Cushing's Syndrome

1. Disease Information

1.1 Definition and current understanding

Cushing’s syndrome is defined as a “prolonged increase in plasma cortisol levels that is not due to a physiological etiology.” (Reincke & Fleseriu, JAMA, published 2023-07, URL: https://doi.org/10.1001/jama.2023.11305) (reincke2023cushingsyndromea pages 1-2)

1.2 Key identifiers and synonyms

Only identifiers explicitly available in the retrieved evidence are included here.

Table: This table summarizes the core disease concept and major clinical subtypes of Cushing's syndrome, with concise definitions, common synonyms, and only those IDs explicitly supported in the available evidence. It is useful for knowledge-base normalization and concept mapping without introducing unsupported coding terms.

Notes on missing identifiers: ICD-10/ICD-11 codes, MeSH IDs, OMIM/Orphanet identifiers were not extractable from the retrieved full-text evidence in this run and are therefore not reported.

1.3 Evidence source types

The synthesis below draws predominantly from: - Aggregated disease-level resources (high-citation review and cohorts) (reincke2023cushingsyndromea pages 1-2, loughrey2024insightsonepidemiology pages 1-2) - Registry/cohort observational studies (human clinical) (loughrey2024insightsonepidemiology pages 1-2) - Interventional and real-world pharmacotherapy studies (human clinical) (gadelha2023longtermefficacyand pages 1-2, feelders2023longtermefficacyand pages 1-2) - Systematic review evidence for iatrogenic pediatric CS (human clinical) (abdalla2024cushingssyndromeand pages 1-2)

2. Etiology

2.1 Primary causes

Endogenous CS etiologic distribution (current clinical framing): - ACTH-dependent (pituitary) Cushing disease: ~60–70% of endogenous CS (reincke2023cushingsyndromea pages 1-2, reincke2023cushingsyndromea pages 2-3) - ACTH-independent adrenal cortisol production: ~20–30% (reincke2023cushingsyndromea pages 2-3) - Ectopic ACTH-dependent CS: ~6–10% (reincke2023cushingsyndromea pages 2-3)

Key mechanistic statement (authoritative review): evaluation “begins with ruling out exogenous steroid use.” (reincke2023cushingsyndromea pages 1-2)

2.2 Risk factors

Clinical risk enrichment groups (examples): In the context of hypertension work-up, a targeted screening phenotype includes younger age (<40 years), rapidly evolving hypertension, adrenal adenomas/incidentalomas, or pituitary lesions. (De Martino et al., J Endocrinol Invest, published 2025-03, URL: https://doi.org/10.1007/s40618-024-02453-9) (m.c.2025hypertensionandcushing’s pages 1-2)

2.3 Protective factors

No protective genetic or environmental factors were identified in the retrieved evidence for CS.

2.4 Gene–environment or drug–drug interactions

A dominant “environmental” driver of CS is exogenous glucocorticoid exposure, including non-oral routes; prevention therefore includes correct prescribing/monitoring and avoiding unrecognized exposure sources. (reincke2023cushingsyndromea pages 1-2, abdalla2024cushingssyndromeand pages 1-2)

3. Phenotypes

3.1 Core phenotype pattern

CS presents with a multisystem phenotype combining: - Cutaneous findings (e.g., facial plethora, easy bruising, purple striae) (reincke2023cushingsyndromea pages 1-2) - Cardiometabolic findings (e.g., hypertension, hyperglycemia/diabetes, dyslipidemia, central adiposity) (reincke2023cushingsyndromea pages 1-2, reincke2023cushingsyndromea pages 4-5) - Neuropsychiatric manifestations (neurocognitive changes, mood disorders) (reincke2023cushingsyndromea pages 1-2, reincke2023cushingsyndromea pages 3-4) - Muscle/bone catabolism (proximal weakness, osteopenia/osteoporosis) (reincke2023cushingsyndromea pages 3-4)

3.2 Phenotype frequencies and HPO mapping

The 2023 JAMA review reports a range of symptom frequencies (e.g., weight gain 70–95%, hypertension 60–90%, depression 50–80%, hirsutism 50–75%; purple striae <50%), emphasizing that no single symptom is pathognomonic. (reincke2023cushingsyndromea pages 4-5, reincke2023cushingsyndromea pages 3-4)

Table: This table maps major clinical features of Cushing syndrome to suggested Human Phenotype Ontology terms, with frequency ranges drawn from the 2023 JAMA review and supporting recent evidence. It is useful for structuring phenotype annotations in a disease knowledge base.

3.3 Laboratory abnormalities

Typical laboratory abnormalities include hyperglycemia/insulin changes, dyslipidemia, leukocytosis with relative lymphopenia, and hypokalemia (especially prominent in ectopic ACTH syndrome). (reincke2023cushingsyndromea pages 4-5, stachowska2020etiologybaselineclinical pages 1-2)

3.4 Quality-of-life impact

While QoL is widely recognized as impaired in CS and treatment trials include patient-reported outcomes, quantitative QoL instrument values (e.g., SF-36, CushingQoL) were not extractable from the retrieved evidence excerpts in this run. Trials and extension studies explicitly track HRQoL as outcomes. (gadelha2023longtermefficacyand pages 1-2)

4. Genetic / Molecular Information

4.1 Causal genes and variant classes (selected, evidence-supported)

CS is often tumor-driven and therefore commonly involves somatic drivers (pituitary or adrenal lesions), but several germline syndromic etiologies exist.

Table: This table summarizes the main endogenous Cushing syndrome etiologies, their approximate frequencies, and the best-supported genes and pathways from the cited evidence. It is useful for linking disease subtypes to lesion source, inheritance context, and molecular mechanisms.

4.2 Recent developments (2024)

Recent molecular work continues to refine corticotroph tumorigenesis. For example, an analysis/systematic review of USP8 highlights that activating USP8 alterations are implicated in ACTH secretion and cell proliferation in corticotroph adenomas and motivates EGFR and USP8 pathway targeting as a research direction. (Hashemi‑Madani et al., BMC Endocr Disord, published 2024-06, URL: https://doi.org/10.1186/s12902-024-01619-z) (reincke2023cushingsyndromea pages 9-10)

5. Environmental Information

5.1 Exogenous/iatrogenic CS

Exogenous glucocorticoids are the most common cause of CS overall, and iatrogenic CS can occur via multiple routes. (reincke2023cushingsyndromea pages 1-2)

A pediatric systematic review of topical corticosteroid-associated iatrogenic CS reported (n=63): 81% recovered, 3.2% partially recovered, and 6.3% died, with a mean exposure duration of 25.4 weeks; discontinuation of the offending steroid was universal, and oral hydrocortisone replacement was commonly used. (Abdalla et al., published 2024-09, URL: https://doi.org/10.58742/bmj.v2i3.104) (abdalla2024cushingssyndromeand pages 1-2)

6. Mechanism / Pathophysiology

6.1 Causal chain (high-level)

1. Upstream trigger: autonomous cortisol secretion (adrenal tumor/hyperplasia) or ACTH excess (pituitary/ectopic tumor) (reincke2023cushingsyndromea pages 1-2, reincke2023cushingsyndromea pages 2-3)
2. Hormonal state: sustained hypercortisolemia (reincke2023cushingsyndromea pages 1-2)
3. Downstream systemic effects: protein catabolism (myopathy), insulin resistance/hyperglycemia, immunosuppression (infection risk), neuropsychiatric effects, and cardiovascular remodeling (hypertension, atherosclerotic risk). (reincke2023cushingsyndromea pages 1-2, reincke2023cushingsyndromea pages 3-4)

6.2 Hypertension mechanism (example of downstream pathway)

Excess cortisol can overwhelm 11β-HSD2 protection, allowing mineralocorticoid receptor activation with sodium retention and hypokalemia, and can amplify vascular pressor responses, contributing to the ~80% hypertension prevalence reported in endogenous CS. (m.c.2025hypertensionandcushing’s pages 1-2)

6.3 Adrenal genetic pathway theme

Multiple adrenal etiologies converge on cAMP/PKA signaling dysregulation (e.g., PRKAR1A in PPNAD; ARMC5 in PBMAH; other lesion-specific genes), consistent with endocrine control of adrenal steroidogenesis. (reincke2023cushingsyndromea pages 8-9)

Suggested ontology terms (mechanism; not evidence-derived): - GO:0006954 inflammatory response (downstream infection susceptibility context) - GO:0008283 cell population proliferation (pituitary/adrenal tumor growth) - GO:0010817 regulation of hormone levels

7. Anatomical Structures Affected

7.1 Primary organs and systems

• Hypothalamic–pituitary–adrenal (HPA) axis, including pituitary corticotroph tumors (Cushing disease) and adrenal cortisol-producing lesions (reincke2023cushingsyndromea pages 1-2, loughrey2024insightsonepidemiology pages 1-2)
• Cardiovascular system (hypertension, myocardial infarction risk) (reincke2023cushingsyndromea pages 9-10)
• Skeletal system (osteopenia/osteoporosis, fractures) (reincke2023cushingsyndromea pages 9-10, stachowska2020etiologybaselineclinical pages 11-12)
• Immune system (immunosuppression/infection) (reincke2023cushingsyndromea pages 1-2, reincke2023cushingsyndromea pages 9-10)

Suggested anatomy ontology terms (not evidence-derived): - UBERON:0000007 pituitary gland - UBERON:0002369 adrenal gland

8. Temporal Development

8.1 Onset and course

CS is typically subacute-to-chronic and often underdiagnosed; cohort data highlight diagnostic challenges (e.g., microadenomas frequently occult on imaging). (reincke2023cushingsyndromea pages 2-3, loughrey2024insightsonepidemiology pages 1-2)

8.2 Post-cure recovery dynamics

After curative treatment, the median time to normalization of the HPA axis differs by etiology: 0.6 years (ectopic), 1.4 years (Cushing disease), 2.5 years (adrenal CS). (reincke2023cushingsyndromea pages 8-9)

9. Inheritance and Population

9.1 Epidemiology

• Endogenous CS incidence: 2–8 per million per year (reincke2023cushingsyndromea pages 1-2, reincke2023cushingsyndromea pages 9-10)
• In a Northern Ireland cohort (2000–2019), annual incidence of Cushing disease was 1.39–1.57 per million per year, and 72% were female. (Loughrey et al., published 2024-06, URL: https://doi.org/10.1530/erc-24-0028) (loughrey2024insightsonepidemiology pages 1-2)

9.2 Inheritance patterns (selected)

While most pituitary/adrenal tumors are sporadic, germline causes are important in specific subtypes: - PPNAD/Carney complex: commonly PRKAR1A germline pathogenic variants (reincke2023cushingsyndromea pages 8-9)

10. Diagnostics

10.1 Evidence-based diagnostic strategy

The diagnostic process requires biochemical confirmation; elevated cortisol alone is insufficient and most patients require more than one screening test. The recommended first-line screening tests are: - 24-hour UFC - Late-night salivary cortisol - 1-mg overnight dexamethasone suppression test (DST) with 2–3 samples recommended for UFC and late-night salivary cortisol due to intrapatient variability. (reincke2023cushingsyndromea pages 4-5, reincke2023cushingsyndromea pages 2-3)

After biochemical confirmation, plasma ACTH separates ACTH-independent adrenal causes (suppressed ACTH) from ACTH-dependent causes (midnormal/elevated ACTH). Localization may require pituitary MRI and/or bilateral inferior petrosal sinus sampling (IPSS); these are not screening tools. (reincke2023cushingsyndromea pages 1-2, reincke2023cushingsyndromea pages 2-3)

10.2 Diagnostic algorithm figure (real-world implementation)

A stepwise diagnostic algorithm for suspected CS, including screening tests and subsequent etiologic classification/localization, is shown in the JAMA review (Figure 2). (reincke2023cushingsyndromea media 4775d5aa)

10.3 Test performance examples

Assay-specific LNSC cutoffs vary; in one prospective study, a cutoff of 10.1 nmol/L yielded 94% sensitivity and 84% specificity for hypercortisolism. (reincke2023cushingsyndromea pages 4-5)

DST false positives can arise from inadequate dexamethasone exposure; measuring dexamethasone and using method-specific cortisol thresholds improved clinical specificity from 67.5% to 92.4% while preserving 100% sensitivity in one LC–MS/MS-based evaluation. (reincke2023cushingsyndromea pages 4-5)

Table: This table summarizes the main diagnostic tests used in Cushing syndrome, separating first-line screening from etiology and localization studies. It also includes assay-specific performance values when they were available in the evidence.

11. Outcome / Prognosis

11.1 Mortality

Endogenous CS is associated with persistent excess mortality. A meta-analysis reported standardized mortality ratio (SMR) 3.0 (95% CI 2.3–3.9), and pooled data attribute many deaths to atherosclerotic disease, thromboembolism, and infection. (reincke2023cushingsyndromea pages 9-10)

In a regional neurosurgical cohort of Cushing disease in Northern Ireland, mortality was substantially elevated versus the general population (SMR 8.10, 95% CI 3.3–16.7). (loughrey2024insightsonepidemiology pages 1-2)

11.2 Major complications and temporal signal

Registry data indicate markedly elevated standardized incidence rates for complications in the 3 years before diagnosis, including myocardial infarction, fractures, and deep vein thrombosis (values reported as 4.4, 4.9, and 13.8, respectively). (reincke2023cushingsyndromea pages 9-10)

11.3 Recurrence and remission patterns

Recurrence after transsphenoidal surgery for Cushing disease can occur in up to 35% of patients. (reincke2023cushingsyndromea pages 8-9)

12. Treatment

12.1 First-line and escalation strategy (authoritative view)

For endogenous CS, “first-line therapy… is surgery to remove the underlying tumor”, with additional medical therapy, radiation, or bilateral adrenalectomy used when needed. (reincke2023cushingsyndromea pages 9-10)

12.2 Current applications and real-world implementations (selected quantitative data)

Table: This table summarizes major treatment modalities for endogenous Cushing syndrome and Cushing disease, including real-world implementation patterns and quantitative outcomes where available. It is useful for comparing first-line surgery with newer medical therapies such as osilodrostat and pasireotide, alongside key safety considerations.

Key recent quantitative examples: - Osilodrostat (LINC 4 extension, 2023): 72.4% achieved normal mean UFC at end-of-trial, with sustained clinical improvements over long-term therapy. (Gadelha et al., published 2023-08, URL: https://doi.org/10.3389/fendo.2023.1236465) (gadelha2023longtermefficacyand pages 1-2) - Pasireotide ± cabergoline (Phase II, 2023): 50.0% achieved mean UFC ≤ ULN at week 35; hyperglycemia occurred in 51.5%. (Feelders et al., published 2023-10, URL: https://doi.org/10.3389/fendo.2023.1165681) (feelders2023longtermefficacyand pages 1-2)

12.3 MAXO term suggestions (not evidence-derived)

• MAXO:0000605 Surgical excision
• MAXO:0000504 Drug therapy
• MAXO:0000647 Radiation therapy

13. Prevention

13.1 Primary prevention (iatrogenic disease prevention)

Because exogenous glucocorticoids are the most common overall cause, a core preventive step is to identify and avoid unnecessary glucocorticoid exposure, including non-oral preparations. (reincke2023cushingsyndromea pages 1-2)

In pediatric topical-steroid iatrogenic CS, prevention recommendations include specialist supervision of topical corticosteroid administration and caregiver education on correct use and side effects. (abdalla2024cushingssyndromeand pages 1-2)

13.2 Secondary prevention (targeted screening)

Screening is recommended in selected high-risk clinical contexts (e.g., adrenal adenomas; hypertensive patients with red-flag phenotype), using UFC, DST, or LNSC rather than indiscriminate testing. (reincke2023cushingsyndromea pages 2-3, m.c.2025hypertensionandcushing’s pages 1-2)

14. Other Species / Natural Disease

Veterinary or cross-species data were not retrieved in evidence suitable for synthesis in this run.

15. Model Organisms

Model-organism evidence was not retrieved in evidence suitable for synthesis in this run.

Key gaps and limitations of this report

• ICD-10/ICD-11, MeSH, OMIM/Orphanet identifiers were not accessible from the retrieved evidence and are therefore not reported.
• Many primary sources in the retrieved evidence do not expose PMIDs in the accessible text; this report provides DOIs/URLs and publication months/years where available.
• Quantitative QoL instrument scores and detailed test sensitivity/specificity across multiple assays were not fully extractable beyond the included examples.

References

1. (reincke2023cushingsyndromea pages 1-2): Martin Reincke and Maria Fleseriu. Cushing syndrome: a review. JAMA, 330 2:170-181, Jul 2023. URL: https://doi.org/10.1001/jama.2023.11305, doi:10.1001/jama.2023.11305. This article has 229 citations.

2. (reincke2023cushingsyndromea pages 2-3): Martin Reincke and Maria Fleseriu. Cushing syndrome: a review. JAMA, 330 2:170-181, Jul 2023. URL: https://doi.org/10.1001/jama.2023.11305, doi:10.1001/jama.2023.11305. This article has 229 citations.

3. (m.c.2025hypertensionandcushing’s pages 1-2): De Martino M.C., L. Canu, I. Bonaventura, C. Vitiello, C. Sparano, and A. Cozzolino. Hypertension and cushing’s syndrome: hunt for the red flag. Journal of Endocrinological Investigation, 48:1909-1918, Mar 2025. URL: https://doi.org/10.1007/s40618-024-02453-9, doi:10.1007/s40618-024-02453-9. This article has 6 citations and is from a peer-reviewed journal.

4. (loughrey2024insightsonepidemiology pages 1-2): Paul Benjamin Loughrey, Brian Herron, Stephen Cooke, Philip Weir, Jayna Elizabeth Smyth, Karen R Mullan, Estelle G Healy, Jane Evanson, Stephanie G Craig, Jacqueline A James, Márta Korbonits, and Steven J Hunter. Insights on epidemiology, morbidity and mortality of cushing’s disease in northern ireland. Endocrine-Related Cancer, Jun 2024. URL: https://doi.org/10.1530/erc-24-0028, doi:10.1530/erc-24-0028. This article has 9 citations and is from a domain leading peer-reviewed journal.

5. (gadelha2023longtermefficacyand pages 1-2): Mônica Gadelha, Peter J. Snyder, Przemysław Witek, Marie Bex, Zhanna Belaya, Adina F. Turcu, Richard A. Feelders, Anthony P. Heaney, Michaela Paul, Alberto M. Pedroncelli, and Richard J. Auchus. Long-term efficacy and safety of osilodrostat in patients with cushing’s disease: results from the linc 4 study extension. Frontiers in Endocrinology, Aug 2023. URL: https://doi.org/10.3389/fendo.2023.1236465, doi:10.3389/fendo.2023.1236465. This article has 44 citations.

6. (feelders2023longtermefficacyand pages 1-2): Richard A. Feelders, Maria Fleseriu, Pinar Kadioglu, Marie Bex, Deyanira González-Devia, Cesar Luiz Boguszewski, Dilek Gogas Yavuz, Heather Patino, Alberto M. Pedroncelli, Ricardo Maamari, Arghya Chattopadhyay, Beverly M. K. Biller, and Rosario Pivonello. Long-term efficacy and safety of subcutaneous pasireotide alone or in combination with cabergoline in cushing’s disease. Frontiers in Endocrinology, Oct 2023. URL: https://doi.org/10.3389/fendo.2023.1165681, doi:10.3389/fendo.2023.1165681. This article has 26 citations.

7. (abdalla2024cushingssyndromeand pages 1-2): Berun A. Abdalla, Maria A. Rasool, Goran J. Baiz, Zanyar Kh. Hama, Karokh K. Mohammed, Yousif M. Mahmood, Ronak S. Ahmed, Wirya N. Sabr, Khdir Hussein Hamad Khoshnaw, Soran M. Ahmed, Karzan M. Hasan, Bilal A. Mohammed, Honar O. Kareem, and Dyari Q. Hamad. Cushing's syndrome and topical corticosteroids in pediatrics: a systematic review. Barw Medical Journal, Sep 2024. URL: https://doi.org/10.58742/bmj.v2i3.104, doi:10.58742/bmj.v2i3.104. This article has 3 citations.

8. (reincke2023cushingsyndromea pages 4-5): Martin Reincke and Maria Fleseriu. Cushing syndrome: a review. JAMA, 330 2:170-181, Jul 2023. URL: https://doi.org/10.1001/jama.2023.11305, doi:10.1001/jama.2023.11305. This article has 229 citations.

9. (reincke2023cushingsyndromea pages 3-4): Martin Reincke and Maria Fleseriu. Cushing syndrome: a review. JAMA, 330 2:170-181, Jul 2023. URL: https://doi.org/10.1001/jama.2023.11305, doi:10.1001/jama.2023.11305. This article has 229 citations.

10. (reincke2023cushingsyndromea pages 9-10): Martin Reincke and Maria Fleseriu. Cushing syndrome: a review. JAMA, 330 2:170-181, Jul 2023. URL: https://doi.org/10.1001/jama.2023.11305, doi:10.1001/jama.2023.11305. This article has 229 citations.

11. (stachowska2020etiologybaselineclinical pages 1-2): Barbara Stachowska, Justyna Kuliczkowska-Płaksej, Marcin Kałużny, Jędrzej Grzegrzółka, Maja Jończyk, and Marek Bolanowski. Etiology, baseline clinical profile and comorbidities of patients with cushing’s syndrome at a single endocrinological center. Endocrine, 70:616-628, Sep 2020. URL: https://doi.org/10.1007/s12020-020-02468-1, doi:10.1007/s12020-020-02468-1. This article has 9 citations and is from a peer-reviewed journal.

12. (reincke2023cushingsyndromea pages 8-9): Martin Reincke and Maria Fleseriu. Cushing syndrome: a review. JAMA, 330 2:170-181, Jul 2023. URL: https://doi.org/10.1001/jama.2023.11305, doi:10.1001/jama.2023.11305. This article has 229 citations.

13. (stachowska2020etiologybaselineclinical pages 11-12): Barbara Stachowska, Justyna Kuliczkowska-Płaksej, Marcin Kałużny, Jędrzej Grzegrzółka, Maja Jończyk, and Marek Bolanowski. Etiology, baseline clinical profile and comorbidities of patients with cushing’s syndrome at a single endocrinological center. Endocrine, 70:616-628, Sep 2020. URL: https://doi.org/10.1007/s12020-020-02468-1, doi:10.1007/s12020-020-02468-1. This article has 9 citations and is from a peer-reviewed journal.

14. (reincke2023cushingsyndromea media 4775d5aa): Martin Reincke and Maria Fleseriu. Cushing syndrome: a review. JAMA, 330 2:170-181, Jul 2023. URL: https://doi.org/10.1001/jama.2023.11305, doi:10.1001/jama.2023.11305. This article has 229 citations.

15. (araujocastro2025realworlddataon pages 12-13): Marta Araujo-Castro, Rogelio García-Centeno, Laura González, Felicia A. Hanzu, Aida Orois, Rosa Camara, María Dolores Ollero García, Ana Irigaray Echarri, Paola Gracia Gimeno, Eider Pascual-Corrales, Betina Biagetti, Andrés Cardona, Inmaculada González Molero, Andreu Simo-Servat, Fernando Guerrero Pérez, Rocío Villar-Taibo, Ignacio Bernabéu, Carmen Fajardo-Montañana, Cristina Novo-Rodríguez, Carmen Tenorio Jimenéz, María Calatayud, María Dolores Moure Rodríguez, Fernando Cordido, Ana Castro, Lucía Manzano Valero, Miguel Paja Fano, Jessica Goi, Anna Aulinas, Pablo Abellán, Pedro Iglesias, and Alfonso Soto-Moreno. Real-world data on the efficacy and safety of osilodrostat in patients with cushing’s disease in spain. Journal of Clinical Medicine, 14:7575, Oct 2025. URL: https://doi.org/10.3390/jcm14217575, doi:10.3390/jcm14217575. This article has 2 citations.

16. (dzialach2025realworldexperiencewith pages 1-2): Lukasz Dzialach, Wioleta Respondek, and Przemyslaw Witek. Real-world experience with pasireotide-lar in cushing’s disease: single-center 12-month observational study. Journal of Clinical Medicine, 14:2794, Apr 2025. URL: https://doi.org/10.3390/jcm14082794, doi:10.3390/jcm14082794. This article has 3 citations.

17. (mondin2025reallifedataon pages 1-2): Alessandro Mondin, Filippo Ceccato, Carla Scaroni, Luca Denaro, Renzo Manara, Umberto Maria Robertazzo, and Mattia Barbot. Real-life data on pasireotide in monotherapy or combined in active cushing’s disease. Frontiers in Endocrinology, Nov 2025. URL: https://doi.org/10.3389/fendo.2025.1695342, doi:10.3389/fendo.2025.1695342. This article has 0 citations.