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.

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

• Glucocorticoid Resistance, PMID 31588529
• Hormones (Athens) review, PMID 28742501
• Chrousos 1982, PMC370198
• Hurley 1991, PMC296359
• Q&A: Primary generalized glucocorticoid resistance, PMC3086527
• Endotext: primary generalized glucocorticoid resistance syndrome
• Endotext: glucocorticoid resistance syndromes and states

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

Term Validation

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

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