Glucocorticoid Resistance

Mendelian MONDO:0014421 Pathograph 20 Show in embeddings browser Adrenogenital syndrome

Primary generalized glucocorticoid resistance (Chrousos syndrome) is a rare genetic disorder of generalized, partial target-tissue insensitivity to glucocorticoids caused by inactivating variants in NR3C1, which encodes the human glucocorticoid receptor. Because peripheral tissues respond poorly to cortisol, hypothalamic-pituitary-adrenal negative feedback is blunted and the axis is compensatorily upregulated, raising cortisol and ACTH. The excess ACTH drives adrenal overproduction of steroids with mineralocorticoid activity (deoxycorticosterone, corticosterone) and of adrenal androgens, so affected individuals present with hypertension, hypokalemic alkalosis, and/or hyperandrogenism, together with adrenal hyperplasia, while cortisol-dependent functions are largely preserved and stigmata of Cushing's syndrome are absent. The clinical spectrum ranges from asymptomatic to severe; homozygous or compound-heterozygous defects present earlier and more severely than heterozygous ones. This entry covers the primary (NR3C1-based) Mendelian disorder, not acquired or tissue-specific glucocorticoid resistance seen in conditions such as asthma, inflammatory disease, or hematologic malignancy.

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2
Inheritance
8
Pathophys.
9
Phenotypes
20
Pathograph
1
Genes
2
Variants
1
Medical Actions
1
Differentials
13
References
1
Deep Research
👪

Inheritance

2
Autosomal dominant inheritance HP:0000006
Heterozygous NR3C1 variants that exert a dominant-negative effect on the wild-type receptor cause autosomal dominant disease; the I747M ligand-binding domain variant is a worked example.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:12050230 SUPPORT DIRECT In Vitro
"We conclude that the mutation at amino acid 747 of the GR causes familial, autosomal dominant glucocorticoid resistance by decreasing ligand binding affinity and transcriptional activity, and by exerting a negative transdominant effect on the wild-type receptor."
Establishes a dominant-negative, autosomal dominant mechanism for an NR3C1 ligand-binding-domain variant.
Autosomal recessive inheritance HP:0000007
NR3C1 variants that do not exert a dominant-negative effect transmit recessively; homozygous or compound-heterozygous defects produce the most severe, early-onset presentations.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:15070967 SUPPORT DIRECT In Vitro
"each of the above hGRalpha mutations imparts different functional defects upon the glucocorticoid signal transduction pathway, which explains the autosomal recessive or dominant transmission of the disorder"
Functional differences among mutant receptors account for both recessive and dominant transmission.
⚙

Pathophysiology

8
NR3C1 Inactivating Variant
Point mutations, insertions, or deletions in NR3C1 impair the human glucocorticoid receptor. All reported Chrousos syndrome cases to date carry an NR3C1 defect.
NR3C1 hgnc:7978 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NR3C1 (hgnc:7978). hgnc:7978 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
nuclear glucocorticoid receptor activity GO:0004883 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased nuclear glucocorticoid receptor activity (GO:0004883). GO:0004883 is a molecular function from the Gene Ontology.
Downstream
Impaired Glucocorticoid Receptor Signal Transduction
Show evidence (2 references)
PMID:31588529 SUPPORT DIRECT REVIEW SYNTHESIS Other
"It is characterized by generalized, partial tissue insensitivity to glucocorticoids caused by genetic defects in the NR3C1 gene."
Attributes the disorder to NR3C1 defects.
PMID:25715669 SUPPORT DIRECT REVIEW SYNTHESIS Other
"All reported cases have been associated with point mutations or deletions in the NR3C1 gene."
Confirms NR3C1 as the sole established cause.
Impaired Glucocorticoid Receptor Signal Transduction
Mutant receptors show reduced ligand-binding affinity, reduced transactivation of glucocorticoid-responsive genes, delayed nuclear translocation, and abnormal coactivator interaction. DNA-binding is usually preserved.
nuclear receptor-mediated glucocorticoid signaling pathway GO:0042921 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased nuclear receptor-mediated glucocorticoid signaling pathway (GO:0042921). GO:0042921 is a biological process from the Gene Ontology.
Downstream
Generalized Target-Tissue Glucocorticoid Insensitivity
Show evidence (2 references)
PMID:15070967 SUPPORT DIRECT In Vitro
"All five mutants studied demonstrate varying degrees of decreased affinity for the ligand in a standard dexamethasone binding assay, but preserve their ability to bind DNA."
Reduced ligand affinity with preserved DNA binding across mutant receptors.
PMID:15070967 SUPPORT DIRECT In Vitro
"The nondominant negative mutants, hGRalphaV571A, D641V, and V729I, show delayed translocation into the nucleus after exposure to ligand."
Documents delayed nuclear translocation of mutant receptors.
Generalized Target-Tissue Glucocorticoid Insensitivity
Reduced receptor signaling leaves all glucocorticoid-responsive tissues partially insensitive to cortisol.
cellular response to glucocorticoid stimulus GO:0071385 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cellular response to glucocorticoid stimulus (GO:0071385). GO:0071385 is a biological process from the Gene Ontology.
Downstream
Blunted HPA-Axis Negative Feedback
Hypoglycemia In neonates and young children with complete resistance, reduced glucocorticoid action in the liver can cause severe hypoglycemia.
Show evidence (1 reference)
PMID:31588529 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Primary generalized glucocorticoid resistance or Chrousos syndrome is a rare disorder, which affects all tissues expressing the human glucocorticoid receptor."
Describes generalized tissue insensitivity.
Blunted HPA-Axis Negative Feedback
Target-tissue insensitivity extends to the hypothalamus and pituitary, so cortisol fails to suppress CRH and ACTH normally. This is demonstrated clinically as resistance to dexamethasone suppression.
Downstream
Compensatory HPA-Axis Activation
Show evidence (1 reference)
PMID:6282933 SUPPORT DIRECT Human Clinical
"Plasma ACTH concentration was high, and both were resistant to adrenal suppression by dexamethasone."
Demonstrates failure of glucocorticoid negative feedback.
Compensatory HPA-Axis Activation
The axis is upregulated to overcome peripheral resistance, raising CRH, ACTH, and cortisol. Cortisol rises until it partially overcomes the resistance, at the expense of ACTH hypersecretion-related pathology.
corticotropin-releasing hormone secretion GO:0043396 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased corticotropin-releasing hormone secretion (GO:0043396). GO:0043396 is a biological process from the Gene Ontology.
Downstream
Adrenal Steroidogenesis Stimulation
Increased circulating cortisol level
Increased circulating ACTH level
Show evidence (1 reference)
PMID:18319312 SUPPORT DIRECT REVIEW SYNTHESIS Other
"A consequent increase in the activity of the hypothalamic-pituitary-adrenal axis compensates for the reduced sensitivity of peripheral tissues to glucocorticoids at the expense of ACTH hypersecretion-related pathology."
Describes compensatory HPA-axis activation and ACTH hypersecretion.
Adrenal Steroidogenesis Stimulation
Hypersecreted ACTH stimulates the adrenal cortex to overproduce steroids with mineralocorticoid activity and adrenal androgens, in addition to cortisol, and drives adrenal growth.
positive regulation of steroid hormone secretion GO:2000833 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of steroid hormone secretion (GO:2000833). GO:2000833 is a biological process from the Gene Ontology.
adrenal cortex UBERON:0001235 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in adrenal cortex (UBERON:0001235). UBERON:0001235 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Mineralocorticoid Excess
Adrenal Androgen Excess
Adrenal hyperplasia
Show evidence (1 reference)
PMID:25905168 SUPPORT DIRECT REVIEW SYNTHESIS Other
"hyper-secreted adrenocorticotropic hormone (ACTH) stimulates production of adrenal mineralocorticoids and/or androgens in addition to the glucocorticoid cortisol"
ACTH drives adrenal overproduction of mineralocorticoids and androgens.
Mineralocorticoid Excess
Elevated deoxycorticosterone and corticosterone, together with cortisol spillover onto the mineralocorticoid receptor, produce a mineralocorticoid excess state with low renin.
nuclear receptor-mediated mineralocorticoid signaling pathway GO:0031959 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased nuclear receptor-mediated mineralocorticoid signaling pathway (GO:0031959). GO:0031959 is a biological process from the Gene Ontology.
Downstream
Hypertension
Hypokalemia
Metabolic alkalosis
Show evidence (1 reference)
PMID:6282933 SUPPORT DIRECT Human Clinical
"The father appeared to have mineralocorticoid excess resulting in hypertension, hypokalemia, and metabolic alkalosis. This was found to be due to markedly elevated plasma levels of deoxycorticosterone and corticosterone."
First kindred demonstrating mineralocorticoid excess from DOC and corticosterone.
Adrenal Androgen Excess
Chronic ACTH drive raises adrenal androgens, producing signs of hyperandrogenism.
Downstream
Signs of androgen excess
Show evidence (2 references)
PMID:1704018 SUPPORT DIRECT Human Clinical
"Familial glucocorticoid resistance is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations in the absence of stigmata of Cushing's syndrome."
Characterizes the disorder as hyperandrogenic.
PMID:41038576 SUPPORT DIRECT Human Clinical
"The most frequent clinical manifestations were symptoms of androgen excess (43.3%), followed by mineralocorticoid excess (38.8%) and glucocorticoid deficiency (14.9%)."
Androgen excess is the most frequent manifestation across the pooled cohort, quantifying this node.
⬡

Pathograph

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

Phenotypes

9
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.
Show evidence (1 reference)
PMID:25905168 SUPPORT DIRECT REVIEW SYNTHESIS Other
"these patients develop hypertension and/or signs of hyperandrogenism, because hyper-secreted adrenocorticotropic hormone (ACTH) stimulates production of adrenal mineralocorticoids and/or androgens"
Hypertension from ACTH-driven mineralocorticoid excess is a core manifestation.
Endocrine 4
Signs of androgen excess FREQUENT Increased circulating androgen concentration HP:0030348 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Signs of androgen excess, annotated with Increased circulating androgen concentration (HP:0030348). HP:0030348 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41038576 SUPPORT DIRECT Human Clinical
"The most frequent clinical manifestations were symptoms of androgen excess (43.3%), followed by mineralocorticoid excess (38.8%) and glucocorticoid deficiency (14.9%)."
Androgen excess is the most frequent manifestation at 43.3% of the pooled cases, which supports both the phenotype and the FREQUENT band.
PMID:25905168 SUPPORT DIRECT REVIEW SYNTHESIS Other
"these patients develop hypertension and/or signs of hyperandrogenism, because hyper-secreted adrenocorticotropic hormone (ACTH) stimulates production of adrenal mineralocorticoids and/or androgens"
Attributes the signs of hyperandrogenism to ACTH-driven adrenal androgen production.
Adrenal hyperplasia 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:41038576 SUPPORT DIRECT Human Clinical
"Adrenal computed tomography revealed hyperplasia or adenomas in 68.8% of evaluated patients."
Adrenal hyperplasia or adenoma frequency from a systematic review of 71 cases.
Increased circulating cortisol level HP:0003118 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating cortisol level (HP:0003118). HP:0003118 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:6282933 SUPPORT DIRECT Human Clinical
"high 24-h mean plasma cortisol levels (27.4 micrograms/dl) and no stigmata of Cushing's syndrome"
Elevated plasma cortisol without Cushingoid stigmata.
Increased circulating ACTH level HP:0003154 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating ACTH level (HP:0003154). HP:0003154 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:6282933 SUPPORT DIRECT Human Clinical
"Plasma ACTH concentration was high, and both were resistant to adrenal suppression by dexamethasone."
Elevated plasma ACTH reported in the first kindred.
Metabolism 3
Hypokalemia HP:0002900 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypokalemia (HP:0002900). HP:0002900 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:6282933 SUPPORT DIRECT Human Clinical
"The father appeared to have mineralocorticoid excess resulting in hypertension, hypokalemia, and metabolic alkalosis."
Hypokalemia reported in the first kindred.
Metabolic alkalosis HP:0200114 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic alkalosis (HP:0200114). HP:0200114 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:6282933 SUPPORT DIRECT Human Clinical
"The father appeared to have mineralocorticoid excess resulting in hypertension, hypokalemia, and metabolic alkalosis."
Metabolic alkalosis reported in the first kindred.
Hypoglycemia HP:0001943 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoglycemia (HP:0001943). HP:0001943 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19933394 SUPPORT DIRECT Human Clinical
"The patient presented on the first day of life with profound hypoglycemia."
Neonatal hypoglycemia in complete generalized glucocorticoid resistance.
Constitutional 1
Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18319312 SUPPORT DIRECT REVIEW SYNTHESIS Other
"ranging from asymptomatic to severe cases of hyperandrogenism, fatigue, and/or mineralocorticoid excess"
Fatigue is named directly in the reported clinical spectrum.
🧬

Genetic Associations

1
NR3C1 (Inactivating germline variants in NR3C1 (point mutations, insertions, deletions))
Gene: NR3C1 hgnc:7978 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NR3C1 (hgnc:7978). hgnc:7978 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:28742501 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Any genetic defects in the NR3C1gene that encodes the hGR may cause Primary Generalized Glucocorticoid Resistance or Hypersensitivity Syndromes"
Establishes NR3C1 defects as the cause of the disorder.
PMID:28742501 SUPPORT DIRECT REVIEW SYNTHESIS Other
"there are patients who present with clinical manifestations suggestive of the above syndromes and do not harbor an inactivating or activating point mutation, insertion or deletion in the NR3C1gene"
Supports the note that some compatible phenotypes lack an NR3C1 variant.
Variants (2)
D641V
Valine for aspartate at residue 641 in the ligand-binding domain, the first NR3C1 point mutation identified in this disorder; it reduces ligand-binding affinity and transactivation without a dominant-negative effect.
Show evidence (2 references)
PMID:1704018 SUPPORT DIRECT Human Clinical
"which substituted valine for aspartic acid at amino acid residue 641. The propositus was homozygous while the other relatives were heterozygous for the mutation."
Identifies the D641V ligand-binding-domain substitution and its zygosity from sequencing the first reported kindred.
PMID:1704018 SUPPORT DIRECT In Vitro
"The binding affinity for dexamethasone of the Val 641-mutant receptor was threefold lower than that of the wild type receptor."
Reduced ligand-binding affinity of the mutant receptor.
I747M
Isoleucine to methionine at residue 747 near helix 12 of the ligand-binding domain; it decreases ligand binding and transactivation and acts as a dominant-negative inhibitor of the wild-type receptor via abnormal p160 coactivator interaction.
Show evidence (1 reference)
PMID:12050230 SUPPORT DIRECT In Vitro
"the mutant GR functioned as a dominant negative inhibitor of wild-type receptor-induced transactivation"
Establishes the dominant-negative behavior of the I747M variant.
💊

Medical Actions

1
High-dose dexamethasone
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: dexamethasone CHEBI:41879 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dexamethasone (CHEBI:41879). CHEBI:41879 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
High doses of a mineralocorticoid-sparing synthetic glucocorticoid (dexamethasone) stimulate the mutant and/or wild-type receptor and suppress endogenous ACTH, reducing adrenal overproduction of mineralocorticoids and androgens.
Mechanism Target:
Compensatory HPA-Axis Activation — Dexamethasone suppresses the upregulated HPA axis and ACTH hypersecretion.
Show evidence (1 reference)
PMID:25905168 SUPPORT DIRECT REVIEW SYNTHESIS Other
"suppress the endogenous secretion of ACTH and adrenal steroids in the affected subjects"
Treatment acts by suppressing ACTH hypersecretion.
Show evidence (1 reference)
PMID:25905168 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Treatment involves administration of high doses of mineralocorticoid activity-sparing pure glucocorticoids like dexamethasone, which stimulate the mutant and/or the wild-type hGR, and suppress the endogenous secretion of ACTH and adrenal steroids in the affected subjects."
Describes the standard dexamethasone treatment and its mechanism.
🔬

Biochemical Markers

1
Serum cortisol
Context: Mean plasma cortisol and 24-hour urinary free cortisol are elevated, but the normal diurnal rhythm is preserved and there are no Cushingoid features.
Show evidence (1 reference)
PMID:25905168 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Affected subjects demonstrate elevation of serum cortisol without Cushingoid manifestations, as the hypothalamic-pituitary-adrenal (HPA) axis is upregulated to compensate for the reduced action of this steroid in local tissues."
Elevated cortisol with preserved axis compensation and no Cushingoid signs.
🔬

Diagnosis

1
Endocrine evaluation and NR3C1 sequencing
Diagnosis rests on elevated diurnal serum cortisol and plasma ACTH with preserved circadian rhythm, elevated 24-hour urinary free cortisol, resistance to dexamethasone suppression, and absence of Cushingoid stigmata, confirmed by NR3C1 sequencing and functional characterization of the variant.
Genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:25905168 SUPPORT DIRECT REVIEW SYNTHESIS Other
"The diagnosis of this syndrome should be confirmed by sequencing of the NR3C1 gene including exon/intron junctions and subsequent validation of functional defects of the mutated receptors."
Molecular confirmation by NR3C1 sequencing plus functional validation.
PMID:25905168 SUPPORT DIRECT REVIEW SYNTHESIS Other
"determination of the 24-hour urinary free cortisol excretion to identify upregulation of the HPA axis with preservation of the normal circadian rhythmicity"
Describes the biochemical diagnostic workup.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
A 2026 systematic review assembled 71 cases from 43 unrelated families encompassing 39 distinct NR3C1 mutations; the condition is described as a rare genetic disorder.
Show evidence (1 reference)
PMID:41038576 SUPPORT DIRECT Human Clinical
"71 cases from 43 unrelated families were analyzed, encompassing 39 distinct NR3C1 mutations."
Reported case/family count supporting ultra-rare classification.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Glucocorticoid Resistance:

Cushing syndrome
Overlapping Features Cushing syndrome also presents with hypercortisolism but with Cushingoid stigmata and suppressible or autonomous cortisol; glucocorticoid resistance is distinguished by the absence of Cushingoid features despite high cortisol.
Show evidence (1 reference)
PMID:6282933 SUPPORT DIRECT Human Clinical
"high 24-h mean plasma cortisol levels (27.4 micrograms/dl) and no stigmata of Cushing's syndrome"
Hypercortisolism without Cushingoid stigmata distinguishes it from Cushing syndrome.
{ }

Source YAML

click to show 
name: Glucocorticoid Resistance
creation_date: "2026-10-12T04:05:10Z"
category: Mendelian
synonyms:
- Chrousos syndrome
- Primary generalized glucocorticoid resistance
- Generalized glucocorticoid resistance
- Familial glucocorticoid resistance
- Primary cortisol resistance
- Cortisol resistance syndrome
description: >-
  Primary generalized glucocorticoid resistance (Chrousos syndrome) is a rare
  genetic disorder of generalized, partial target-tissue insensitivity to
  glucocorticoids caused by inactivating variants in NR3C1, which encodes the
  human glucocorticoid receptor. Because peripheral tissues respond poorly to
  cortisol, hypothalamic-pituitary-adrenal negative feedback is blunted and the
  axis is compensatorily upregulated, raising cortisol and ACTH. The excess ACTH
  drives adrenal overproduction of steroids with mineralocorticoid activity
  (deoxycorticosterone, corticosterone) and of adrenal androgens, so affected
  individuals present with hypertension, hypokalemic alkalosis, and/or
  hyperandrogenism, together with adrenal hyperplasia, while cortisol-dependent
  functions are largely preserved and stigmata of Cushing's syndrome are absent.
  The clinical spectrum ranges from asymptomatic to severe; homozygous or
  compound-heterozygous defects present earlier and more severely than
  heterozygous ones. This entry covers the primary (NR3C1-based) Mendelian
  disorder, not acquired or tissue-specific glucocorticoid resistance seen in
  conditions such as asthma, inflammatory disease, or hematologic malignancy.
disease_term:
  preferred_term: glucocorticoid resistance
  term:
    id: MONDO:0014421
    label: glucocorticoid resistance
parents:
- Adrenogenital syndrome
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous NR3C1 variants that exert a dominant-negative effect on the
    wild-type receptor cause autosomal dominant disease; the I747M ligand-binding
    domain variant is a worked example.
  evidence:
  - reference: PMID:12050230
    reference_title: A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: We conclude that the mutation at amino acid 747 of the GR causes familial, autosomal dominant glucocorticoid resistance by decreasing ligand binding affinity and transcriptional activity, and by exerting a negative transdominant effect on the wild-type receptor.
    explanation: Establishes a dominant-negative, autosomal dominant mechanism for an NR3C1 ligand-binding-domain variant.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    NR3C1 variants that do not exert a dominant-negative effect transmit
    recessively; homozygous or compound-heterozygous defects produce the most
    severe, early-onset presentations.
  evidence:
  - reference: PMID:15070967
    reference_title: 'Natural glucocorticoid receptor mutants causing generalized glucocorticoid resistance: molecular genotype, genetic transmission, and clinical phenotype.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: each of the above hGRalpha mutations imparts different functional defects upon the glucocorticoid signal transduction pathway, which explains the autosomal recessive or dominant transmission of the disorder
    explanation: Functional differences among mutant receptors account for both recessive and dominant transmission.
pathophysiology:
- name: NR3C1 Inactivating Variant
  description: >-
    Point mutations, insertions, or deletions in NR3C1 impair the human
    glucocorticoid receptor. All reported Chrousos syndrome cases to date carry
    an NR3C1 defect.
  biological_scale: MOLECULAR
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: NR3C1
    term:
      id: hgnc:7978
      label: NR3C1
  molecular_functions:
  - preferred_term: nuclear glucocorticoid receptor activity
    modifier: DECREASED
    term:
      id: GO:0004883
      label: nuclear glucocorticoid receptor activity
  evidence:
  - reference: PMID:31588529
    reference_title: Glucocorticoid Resistance.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: It is characterized by generalized, partial tissue insensitivity to glucocorticoids caused by genetic defects in the NR3C1 gene.
    explanation: Attributes the disorder to NR3C1 defects.
  - reference: PMID:25715669
    reference_title: 'Chrousos syndrome: from molecular pathogenesis to therapeutic management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: All reported cases have been associated with point mutations or deletions in the NR3C1 gene.
    explanation: Confirms NR3C1 as the sole established cause.
  downstream:
  - target: Impaired Glucocorticoid Receptor Signal Transduction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18319312
      reference_title: 'Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The molecular basis of the condition has been ascribed to mutations in the human glucocorticoid receptor (hGR) gene, which impair glucocorticoid signal transduction and reduce tissue sensitivity to glucocorticoids.
      explanation: Links the NR3C1 variant to impaired receptor signal transduction.
- name: Impaired Glucocorticoid Receptor Signal Transduction
  description: >-
    Mutant receptors show reduced ligand-binding affinity, reduced
    transactivation of glucocorticoid-responsive genes, delayed nuclear
    translocation, and abnormal coactivator interaction. DNA-binding is usually
    preserved.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: nuclear receptor-mediated glucocorticoid signaling pathway
    term:
      id: GO:0042921
      label: nuclear receptor-mediated glucocorticoid signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:15070967
    reference_title: 'Natural glucocorticoid receptor mutants causing generalized glucocorticoid resistance: molecular genotype, genetic transmission, and clinical phenotype.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: All five mutants studied demonstrate varying degrees of decreased affinity for the ligand in a standard dexamethasone binding assay, but preserve their ability to bind DNA.
    explanation: Reduced ligand affinity with preserved DNA binding across mutant receptors.
  - reference: PMID:15070967
    reference_title: 'Natural glucocorticoid receptor mutants causing generalized glucocorticoid resistance: molecular genotype, genetic transmission, and clinical phenotype.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: The nondominant negative mutants, hGRalphaV571A, D641V, and V729I, show delayed translocation into the nucleus after exposure to ligand.
    explanation: Documents delayed nuclear translocation of mutant receptors.
  downstream:
  - target: Generalized Target-Tissue Glucocorticoid Insensitivity
    causal_link_type: DIRECT
- name: Generalized Target-Tissue Glucocorticoid Insensitivity
  description: >-
    Reduced receptor signaling leaves all glucocorticoid-responsive tissues
    partially insensitive to cortisol.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: cellular response to glucocorticoid stimulus
    term:
      id: GO:0071385
      label: cellular response to glucocorticoid stimulus
    modifier: DECREASED
  evidence:
  - reference: PMID:31588529
    reference_title: Glucocorticoid Resistance.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Primary generalized glucocorticoid resistance or Chrousos syndrome is a rare disorder, which affects all tissues expressing the human glucocorticoid receptor.
    explanation: Describes generalized tissue insensitivity.
  downstream:
  - target: Blunted HPA-Axis Negative Feedback
    causal_link_type: DIRECT
  - target: Hypoglycemia
    description: >-
      In neonates and young children with complete resistance, reduced
      glucocorticoid action in the liver can cause severe hypoglycemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25905168
      reference_title: Primary Generalized Glucocorticoid Resistance Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: In neonates and young children, severe hypoglycemia and loss of consciousness due to reduced actions of glucocorticoids in the liver may be present as initial manifestations in addition to hypertension and/or genital abnormalities.
      explanation: Links hepatic glucocorticoid insensitivity to neonatal hypoglycemia.
- name: Blunted HPA-Axis Negative Feedback
  description: >-
    Target-tissue insensitivity extends to the hypothalamus and pituitary, so
    cortisol fails to suppress CRH and ACTH normally. This is demonstrated
    clinically as resistance to dexamethasone suppression.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:6282933
    reference_title: Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Plasma ACTH concentration was high, and both were resistant to adrenal suppression by dexamethasone.
    explanation: Demonstrates failure of glucocorticoid negative feedback.
  downstream:
  - target: Compensatory HPA-Axis Activation
    causal_link_type: DIRECT
- name: Compensatory HPA-Axis Activation
  description: >-
    The axis is upregulated to overcome peripheral resistance, raising CRH, ACTH,
    and cortisol. Cortisol rises until it partially overcomes the resistance, at
    the expense of ACTH hypersecretion-related pathology.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: corticotropin-releasing hormone secretion
    term:
      id: GO:0043396
      label: corticotropin-releasing hormone secretion
    modifier: INCREASED
  evidence:
  - reference: PMID:18319312
    reference_title: 'Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: A consequent increase in the activity of the hypothalamic-pituitary-adrenal axis compensates for the reduced sensitivity of peripheral tissues to glucocorticoids at the expense of ACTH hypersecretion-related pathology.
    explanation: Describes compensatory HPA-axis activation and ACTH hypersecretion.
  downstream:
  - target: Adrenal Steroidogenesis Stimulation
    causal_link_type: DIRECT
  - target: Increased circulating cortisol level
    causal_link_type: DIRECT
  - target: Increased circulating ACTH level
    causal_link_type: DIRECT
- name: Adrenal Steroidogenesis Stimulation
  description: >-
    Hypersecreted ACTH stimulates the adrenal cortex to overproduce steroids with
    mineralocorticoid activity and adrenal androgens, in addition to cortisol, and
    drives adrenal growth.
  biological_scale: TISSUE
  locations:
  - preferred_term: adrenal cortex
    term:
      id: UBERON:0001235
      label: adrenal cortex
  biological_processes:
  - preferred_term: positive regulation of steroid hormone secretion
    term:
      id: GO:2000833
      label: positive regulation of steroid hormone secretion
    modifier: INCREASED
  evidence:
  - reference: PMID:25905168
    reference_title: Primary Generalized Glucocorticoid Resistance Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: hyper-secreted adrenocorticotropic hormone (ACTH) stimulates production of adrenal mineralocorticoids and/or androgens in addition to the glucocorticoid cortisol
    explanation: ACTH drives adrenal overproduction of mineralocorticoids and androgens.
  downstream:
  - target: Mineralocorticoid Excess
    causal_link_type: DIRECT
  - target: Adrenal Androgen Excess
    causal_link_type: DIRECT
  - target: Adrenal hyperplasia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30006372
      reference_title: 'Bilateral adrenal hyperplasia and NR3C1 mutations causing glucocorticoid resistance: Is there an association?'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: One of the clinical manifestations of this rare endocrine condition is bilateral adrenal hyperplasia due to compensatory elevations of plasma ACTH concentrations.
      explanation: Links chronic ACTH drive to adrenal hyperplasia.
- name: Mineralocorticoid Excess
  description: >-
    Elevated deoxycorticosterone and corticosterone, together with cortisol
    spillover onto the mineralocorticoid receptor, produce a mineralocorticoid
    excess state with low renin.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: nuclear receptor-mediated mineralocorticoid signaling pathway
    term:
      id: GO:0031959
      label: nuclear receptor-mediated mineralocorticoid signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:6282933
    reference_title: Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The father appeared to have mineralocorticoid excess resulting in hypertension, hypokalemia, and metabolic alkalosis. This was found to be due to markedly elevated plasma levels of deoxycorticosterone and corticosterone.
    explanation: First kindred demonstrating mineralocorticoid excess from DOC and corticosterone.
  downstream:
  - target: Hypertension
    causal_link_type: DIRECT
  - target: Hypokalemia
    causal_link_type: DIRECT
  - target: Metabolic alkalosis
    causal_link_type: DIRECT
- name: Adrenal Androgen Excess
  description: >-
    Chronic ACTH drive raises adrenal androgens, producing signs of
    hyperandrogenism.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:1704018
    reference_title: Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Familial glucocorticoid resistance is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations in the absence of stigmata of Cushing's syndrome.
    explanation: Characterizes the disorder as hyperandrogenic.
  - reference: PMID:41038576
    reference_title: 'Glucocorticoid Resistance Syndrome: A Systematic Review of the Genotypes, Phenotypes, and Their Relationships.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The most frequent clinical manifestations were symptoms of androgen excess (43.3%), followed by mineralocorticoid excess (38.8%) and glucocorticoid deficiency (14.9%).
    explanation: Androgen excess is the most frequent manifestation across the pooled cohort, quantifying this node.
  downstream:
  - target: Signs of androgen excess
    causal_link_type: DIRECT
phenotypes:
- name: Hypertension
  category: Cardiovascular
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:25905168
    reference_title: Primary Generalized Glucocorticoid Resistance Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: these patients develop hypertension and/or signs of hyperandrogenism, because hyper-secreted adrenocorticotropic hormone (ACTH) stimulates production of adrenal mineralocorticoids and/or androgens
    explanation: Hypertension from ACTH-driven mineralocorticoid excess is a core manifestation.
- name: Hypokalemia
  category: Metabolic
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:6282933
    reference_title: Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The father appeared to have mineralocorticoid excess resulting in hypertension, hypokalemia, and metabolic alkalosis.
    explanation: Hypokalemia reported in the first kindred.
- name: Metabolic alkalosis
  category: Metabolic
  phenotype_term:
    preferred_term: Metabolic alkalosis
    term:
      id: HP:0200114
      label: Metabolic alkalosis
  evidence:
  - reference: PMID:6282933
    reference_title: Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The father appeared to have mineralocorticoid excess resulting in hypertension, hypokalemia, and metabolic alkalosis.
    explanation: Metabolic alkalosis reported in the first kindred.
- name: Signs of androgen excess
  category: Endocrine
  description: >-
    Clinical androgen excess driven by the ACTH-stimulated rise in adrenal
    androgens. The sources name the category and its frequency rather than each
    individual sign, and HPO has no clinical hyperandrogenism term, so this is
    bound to the laboratory androgen term and the preferred_term carries the
    clinical meaning.
  phenotype_term:
    preferred_term: Signs of androgen excess
    term:
      id: HP:0030348
      label: Increased circulating androgen concentration
  frequency: FREQUENT
  evidence:
  - reference: PMID:41038576
    reference_title: 'Glucocorticoid Resistance Syndrome: A Systematic Review of the Genotypes, Phenotypes, and Their Relationships.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The most frequent clinical manifestations were symptoms of androgen excess (43.3%), followed by mineralocorticoid excess (38.8%) and glucocorticoid deficiency (14.9%).
    explanation: Androgen excess is the most frequent manifestation at 43.3% of the pooled cases, which supports both the phenotype and the FREQUENT band.
  - reference: PMID:25905168
    reference_title: Primary Generalized Glucocorticoid Resistance Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: these patients develop hypertension and/or signs of hyperandrogenism, because hyper-secreted adrenocorticotropic hormone (ACTH) stimulates production of adrenal mineralocorticoids and/or androgens
    explanation: Attributes the signs of hyperandrogenism to ACTH-driven adrenal androgen production.
- name: Fatigue
  category: Constitutional
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:18319312
    reference_title: 'Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: ranging from asymptomatic to severe cases of hyperandrogenism, fatigue, and/or mineralocorticoid excess
    explanation: Fatigue is named directly in the reported clinical spectrum.
- name: Adrenal hyperplasia
  category: Endocrine
  phenotype_term:
    preferred_term: Adrenal hyperplasia
    term:
      id: HP:0008221
      label: Adrenal hyperplasia
  evidence:
  - reference: PMID:41038576
    reference_title: 'Glucocorticoid Resistance Syndrome: A Systematic Review of the Genotypes, Phenotypes, and Their Relationships.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Adrenal computed tomography revealed hyperplasia or adenomas in 68.8% of evaluated patients.
    explanation: Adrenal hyperplasia or adenoma frequency from a systematic review of 71 cases.
- name: Increased circulating cortisol level
  category: Laboratory
  phenotype_term:
    preferred_term: Increased circulating cortisol level
    term:
      id: HP:0003118
      label: Increased circulating cortisol level
  evidence:
  - reference: PMID:6282933
    reference_title: Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: high 24-h mean plasma cortisol levels (27.4 micrograms/dl) and no stigmata of Cushing's syndrome
    explanation: Elevated plasma cortisol without Cushingoid stigmata.
- name: Increased circulating ACTH level
  category: Laboratory
  phenotype_term:
    preferred_term: Increased circulating ACTH level
    term:
      id: HP:0003154
      label: Increased circulating ACTH level
  evidence:
  - reference: PMID:6282933
    reference_title: Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: Plasma ACTH concentration was high, and both were resistant to adrenal suppression by dexamethasone.
    explanation: Elevated plasma ACTH reported in the first kindred.
- name: Hypoglycemia
  category: Metabolic
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:19933394
    reference_title: Neonatal complete generalized glucocorticoid resistance and growth hormone deficiency caused by a novel homozygous mutation in Helix 12 of the ligand binding domain of the glucocorticoid receptor gene (NR3C1).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: The patient presented on the first day of life with profound hypoglycemia.
    explanation: Neonatal hypoglycemia in complete generalized glucocorticoid resistance.
genetic:
- name: NR3C1
  association: Inactivating germline variants in NR3C1 (point mutations, insertions, deletions)
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: NR3C1
    term:
      id: hgnc:7978
      label: NR3C1
  notes: >-
    NR3C1 is the only established cause of primary generalized glucocorticoid
    resistance. Some patients with a compatible phenotype carry no detectable
    NR3C1 variant, and other glucocorticoid-signaling factors are suspected in
    those cases. Dominant-negative ligand-binding-domain variants transmit as
    autosomal dominant; others transmit recessively, so inheritance and severity
    depend on the specific functional defect. No ClinGen gene-disease validity
    assertion exists for this gene-disease pair, so no gene_disease_validity is
    recorded.
  variants:
  - name: D641V
    description: >-
      Valine for aspartate at residue 641 in the ligand-binding domain, the first
      NR3C1 point mutation identified in this disorder; it reduces ligand-binding
      affinity and transactivation without a dominant-negative effect.
    evidence:
    - reference: PMID:1704018
      reference_title: Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: which substituted valine for aspartic acid at amino acid residue 641. The propositus was homozygous while the other relatives were heterozygous for the mutation.
      explanation: Identifies the D641V ligand-binding-domain substitution and its zygosity from sequencing the first reported kindred.
    - reference: PMID:1704018
      reference_title: Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: The binding affinity for dexamethasone of the Val 641-mutant receptor was threefold lower than that of the wild type receptor.
      explanation: Reduced ligand-binding affinity of the mutant receptor.
  - name: I747M
    description: >-
      Isoleucine to methionine at residue 747 near helix 12 of the ligand-binding
      domain; it decreases ligand binding and transactivation and acts as a
      dominant-negative inhibitor of the wild-type receptor via abnormal p160
      coactivator interaction.
    evidence:
    - reference: PMID:12050230
      reference_title: A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: the mutant GR functioned as a dominant negative inhibitor of wild-type receptor-induced transactivation
      explanation: Establishes the dominant-negative behavior of the I747M variant.
  evidence:
  - reference: PMID:28742501
    reference_title: Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Any genetic defects in the NR3C1gene that encodes the hGR may cause Primary Generalized Glucocorticoid Resistance or Hypersensitivity Syndromes
    explanation: Establishes NR3C1 defects as the cause of the disorder.
  - reference: PMID:28742501
    reference_title: Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: there are patients who present with clinical manifestations suggestive of the above syndromes and do not harbor an inactivating or activating point mutation, insertion or deletion in the NR3C1gene
    explanation: Supports the note that some compatible phenotypes lack an NR3C1 variant.
biochemical:
- name: Serum cortisol
  context: >-
    Mean plasma cortisol and 24-hour urinary free cortisol are elevated, but the
    normal diurnal rhythm is preserved and there are no Cushingoid features.
  evidence:
  - reference: PMID:25905168
    reference_title: Primary Generalized Glucocorticoid Resistance Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Affected subjects demonstrate elevation of serum cortisol without Cushingoid manifestations, as the hypothalamic-pituitary-adrenal (HPA) axis is upregulated to compensate for the reduced action of this steroid in local tissues.
    explanation: Elevated cortisol with preserved axis compensation and no Cushingoid signs.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A 2026 systematic review assembled 71 cases from 43 unrelated families
    encompassing 39 distinct NR3C1 mutations; the condition is described as a rare
    genetic disorder.
  evidence:
  - reference: PMID:41038576
    reference_title: 'Glucocorticoid Resistance Syndrome: A Systematic Review of the Genotypes, Phenotypes, and Their Relationships.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: 71 cases from 43 unrelated families were analyzed, encompassing 39 distinct NR3C1 mutations.
    explanation: Reported case/family count supporting ultra-rare classification.
diagnosis:
- name: Endocrine evaluation and NR3C1 sequencing
  description: >-
    Diagnosis rests on elevated diurnal serum cortisol and plasma ACTH with
    preserved circadian rhythm, elevated 24-hour urinary free cortisol,
    resistance to dexamethasone suppression, and absence of Cushingoid stigmata,
    confirmed by NR3C1 sequencing and functional characterization of the variant.
  diagnosis_term:
    preferred_term: Genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:25905168
    reference_title: Primary Generalized Glucocorticoid Resistance Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The diagnosis of this syndrome should be confirmed by sequencing of the NR3C1 gene including exon/intron junctions and subsequent validation of functional defects of the mutated receptors.
    explanation: Molecular confirmation by NR3C1 sequencing plus functional validation.
  - reference: PMID:25905168
    reference_title: Primary Generalized Glucocorticoid Resistance Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: determination of the 24-hour urinary free cortisol excretion to identify upregulation of the HPA axis with preservation of the normal circadian rhythmicity
    explanation: Describes the biochemical diagnostic workup.
differential_diagnoses:
- name: Cushing syndrome
  description: >-
    Cushing syndrome also presents with hypercortisolism but with Cushingoid
    stigmata and suppressible or autonomous cortisol; glucocorticoid resistance is
    distinguished by the absence of Cushingoid features despite high cortisol.
  evidence:
  - reference: PMID:6282933
    reference_title: Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: high 24-h mean plasma cortisol levels (27.4 micrograms/dl) and no stigmata of Cushing's syndrome
    explanation: Hypercortisolism without Cushingoid stigmata distinguishes it from Cushing syndrome.
treatments:
- name: High-dose dexamethasone
  description: >-
    High doses of a mineralocorticoid-sparing synthetic glucocorticoid
    (dexamethasone) stimulate the mutant and/or wild-type receptor and suppress
    endogenous ACTH, reducing adrenal overproduction of mineralocorticoids and
    androgens.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dexamethasone
      term:
        id: CHEBI:41879
        label: dexamethasone
  evidence:
  - reference: PMID:25905168
    reference_title: Primary Generalized Glucocorticoid Resistance Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Treatment involves administration of high doses of mineralocorticoid activity-sparing pure glucocorticoids like dexamethasone, which stimulate the mutant and/or the wild-type hGR, and suppress the endogenous secretion of ACTH and adrenal steroids in the affected subjects.
    explanation: Describes the standard dexamethasone treatment and its mechanism.
  target_mechanisms:
  - target: Compensatory HPA-Axis Activation
    description: Dexamethasone suppresses the upregulated HPA axis and ACTH hypersecretion.
    evidence:
    - reference: PMID:25905168
      reference_title: Primary Generalized Glucocorticoid Resistance Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: suppress the endogenous secretion of ACTH and adrenal steroids in the affected subjects
      explanation: Treatment acts by suppressing ACTH hypersecretion.
references:
- reference: PMID:6282933
  title: Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease.
- reference: PMID:1704018
  title: Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance.
- reference: PMID:12050230
  title: A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators.
- reference: PMID:15070967
  title: 'Natural glucocorticoid receptor mutants causing generalized glucocorticoid resistance: molecular genotype, genetic transmission, and clinical phenotype.'
- reference: PMID:18319312
  title: 'Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder.'
- reference: PMID:19933394
  title: Neonatal complete generalized glucocorticoid resistance and growth hormone deficiency caused by a novel homozygous mutation in Helix 12 of the ligand binding domain of the glucocorticoid receptor gene (NR3C1).
- reference: PMID:25715669
  title: 'Chrousos syndrome: from molecular pathogenesis to therapeutic management.'
- reference: PMID:25905168
  title: Primary Generalized Glucocorticoid Resistance Syndrome.
- reference: PMID:28742501
  title: Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes.
- reference: PMID:29444898
  title: 'Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study.'
- reference: PMID:30006372
  title: 'Bilateral adrenal hyperplasia and NR3C1 mutations causing glucocorticoid resistance: Is there an association?'
- reference: PMID:31588529
  title: Glucocorticoid Resistance.
- reference: PMID:41038576
  title: 'Glucocorticoid Resistance Syndrome: A Systematic Review of the Genotypes, Phenotypes, and Their Relationships.'
notes: >-
  Zygosity shapes severity: a 2026 systematic review found homozygous or
  compound-heterozygous cases present earlier and with markedly higher rates of
  hypertension and hypokalemia than heterozygous cases. Heterozygous NR3C1
  variants are more common than once thought; the French MUTA-GR study found a 5%
  prevalence of heterozygous NR3C1 mutations among patients with bilateral
  adrenal incidentalomas and biochemical hypercortisolism without Cushing's
  signs. No GeneReviews chapter exists for this disorder (the only Bookshelf hit
  for "glucocorticoid" in the cached index is StatPearls NBK560897, a general
  glucocorticoid physiology chapter, which is not a disease baseline). Acquired
  or tissue-specific glucocorticoid resistance (asthma, inflammatory disease,
  glucocorticoid-resistant leukemia) is a distinct entity and is out of scope
  here.
📚

References & Deep Research

References

13
PMID:6282933
Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease.
No top-level findings curated for this source.
PMID:1704018
Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance.
No top-level findings curated for this source.
PMID:12050230
A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators.
No top-level findings curated for this source.
PMID:15070967
Natural glucocorticoid receptor mutants causing generalized glucocorticoid resistance: molecular genotype, genetic transmission, and clinical phenotype.
No top-level findings curated for this source.
PMID:18319312
Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder.
No top-level findings curated for this source.
PMID:19933394
Neonatal complete generalized glucocorticoid resistance and growth hormone deficiency caused by a novel homozygous mutation in Helix 12 of the ligand binding domain of the glucocorticoid receptor gene (NR3C1).
No top-level findings curated for this source.
PMID:25715669
Chrousos syndrome: from molecular pathogenesis to therapeutic management.
No top-level findings curated for this source.
PMID:25905168
Primary Generalized Glucocorticoid Resistance Syndrome.
No top-level findings curated for this source.
PMID:28742501
Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes.
No top-level findings curated for this source.
PMID:29444898
Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study.
No top-level findings curated for this source.
PMID:30006372
Bilateral adrenal hyperplasia and NR3C1 mutations causing glucocorticoid resistance: Is there an association?
No top-level findings curated for this source.
PMID:31588529
Glucocorticoid Resistance.
No top-level findings curated for this source.
PMID:41038576
Glucocorticoid Resistance Syndrome: A Systematic Review of the Genotypes, Phenotypes, and Their Relationships.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Glucocorticoid_Resistance · 2026-10-12T04:29:46Z · View source

De-novo curation of primary generalized glucocorticoid resistance (Chrousos syndrome), MONDO:0014421, NR3C1-based Mendelian disorder. The thin claude_code deep-research report was used for leads only; all primary sources were located via PubMed esearch and fetched with fetch-reference, and every claim is snippet-verified against the cache. Built a causal pathograph (NR3C1 inactivating variant -> impaired GR signal transduction -> generalized tissue insensitivity -> blunted HPA feedback -> compensatory HPA activation -> adrenal steroidogenesis -> mineralocorticoid/androgen excess branches) wiring the phenotypes into the pathograph (Fatigue left disconnected as its mechanism is uncertain). Both AD (dominant-negative I747M) and AR inheritance recorded with bound HP terms. No ClinGen validity assertion exists for NR3C1-GGR so gene_disease_validity was correctly omitted; no GeneReviews chapter exists (confirmed offline via bookshelf index, only StatPearls general glucocorticoid physiology). Treatment: high-dose dexamethasone with CHEBI agent and target_mechanisms edge. 13 distinct references. Validation: validate-disorders passed (40 snippets, 53 titles, 0 issues); count-verified 40/40; compliance 85.8%.

Claude Code ▸
Glucocorticoid Resistance (primary generalized glucocorticoid resistance, Chrousos syndrome): research report
claude-haiku-5-5, claude-sonnet-5-5 7 citations 2026-10-12T04:06:25.652431

Glucocorticoid Resistance (primary generalized glucocorticoid resistance, Chrousos syndrome): research report

Verification status. I ran three web searches in this session. Claims with a PMID and a "verified" tag come from those results. Everything else is from background knowledge and carries "unverified". Before it goes into the KB, run just fetch-reference on every PMID and check each snippet. Check every CURIE against its ontology lookup. That includes the template's MONDO:0014421 and the ORPHA, OMIM and HGNC identifiers below. Do not bind any unverified CURIE from this report.

1. Disease information

Overview. Primary generalized glucocorticoid resistance (GGR) is also called Chrousos syndrome, familial or sporadic glucocorticoid resistance, or cortisol resistance. It is a rare condition with generalized, partial tissue insensitivity to glucocorticoids. The cause is usually an inactivating defect in the glucocorticoid receptor gene (NR3C1). - The hypothalamic-pituitary-adrenal (HPA) axis is compensatorily activated to overcome the resistance, giving raised ACTH and cortisol. - Raised ACTH also drives adrenal steroids with mineralocorticoid and androgen activity. - Patients therefore show mineralocorticoid excess and hyperandrogenism, but no Cushingoid features. - Verified: Charmandari et al. 2008 (PMID:18319312) report that the spectrum runs from asymptomatic to severe cases of hyperandrogenism, fatigue, and/or mineralocorticoid excess. - Verified: compensatory HPA-axis activation drives ACTH hypersecretion because the reduced sensitivity of peripheral tissues is offset by increased HPA activity.

Identifiers (all unverified, look up before use). - OMIM #615962 (glucocorticoid resistance, generalized). The older entry was OMIM 138040. - The template gives MONDO:0014421. - Orphanet, ICD-10/11 and MeSH ("Glucocorticoid resistance" or "Cortisol resistance") were not looked up. - HGNC for NR3C1 is probably 7978. In this KB it would be written hgnc:7978.

Synonyms. Chrousos syndrome; familial glucocorticoid resistance; generalized glucocorticoid resistance; cortisol resistance; primary cortisol resistance.

Data source. The information is aggregated at disease level from case reports and kindreds, not from EHR. About 100 or fewer families have been reported (unverified).

Scope note. Acquired, tissue-specific glucocorticoid resistance is a separate matter. It occurs in asthma, rheumatoid arthritis, inflammatory bowel disease, and leukemia, and is mediated by GRβ, cytokines, and the like. This report covers the Mendelian entry. Other states belong in a mechanism module or a grouping, not here.

Reviews. - Charmandari 2008, PMID:18319312, verified. - Nicolaides & Charmandari, Eur J Clin Invest 2015, from the search result, PMID not retrieved. - "Glucocorticoid Resistance", Exp Suppl 2019, PMID:31588529, verified. - Hormones (Athens) 2017, PMID:28742501. It also covers patients with similar features but no detectable NR3C1 mutation. - Endotext chapter by Chrousos and Charmandari: primary generalized glucocorticoid resistance syndrome. - Q&A: Primary generalized glucocorticoid resistance (PMC3086527).

2. Etiology

Causal factors. - Germline NR3C1 variants (chromosome 5q31.3) reduce the receptor's function. - Verified: the first familial defect was an abnormal receptor with decreased affinity for cortisol, in Chrousos 1982 (PMID:6282933). The father had mineralocorticoid excess with hypertension and hypokalemia. He and his son had high cortisol without Cushing's stigmata. - Verified: Vingerhoeds 1976 (J Clin Endocrinol Metab 43:1128–1133) was the earlier "Spontaneous hypercortisolism without Cushing's syndrome" report. I did not find its PMID. - Verified: Hurley 1991 (PMID:1704018) found a point mutation in the hormone-binding domain, with a Val 641 mutant receptor. It reports a two- to threefold reduction in receptor-ligand binding affinity in the propositus, and threefold lower dexamethasone binding for the mutant. The D641V shorthand was not confirmed in the retrieved text. - Verified: Karl et al. 1993 described the first family with glucocorticoid receptor haploinsufficiency, a different mechanism from the affinity defect. - Genetic heterogeneity: some patients with a similar phenotype have no NR3C1 mutation (PMID:28742501). Other glucocorticoid-signaling factors are suspected, such as co-chaperones and coregulators.

Risk factors. Genetic factors are the dominant ones. Environmental risk factors are not established. Related polymorphisms (BclI, N363S, ER22/23EK) modulate sensitivity in the general population and are not causal for this disease (unverified).

Protective factors. None known.

Gene-environment interactions. Not established for the Mendelian disease. Stress and illness may unmask or worsen it, but I have no source.

3. Phenotypes

Presentation depends on the degree of resistance and on the excess of ACTH-driven adrenal steroids. All frequencies below are qualitative and from background knowledge unless tagged. Suggested HPO terms are unverified, so look each up.

Phenotype Type Notes Suggested HPO (verify)
Hypertension sign From mineralocorticoid excess (deoxycorticosterone, corticosterone, cortisol spillover on MR) Hypertension
Hypokalemia, metabolic alkalosis laboratory Mineralocorticoid excess Hypokalemia; Metabolic alkalosis
Hyperandrogenism sign Acne, hirsutism, male-pattern hair loss, oligo/amenorrhea and anovulation, infertility in women Hirsutism; Acne; Oligomenorrhea; Infertility
Precocious puberty sign Children, adrenal androgen excess Precocious puberty
Fatigue symptom Reported Fatigue
Elevated ACTH, cortisol, and urinary free cortisol laboratory Loss of normal diurnal rhythm preserved, but with high levels and resistance to dexamethasone suppression Elevated circulating cortisol level; Elevated circulating ACTH level
Adrenal hyperplasia / adrenal rest tumors sign Chronic ACTH drive; incidentaloma on imaging Adrenal hyperplasia
Male oligospermia sign Reported Oligospermia
Hypoglycemia, failure to thrive sign Rare, neonatal or severe (unverified) Hypoglycemia
Asymptomatic Common in heterozygous relatives

Characteristics. - Onset is any age, from neonatal to adult. Severity is variable, even within a family. - The course is chronic. The disease does not progress in the usual sense, though signs may emerge with age. - Quality of life: no dedicated instrument studies were found. Hyperandrogenism and infertility have the largest effect.

4. Genetic and molecular information

Causal gene. NR3C1 (glucocorticoid receptor, GR). Alternative-splicing isoforms are GRα (the active one) and GRβ.

Variants. - The spectrum includes missense variants in the ligand-binding domain (e.g., Val641, as in Hurley 1991), nonsense and frameshift variants causing haploinsufficiency (Karl 1993), splice-site variants, and deletions. - The Endotext chapter lists the consequences as: - reduced affinity to glucocorticoids or to target DNA; - inability to transactivate glucocorticoid-responsive genes; - slowed cytoplasmic-to-nuclear translocation. - Dominant-negative effects are described for some missense variants (unverified). - Classification per ACMG/AMP, population frequencies from gnomAD, and ClinGen validity were not checked. Run just list-gene-validity and look for a CGGV record. Do not assign a validity tier yourself. - Germline origin throughout.

Modifiers and epigenetics. Not established. Common GR polymorphisms may modulate expression, and I have no source. No chromosomal abnormality is known as a cause.

5. Environmental information

None established as a cause. - Environmental factors, lifestyle factors, and infectious agents: none. - Exogenous glucocorticoids and illness-related stress affect the HPA axis and can confound testing. - The pharmacological dexamethasone suppression test is itself the diagnostic perturbation.

6. Mechanism and pathophysiology

Causal chain. 1. A germline NR3C1 variant reduces functional GRα. The mechanisms are reduced ligand affinity, reduced DNA binding or transactivation, slowed nuclear translocation, or haploinsufficiency. (Demonstrated: Hurley 1991 and others.) 2. Tissues become partially insensitive to cortisol. Negative feedback at the hypothalamus and pituitary is blunted. (Demonstrated: dexamethasone-suppression resistance.) 3. The result is raised CRH and ACTH, which in turn raise adrenal output. Cortisol rises until it partially overcomes the resistance. (Charmandari 2008, PMID:18319312.) 4. The branch, driven by the raised ACTH, goes two ways: - Branch A, mineralocorticoid. Excess cortisol, deoxycorticosterone, and corticosterone act at the mineralocorticoid receptor. Hypertension, hypokalemia, and alkalosis follow. Part of this is inferred. Cortisol is normally inactivated in kidney by 11β-HSD2, so saturation of that enzyme is a proposed contributor. - Branch B, androgen. Adrenal androgens (DHEA, DHEA-S, androstenedione) rise. Hyperandrogenism follows, with acne, hirsutism, oligo-anovulation, and precocious puberty. Androgen excess may also suppress the gonadotropin axis. 5. Chronic ACTH drive causes adrenal hyperplasia. Compensation maintains cortisol-dependent functions in most tissues, so Cushingoid features are absent. (Inferred.)

Cell types and processes (suggested terms, verify). - Cell types: corticotroph (CL), adrenal cortex cell (zona fasciculata, zona reticularis), hypothalamic neurosecretory cell, renal collecting-duct principal cell. - GO processes: glucocorticoid receptor signaling pathway; glucocorticoid metabolic process; negative regulation of hormone secretion; nuclear translocation of the receptor. - Cellular components: cytoplasm and nucleus (GR shuttling).

Metabolic, immune, and molecular profiling information is not available; I did not search. Single-cell, spatial, and multi-omics data are not available.

7. Anatomical structures affected

  • Primary: hypothalamus, pituitary, adrenal cortex, and the glucocorticoid-responsive peripheral tissues.
  • Secondary: kidney (mineralocorticoid effect), skin and pilosebaceous unit, ovary and testis.
  • UBERON ids were not checked.
  • Lateralization is not applicable.

8. Temporal development

  • Onset is variable, from infancy to adulthood. Many carriers are asymptomatic and found by family screening.
  • Chronic and lifelong. No staging system exists. Spontaneous remission is not described.
  • Critical periods: pubertal timing and fertility. I have no source on this.

9. Inheritance and population

  • Inheritance. Both autosomal dominant (haploinsufficiency or dominant-negative variants) and autosomal recessive or homozygous forms (more severe) are described. Both are unverified here. Bind the mode-of-inheritance HPO term after lookup.
  • Penetrance and expressivity. Incomplete penetrance and variable expressivity are well described.
  • Prevalence. Very rare. I found no figure, so use prevalence_class: NOT_YET_DOCUMENTED or CASES_IN_LITERATURE rather than inventing a rate.
  • Population data. Founder effects, sex ratio, consanguinity, and geographic distribution were not researched. Note that women are often detected earlier because of hyperandrogenism.

10. Diagnostics

  • Laboratory. Elevated 24-hour urinary free cortisol, plasma cortisol, and ACTH, with preserved circadian rhythm. The 1 mg overnight dexamethasone suppression test is abnormal. Elevated adrenal androgens. Hypokalemia. LOINC codes were not checked and must be sourced through just loinc-seed-cache.
  • Imaging. Adrenal CT or MRI shows hyperplasia or adrenal masses.
  • Genetic testing. Single-gene or panel testing of NR3C1. Exome and genome sequencing are alternatives. Deletion/duplication analysis is a reasonable adjunct.
  • Functional. Glucocorticoid receptor binding assays in lymphocytes or fibroblasts, and reporter assays, can show reduced function (these are what the original studies used).
  • Differential. Cushing's syndrome (distinguished by absent Cushingoid features), apparent mineralocorticoid excess, congenital adrenal hyperplasia, PCOS, primary aldosteronism, pseudo-Cushing states, and depression. Hyperandrogenism with high cortisol and no Cushingoid features is the key clue.
  • Screening. No population screening. Cascade testing of relatives is appropriate.

11. Outcome and prognosis

  • Life expectancy is probably normal. No survival data were found.
  • Complications are hypertension and hypokalemia, infertility, and the effects of long-standing hyperandrogenism. Adrenal incidentalomas occur.
  • Treatment-related risk matters: over-treatment with glucocorticoids can produce iatrogenic Cushing's.
  • Prognostic factors and biomarkers: not studied.

12. Treatment

All of this is unverified; check against the Endotext chapter.

  • Principle. Suppress the excess ACTH drive with a high dose of a synthetic glucocorticoid with little mineralocorticoid activity, usually dexamethasone. The dose is titrated to the hormone and blood-pressure response, and cortisol alone is not the target.
  • Pharmacotherapy.
  • Dexamethasone (CHEBI/NCIT agent). NCIT treatment term: Pharmacotherapy NCIT:C15986, with therapeutic_agent.
  • Mineralocorticoid receptor antagonists (spironolactone, eplerenone) for hypertension and hypokalemia. Spironolactone also has antiandrogen activity.
  • Antiandrogens or combined oral contraceptives for hyperandrogenism in women.
  • Advanced therapeutics. None. Gene therapy and cell therapy are not applicable.
  • Surgery. Not indicated except for an adrenal mass.
  • Supportive care. Fertility counseling and management.
  • Clinical trials. None identified. I did not search ClinicalTrials.gov.
  • Pharmacogenomics. Not established.

13. Prevention

  • Primary prevention is not possible. Genetic counseling and cascade testing of relatives are the main measures.
  • Prenatal diagnosis and preimplantation testing are options where the variant is known.
  • Prophylaxis: none.
  • Tertiary prevention is blood-pressure and potassium monitoring, and avoiding glucocorticoid over-treatment.

14. Other species and natural disease

  • NR3C1 is conserved across mammals (human NCBITaxon:9606).
  • Spontaneous glucocorticoid resistance has been described in New World primates (e.g., squirrel monkey, cotton-top tamarin) with naturally high cortisol and low receptor affinity (unverified, from background knowledge).
  • OMIA, breed, and zoonosis data were not searched. They are likely not applicable.

15. Model organisms

  • All of this is unverified, from background knowledge, and needs a literature search before use.
  • The Nr3c1 knockout mouse is lethal at birth from lung failure, so it is not a model of this disease. Heterozygous mice and tissue-specific conditional knockouts, and GR-dimerization-deficient (GR-dim) knock-in mice, are used instead.
  • Heterozygous Nr3c1 mice show HPA-axis hyperactivity. Fidelity to the human phenotype (hypertension, hyperandrogenism) is unknown.
  • Cell models: patient fibroblasts and lymphocytes, and transfection systems for variant functional assays.
  • Resources: MGI, IMPC, ZFIN, and the Alliance of Genome Resources.
  • If the entry carries a model, record modeled_mechanisms with fidelity and limitations, and use HUMAN_MODEL_MISMATCH if the knockout lethality is relevant.

Gaps

  • Not retrieved: the 2015 Nicolaides PMID, the Vingerhoeds PMID, the Karl 1993 PMID, any quantitative frequencies, treatment evidence, and all ontology identifiers.
  • Before curation, run the GeneReviews check (just check-genereviews) to see whether a chapter exists. Also check whether a ClinGen assertion exists for NR3C1.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
On topic 6
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 3
Resolved 3
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0

Every term resolved, and every label the report gave matched.