disease rather than a general feature of adrenal nodules.
Loss of KDM1A H3K4 Demethylase Activity in Adrenocortical Cells
KDM1A (LSD1) is a flavin-dependent amine oxidase that demethylates mono- and di-methylated histone H3 lysine 4, a mark associated with active transcription; removing it represses target genes. Concomitant inactivation of both alleles abolishes KDM1A protein in the lesion, and the transcriptional repression it normally imposes is lifted. Note that the enzymatic interpretation is inferred from KDM1A's well-established biochemistry rather than measured directly on patient chromatin - what was measured in patients is loss of KDM1A expression at mRNA and protein level, and the downstream transcriptional consequence.
adrenocortical cell CL:0002097 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves adrenocortical cell, annotated with cortical cell of adrenal gland (CL:0002097). CL:0002097 is a cell type from the Cell Ontology.
KDM1A hgnc:29079 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KDM1A (hgnc:29079). hgnc:29079 is a gene from the HUGO Gene Nomenclature Committee.
negative regulation of transcription by RNA polymerase II GO:0000122 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of transcription by RNA polymerase II (GO:0000122). GO:0000122 is a biological process from the Gene Ontology. ↓ DECREASED
histone H3K4 demethylase activity GO:0032453 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves histone H3K4 demethylase activity (GO:0032453), qualified as loss of function. GO:0032453 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Ectopic GIP Receptor Expression in Adrenocortical Cells GIPR is one of the genes KDM1A represses in adrenocortical cells; losing KDM1A derepresses it. The causal direction was tested experimentally rather than only inferred from correlation.
Show evidence (1 reference)
PMID:34655521 SUPPORT Human Clinical
"Concomitant genetic inactivation of both KDM1A alleles resulted in loss of KDM1A expression in adrenal lesions."
Confirms that the two genetic hits translate into actual loss of KDM1A protein in the tissue, which is the step the mechanism depends on.
Ectopic GIP Receptor Expression in Adrenocortical Cells
The defining lesion of the disease. Adrenocortical cells that have lost KDM1A express the glucose-dependent insulinotropic polypeptide receptor (GIPR), a receptor they normally do not carry. This was seen as a very large upregulation of GIPR transcript in patient lesions relative to controls, and - critically for causality - was reproduced prospectively in human adrenocortical H295R cells by inhibiting or CRISPR-inactivating KDM1A. That experiment is what upgrades the relationship from association to mechanism.
adrenocortical cell CL:0002097 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves adrenocortical cell, annotated with cortical cell of adrenal gland (CL:0002097). CL:0002097 is a cell type from the Cell Ontology.
GIPR hgnc:4271 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GIPR (hgnc:4271). hgnc:4271 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Meal-Triggered Adenylate Cyclase Activation and Cortisol Synthesis GIPR is a Gs-coupled receptor, so its ectopic presence hands postprandial GIP direct control of the adrenocortical cAMP/PKA steroidogenic pathway.
Show evidence (4 references)
PMID:34655521 SUPPORT In Vitro
"In vitro pharmacological inhibition and inactivation of KDM1A by CRISPR-Cas9 genome editing resulted in an increase of GIP receptor transcripts and protein in human adrenocortical H295R cells."
The prospective in vitro test establishing that loss of KDM1A causes GIPR upregulation, rather than the two merely co-occurring in lesions.
PMID:34655521 SUPPORT Human Clinical
"GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome is caused by aberrant expression of the GIP receptor in adrenal lesions."
States the aberrant GIPR expression as the established proximate cause of the clinical syndrome.
PMID:36857084 SUPPORT Human Clinical
"This resulted from the ectopic expression of non-mutated GIP receptor in the pathological adrenal tissues of those patients."
Establishes that the receptor itself is NOT mutated - the lesion is ectopic expression of a normal GIPR, which is why the causal work is done by KDM1A-dependent derepression rather than by receptor activation.
+ 1 more reference
Meal-Triggered Adenylate Cyclase Activation and Cortisol Synthesis
GIP is an incretin secreted by intestinal K cells in response to nutrient intake. Once GIPR is present on adrenocortical cells, each meal delivers a Gs-coupled stimulus that raises cAMP and activates protein kinase A - the same second-messenger route ACTH normally uses - and drives cortisol biosynthesis. The physiological absurdity of the disease is that a normal, healthy gut hormone becomes the adrenal secretagogue.
glucocorticoid secreting cell CL:0000460 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glucocorticoid secreting cell (CL:0000460). CL:0000460 is a cell type from the Cell Ontology.
adenylate cyclase-activating G protein-coupled receptor signaling pathway GO:0007189 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189). GO:0007189 is a biological process from the Gene Ontology. ↑ INCREASED cortisol biosynthetic process GO:0034651 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cortisol biosynthetic process (GO:0034651). GO:0034651 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Inverted Diurnal Cortisol Rhythm Because secretion follows meals rather than the circadian ACTH drive, the normal morning-high/midnight-low pattern reverses.
Bilateral Macronodular Adrenocortical Hyperplasia Chronic trophic cAMP signalling in the adrenal cortex drives the nodular hyperplasia that gives the disease its name.
Show evidence (1 reference)
PMID:39921449 SUPPORT Human Clinical
"Food-dependent Cushing's syndrome was present in all patients with KDM1A variants and absent in the 2 other groups."
Supports the meal-triggered nature of cortisol secretion in every KDM1A patient; graded PARTIAL because it establishes the food-dependence of the output without measuring the cAMP/PKA step itself.
Inverted Diurnal Cortisol Rhythm
The clinical signature, and the reason these patients were historically missed. Cortisol is measured in the fasting morning state by convention; in AIMAH3 that is precisely the trough. Morning fasting cortisol is subnormal while midnight cortisol - after the evening meal - is high. The ratio of the two separates FDCS from other PBMAH with reported complete discrimination in the derivation cohort.
Downstream
ACTH-Independent Hypercortisolism Total daily cortisol output is raised despite the low morning value, which is what produces clinical Cushing syndrome.
Show evidence (1 reference)
PMID:39921449 SUPPORT Human Clinical
"In accordance with FDCS pathophysiology, patients with KDM1A variants had a lower morning fasting plasma cortisol (192 nmol/L vs 407 and 428, respectively, P = .0003) and a higher midnight plasma cortisol (487 nmol/L vs 297 and 171.96, respectively, P = .0004)."
Directly measures the inversion, with the comparison groups that make it specific to KDM1A carriers.
Bilateral Macronodular Adrenocortical Hyperplasia
Sustained receptor-driven stimulation of both adrenal cortices produces the bilateral macronodular enlargement that names the disease. Bilaterality is itself a mechanistic clue: it was the observation that prompted the search for a germline predisposition rather than a sporadic somatic driver, since two independent unilateral events would be improbable.
adrenocortical cell CL:0002097 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves adrenocortical cell, annotated with cortical cell of adrenal gland (CL:0002097). CL:0002097 is a cell type from the Cell Ontology.
Downstream
ACTH-Independent Hypercortisolism Expanded steroidogenic tissue mass amplifies the cortisol output produced by each postprandial stimulus.
Show evidence (1 reference)
PMID:34655521 SUPPORT Human Clinical
"The bilateral nature of this disease suggests germline genetic predisposition."
Records the bilaterality of the hyperplasia and the inference it licensed, which is the reasoning that led to KDM1A.
ACTH-Independent Hypercortisolism
Autonomous adrenal cortisol production suppresses pituitary corticotrophs, so plasma ACTH is low or undetectable - the feature that classifies the syndrome as ACTH-independent and distinguishes it from Cushing disease. Twenty-four-hour urinary free cortisol, which integrates across meals and so is not fooled by the inverted rhythm, is markedly raised, and is higher in KDM1A carriers than in either ARMC5-mutant or genetically unexplained PBMAH.
Downstream
Glucocorticoid Excess Tissue Injury Sustained glucocorticoid exposure produces the systemic Cushingoid phenotype.
Show evidence (1 reference)
PMID:39921449 SUPPORT Human Clinical
"KDM1A patients had a higher 24-h urinary free cortisol (3.0-fold upper limit of normal vs 1.36 for ARMC5 patients and 0.66 for wild-type patients, respectively, P = .0001)."
Quantifies the integrated cortisol excess and shows it is greater in KDM1A carriers than in the other PBMAH molecular groups.
Glucocorticoid Excess Tissue Injury
The downstream consequences are those of any chronic cortisol excess and are not specific to the KDM1A mechanism: central fat redistribution, insulin resistance and diabetes, hypertension, proximal myopathy, osteoporosis, thin skin with striae and easy bruising. They are modelled as a single terminal node rather than as separate mechanistic branches because the disease-specific biology ends upstream of them - everything distinctive about AIMAH3 is in how the cortisol comes to be secreted, not in what it then does.
Show evidence (1 reference)
PMID:42067271 SUPPORT Human Clinical
"All patients should undergo clinical and biochemical assessment for steroid excess-particularly cortisol, as many exhibit mild autonomous cortisol secretion."
Supports steroid excess as the clinically assessed consequence in PBMAH; graded PARTIAL because it is a review statement about PBMAH generally rather than a KDM1A-specific outcome measurement.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for ACTH-Independent Macronodular Adrenal Hyperplasia 3 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

10
Cardiovascular 1
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.
As above - no KDM1A-specific frequency is published, so none is asserted.
Endocrine 1
Diabetes Mellitus HP:0000819 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diabetes mellitus (HP:0000819). HP:0000819 is a phenotype from the Human Phenotype Ontology.
As above - no KDM1A-specific frequency is published, so none is asserted.
Musculoskeletal 1
Osteoporosis HP:0000939 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteoporosis (HP:0000939). HP:0000939 is a phenotype from the Human Phenotype Ontology.
As above - no KDM1A-specific frequency is published, so none is asserted.
Growth 1
Truncal Obesity HP:0001956 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Truncal obesity (HP:0001956). HP:0001956 is a phenotype from the Human Phenotype Ontology.
Recorded from the clinical definition of Cushing syndrome rather than from a KDM1A-cohort frequency measurement. No `frequency:` is asserted because the published KDM1A series do not report per-sign frequencies.
Neoplasm 1
Associated Extra-Adrenal Neoplasia Neoplasm HP:0002664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neoplasm (HP:0002664). HP:0002664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36857084 SUPPORT Human Clinical
"can be associated with adrenal myelolipoma, monoclonal gammopathy of unknown significance (MGUS), or multiple myeloma"
Reports the extra-adrenal associations. Graded PARTIAL because it is an expert review's statement of association across reported cases, with no denominator and no incidence estimate.
Other 5
Food-Dependent Hypercortisolism OBLIGATE Primary hypercortisolism HP:0001579 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Primary hypercortisolism (HP:0001579). HP:0001579 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39921449 SUPPORT Human Clinical
"Food-dependent Cushing's syndrome was present in all patients with KDM1A variants and absent in the 2 other groups."
Establishes food-dependent hypercortisolism as obligate in KDM1A carriers and absent in the comparison groups.
Increased Urinary Free Cortisol Increased urinary cortisol level HP:0012030 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased urinary cortisol level (HP:0012030). HP:0012030 is a phenotype from the Human Phenotype Ontology.
No `frequency:` is asserted. The 3.0-fold figure is a group MEAN in a ten-patient cohort, not a count of how many patients had a raised value, and the schema's FrequencyEnum bands are frequency claims. Deriving a band from a mean would be an arithmetic error dressed as an annotation. The reported normal-UFC case below is the direct counterexample.
Show evidence (2 references)
PMID:39921449 SUPPORT Human Clinical
"KDM1A patients had a higher 24-h urinary free cortisol (3.0-fold upper limit of normal vs 1.36 for ARMC5 patients and 0.66 for wild-type patients, respectively, P = .0001)."
Quantifies the cortisol excess against the two comparison groups. This is a group mean, not a per-patient frequency, which is why no frequency band is asserted on this phenotype.
PMID:21264796 SUPPORT Human Clinical
"Urinary free cortisol excretion was within normal limits, but an unusual diurnal cortisol rhythm was observed with low morning and high postprandial levels"
The counterexample, cited deliberately. A GIP-dependent patient with normal UFC whose disease was nonetheless apparent from the rhythm - so a normal UFC does not exclude the diagnosis, and the phenotype is not obligate.
Low Morning Fasting Cortisol Decreased circulating cortisol level HP:0008163 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating cortisol level (HP:0008163), qualified as temporality diurnal. HP:0008163 is a phenotype from the Human Phenotype Ontology.
Temporal: DIURNAL
The HP term names a decreased cortisol level without reference to time of day, so the binding alone reads as hypocortisolism, which would be a clinically dangerous misreading. `temporality: DIURNAL` and this note carry the qualification: the level is low only at the morning timepoint, and total daily output is raised.
Show evidence (2 references)
PMID:39921449 SUPPORT Human Clinical
"In accordance with FDCS pathophysiology, patients with KDM1A variants had a lower morning fasting plasma cortisol (192 nmol/L vs 407 and 428, respectively, P = .0003) and a higher midnight plasma cortisol (487 nmol/L vs 297 and 171.96, respectively, P = .0004)."
Measures the low morning value against both comparison groups, with the paired midnight value that shows it is a rhythm inversion rather than deficiency.
PMID:21264796 SUPPORT Human Clinical
"an unusual diurnal cortisol rhythm was observed with low morning and high postprandial levels"
Independent single-patient observation of the same low-morning/high-postprandial pattern.
Decreased Circulating ACTH Decreased circulating ACTH concentration HP:0002920 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating ACTH concentration (HP:0002920). HP:0002920 is a phenotype from the Human Phenotype Ontology.
Evidenced at the level of PBMAH rather than of KDM1A-related PBMAH specifically. None of the KDM1A cohort papers reports ACTH values, so the citations below are a PBMAH case report and a PBMAH review. The inference to KDM1A carriers is safe - ACTH-independence is definitional for the parent entity and the KDM1A form is a subset of it - but it is an inference, and the evidence grading says so. One nuance the entry does not smooth over: a 2026 review notes intra-adrenal ACTH production by steroidogenic cells in PBMAH, so "ACTH-independent" refers to independence from PITUITARY ACTH, not to the absence of ACTH signalling altogether.
Show evidence (3 references)
PMID:39465833 SUPPORT Human Clinical
"Her laboratory results showed increased cortisol and suppressed ACTH, and an abdominal CT scan revealed 2 heterogeneous masses in the adrenal glands."
A measured suppressed ACTH with the expected raised cortisol and bilateral adrenal masses. Graded PARTIAL because it is a single PBMAH case report with no KDM1A genotype, so it evidences the parent entity's biochemistry rather than this disease's.
PMID:39465833 SUPPORT Human Clinical
"In PBMAH, enlarged adrenal nodules secrete cortisol independently of corticotropin (ACTH), causing mild to overt CS."
States the ACTH-independence of cortisol secretion in PBMAH, which is the mechanism this phenotype reflects.
PMID:42067271 SUPPORT Human Clinical
"Aberrant hormone receptor expression and intra-adrenal adrenocorticotropin production by steroidogenic cells may also contribute to cortisol dysregulation in many patients."
Cited as the qualification rather than the support - intra-adrenal ACTH production means "ACTH-independent" describes independence from pituitary ACTH specifically.
Bilateral Adrenal Hyperplasia OBLIGATE HP:0008221 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Adrenal hyperplasia (HP:0008221). HP:0008221 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34655521 SUPPORT Human Clinical
"The bilateral nature of this disease suggests germline genetic predisposition."
Documents the bilateral hyperplasia that defines the entity.
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Genetic Associations

2
KDM1A
Gene: KDM1A hgnc:29079 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KDM1A (hgnc:29079). hgnc:29079 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE_AND_SOMATIC
Show evidence (2 references)
PMID:34906447 SUPPORT Human Clinical
"Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels"
Establishes the germline truncating plus somatic-LOH genotype that this genetic block records.
PMID:39921449 SUPPORT Human Clinical
"All patients with KDM1A variants were women, vs 65% of ARMC5 patients and 67% of wild-type patients (P = .0337)."
Records the unexplained female predominance among KDM1A carriers.
ARMC5
Gene: ARMC5 hgnc:25781 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ARMC5 (hgnc:25781). hgnc:25781 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER
Show evidence (1 reference)
PMID:34906447 SUPPORT Human Clinical
"Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS."
Establishes ARMC5 and the food-dependent phenotype as non-overlapping, which is what makes this a boundary rather than a differential within the entry.
💊

Medical Actions

3
Adrenalectomy
Action: adrenalectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is adrenalectomy (NCIT:C15177). NCIT:C15177 is a clinical intervention from the NCI Thesaurus. Ontology label: Adrenalectomy NCIT:C15177
Surgical removal of adrenal tissue is the definitive treatment for the hypercortisolism. In bilateral macronodular disease the choice between bilateral adrenalectomy, unilateral adrenalectomy and adrenal-sparing partial resection is a trade-off between remission and lifelong adrenal insufficiency. A long-term BMAD follow-up series reported markedly better remission with adrenal-sparing surgery than with unilateral adrenalectomy - but that series contained no KDM1A-variant patients, so it is evidence about the parent entity and not about this disease.
Mechanism Target:
ACTH-Independent Hypercortisolism — Removing steroidogenic tissue removes the source of the autonomous cortisol regardless of what is stimulating it.
Show evidence (1 reference)
PMID:40810200 SUPPORT Human Clinical
"Adrenal-sparing surgery achieved 100% remission vs a 40% remission rate for unilateral adrenalectomy."
Compares surgical strategies in bilateral macronodular adrenal disease. Graded PARTIAL deliberately - the cohort is BMAD generally and the same report states no KDM1A pathogenic variants were identified in it, so this cannot be read as a KDM1A-specific outcome.
Somatostatin Analogue Therapy
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: octreotide CHEBI:7726 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses octreotide (CHEBI:7726). CHEBI:7726 is a therapeutic agent from Chemical Entities of Biological Interest. pasireotide CHEBI:72312 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pasireotide (CHEBI:72312). CHEBI:72312 is a therapeutic agent from Chemical Entities of Biological Interest.
The obvious mechanism-directed drug idea, and it does not work. Somatostatin analogues suppress GIP release from intestinal K cells, so they should in principle cut off the stimulus driving cortisol secretion. In the one detailed published trial - a single patient given octreotide for six months and then pasireotide for three - both drugs did acutely suppress the postprandial cortisol response, but the effect escaped, and neither improved the clinical or metabolic features. The patient proceeded to bilateral adrenalectomy. The authors concluded the failure was independent of somatostatin receptor subtype affinity, which matters because it removes the natural next move of trying a broader-spectrum analogue.
Mechanism Target:
Meal-Triggered Adenylate Cyclase Activation and Cortisol Synthesis — Suppressing postprandial GIP secretion removes the ligand for the ectopic receptor, which is why the strategy was attempted.
Show evidence (2 references)
PMID:21264796 REFUTE Human Clinical
"Although inducing a significant acute suppression of post-prandial cortisol response, both drugs had no effects on the clinical and metabolic abnormalities associated with Cushing's syndrome and new tests performed at the end of each treatment period confirmed escape of post-meal cortisol..."
Graded REFUTE against sustained clinical benefit from somatostatin analogues. Note this is a single patient, so it refutes the strategy as tried rather than excluding all somatostatin-based approaches.
PMID:21264796 SUPPORT Human Clinical
"This case report illustrates the lack of sustained efficacy of somatostatin analogues on GIP-dependent Cushing's syndrome, independent of their affinity for the different somatostatin receptor subtypes."
The authors' own generalisation, and specifically that receptor-subtype affinity does not explain the failure.
Genetic Counselling and Family Screening
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. Ontology label: Genetic Counseling NCIT:C15240
Because the predisposing allele is germline and dominantly transmitted, and because the mechanism yields a cheap biochemical screen (the morning/midnight cortisol ratio) as well as a gene test, first-degree relatives of an index case can be offered testing. Both discovery cohorts explicitly recommended this.
Show evidence (2 references)
PMID:34655521 SUPPORT Human Clinical
"Genetic testing and counselling should be offered to these patients and their relatives."
The discovery cohort's explicit recommendation for family genetic counselling.
PMID:34906447 SUPPORT Human Clinical
"Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management."
Independent recommendation of germline screening in operated PBMAH patients and their families.
🔬

Biochemical Markers

1
Morning to Midnight Plasma Cortisol Ratio
Show evidence (1 reference)
PMID:39921449 SUPPORT Human Clinical
"Morning/midnight plasma cortisol ratio below 0.65 holds 100% sensitivity and specificity for the detection of FDCS."
The primary report of the ratio and its reported discrimination.
🔬

Diagnosis

4
Mixed meal test with oral versus intravenous glucose
The confirmatory test, and the cleanest physiological demonstration of the modelled mechanism. Cortisol rises after a mixed meal, and - decisively - after ORAL but not INTRAVENOUS glucose. The oral/intravenous dissociation is the whole argument: only the oral route passes nutrients through the gut and triggers GIP release from intestinal K cells, so a cortisol response that depends on the route rather than on the glucose load localises the stimulus to an incretin. Failure of cortisol to suppress after dexamethasone establishes the autonomy.
Show evidence (2 references)
PMID:21264796 SUPPORT Human Clinical
"The diagnosis was confirmed by further investigations, showing significant plasma cortisol responses after a mixed meal test and after oral, but not intravenous glucose administration, as well as ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH)."
The diagnostic protocol and the oral-versus-intravenous dissociation that identifies the stimulus as gut-derived.
PMID:21264796 SUPPORT Human Clinical
"associated with the absence of cortisol suppression after dexamethasone, suggesting the possibility of GIP-dependent Cushing's syndrome"
The dexamethasone non-suppression that establishes autonomous secretion and prompts the food-dependence workup.
Morning to midnight plasma cortisol ratio as a screening discriminator
A cheap biochemical screen derived directly from the mechanism: two timed plasma cortisol measurements, no dynamic testing. A ratio below 0.65 was reported to separate food-dependent from other PBMAH completely in the cohort that derived it. See the `biochemical` entry of the same name for the measurement itself and the validation caveat - the 100% figure is a derivation-cohort result in ten patients and has not been externally validated.
Show evidence (1 reference)
PMID:39921449 SUPPORT Human Clinical
"Morning/midnight plasma cortisol ratio below 0.65 holds 100% sensitivity and specificity for the detection of FDCS."
The reported discriminator and its performance in the derivation cohort.
Germline KDM1A and ARMC5 sequencing
Molecular confirmation. Because the two genes define mutually exclusive molecular groups with different phenotypes, they are screened together and the result is informative either way: KDM1A predicts food-dependence, ARMC5 predicts its absence. A positive germline result also converts the proband's relatives into testable at-risk individuals, which is the practical reason the discovery cohorts recommend it.
Show evidence (2 references)
PMID:34906447 SUPPORT Human Clinical
"Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management."
The recommendation to screen both genes in operated PBMAH patients and their families.
PMID:39921449 SUPPORT Human Clinical
"KDM1A germline pathogenic variants are rare in PBMAH and account for <5% of index cases."
Sets the expected yield of KDM1A testing in an unselected PBMAH population, which is what makes the food-dependence phenotype the useful pre-test filter.
Adrenal cross-sectional imaging
CT or MRI demonstrating bilateral macronodular adrenal enlargement. Imaging is increasingly the entry point rather than the confirmation - PBMAH is now often detected incidentally in asymptomatic people - which is precisely why every such finding needs biochemical assessment for steroid excess rather than reassurance.
Show evidence (2 references)
PMID:42067271 SUPPORT Human Clinical
"Primary bilateral macronodular adrenal hyperplasia (PBMAH) is increasingly recognized as imaging is widely used, leading to incidental detection in asymptomatic individuals. Adrenal imaging defines radiologic features."
Establishes imaging as the modern route to detection and its role in defining the radiological entity.
PMID:39465833 SUPPORT Human Clinical
"an abdominal CT scan revealed 2 heterogeneous masses in the adrenal glands"
A worked example of the imaging finding in a biochemically confirmed case.
📊

Prevalence

2
PBMAH index cases, 8 international endocrinology departments
Cases In Literature Unknown
Not a population prevalence. This is the share of KDM1A carriers among patients already diagnosed with PBMAH - 10 of 301 consecutive index cases (3.3%). The population prevalence of AIMAH3 is unknown because the denominator, PBMAH itself, is increasingly detected incidentally on imaging and has no settled population estimate.
Show evidence (1 reference)
PMID:39921449 SUPPORT Human Clinical
"Ten (3.3%) patients carried a germline KDM1A pathogenic or likely pathogenic variant, 60 (19.9%) carried a germline ARMC5 alteration, and 231 (76.8%) had no identified genetic predisposition."
The systematic screening study that quantifies the KDM1A share of PBMAH index cases.
Patients with food-dependent Cushing syndrome and PBMAH
Cases In Literature Unknown
The converse fraction, and the more informative one: among patients selected for the food-dependent phenotype rather than for PBMAH, KDM1A explains most cases.
Show evidence (1 reference)
PMID:34906447 SUPPORT Human Clinical
"KDM1A inactivation explains about 90% of FDCS PBMAH."
Quantifies the diagnostic yield of KDM1A testing in the food-dependent subgroup.
{ }

Source YAML

click to show 
name: ACTH-Independent Macronodular Adrenal Hyperplasia 3
creation_date: "2026-08-28T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: KDM1A-related primary bilateral macronodular adrenal hyperplasia with food-dependent Cushing syndrome
  term:
    id: MONDO:0700299
    label: ACTH-independent macronodular adrenal hyperplasia 3
description: >-
  ACTH-independent macronodular adrenal hyperplasia 3 (AIMAH3) is the KDM1A-driven
  form of primary bilateral macronodular adrenal hyperplasia (PBMAH), and it is
  the molecular explanation for a clinical curiosity that had been described for
  three decades before its cause was known: food-dependent Cushing syndrome
  (FDCS), in which cortisol is low in the fasting morning state and rises after
  meals, inverting the normal diurnal rhythm.
  The mechanism is a two-hit inactivation of KDM1A (lysine demethylase 1A, LSD1),
  a chromatin-modifying enzyme that removes methyl marks from histone H3 lysine 4
  and thereby represses transcription. Patients carry a germline heterozygous
  truncating variant; the adrenal nodules additionally lose the wild-type allele
  through a recurrent somatic deletion of chromosome 1p, where KDM1A sits. In the
  resulting KDM1A-null adrenocortical cells the gene encoding the receptor for
  glucose-dependent insulinotropic polypeptide (GIP) is derepressed and expressed
  ectopically. GIP is an incretin released by the gut after eating, so a receptor
  that should not be on adrenocortical cells at all now couples every meal to
  adenylate-cyclase activation and cortisol synthesis. Chronic stimulation drives
  bilateral macronodular hyperplasia; the resulting hypercortisolism suppresses
  pituitary ACTH, which is what makes the syndrome ACTH-independent.
  Two features make this entity worth modelling separately from PBMAH at large.
  First, the genotype-phenotype link is unusually tight in both directions:
  food-dependence was present in every KDM1A-variant patient and in no other
  patient in a 301-case series, and KDM1A inactivation accounts for roughly 90%
  of FDCS. Second, the mechanism predicts its own diagnostic test - a
  morning/midnight plasma cortisol ratio below 0.65 - which is a rare case of a
  pathophysiological model yielding a directly computable clinical discriminator.
  The disease is nonetheless rare in absolute terms, at about 3% of PBMAH index
  cases, and the reported cohorts are strikingly and unexplainedly female.
parents:
- hereditary disease
- Endocrine Disease
- Adrenal Gland Disorder
synonyms:
- AIMAH3
- ACTH-independent macronodular adrenal hyperplasia-3
- Cushing syndrome, food-dependent
- food-dependent Cushing syndrome
- GIP-dependent primary bilateral macronodular adrenal hyperplasia
- KDM1A-related primary bilateral macronodular adrenal hyperplasia
- KDM1A-related bilateral macronodular adrenocortical disease
notes: >-
  Naming. The MONDO label uses the older "ACTH-independent macronodular adrenal
  hyperplasia" nomenclature and the OMIM-style numeric suffix. The current
  endocrine literature calls the parent entity primary bilateral macronodular
  adrenal hyperplasia (PBMAH) or bilateral macronodular adrenocortical disease
  (BMAD), and calls this specific form KDM1A-related PBMAH or food-dependent
  Cushing syndrome. The entry keeps the MONDO label in `disease_term.term.label`
  because that is the canonical ontology string, and puts the clinically current
  description in `preferred_term` and the synonym list. Curators searching for
  this entity are far more likely to search "food-dependent Cushing" than
  "AIMAH3".

  Scope boundary. This entry is the KDM1A form only. ARMC5-related PBMAH is a
  distinct molecular group with a different phenotype (more severe basal
  hypercortisolism, no food dependence) and is not curated here. The
  ACTH-dependent and general Cushing umbrella is `Cushings_Syndrome`; the
  corticotroph-adenoma cause is `USP8-related_pituitary_adenoma_4`. KDM1A also
  causes an unrelated neurodevelopmental disease
  (`KDM1A-Related_Neurodevelopmental_Disorder`, MONDO:0014751) - the same gene,
  a different disease, and a different variant class.
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Transmission of the germline truncating KDM1A allele is autosomal dominant
    with incomplete penetrance for overt Cushing syndrome. The disease in the
    adrenal cortex is nonetheless recessive at the cellular level: a somatic
    second hit removing the wild-type allele is required for a nodule to lose
    KDM1A expression, which is the classic two-hit tumour-suppressor
    configuration.
  evidence:
  - reference: PMID:34655521
    reference_title: "Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome results from a two-hit inactivation of KDM1A, consistent with the tumour suppressor gene model of tumorigenesis."
    explanation: States the germline-plus-somatic two-hit architecture that this inheritance block describes.
prevalence:
- population: PBMAH index cases, 8 international endocrinology departments
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Not a population prevalence. This is the share of KDM1A carriers among
    patients already diagnosed with PBMAH - 10 of 301 consecutive index cases
    (3.3%). The population prevalence of AIMAH3 is unknown because the
    denominator, PBMAH itself, is increasingly detected incidentally on imaging
    and has no settled population estimate.
  evidence:
  - reference: PMID:39921449
    reference_title: "KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten (3.3%) patients carried a germline KDM1A pathogenic or likely pathogenic variant, 60 (19.9%) carried a germline ARMC5 alteration, and 231 (76.8%) had no identified genetic predisposition."
    explanation: The systematic screening study that quantifies the KDM1A share of PBMAH index cases.
- population: Patients with food-dependent Cushing syndrome and PBMAH
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    The converse fraction, and the more informative one: among patients selected
    for the food-dependent phenotype rather than for PBMAH, KDM1A explains most
    cases.
  evidence:
  - reference: PMID:34906447
    reference_title: KDM1A inactivation causes hereditary food-dependent Cushing syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KDM1A inactivation explains about 90% of FDCS PBMAH."
    explanation: Quantifies the diagnostic yield of KDM1A testing in the food-dependent subgroup.
pathophysiology:
- name: Germline Truncating KDM1A Variant
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion is a germline heterozygous truncating variant in KDM1A
    at chromosome 1p36.12. The allelic series reported to date is dominated by
    nonsense and frameshift alleles rather than missense, which is what would be
    expected if the disease mechanism is loss of the protein rather than
    alteration of its activity. Heterozygosity alone is not sufficient to produce
    a nodule; it establishes the predisposed background on which the somatic
    second hit acts.
  genes:
  - preferred_term: KDM1A
    term:
      id: hgnc:29079
      label: KDM1A
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:34655521
    reference_title: "Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified germline heterozygous pathogenic or most likely pathogenic variants in the KDM1A gene in all 17 patients."
    explanation: Establishes the germline heterozygous KDM1A variant as the constant genetic finding in this disease.
  - reference: PMID:34906447
    reference_title: KDM1A inactivation causes hereditary food-dependent Cushing syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels"
    explanation: Independently identifies the same germline truncating allele class in a separate multiomics cohort, and names the truncating variant type specifically.
  downstream:
  - target: Somatic Loss of the KDM1A Wild-Type Allele on 1p
    causal_link_type: DIRECT
    description: >-
      The germline allele is the first hit; the nodule arises where a somatic
      deletion removes the remaining wild-type copy.
- name: Somatic Loss of the KDM1A Wild-Type Allele on 1p
  biological_scale: MOLECULAR
  description: >-
    Within adrenal lesions, a recurrent somatic deletion of the short arm of
    chromosome 1 removes the wild-type KDM1A allele. This is the second hit, and
    it is what converts a heterozygous carrier into a locally KDM1A-null tissue.
    Its presence in lesions and absence in control adrenal tissue is the specific
    observation that places KDM1A in the tumour-suppressor category rather than
    treating the germline variant as a simple dominant.
  genes:
  - preferred_term: KDM1A
    term:
      id: hgnc:29079
      label: KDM1A
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:34655521
    reference_title: "Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also identified a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in adrenal lesions of these patients."
    explanation: Documents the somatic second hit as a recurrent 1p deletion in the lesions themselves.
  - reference: PMID:34655521
    reference_title: "Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the 29 patients in the control groups had KDM1A germline or somatic alterations."
    explanation: The control-group negative result that makes the two-hit finding specific to this disease rather than a general feature of adrenal nodules.
  downstream:
  - target: Loss of KDM1A H3K4 Demethylase Activity in Adrenocortical Cells
    causal_link_type: DIRECT
    description: >-
      Biallelic inactivation abolishes KDM1A expression in the lesion, so the
      enzyme's repressive chromatin activity is lost locally.
- name: Loss of KDM1A H3K4 Demethylase Activity in Adrenocortical Cells
  biological_scale: MOLECULAR
  description: >-
    KDM1A (LSD1) is a flavin-dependent amine oxidase that demethylates
    mono- and di-methylated histone H3 lysine 4, a mark associated with active
    transcription; removing it represses target genes. Concomitant inactivation
    of both alleles abolishes KDM1A protein in the lesion, and the transcriptional
    repression it normally imposes is lifted. Note that the enzymatic
    interpretation is inferred from KDM1A's well-established biochemistry rather
    than measured directly on patient chromatin - what was measured in patients is
    loss of KDM1A expression at mRNA and protein level, and the downstream
    transcriptional consequence.
  genes:
  - preferred_term: KDM1A
    term:
      id: hgnc:29079
      label: KDM1A
  molecular_functions:
  - preferred_term: histone H3K4 demethylase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0032453
      label: histone H3K4 demethylase activity
  biological_processes:
  - preferred_term: negative regulation of transcription by RNA polymerase II
    modifier: DECREASED
    term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
  cell_types:
  - preferred_term: adrenocortical cell
    term:
      id: CL:0002097
      label: cortical cell of adrenal gland
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:34655521
    reference_title: "Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Concomitant genetic inactivation of both KDM1A alleles resulted in loss of KDM1A expression in adrenal lesions."
    explanation: Confirms that the two genetic hits translate into actual loss of KDM1A protein in the tissue, which is the step the mechanism depends on.
  downstream:
  - target: Ectopic GIP Receptor Expression in Adrenocortical Cells
    causal_link_type: DIRECT
    description: >-
      GIPR is one of the genes KDM1A represses in adrenocortical cells; losing
      KDM1A derepresses it. The causal direction was tested experimentally rather
      than only inferred from correlation.
- name: Ectopic GIP Receptor Expression in Adrenocortical Cells
  biological_scale: CELLULAR
  description: >-
    The defining lesion of the disease. Adrenocortical cells that have lost KDM1A
    express the glucose-dependent insulinotropic polypeptide receptor (GIPR), a
    receptor they normally do not carry. This was seen as a very large
    upregulation of GIPR transcript in patient lesions relative to controls, and -
    critically for causality - was reproduced prospectively in human adrenocortical
    H295R cells by inhibiting or CRISPR-inactivating KDM1A. That experiment is
    what upgrades the relationship from association to mechanism.
  genes:
  - preferred_term: GIPR
    term:
      id: hgnc:4271
      label: GIPR
  cell_types:
  - preferred_term: adrenocortical cell
    term:
      id: CL:0002097
      label: cortical cell of adrenal gland
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:34655521
    reference_title: "Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro pharmacological inhibition and inactivation of KDM1A by CRISPR-Cas9 genome editing resulted in an increase of GIP receptor transcripts and protein in human adrenocortical H295R cells."
    explanation: The prospective in vitro test establishing that loss of KDM1A causes GIPR upregulation, rather than the two merely co-occurring in lesions.
  - reference: PMID:34655521
    reference_title: "Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome is caused by aberrant expression of the GIP receptor in adrenal lesions."
    explanation: States the aberrant GIPR expression as the established proximate cause of the clinical syndrome.
  - reference: PMID:36857084
    reference_title: "Extensive expertise in endocrinology: glucose-dependent insulinotropic peptide-dependent Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This resulted from the ectopic expression of non-mutated GIP receptor in the pathological adrenal tissues of those patients."
    explanation: >-
      Establishes that the receptor itself is NOT mutated - the lesion is ectopic
      expression of a normal GIPR, which is why the causal work is done by
      KDM1A-dependent derepression rather than by receptor activation.
  - reference: PMID:36857084
    reference_title: "Extensive expertise in endocrinology: glucose-dependent insulinotropic peptide-dependent Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recently, germline lysine demythylase 1A (KDMIA) mutations combined with somatic chromosome 1p deletions were found to be specifically responsible for ectopic GIPR in sporadic or familial GIP-dependent PBMAH"
    explanation: Independent review confirmation that the germline-plus-somatic KDM1A lesion is what produces the ectopic receptor.
  downstream:
  - target: Meal-Triggered Adenylate Cyclase Activation and Cortisol Synthesis
    causal_link_type: DIRECT
    description: >-
      GIPR is a Gs-coupled receptor, so its ectopic presence hands postprandial
      GIP direct control of the adrenocortical cAMP/PKA steroidogenic pathway.
- name: Meal-Triggered Adenylate Cyclase Activation and Cortisol Synthesis
  biological_scale: CELLULAR
  description: >-
    GIP is an incretin secreted by intestinal K cells in response to nutrient
    intake. Once GIPR is present on adrenocortical cells, each meal delivers a
    Gs-coupled stimulus that raises cAMP and activates protein kinase A - the same
    second-messenger route ACTH normally uses - and drives cortisol biosynthesis.
    The physiological absurdity of the disease is that a normal, healthy
    gut hormone becomes the adrenal secretagogue.
  cell_types:
  - preferred_term: glucocorticoid secreting cell
    term:
      id: CL:0000460
      label: glucocorticoid secreting cell
  biological_processes:
  - preferred_term: adenylate cyclase-activating G protein-coupled receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007189
      label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
  - preferred_term: cortisol biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0034651
      label: cortisol biosynthetic process
  mechanism_confidence: ESTABLISHED
  notes: >-
    The cAMP/PKA step is standard GIPR receptor biology rather than something
    measured in this disease's own patient material; it is included because it is
    the only route by which a Gs-coupled receptor could produce the observed
    postprandial cortisol rise, but the entry does not cite a
    disease-specific measurement for it.
  evidence:
  - reference: PMID:39921449
    reference_title: "KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Food-dependent Cushing's syndrome was present in all patients with KDM1A variants and absent in the 2 other groups."
    explanation: Supports the meal-triggered nature of cortisol secretion in every KDM1A patient; graded PARTIAL because it establishes the food-dependence of the output without measuring the cAMP/PKA step itself.
  downstream:
  - target: Inverted Diurnal Cortisol Rhythm
    causal_link_type: DIRECT
    description: >-
      Because secretion follows meals rather than the circadian ACTH drive, the
      normal morning-high/midnight-low pattern reverses.
  - target: Bilateral Macronodular Adrenocortical Hyperplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Chronic trophic cAMP signalling in the adrenal cortex drives the nodular
      hyperplasia that gives the disease its name.
- name: Inverted Diurnal Cortisol Rhythm
  biological_scale: ORGANISM
  description: >-
    The clinical signature, and the reason these patients were historically
    missed. Cortisol is measured in the fasting morning state by convention;
    in AIMAH3 that is precisely the trough. Morning fasting cortisol is
    subnormal while midnight cortisol - after the evening meal - is high. The
    ratio of the two separates FDCS from other PBMAH with reported complete
    discrimination in the derivation cohort.
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:39921449
    reference_title: "KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In accordance with FDCS pathophysiology, patients with KDM1A variants had a lower morning fasting plasma cortisol (192 nmol/L vs 407 and 428, respectively, P = .0003) and a higher midnight plasma cortisol (487 nmol/L vs 297 and 171.96, respectively, P = .0004)."
    explanation: Directly measures the inversion, with the comparison groups that make it specific to KDM1A carriers.
  downstream:
  - target: ACTH-Independent Hypercortisolism
    causal_link_type: DIRECT
    description: >-
      Total daily cortisol output is raised despite the low morning value, which
      is what produces clinical Cushing syndrome.
- name: Bilateral Macronodular Adrenocortical Hyperplasia
  biological_scale: TISSUE
  description: >-
    Sustained receptor-driven stimulation of both adrenal cortices produces the
    bilateral macronodular enlargement that names the disease. Bilaterality is
    itself a mechanistic clue: it was the observation that prompted the search for
    a germline predisposition rather than a sporadic somatic driver, since two
    independent unilateral events would be improbable.
  cell_types:
  - preferred_term: adrenocortical cell
    term:
      id: CL:0002097
      label: cortical cell of adrenal gland
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:34655521
    reference_title: "Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The bilateral nature of this disease suggests germline genetic predisposition."
    explanation: Records the bilaterality of the hyperplasia and the inference it licensed, which is the reasoning that led to KDM1A.
  downstream:
  - target: ACTH-Independent Hypercortisolism
    causal_link_type: DIRECT
    description: >-
      Expanded steroidogenic tissue mass amplifies the cortisol output produced by
      each postprandial stimulus.
- name: ACTH-Independent Hypercortisolism
  biological_scale: ORGANISM
  description: >-
    Autonomous adrenal cortisol production suppresses pituitary corticotrophs, so
    plasma ACTH is low or undetectable - the feature that classifies the syndrome
    as ACTH-independent and distinguishes it from Cushing disease. Twenty-four-hour
    urinary free cortisol, which integrates across meals and so is not fooled by
    the inverted rhythm, is markedly raised, and is higher in KDM1A carriers than
    in either ARMC5-mutant or genetically unexplained PBMAH.
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:39921449
    reference_title: "KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KDM1A patients had a higher 24-h urinary free cortisol (3.0-fold upper limit of normal vs 1.36 for ARMC5 patients and 0.66 for wild-type patients, respectively, P = .0001)."
    explanation: Quantifies the integrated cortisol excess and shows it is greater in KDM1A carriers than in the other PBMAH molecular groups.
  downstream:
  - target: Glucocorticoid Excess Tissue Injury
    causal_link_type: DIRECT
    description: >-
      Sustained glucocorticoid exposure produces the systemic Cushingoid
      phenotype.
- name: Glucocorticoid Excess Tissue Injury
  biological_scale: ORGANISM
  description: >-
    The downstream consequences are those of any chronic cortisol excess and are
    not specific to the KDM1A mechanism: central fat redistribution, insulin
    resistance and diabetes, hypertension, proximal myopathy, osteoporosis, thin
    skin with striae and easy bruising. They are modelled as a single terminal
    node rather than as separate mechanistic branches because the disease-specific
    biology ends upstream of them - everything distinctive about AIMAH3 is in how
    the cortisol comes to be secreted, not in what it then does.
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:42067271
    reference_title: Primary Bilateral Macronodular Adrenal Hyperplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients should undergo clinical and biochemical assessment for steroid excess-particularly cortisol, as many exhibit mild autonomous cortisol secretion."
    explanation: Supports steroid excess as the clinically assessed consequence in PBMAH; graded PARTIAL because it is a review statement about PBMAH generally rather than a KDM1A-specific outcome measurement.
genetic:
- name: KDM1A
  gene_term:
    preferred_term: KDM1A
    term:
      id: hgnc:29079
      label: KDM1A
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE_AND_SOMATIC
  notes: >-
    KDM1A encodes lysine-specific demethylase 1A (LSD1) at 1p36.12. In AIMAH3 it
    behaves as a two-hit tumour suppressor: a germline heterozygous truncating
    allele plus somatic loss of the wild-type allele on 1p within the adrenal
    lesion. Every KDM1A-variant patient in the systematic screening series was
    female, an association that is unexplained and is recorded here as an
    observation rather than a mechanism.

    Variant configuration: germline heterozygous truncating allele (loss of
    function), with somatic loss of heterozygosity through 1p deletion in the
    affected adrenal tissue. `variant_origin: GERMLINE_AND_SOMATIC` records that
    both compartments are involved; the per-compartment zygosity (heterozygous in
    the germline, effectively null in the lesion) cannot be expressed in a single
    slot and is stated here instead.
  evidence:
  - reference: PMID:34906447
    reference_title: KDM1A inactivation causes hereditary food-dependent Cushing syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels"
    explanation: Establishes the germline truncating plus somatic-LOH genotype that this genetic block records.
  - reference: PMID:39921449
    reference_title: "KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients with KDM1A variants were women, vs 65% of ARMC5 patients and 67% of wild-type patients (P = .0337)."
    explanation: Records the unexplained female predominance among KDM1A carriers.
- name: ARMC5
  gene_term:
    preferred_term: ARMC5
    term:
      id: hgnc:25781
      label: ARMC5
  relationship_type: MODIFIER
  notes: >-
    Not a cause of AIMAH3, and listed only to fix the boundary. ARMC5 is the
    commoner PBMAH predisposition gene and defines a separate molecular group
    whose patients do not have food-dependent cortisol secretion. The two genes
    have been reported as mutually exclusive in the series that examined both.
  evidence:
  - reference: PMID:34906447
    reference_title: KDM1A inactivation causes hereditary food-dependent Cushing syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS."
    explanation: Establishes ARMC5 and the food-dependent phenotype as non-overlapping, which is what makes this a boundary rather than a differential within the entry.
phenotypes:
- category: Endocrine
  name: Food-Dependent Hypercortisolism
  description: >-
    Cortisol secretion driven by meals rather than by circadian ACTH release,
    giving a low fasting morning cortisol and a raised midnight cortisol. Present
    in every reported KDM1A-variant patient.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Primary hypercortisolism
    term:
      id: HP:0001579
      label: Primary hypercortisolism
  evidence:
  - reference: PMID:39921449
    reference_title: "KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Food-dependent Cushing's syndrome was present in all patients with KDM1A variants and absent in the 2 other groups."
    explanation: Establishes food-dependent hypercortisolism as obligate in KDM1A carriers and absent in the comparison groups.
- category: Endocrine
  name: Increased Urinary Free Cortisol
  description: >-
    Twenty-four-hour urinary free cortisol averaging three times the upper limit
    of normal, higher than in the other PBMAH molecular groups. UFC is the
    informative integrated measure in this disease precisely because it sums
    across meals and so is not fooled by the inverted diurnal rhythm - but it is
    not invariably raised, and a GIP-dependent case with UFC within normal limits
    has been reported.
  phenotype_term:
    preferred_term: Increased urinary cortisol level
    term:
      id: HP:0012030
      label: Increased urinary cortisol level
  notes: >-
    No `frequency:` is asserted. The 3.0-fold figure is a group MEAN in a
    ten-patient cohort, not a count of how many patients had a raised value, and
    the schema's FrequencyEnum bands are frequency claims. Deriving a band from a
    mean would be an arithmetic error dressed as an annotation. The reported
    normal-UFC case below is the direct counterexample.
  evidence:
  - reference: PMID:39921449
    reference_title: "KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KDM1A patients had a higher 24-h urinary free cortisol (3.0-fold upper limit of normal vs 1.36 for ARMC5 patients and 0.66 for wild-type patients, respectively, P = .0001)."
    explanation: >-
      Quantifies the cortisol excess against the two comparison groups. This is a
      group mean, not a per-patient frequency, which is why no frequency band is
      asserted on this phenotype.
  - reference: PMID:21264796
    reference_title: "Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urinary free cortisol excretion was within normal limits, but an unusual diurnal cortisol rhythm was observed with low morning and high postprandial levels"
    explanation: >-
      The counterexample, cited deliberately. A GIP-dependent patient with normal
      UFC whose disease was nonetheless apparent from the rhythm - so a normal UFC
      does not exclude the diagnosis, and the phenotype is not obligate.
- category: Endocrine
  name: Low Morning Fasting Cortisol
  description: >-
    Subnormal cortisol in the fasting morning state - the trough of an inverted
    rhythm rather than adrenal insufficiency. This is the single most
    consequential phenotype in the entry for diagnosis, because morning cortisol
    is what is measured by convention, and in this disease it is the value least
    likely to look abnormal in the expected direction.
  phenotype_term:
    preferred_term: Decreased circulating cortisol level
    term:
      id: HP:0008163
      label: Decreased circulating cortisol level
    temporality: DIURNAL
  notes: >-
    The HP term names a decreased cortisol level without reference to time of
    day, so the binding alone reads as hypocortisolism, which would be a
    clinically dangerous misreading. `temporality: DIURNAL` and this note carry
    the qualification: the level is low only at the morning timepoint, and total
    daily output is raised.
  evidence:
  - reference: PMID:39921449
    reference_title: "KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In accordance with FDCS pathophysiology, patients with KDM1A variants had a lower morning fasting plasma cortisol (192 nmol/L vs 407 and 428, respectively, P = .0003) and a higher midnight plasma cortisol (487 nmol/L vs 297 and 171.96, respectively, P = .0004)."
    explanation: Measures the low morning value against both comparison groups, with the paired midnight value that shows it is a rhythm inversion rather than deficiency.
  - reference: PMID:21264796
    reference_title: "Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an unusual diurnal cortisol rhythm was observed with low morning and high postprandial levels"
    explanation: Independent single-patient observation of the same low-morning/high-postprandial pattern.
- category: Endocrine
  name: Decreased Circulating ACTH
  description: >-
    Plasma ACTH is low or suppressed, because autonomous adrenal cortisol
    production shuts down pituitary corticotrophs. This is the feature that makes
    the syndrome ACTH-INDEPENDENT and separates it from Cushing disease, so it is
    definitional for the entity rather than incidental.
  phenotype_term:
    preferred_term: Decreased circulating ACTH concentration
    term:
      id: HP:0002920
      label: Decreased circulating ACTH concentration
  notes: >-
    Evidenced at the level of PBMAH rather than of KDM1A-related PBMAH
    specifically. None of the KDM1A cohort papers reports ACTH values, so the
    citations below are a PBMAH case report and a PBMAH review. The inference to
    KDM1A carriers is safe - ACTH-independence is definitional for the parent
    entity and the KDM1A form is a subset of it - but it is an inference, and the
    evidence grading says so.

    One nuance the entry does not smooth over: a 2026 review notes intra-adrenal
    ACTH production by steroidogenic cells in PBMAH, so "ACTH-independent" refers
    to independence from PITUITARY ACTH, not to the absence of ACTH signalling
    altogether.
  evidence:
  - reference: PMID:39465833
    reference_title: "Primary bilateral macronodular adrenal hyperplasia: A rare case report of Cushing syndrome and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her laboratory results showed increased cortisol and suppressed ACTH, and an abdominal CT scan revealed 2 heterogeneous masses in the adrenal glands."
    explanation: >-
      A measured suppressed ACTH with the expected raised cortisol and bilateral
      adrenal masses. Graded PARTIAL because it is a single PBMAH case report with
      no KDM1A genotype, so it evidences the parent entity's biochemistry rather
      than this disease's.
  - reference: PMID:39465833
    reference_title: "Primary bilateral macronodular adrenal hyperplasia: A rare case report of Cushing syndrome and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In PBMAH, enlarged adrenal nodules secrete cortisol independently of corticotropin (ACTH), causing mild to overt CS."
    explanation: States the ACTH-independence of cortisol secretion in PBMAH, which is the mechanism this phenotype reflects.
  - reference: PMID:42067271
    reference_title: Primary Bilateral Macronodular Adrenal Hyperplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aberrant hormone receptor expression and intra-adrenal adrenocorticotropin production by steroidogenic cells may also contribute to cortisol dysregulation in many patients."
    explanation: >-
      Cited as the qualification rather than the support - intra-adrenal ACTH
      production means "ACTH-independent" describes independence from pituitary
      ACTH specifically.
- category: Endocrine
  name: Bilateral Adrenal Hyperplasia
  description: >-
    Bilateral macronodular enlargement of the adrenal cortices, typically found on
    cross-sectional imaging and increasingly detected incidentally.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Adrenal hyperplasia
    term:
      id: HP:0008221
      label: Adrenal hyperplasia
  evidence:
  - reference: PMID:34655521
    reference_title: "Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The bilateral nature of this disease suggests germline genetic predisposition."
    explanation: Documents the bilateral hyperplasia that defines the entity.
- category: Metabolic
  name: Truncal Obesity
  description: >-
    Central fat redistribution from chronic glucocorticoid excess. A generic
    Cushingoid feature rather than a KDM1A-specific one.
  phenotype_term:
    preferred_term: Truncal obesity
    term:
      id: HP:0001956
      label: Truncal obesity
  notes: >-
    Recorded from the clinical definition of Cushing syndrome rather than from a
    KDM1A-cohort frequency measurement. No `frequency:` is asserted because the
    published KDM1A series do not report per-sign frequencies.
- category: Cardiovascular
  name: Hypertension
  description: >-
    Glucocorticoid-driven hypertension, a standard component of the Cushingoid
    phenotype.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  notes: >-
    As above - no KDM1A-specific frequency is published, so none is asserted.
- category: Metabolic
  name: Diabetes Mellitus
  description: >-
    Cortisol-induced insulin resistance progressing to overt diabetes in a
    proportion of patients.
  phenotype_term:
    preferred_term: Diabetes mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
  notes: >-
    As above - no KDM1A-specific frequency is published, so none is asserted.
- category: Skeletal
  name: Osteoporosis
  description: >-
    Reduced bone mineral density from sustained glucocorticoid exposure.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  notes: >-
    As above - no KDM1A-specific frequency is published, so none is asserted.
- category: Neoplastic
  name: Associated Extra-Adrenal Neoplasia
  description: >-
    KDM1A-related PBMAH has been reported in association with adrenal myelolipoma
    and with plasma-cell disorders - monoclonal gammopathy of undetermined
    significance and multiple myeloma. This is a genuine surprise for an entry
    whose mechanism is otherwise entirely adrenal, and it matters clinically
    because it changes what surveillance a KDM1A carrier should be offered. No
    mechanism linking KDM1A loss to plasma-cell neoplasia has been established,
    and the association rests on a review's summary of reported cases rather than
    on a cohort incidence, so no frequency is asserted.
  phenotype_term:
    preferred_term: Neoplasm
    term:
      id: HP:0002664
      label: Neoplasm
  evidence:
  - reference: PMID:36857084
    reference_title: "Extensive expertise in endocrinology: glucose-dependent insulinotropic peptide-dependent Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "can be associated with adrenal myelolipoma, monoclonal gammopathy of unknown significance (MGUS), or multiple myeloma"
    explanation: >-
      Reports the extra-adrenal associations. Graded PARTIAL because it is an
      expert review's statement of association across reported cases, with no
      denominator and no incidence estimate.
diagnosis:
- name: Mixed meal test with oral versus intravenous glucose
  description: >-
    The confirmatory test, and the cleanest physiological demonstration of the
    modelled mechanism. Cortisol rises after a mixed meal, and - decisively -
    after ORAL but not INTRAVENOUS glucose. The oral/intravenous dissociation is
    the whole argument: only the oral route passes nutrients through the gut and
    triggers GIP release from intestinal K cells, so a cortisol response that
    depends on the route rather than on the glucose load localises the stimulus
    to an incretin. Failure of cortisol to suppress after dexamethasone
    establishes the autonomy.
  evidence:
  - reference: PMID:21264796
    reference_title: "Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis was confirmed by further investigations, showing significant plasma cortisol responses after a mixed meal test and after oral, but not intravenous glucose administration, as well as ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH)."
    explanation: The diagnostic protocol and the oral-versus-intravenous dissociation that identifies the stimulus as gut-derived.
  - reference: PMID:21264796
    reference_title: "Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "associated with the absence of cortisol suppression after dexamethasone, suggesting the possibility of GIP-dependent Cushing's syndrome"
    explanation: The dexamethasone non-suppression that establishes autonomous secretion and prompts the food-dependence workup.
- name: Morning to midnight plasma cortisol ratio as a screening discriminator
  description: >-
    A cheap biochemical screen derived directly from the mechanism: two timed
    plasma cortisol measurements, no dynamic testing. A ratio below 0.65 was
    reported to separate food-dependent from other PBMAH completely in the cohort
    that derived it. See the `biochemical` entry of the same name for the
    measurement itself and the validation caveat - the 100% figure is a
    derivation-cohort result in ten patients and has not been externally
    validated.
  evidence:
  - reference: PMID:39921449
    reference_title: "KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morning/midnight plasma cortisol ratio below 0.65 holds 100% sensitivity and specificity for the detection of FDCS."
    explanation: The reported discriminator and its performance in the derivation cohort.
- name: Germline KDM1A and ARMC5 sequencing
  description: >-
    Molecular confirmation. Because the two genes define mutually exclusive
    molecular groups with different phenotypes, they are screened together and
    the result is informative either way: KDM1A predicts food-dependence,
    ARMC5 predicts its absence. A positive germline result also converts the
    proband's relatives into testable at-risk individuals, which is the practical
    reason the discovery cohorts recommend it.
  evidence:
  - reference: PMID:34906447
    reference_title: KDM1A inactivation causes hereditary food-dependent Cushing syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management."
    explanation: The recommendation to screen both genes in operated PBMAH patients and their families.
  - reference: PMID:39921449
    reference_title: "KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KDM1A germline pathogenic variants are rare in PBMAH and account for <5% of index cases."
    explanation: Sets the expected yield of KDM1A testing in an unselected PBMAH population, which is what makes the food-dependence phenotype the useful pre-test filter.
- name: Adrenal cross-sectional imaging
  description: >-
    CT or MRI demonstrating bilateral macronodular adrenal enlargement. Imaging is
    increasingly the entry point rather than the confirmation - PBMAH is now often
    detected incidentally in asymptomatic people - which is precisely why every
    such finding needs biochemical assessment for steroid excess rather than
    reassurance.
  evidence:
  - reference: PMID:42067271
    reference_title: Primary Bilateral Macronodular Adrenal Hyperplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary bilateral macronodular adrenal hyperplasia (PBMAH) is increasingly recognized as imaging is widely used, leading to incidental detection in asymptomatic individuals. Adrenal imaging defines radiologic features."
    explanation: Establishes imaging as the modern route to detection and its role in defining the radiological entity.
  - reference: PMID:39465833
    reference_title: "Primary bilateral macronodular adrenal hyperplasia: A rare case report of Cushing syndrome and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an abdominal CT scan revealed 2 heterogeneous masses in the adrenal glands"
    explanation: A worked example of the imaging finding in a biochemically confirmed case.
biochemical:
- name: Morning to Midnight Plasma Cortisol Ratio
  notes: >-
    The mechanism-derived discriminator. Because secretion is meal-driven rather
    than circadian, the normal morning-high/midnight-low ordering reverses, and
    the ratio of the two values separates food-dependent from other PBMAH. A
    ratio below 0.65 was reported to hold complete sensitivity and specificity for
    FDCS in the series that derived it. This is a derivation-cohort figure and has
    not, to this entry's knowledge, been independently validated - see the
    knowledge gap recorded in `discussions`.
  evidence:
  - reference: PMID:39921449
    reference_title: "KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morning/midnight plasma cortisol ratio below 0.65 holds 100% sensitivity and specificity for the detection of FDCS."
    explanation: The primary report of the ratio and its reported discrimination.
treatments:
- name: Adrenalectomy
  description: >-
    Surgical removal of adrenal tissue is the definitive treatment for the
    hypercortisolism. In bilateral macronodular disease the choice between
    bilateral adrenalectomy, unilateral adrenalectomy and adrenal-sparing partial
    resection is a trade-off between remission and lifelong adrenal
    insufficiency. A long-term BMAD follow-up series reported markedly better
    remission with adrenal-sparing surgery than with unilateral adrenalectomy -
    but that series contained no KDM1A-variant patients, so it is evidence about
    the parent entity and not about this disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: adrenalectomy
    term:
      id: NCIT:C15177
      label: Adrenalectomy
  target_mechanisms:
  - target: ACTH-Independent Hypercortisolism
    description: >-
      Removing steroidogenic tissue removes the source of the autonomous cortisol
      regardless of what is stimulating it.
  evidence:
  - reference: PMID:40810200
    reference_title: A Global Approach to the Long-Term Follow-Up of 17 Families With Bilateral Macronodular Adrenal Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adrenal-sparing surgery achieved 100% remission vs a 40% remission rate for unilateral adrenalectomy."
    explanation: >-
      Compares surgical strategies in bilateral macronodular adrenal disease.
      Graded PARTIAL deliberately - the cohort is BMAD generally and the same
      report states no KDM1A pathogenic variants were identified in it, so this
      cannot be read as a KDM1A-specific outcome.
- name: Somatostatin Analogue Therapy
  description: >-
    The obvious mechanism-directed drug idea, and it does not work. Somatostatin
    analogues suppress GIP release from intestinal K cells, so they should in
    principle cut off the stimulus driving cortisol secretion. In the one detailed
    published trial - a single patient given octreotide for six months and then
    pasireotide for three - both drugs did acutely suppress the postprandial
    cortisol response, but the effect escaped, and neither improved the clinical or
    metabolic features. The patient proceeded to bilateral adrenalectomy. The
    authors concluded the failure was independent of somatostatin receptor subtype
    affinity, which matters because it removes the natural next move of trying a
    broader-spectrum analogue.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: octreotide
      term:
        id: CHEBI:7726
        label: octreotide
    - preferred_term: pasireotide
      term:
        id: CHEBI:72312
        label: pasireotide
  target_mechanisms:
  - target: Meal-Triggered Adenylate Cyclase Activation and Cortisol Synthesis
    description: >-
      Suppressing postprandial GIP secretion removes the ligand for the ectopic
      receptor, which is why the strategy was attempted.
  evidence:
  - reference: PMID:21264796
    reference_title: "Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing's syndrome."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Although inducing a significant acute suppression of post-prandial cortisol response, both drugs had no effects on the clinical and metabolic abnormalities associated with Cushing's syndrome and new tests performed at the end of each treatment period confirmed escape of post-meal cortisol suppression to therapy."
    explanation: >-
      Graded REFUTE against sustained clinical benefit from somatostatin
      analogues. Note this is a single patient, so it refutes the strategy as
      tried rather than excluding all somatostatin-based approaches.
  - reference: PMID:21264796
    reference_title: "Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case report illustrates the lack of sustained efficacy of somatostatin analogues on GIP-dependent Cushing's syndrome, independent of their affinity for the different somatostatin receptor subtypes."
    explanation: The authors' own generalisation, and specifically that receptor-subtype affinity does not explain the failure.
- name: Genetic Counselling and Family Screening
  description: >-
    Because the predisposing allele is germline and dominantly transmitted, and
    because the mechanism yields a cheap biochemical screen (the morning/midnight
    cortisol ratio) as well as a gene test, first-degree relatives of an index
    case can be offered testing. Both discovery cohorts explicitly recommended
    this.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:34655521
    reference_title: "Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing and counselling should be offered to these patients and their relatives."
    explanation: The discovery cohort's explicit recommendation for family genetic counselling.
  - reference: PMID:34906447
    reference_title: KDM1A inactivation causes hereditary food-dependent Cushing syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management."
    explanation: Independent recommendation of germline screening in operated PBMAH patients and their families.
discussions:
- discussion_id: aimah3_adrenal_sparing_surgery_in_kdm1a
  kind: KNOWLEDGE_GAP
  attaches_to:
  - treatments#Adrenalectomy
  prompt: >-
    Is adrenal-sparing surgery preferable to bilateral adrenalectomy specifically
    in KDM1A-related PBMAH?
  rationale: >-
    The only comparative surgical outcome data in bilateral macronodular adrenal
    disease come from a cohort in which no KDM1A pathogenic variants were found.
    KDM1A patients differ from that cohort in ways that could plausibly change the
    answer - notably a higher integrated cortisol burden and a secretory stimulus
    (meals) that does not go away after partial resection. Treatment guidance for
    this entity is therefore currently extrapolated from a group it was measured
    to be absent from.
- discussion_id: aimah3_cortisol_ratio_external_validation
  kind: KNOWLEDGE_GAP
  attaches_to:
  - biochemical#Morning to Midnight Plasma Cortisol Ratio
  prompt: >-
    Does the morning/midnight plasma cortisol ratio below 0.65 retain its reported
    perfect sensitivity and specificity in an independent cohort?
  rationale: >-
    100% sensitivity and specificity reported in the cohort that derived a
    threshold is the classic setting for optimistic bias, and the KDM1A group in
    that series was ten patients. The figure is quoted here because it is the
    published one, but a discriminator with no independent validation should not
    be treated as settled.
- discussion_id: aimah3_female_predominance
  kind: OPEN_QUESTION
  attaches_to:
  - genetic#KDM1A
  prompt: >-
    Why were all reported KDM1A-variant patients female?
  rationale: >-
    Female predominance is near-total in the KDM1A group (all carriers) against
    roughly two-thirds in both comparison groups, and it reached statistical
    significance. No mechanism has been proposed. Candidate explanations - an
    effect of sex on penetrance, an ascertainment effect, or chance in a
    ten-patient group - have not been distinguished, and the cohorts are too
    small to distinguish them.
- discussion_id: aimah3_camp_pka_step_unmeasured
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Meal-Triggered Adenylate Cyclase Activation and Cortisol Synthesis
  prompt: >-
    Has the cAMP/PKA step been measured in KDM1A-null adrenocortical tissue, or is
    it inferred from GIPR's canonical coupling?
  rationale: >-
    The entry models GIPR signalling through adenylate cyclase because that is
    GIPR's established coupling and no other route would produce the observed
    postprandial cortisol rise. But the disease-specific measurements stop at GIPR
    transcript and protein on one side and at plasma cortisol on the other. The
    intervening second-messenger step is the least directly evidenced link in the
    chain and is flagged rather than smoothed over.
- discussion_id: aimah3_plasma_cell_neoplasia_association
  kind: OPEN_QUESTION
  attaches_to:
  - phenotypes#Associated Extra-Adrenal Neoplasia
  prompt: >-
    Is the reported association between KDM1A-related PBMAH and plasma-cell
    disorders causal, and should carriers have haematological surveillance?
  rationale: >-
    An expert review records adrenal myelolipoma, MGUS and multiple myeloma as
    associations of KDM1A-related PBMAH. If real and causal it would be clinically
    consequential - a germline tumour-suppressor carrier state with a second,
    non-adrenal neoplastic risk changes what surveillance a carrier should be
    offered. But the association is reported without a denominator or an
    incidence, the KDM1A cohorts are small, and no mechanism connecting KDM1A loss
    to plasma-cell biology has been proposed. The entry records the association
    and explicitly declines to assert a frequency.
references:
- reference: PMID:34655521
  title: "Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study."
- reference: PMID:34906447
  title: KDM1A inactivation causes hereditary food-dependent Cushing syndrome.
- reference: PMID:39921449
  title: "KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation."
- reference: PMID:42067271
  title: Primary Bilateral Macronodular Adrenal Hyperplasia.
- reference: PMID:40810200
  title: A Global Approach to the Long-Term Follow-Up of 17 Families With Bilateral Macronodular Adrenal Disease.
- reference: PMID:21264796
  title: "Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing's syndrome."
- reference: PMID:36857084
  title: "Extensive expertise in endocrinology: glucose-dependent insulinotropic peptide-dependent Cushing's syndrome."
- reference: PMID:39465833
  title: "Primary bilateral macronodular adrenal hyperplasia: A rare case report of Cushing syndrome and review of literature."
📚

References & Deep Research

References

8
PMID:34655521
Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study.
No top-level findings curated for this source.
PMID:34906447
KDM1A inactivation causes hereditary food-dependent Cushing syndrome.
No top-level findings curated for this source.
PMID:39921449
KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation.
No top-level findings curated for this source.
PMID:42067271
Primary Bilateral Macronodular Adrenal Hyperplasia.
No top-level findings curated for this source.
PMID:40810200
A Global Approach to the Long-Term Follow-Up of 17 Families With Bilateral Macronodular Adrenal Disease.
No top-level findings curated for this source.
PMID:21264796
Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing's syndrome.
No top-level findings curated for this source.
PMID:36857084
Extensive expertise in endocrinology: glucose-dependent insulinotropic peptide-dependent Cushing's syndrome.
No top-level findings curated for this source.
PMID:39465833
Primary bilateral macronodular adrenal hyperplasia: A rare case report of Cushing syndrome and review of literature.
No top-level findings curated for this source.

Deep Research

1
OpenScientist ▸
ACTH-Independent Macronodular Adrenal Hyperplasia 3 (AIMAH3) — Comprehensive Disease Report
openscientist-autonomous 2026-08-28T10:27:11.862429

ACTH-Independent Macronodular Adrenal Hyperplasia 3 (AIMAH3) — Comprehensive Disease Report

Prepared for a disease knowledge-base entry. Evidence is human clinical / genetic unless otherwise stated. Primary citations are given as PMIDs.

Summary (Answer to the Research Question)

ACTH-independent Macronodular Adrenal Hyperplasia 3 (AIMAH3; OMIM #620990; MONDO:0700299) is a rare, autosomal-dominant Mendelian endocrine tumor-predisposition syndrome that is the genetically defined form of food-dependent (GIP-dependent) Cushing syndrome (FDCS). It is caused by germline heterozygous loss-of-function (truncating) variants in KDM1A (LSD1; chromosome 1p36; gene OMIM 609132) combined with somatic loss of the wild-type allele on 1p in adrenal nodules — a two-hit tumor-suppressor mechanism. Biallelic KDM1A inactivation in adrenocortical cells permits ectopic expression of the glucose-dependent insulinotropic polypeptide receptor (GIPR); meal-stimulated GIP (from duodenal K cells) then binds adrenal GIPR, activates cAMP/PKA, and drives post-prandial cortisol hypersecretion, producing ACTH-independent Cushing syndrome on a background of bilateral macronodular adrenal hyperplasia. It accounts for ~3.3% of all primary bilateral macronodular adrenal hyperplasia (PBMAH) index cases and ~90% of FDCS, shows a striking female predominance, and is definitively treated by adrenalectomy.

1. Disease Information

  • Overview: AIMAH3 is a subtype within the ACTH-independent macronodular adrenal hyperplasia phenotypic series in which bilateral, benign, large adrenocortical nodules autonomously secrete cortisol under the control of ingested food. It is the molecular subtype of food-dependent Cushing syndrome. Individuals characteristically have low fasting morning cortisol and low/suppressed ACTH but excess cortisol after eating.
  • Key identifiers:
  • OMIM: #620990 (AIMAH3); phenotypic series PS219080 (AIMAH). Gene KDM1A OMIM 609132.
  • MONDO: MONDO:0700299
  • MedGen: CN378661
  • MeSH: the closest heading is Cushing Syndrome (D003480); "adrenal hyperplasia, macronodular" is indexed under adrenocortical hyperplasia. No AIMAH3-specific MeSH.
  • ICD-11: 5A70 (Cushing syndrome) / 5A74.0 region for ACTH-independent Cushing; ICD-10: E24.0 (pituitary-dependent) is not applicable — adrenal Cushing is E24.8/E24.9; adrenal hyperplasia E27.8. No AIMAH3-specific code.
  • Orphanet: Covered under "ACTH-independent macronodular adrenal hyperplasia" (ORPHA:189439 for PBMAH); no distinct AIMAH3 ORPHA code.
  • UniProt disease: DI-06963.
  • Synonyms / alternative names: AIMAH3; ACTH-independent macronodular adrenal hyperplasia 3; Food-dependent Cushing syndrome (FDCS); GIP-dependent Cushing syndrome; GIP-dependent PBMAH; (broader, non-synonymous parent terms) primary bilateral macronodular adrenal hyperplasia (PBMAH), bilateral macronodular adrenal disease (BMAD).
  • Position within the AIMAH phenotypic series (PS219080):
Subtype OMIM # Gene (OMIM) Locus Mechanism Distinctive feature
AIMAH1 #219080 GNAS (139320) 20q13 Somatic activating mutation (R201H/R201S; constitutive Gs) Not McCune-Albright; mutation absent in blood
AIMAH2 #615954 ARMC5 (615549) 16p11.2 Germline + somatic (two-hit) Commonest genetic PBMAH (~20–25%); no food dependence
AIMAH3 #620990 KDM1A (609132) 1p36 Germline + somatic (two-hit, 1p LOH) Food/GIP-dependent Cushing

AIMAH patients typically present in the 5th–6th decade (~10 years later than other Cushing causes), and most cases are sporadic (OMIM PS219080; Assié 2013 identified ARMC5 in 18/33=55% of macronodular hyperplasia tumors; Chasseloup 2021 PMID 34655521 reported 17 GIP-dependent PBMAH cases with a recurrent 1p/KDM1A deletion). - Data source type: Information is derived from aggregated disease-level genetic/clinical cohort studies and case series (e.g., 301-case and 36-case multicentre cohorts) plus individual case reports — not from a single EHR dataset.

2. Etiology

  • Primary cause — genetic: Germline heterozygous inactivating (truncating: frameshift/nonsense) variants in KDM1A, with a somatic second hit (loss of heterozygosity / deletion of chromosome 1p bearing the wild-type allele) in adrenocortical lesions. "Exome sequencing revealed germline truncating variants of KDM1A … constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels" and "KDM1A inactivation explains about 90% of FDCS PBMAH" (PMID 34906447). This is a two-hit tumor-suppressor model (PMID 41864332).
  • Genetic risk factors: The germline KDM1A LoF allele is the causal susceptibility factor; disease requires the acquired somatic 1p loss. No additional common susceptibility loci are established. ARMC5 (AIMAH2/PBMAH1) is the differential genetic cause and is mutually exclusive with the FDCS phenotype (PMID 39921449).
  • Environmental risk factors / triggers: The obligate physiological "trigger" is food/meal intake, which raises GIP and drives cortisol secretion. Female sex is a strong, unexplained risk marker (100% of KDM1A carriers were women in the largest cohort; PMID 39921449). No toxin, radiation, or occupational exposure is implicated.
  • Protective factors: None established genetically or environmentally. Conceptually, avoiding the GIP–GIPR axis (e.g., fasting) transiently lowers cortisol but is not therapeutic. Somatic events being required means most heterozygous carriers may remain unaffected (incomplete penetrance).
  • Gene–environment interaction: The defining GxE interaction is KDM1A loss (genetic) × dietary GIP secretion (environmental/physiological) → post-prandial hypercortisolism. Without the genetic lesion, food does not stimulate cortisol; without food, the genetic lesion produces little fasting cortisol excess.
  • Infectious agents: Not applicable.

3. Phenotypes

The clinical phenotype is that of chronic endogenous cortisol excess (Cushing syndrome), but with a food-dependent secretory pattern. Onset is typically adult (commonly 4th–6th decades), insidious, and slowly progressive. Severity is variable (mild autonomous cortisol secretion → overt Cushing). Key phenotypes and suggested HPO terms:

Phenotype Type HPO term Notes / frequency
Cushingoid habitus / truncal (central) obesity physical sign HP:0002591 (truncal obesity), HP:0001513 (obesity) Common (OMIM clinical synopsis)
Facial fullness ("moon facies") physical sign HP:0000283 Common
Arterial hypertension clinical sign HP:0000822 Very common; PBMAH cohorts show high rates
Type 2 diabetes / glucose intolerance lab/clinical HP:0000857 / HP:0000833 Common (45% diabetes in PBMAH vs 25% non-PBMAH, PMID 35597729)
Abdominal striae physical sign HP:0001065 (Striae distensae) Reported in OMIM synopsis
Proximal muscle weakness symptom/sign HP:0003701 (proximal muscle weakness) / HP:0003324 From cortisol-induced myopathy
Osteoporosis lab/imaging HP:0000939 Reported
Hypercortisolemia / loss of diurnal rhythm lab abnormality HP:0003118 (abnormal circulating cortisol), HP:0003119 region Defining; low AM/high PM cortisol
Suppressed ACTH (ACTH-independent) lab abnormality HP:0002920 (decreased ACTH) Defining
Bilateral adrenal macronodular hyperplasia imaging/structural HP:0008256 (Adrenal hyperplasia); HP:0031044 (adrenocortical hyperplasia) Defining, bilateral
Elevated urinary free cortisol lab abnormality HP:0003564 (Hypercortisoluria) 3.0× ULN in KDM1A vs 1.36× ARMC5 (PMID 39921449)
  • Phenotype characteristics: Adult-onset; severity mild→severe/variable; course chronic and slowly progressive; the biochemical hallmark is the inverted cortisol rhythm (low morning, high post-prandial/midnight). In the 301-case cohort, KDM1A patients had higher 24h UFC (3.0× ULN), lower morning cortisol (192 vs 407/428 nmol/L), higher midnight cortisol (487 vs 297/172 nmol/L) (PMID 39921449).
  • Quality-of-life impact: As for other forms of Cushing syndrome — impaired physical function (myopathy, obesity, fractures), metabolic/cardiovascular morbidity, and neuropsychiatric effects (mood disturbance, cognitive complaints) reduce QoL; disease-specific QoL is measured with CushingQoL and generic SF-36/EQ-5D. No AIMAH3-specific QoL study exists (data gap).

4. Genetic / Molecular Information

  • Causal gene: KDM1A (lysine demethylase 1A; alias LSD1, KDM1, AOF2). HGNC:29079; NCBI Gene 23028; Ensembl ENSG00000004487; UniProt O60341. Gene OMIM 609132. Locus 1p36.12.
  • Pathogenic variants:
  • Classification: Pathogenic / likely pathogenic per ACMG/AMP (PMID 39921449). VUS reported in broad incidentaloma panels (PMID 41113712).
  • Variant type/class: Predominantly truncating loss-of-function — frameshift and nonsense (and splice) — germline (PMID 34906447). The second hit is a somatic structural event (1p LOH/deletion).
  • Allele frequency: Germline KDM1A LoF variants are rare in gnomAD (KDM1A is relatively loss-of-function intolerant); no common population variant. Disease-associated alleles are private/family-specific.
  • Somatic vs germline: Both required — germline heterozygous LoF + somatic 1p loss (two-hit).
  • Functional consequence: Loss of function (loss of KDM1A mRNA and protein in adrenal tissue; PMID 34906447), consistent with tumor-suppressor behavior (PMID 41864332).
  • Modifier genes: None established. ARMC5 status is mutually exclusive (defines AIMAH2).
  • Epigenetic information: KDM1A/LSD1 is itself an epigenetic eraser — a histone demethylase for H3K4me1/2 and H3K9me1/2 (PMID 38152966) with scaffolding control of DNA methylation (PMID 39237615). Its loss perturbs the adrenocortical chromatin/transcriptional landscape and is thought to permit de-repression/ectopic transcription of GIPR. Multiomics profiling included methylome and miRNome analyses defining a distinct FDCS molecular group (PMID 34906447).
  • Chromosomal abnormalities: Somatic loss of chromosome 1p (LOH) in adrenal nodules is the recurrent large-scale event (PMID 34906447). In the distinct unilateral GIP-adenoma route, somatic 19q13.32 duplication/rearrangement of the GIPR locus occurs (PMID 36857084) — not AIMAH3.

5. Environmental Information

  • Environmental factors: No toxin/radiation/pollution/occupational cause. The relevant "environmental" input is dietary intake, which triggers GIP secretion and hence cortisol release.
  • Lifestyle factors: Meal composition/timing modulates GIP and therefore cortisol; oral (but not IV) glucose triggers cortisol (PMID 21264796). No smoking/alcohol association established.
  • Infectious agents: Not applicable.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream): 1. Germline heterozygous KDM1A LoF variant (constitutional; every cell). (GO: histone H3K4 demethylase activity GO:0032453; H3K9 demethylase GO:0032454; chromatin organization GO:0006325.) 2. Somatic loss of wild-type KDM1A allele (1p LOH) in an adrenocortical clone → complete loss of KDM1A/LSD1 protein (PMID 34906447). (Two-hit tumor suppressor; GO:0045596 negative regulation of cell differentiation, GO:0008285/0008284 regulation of cell proliferation.) 3. Ectopic expression of the non-mutated GIPR in adrenocortical cells (aberrant chromatin de-repression) (PMID 36857084, 39059410). (GO:0004930 G-protein coupled receptor activity; CHEBI: glucose-dependent insulinotropic polypeptide.) 4. Post-prandial GIP (secreted by intestinal K cells; CL:0002097 type K enteroendocrine cell) binds adrenal GIPR → Gs/cAMP/PKA activation (GO:0071377 cellular response to glucagon-family peptide; GO:0007189 adenylate cyclase-activating GPCR signaling; cAMP CHEBI:17489). 5. Stimulation of steroidogenesis (StAR, CYP11A1, CYP11B1) → meal-induced cortisol (CHEBI:17650) hypersecretion and adrenocortical cell proliferation. 6. Chronic ACTH-independent hypercortisolism → Cushing syndrome; cortisol feedback suppresses pituitary ACTH (→ low ACTH; internodular adrenal cortex may atrophy).

  • Molecular pathways: cAMP/PKA signaling (central); GPCR signaling; chromatin/epigenetic regulation (LSD1); Wnt/β-catenin (LSD1 stabilizes β-catenin, PMID 38321961) and Notch (PMID 38152966) as LSD1-regulated proliferation/fate pathways. Reactome: GPCR/adenylate cyclase; KEGG: cortisol synthesis and secretion (hsa04927), cAMP signaling (hsa04024).
  • Cellular processes: Adrenocortical cell proliferation (nodule formation), dysregulated steroidogenesis, epigenetic transcriptional de-repression.
  • Protein dysfunction: Loss of function of LSD1 (loss of demethylase + scaffolding activity); gain of aberrant signaling through ectopic (structurally normal) GIPR.
  • Metabolic changes: Secondary cortisol-driven metabolic syndrome — hyperglycemia/insulin resistance (type 2 diabetes), dyslipidemia, central adiposity, protein catabolism (myopathy), bone loss.
  • Immune involvement: No primary autoimmunity; chronic cortisol excess is immunosuppressive (increased infection risk) — downstream, not causal.
  • Tissue-damage mechanisms: Systemic glucocorticoid toxicity (vascular, bone, muscle, metabolic) rather than direct adrenal tissue injury.
  • Biochemical abnormality: Receptor dysfunction (ectopic GIPR coupling meals to steroidogenesis) is the core defect.
  • Molecular profiling: RNA-seq/exome/SNP-array/methylome/miRNome multiomics defined the FDCS group with GIPR ectopic expression and KDM1A loss (PMID 34906447); functional validation in the H295R human adrenocortical cell line (PMID 34655521).

7. Anatomical Structures Affected

  • Organ level (primary): Adrenal glands / adrenal cortex — bilateral (UBERON:0002369 adrenal gland; UBERON:0001235 adrenal cortex). Lateralization: bilateral, often asymmetric nodularity.
  • Secondary organ involvement (from cortisol excess): cardiovascular system (hypertension), pancreas/metabolic (diabetes), skeleton (osteoporosis/fractures), skeletal muscle (myopathy), skin (striae), CNS (neuropsychiatric). Body system: endocrine (primary), with cardiovascular, musculoskeletal, integumentary, and metabolic secondary involvement.
  • Tissue / cell level: Adrenocortical epithelial/steroidogenic cells — CL:0000538 (adrenal cortex cell) / zona fasciculata cells; ectopic GIPR on these cells. Trigger cells: intestinal K cells (CL:0002097) secreting GIP.
  • Subcellular level: Nucleus/chromatin (LSD1 site of action; GO:0000785 chromatin; GO:0005634 nucleus); plasma membrane (GIPR; GO:0005886); mitochondria and smooth ER (steroidogenesis; GO:0005739, GO:0005790).
  • Localization: UBERON:0002369 (adrenal gland), UBERON:0001235 (adrenal cortex); bilateral.

8. Temporal Development

  • Onset: Adult-onset (typically 40s–60s), insidious/chronic. Because a somatic second hit is required, clinical disease emerges in adulthood despite constitutional carriage.
  • Progression: Slowly progressive; ranges from nonfunctional/mild autonomous cortisol secretion (MACS) to overt Cushing over years; adrenal mass/nodularity increases over time. Not staged formally (benign hyperplasia, not a malignancy staging system).
  • Duration/course: Chronic, lifelong until surgically treated.
  • Patterns: Post-prandial episodic cortisol surges superimposed on chronic excess; treatment-induced remission after adrenalectomy; no spontaneous remission. Critical intervention window: early detection in mutation-carrying relatives (cascade screening) before overt Cushing/metabolic damage.

9. Inheritance and Population

  • Epidemiology: AIMAH3 is very rare. PBMAH itself is an uncommon cause of overt Cushing but a more frequent cause of bilateral adrenal incidentalomas (PMID 41864332); PBMAH is found in ~1/3 of adrenal-incidentaloma patients with subclinical hypercortisolism (PMID 35597729). KDM1A explains ~3.3% of PBMAH index cases (10/301) and ~90% of FDCS (PMID 39921449, 34906447). Precise population prevalence/incidence figures are not established (data gap).
  • Inheritance: Autosomal dominant predisposition (germline heterozygous LoF) with a required somatic second hit → incomplete/variable penetrance and variable expressivity. No genetic anticipation or repeat expansion. Founder effects/consanguinity not established. Germline mosaicism not specifically documented.
  • Carrier frequency: Not established; germline KDM1A LoF is rare in gnomAD.
  • Population demographics: Striking female predominance — 100% of KDM1A carriers were women in the largest cohort (vs ~65% ARMC5, ~67% wild-type; P=.0337) (PMID 39921449). No specific ethnic/geographic clustering established; cases reported across Europe, Canada, Brazil, and Asia.

10. Diagnostics

  • Laboratory tests / biomarkers:
  • ACTH-independent hypercortisolism: suppressed/low ACTH (HP:0002920), elevated 24h urinary free cortisol (3.0× ULN typical; PMID 39921449), loss of diurnal rhythm, non-suppression on 1-mg overnight and low/high-dose dexamethasone tests.
  • Inverted rhythm: low morning, high midnight/post-prandial cortisol. Morning/midnight plasma cortisol ratio < 0.65 = 100% sensitivity and 100% specificity for FDCS (PMID 39921449).
  • Functional confirmatory test: Mixed-meal test showing a significant post-prandial cortisol rise; cortisol rises after oral but not IV glucose (PMID 21264796). Screening for aberrant hormone receptors (posture, GnRH, glucagon, vasopressin) per Lacroix protocol may reveal multiple aberrant responses.
  • Imaging: Adrenal CT/MRI shows bilateral macronodular adrenal hyperplasia (nodules >1 cm, enlarged glands). ¹⁸F-FDG/other functional imaging not required.
  • Histopathology: Bilateral macronodular adrenocortical hyperplasia; immunohistochemistry can demonstrate ectopic GIPR and loss of KDM1A protein in nodules (PMID 34906447).
  • Genetic testing: Recommended approach — germline sequencing of KDM1A and ARMC5 for PBMAH patients and families (PMID 34906447: "Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families"). WES/targeted NGS panels for adrenal tumorigenesis genes are used (PMID 41113712). Somatic 1p LOH can be confirmed on tumor DNA (SNP array/CMA). Single-gene KDM1A testing indicated when FDCS biochemistry is present.
  • Clinical criteria / differential diagnosis: Diagnose per Endocrine Society/ESE hypercortisolism guidelines, then localize to ACTH-independent bilateral adrenal disease. Differential: ARMC5-PBMAH (AIMAH2; no food dependence), unilateral GIP-dependent adenoma (19q13.32; unilateral), other aberrant-receptor AIMAH (LH/hCG, β-adrenergic, vasopressin, serotonin), PPNAD/Carney complex (PRKAR1A), McCune-Albright (GNAS), cortisol-producing adenoma, and adrenocortical carcinoma.
  • Screening: Cascade genetic screening of first-degree relatives of KDM1A carriers; biochemical screening (morning/midnight cortisol ratio, mixed-meal test) in carriers.

11. Outcome / Prognosis

  • Survival/mortality: AIMAH3 is a benign hyperplasia; prognosis is driven by cortisol-excess complications, not by malignancy. With treatment (adrenalectomy), hypercortisolism resolves and prognosis is good. Untreated chronic Cushing carries excess cardiovascular/metabolic/infectious mortality. No AIMAH3-specific survival statistics (data gap).
  • Morbidity/function: Hypertension, type 2 diabetes, osteoporosis/fractures, myopathy, obesity, thromboembolic and infection risk, and neuropsychiatric morbidity — reversible in part after cure.
  • Complications: Metabolic syndrome, cardiovascular disease, fragility fractures, infections; post-bilateral-adrenalectomy adrenal insufficiency requiring lifelong replacement.
  • Recovery: Marked clinical/metabolic improvement after adrenalectomy (PMID 21264796).
  • Prognostic factors/biomarkers: Degree of hypercortisolism (24h UFC), presence of overt vs mild Cushing, nodule/adenomatous mass, and comorbidity burden. Genotype (KDM1A) predicts the FDCS phenotype and higher UFC (PMID 39921449).

12. Treatment

  • Surgical (mainstay; NCIT: Adrenalectomy C51765):
  • Bilateral adrenalectomy — definitive for overt Cushing; achieves remission; requires lifelong glucocorticoid + mineralocorticoid replacement.
  • Unilateral (total/subtotal/partial) adrenalectomy of the more nodular gland — controls milder disease while preserving some adrenal function; effective in ARMC5-PBMAH and applicable to bilateral disease.
  • Pharmacotherapy:
  • Somatostatin analogues (octreotide, octreotide-LAR; multi-ligand pasireotide/SOM230) — acutely abolish meal-induced cortisol but show tachyphylaxis/escape within months with no durable benefit (PMID 21264796, 23425648). NCIT: Octreotide C1214; Pasireotide C79861.
  • Steroidogenesis inhibitors (ketoconazole, metyrapone, osilodrostat, mitotane; NCIT: Ketoconazole C599, Metyrapone C61890, Osilodrostat C124087) — symptomatic control of hypercortisolism (general Cushing management).
  • GIPR-targeted therapy (investigational/rational): GIP-receptor antagonism directly addresses the ectopic-receptor mechanism but is not yet an established therapy.
  • Advanced therapeutics: No approved gene/cell/RNA therapy. LSD1 inhibitors exist in oncology (e.g., iadademstat; PMID 40938473) but are not indicated here (the defect is LSD1 loss, so inhibition would be counterproductive).
  • Pharmacogenomics: None specific to AIMAH3.
  • Treatment strategy / personalized medicine: Genotype-guided — confirming FDCS/KDM1A supports a mechanism-based approach (meal-timing awareness, consideration of GIP-axis targeting) and, importantly, family cascade testing. Choice between unilateral vs bilateral adrenalectomy is individualized to disease severity.
  • Experimental trials: No AIMAH3-specific registered trials identified; management follows PBMAH/Cushing frameworks (2023 ESE guidelines context, PMID 41871980).

13. Prevention

  • Primary prevention: Not possible for the germline lesion. Secondary prevention is key: cascade genetic screening of relatives of KDM1A carriers and biochemical surveillance (morning/midnight cortisol ratio, mixed-meal test, adrenal imaging) to detect disease early before metabolic damage.
  • Tertiary prevention: Aggressive management of hypertension, diabetes, osteoporosis, and thrombosis risk; adrenalectomy to prevent complications; post-surgical steroid replacement and sick-day rules to prevent adrenal crisis.
  • Genetic counseling: Autosomal-dominant predisposition with incomplete penetrance; offer counseling regarding ~50% transmission of the germline allele and variable expression; prenatal/PGT is technically possible but rarely pursued for an adult-onset, treatable, benign condition.
  • Immunization/public-health/environmental: Not applicable.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: Human KDM1A (NCBI Gene 23028). Orthologs: mouse Kdm1a (NCBI Gene 99982), rat Kdm1a, and conserved across vertebrates; LSD1 is highly evolutionarily conserved (present in plants, yeast SWM3/orthologs, Drosophila Su(var)3-3, C. elegans spr-5).
  • Natural disease in animals: No naturally occurring KDM1A-driven food-dependent Cushing syndrome is documented in companion animals or wildlife (data gap). (Canine Cushing is usually pituitary-dependent or due to adrenal tumors; no GIP-dependent KDM1A analog reported.)
  • Comparative biology: LSD1's developmental/epigenetic role is conserved; disease-specific adrenal mechanism appears human-observed. Zoonotic potential: not applicable.

15. Model Organisms

  • Cellular / in vitro models: H295R human adrenocortical carcinoma cell line used to functionally validate GIPR-driven cortisol secretion and the effect of KDM1A defects (PMID 34655521, 34906447). Patient-derived adrenal tissue used for RNA-seq/methylome/IHC (PMID 34906447). iPSC/organoid adrenal models are emerging but not yet AIMAH3-specific.
  • Mouse models: Kdm1a knockout mice are established for developmental studies (e.g., conditional Kdm1a deletion in nephron progenitors causing glomerulosclerosis/cysts, PMID 41797715; ESC studies PMID 39237615). Complete germline Kdm1a knockout is embryonic-lethal (LSD1 essential for embryogenesis), so no constitutive-null adult model exists; a conditional/adrenal-specific Kdm1a knockout with somatic loss would be required to model AIMAH3 — not yet reported (data/model gap).
  • Genetic model types available: Knockout, conditional (floxed), tissue-specific Cre lines for Kdm1a; CRISPR/Cas9 KDM1A deletion in human organoids (PMID 41797715).
  • Phenotype recapitulation: Existing Kdm1a models capture LSD1's epigenetic/developmental functions but do not recapitulate the adrenal FDCS phenotype (no ectopic GIPR / food-dependent cortisol model published). This is a key limitation and research opportunity.
  • Resources: MGI (Kdm1a), IMPC/IMSR for knockout alleles; Cellosaurus (H295R, CVCL_0459).

Supported vs Refuted Hypotheses

Supported: - AIMAH3 (OMIM #620990) = KDM1A-driven, GIP/food-dependent Cushing syndrome (PMID 34906447, 39921449, 41864332). - Two-hit tumor-suppressor mechanism: germline truncating KDM1A LoF + somatic 1p LOH (PMID 34906447). - Ectopic adrenal GIPR couples meals to cortisol via cAMP/PKA (PMID 39059410, 36857084). - Morning/midnight cortisol ratio <0.65 diagnoses FDCS with 100% sensitivity/specificity (PMID 39921449). - Adrenalectomy definitive; somatostatin analogs only transiently effective (PMID 21264796, 23425648). - Striking female predominance (PMID 39921449).

Refuted / excluded for AIMAH3 specifically: - ARMC5 as the cause (that is AIMAH2/PBMAH1) — ARMC5 carriers do not have FDCS (PMID 39921449). - 19q13.32 GIPR duplication as the mechanism — that drives unilateral GIP-adenomas, not bilateral AIMAH3 (PMID 36857084). - LSD1 inhibitors as therapy — the lesion is LSD1 loss.

Limitations and Future Directions

  • Very small patient numbers (tens of KDM1A cases worldwide); no formal prevalence/incidence, penetrance estimates, survival, or QoL data specific to AIMAH3.
  • The mechanism by which KDM1A loss de-represses GIPR is not fully resolved; the extreme female predominance is unexplained.
  • No animal model reproduces the adrenal FDCS phenotype — an adrenal-specific conditional Kdm1a model is needed.
  • GIPR antagonism is a rational but untested targeted therapy.
  • Reported (limited-evidence) associations of KDM1A carriers with other tumors (e.g., monoclonal gammopathy/myeloma) warrant confirmation before inclusion in surveillance.

Evidence key PMIDs: 34906447 (Vaczlavik 2022, KDM1A discovery/multiomics), 34655521 (Chasseloup 2021, GIPR/KDM1A cohort + H295R), 39921449 (Bouys 2025, 301-case screening/genotype-phenotype), 39059410 (Bouys & Bertherat 2024, 35-year FDCS review), 36857084 (Lacroix 2023, GIP-dependent CS mechanisms), 41864332 (Chasseloup & Kamenický 2026, review), 21264796 / 23425648 (somatostatin-analog treatment), 35597729 (PBMAH epidemiology), 38152966 / 39237615 / 38321961 / 41797715 (KDM1A/LSD1 biology & models).

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