Introduction

Cushing’s syndrome (CS) is a rare endocrine disorder caused by prolonged exposure to supraphysiologic levels of glucocorticoids (GCs), either of endogenous or exogenous origin (1-3).

Endogenous CS is classified into two categories: adrenocorticotropic hormone (ACTH)-dependent, which accounts for 80-85% of cases, and ACTH- independent. Among ACTH-dependent forms, Cushing’s disease (CD), due to a pituitary adenoma secreting ACTH, is the most common cause, followed by ectopic ACTH-producing tumors and, rarely, corticotropin-releasing hormone (CRH)- secreting tumors (3).

The clinical presentation is heterogeneous and depends on the severity and duration of hypercortisolism (4). Patients may develop central obesity, facial plethora, proximal muscle weakness, and violaceous striae (5,6). Because these features are often nonspecific, diagnosis is frequently delayed (7). The diagnostic approach includes exclusion of exogenous GC exposure, biochemical testing such as 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), and the low-dose dexamethasone suppression test (DST), followed by ACTH measurement, imaging, and, in selected cases, bilateral inferior petrosal sinus sampling (BIPSS) (8). Surgery remains the first-line treatment. In cases of persistent or recurrent disease, or when surgery is not feasible, medical and radiotherapeutic options are available (9). Pharmacologic agents include steroidogenesis inhibitors, such as ketoconazole (10,11), osilodrostat (12,13), and metyrapone(14), dopamine agonists (e.g., cabergoline) (15), somatostatin analogs (e.g., pasireotide) (16), and glucocorticoid receptor antagonists (e.g., mifepristone) (17).

Although rare, with an estimated incidence of 3.2 cases per million individuals per year (18), CS carries significant morbidity (19), and mortality may be up to three times higher than in the general population(20). Even after achieving remission, many patients experience persistent complications and reduced quality of life. Although significant advances have been made in the diagnosis and treatment of CS, there remains a substantial knowledge gap regarding its true epidemiology, natural history, and long-term outcomes-particularly in resource-limited settings (2,3). In countries like Colombia, epidemiological information on CS remains scarce and fragmented (21-24). These figures underscore the urgent need for timely diagnosis, effective treatments, long- term follow-up, and context-specific public health strategies.

Patient registries represent a critical tool for characterizing rare conditions such as CS. They enable the collection of homogeneous and systematic clinical data across defined populations, which is essential for understanding disease progression, assessing treatment effectiveness, and establishing quality indicators in healthcare(25). In the context of orphan diseases, marked by low prevalence and high clinical heterogeneity, registries are especially valuable. They help overcome the sample size limitations of clinical trials, facilitate the identification of clinical patterns and prognostic factors, and support the evaluation of therapeutic responses. In addition, they promote collaboration across centers and regions, enhancing the scientific and clinical utility of collected data (26,27). Most registries allow the epidemiological characterization of the disease, the evaluation of medical care, and a better understanding of the natural history; however, they also present challenges related to the design, management, and sustainability of rare disease registries (27).

Given the clinical relevance of CS and the lack of structured data, it is essential to analyze existing population-based registries worldwide. This systematic mapping study aims to identify, describe, and synthesize available information on CS-focused registries, including both dedicated and broader registry systems. The review seeks to highlight their strengths, limitations, and areas for improvement, while also promoting the development of regional registries in Latin America to help close the current knowledge gap. Registries enable comparative assessment of treatment strategies (both surgical and pharmacologic), facilitate clinical outcome monitoring, foster collaborative networks among healthcare centers, and generate evidence to guide clinical and policy decision-making. Additionally, they serve as essential tools for epidemiological surveillance, allowing the identification of prognostic factors and supporting the continuous improvement of care delivery.

In health systems such as Colombia’s- characterized by structural heterogeneity and barriers to access-a national CS registry could provide valuable insights into clinical presentation, therapeutic approaches, short- and long-term outcomes, and health disparities. Furthermore, it could support the identification of optimal clinical practices and the implementation of evidence- based quality improvement strategies tailored to the local context.

Methods

Results

Characteristics and geographic distribution of Cushing’s syndrome registries

The initial literature search yielded 58 results. After screening, two studies involving patients under 18 years of age were excluded, along with two duplicate reports. An additional 29 studies were excluded for not meeting the definition of a registry focused on Cushing’s syndrome. Ultimately, 15 articles were selected for inclusion (28-42) corresponding to 12 distinct population- based registries.

Of these, one was a multinational European registry (ERCUSYN) (42), six were national registries (31-37,39,41), and five were local or single-center initiatives (28-30,38,40). Figure 1 illustrates the geographic distribution of these registries.

Unfortunately, Latin American representation in these initiatives has been limited to a single study conducted in Argentina (29). Orphanet- one of the leading international directories for rare disease registries-lists only two Cushing’s syndrome-specific registries: the German CUSTODES registry (33,35-37) and the European ERCUSYN registry (42). Notably, no Latin American registries are currently included in this database.

The registries reviewed reported key information such as geographic coverage, demographic characteristics of the enrolled populations, and treatment modalities employed, including surgical, pharmacologic, or alternative interventions.

Figure 1: Geographic distribution of Cushing’s syndrome registries worldwide

Source: Own elaboration.

Table 1 summarizes the characteristics of each registry, including the total number of patients, treatment approaches used, and outcomes reported during follow-up.

Table 1: Characteristics and geographic distribution of Cushing’s syndrome registries

Continent/ Country/ Region/City	Year	Num- ber of patients	F (%)	Age at diag- nosis	OS (years)	FU (years)	MA (%)	DC (%)	ACTH- indepen- dent CS (%)	EAS (%)	Ref.
Padua/Italy	2009	45	51.1	-	-	7.7	-	0	100	0	(28)
Buenos Aires/ Argentina	2010	153	82	35.7	-	-	13	100	0	0	(29)
Birmingham/ United Kingdom	2012	72	79.2	40	-	10.9	-	100	0	0	(30)
Denmark	2013	343	74.9	43.8	-	12.1	-	61.5	38.5	0	(31)
Iran	2017	27	77.8	36.5	-	-	17.2	100	0	0	(32)
Germany	2017	196	64	-	-	-	-	65.3	24.5	10.2	(33)
Sweden	2019	502	77	43	-	13	-	100	0	0	(34)
Germany	2019	99	79.8	-	-	1	14.1	100	0	0	(35)
Germany	2020	205	75.6	42.2	-	7.4	-	62.4	37.6	0	(36)
Germany	2020	88	78	49	-	4	-	55.7	38.6	5.7	(37)
Massachusetts/ United States	2020	260	83.3	-	-	5.2	27.8	100	0	0	(38)
Swiss	2020	10	100	41	-	5.7	30	100	0	0	(39)
Vienna/Austria	2021	213	22.5	45.6	3	4.1	-	47.4	46.5	6.1	(40)
Thailand	2023	49	89.8	-	1.4	3.5	29.3	100	0	0	(41)
Europe	2023	1791	88	44.7	2.9	15	45.2	69	25	6	(42)

Note. F: female; OS: onset of symptoms; FU: follow-up time; MA: macroadenoma;

CD: Cushing’s disease; ACTH-independent CS: adrenal Cushing’s syndrome; EAS: ectopic ACTH syndrome.

Source: Own elaboration.

Most of the included studies originated from European populations, comprising one multinational registry, four national registries, and three local initiatives. Additionally, two national studies were identified from Asia and one local study from Latin America. Collectively, these registries account for more than 4,000 patients with Cushing’s syndrome (CS). Five of the studies were based on single-center data, while the largest registry-ERCUSYN-enrolled patients from 57 centers across 26 European countries.

CS was most frequently diagnosed between the fourth and fifth decades of life, with a reported delay of 1.4 to 2.9 years from symptom onset to diagnosis. Follow-up duration reached up to 15 years in the ERCUSYN registry, and the female- to-male ratio across studies was approximately 4.4:1. Pituitary tumors were predominantly microadenomas, with prevalence ranging from 13% in the Argentinian study to 45.2% in the European registry.

The studies from Argentina (29), the United Kingdom (30), Iran (32), Sweden (34), one German sub-analysis (35), the United States (38), Switzerland (39), and Thailand (41) included only patients with ACTH-dependent hypercortisolism of pituitary origin. The Italian study from Padua focused on patients with ACTH-independent adrenal CS. In contrast, ectopic ACTH syndrome (EAS) was reported in a small subset of patients- ranging from 2% to 6%-in one German sub- analysis, the Austrian study, and the ERCUSYN registry.

Comorbidities

The most frequently reported comorbidities were hypertension and type 2 diabetes mellitus, with wide variability in prevalence across populations-ranging from 29% to 94% for hypertension (28-31,33-36,38,40-42) and from 13% to 31% for type 2 diabetes (28,30,31,34,35,40,41). Less commonly reported conditions included dyslipidemia, overweight or obesity, osteoporosis, and fragility fractures (28- 30,38,40,42). A history of cardiovascular events was noted in 6% of patients in the UK registry (30) and 14.6% in the Austrian registry (40) (Table 2).

Discussion

This review identified and analyzed existing population-based registries of Cushing’s syndrome (CS) worldwide. Despite the significant impact of CS on both individual health and healthcare systems, critical gaps remain in the generation of structured population-level data that would enable a global understanding of this rare disease.

Findings from this review reveal a marked geographic concentration of available registries. Europe leads data collection efforts, particularly through the ERCUSYN registry (42), which has enabled for characterization of case distribution, clinical profiles, and long-term outcomes in patients with CS across multiple European countries. However, limited representation from regions such as Latin America, Africa, and much of Asia hinders accurate global estimates of incidence, prevalence, and disease burden. This geographic bias restricts the extrapolation of findings to settings with different demographic, socioeconomic, and healthcare profiles.

The reviewed registries have been instrumental in describing common phenotypic features of CS, diagnostic approaches, treatment strategies, and clinical outcomes. Data from these registries and other studies highlight important variations in clinical presentation and therapeutic practices, including differences in age at diagnosis, rates of ACTH-producing adenomas, and preferred surgical modalities (43). As previously reported, comorbidities such as diabetes mellitus, hypertension, and osteoporosis are highly prevalent among patients with CS (44,45). Treatment outcomes also vary across regions, with surgical remission rates ranging from 60% to 90% in Europe (42), Iran (29), the United States (38), and Argentina (29), but remaining considerably lower in countries like Thailand (41). These findings underscore the need for multicenter, comparative registries to identify practice variations and generate context-specific evidence.

Registry data have also revealed substantial diagnostic delays in CS; however, only three registries explicitly reported the interval from symptom onset to diagnosis, which ranged from 1.4 to 3 years (40-42). This limited reporting highlights a critical gap in the systematic assessment of diagnostic timelines. Delays in recognition and confirmation of CS contribute to the progression of chronic complications and deterioration of patients’ quality of life (20,31,34,40,44,45). Furthermore, the intraindividual variability and differences across analytical methods, as well as the disparities in the definitions of biochemical remission both between and within countries, underscore the need for standardized international protocols to guide diagnosis and long-term follow-up.

Population-based registries play a strategic role in the surveillance of rare diseases such as CS. Their ability to identify patterns of morbidity, assess care quality, monitor treatment access, and support cost-effectiveness studies is essential for evidence- based health planning (27). However, this review shows that existing registries often face structural limitations, including inconsistent data collection methods, ambiguous variable definitions, and limited inclusion of social determinants of health. These elements are critical to understanding disparities in access to care and treatment outcomes, particularly in vulnerable populations.

A key contribution of this review is the identification of an urgent need to develop and strengthen national and international population-based CS registries. The creation of interoperable platforms that integrate clinical, sociodemographic, economic, and quality-of- life data would enable a more comprehensive characterization of the disease, with implications for both individual patient care and public policy.

Major limitations identified among the reviewed registries include the underrepresentation of low- and middle-income countries, limited longitudinal follow-up in many systems, and the absence of systematic mechanisms for external data validation. These limitations must be addressed in future collaborative efforts aimed at improving registry coverage and data quality. The review also revealed significant discrepancies in the analytical methods used (immunoassay vs. LC- MS/MS), hormonal confirmation methods, and remission thresholds, all of which complicate inter-study comparisons. These differences are likely influenced by access to diagnostic technology, physician training, and the clinical guidelines adopted in each setting. Methodological standardization and international consensus on operational definitions of CS are essential steps to improve the reliability and comparability of registry data.

Finally, this review highlights the value of registries as tools to advance translational research and inform health policy. Systematic data collection enables the generation of real-world evidence, the optimization of resource allocation, and the evaluation of healthcare interventions. In rare diseases such as CS, where clinical trials are limited, population-based registries represent a critical source of information to support clinical decision-making and healthcare management.

Conclusion

Population-based registries of Cushing’s syndrome are essential for understanding disease burden, evaluating the effectiveness of interventions, and informing public health policy. However, their limited availability, methodological heterogeneity, and restricted geographic coverage pose critical challenges. This review provides an integrated overview of existing registries, identifies key knowledge gaps, and offers recommendations to support the development of more robust, equitable, and outcome-oriented information systems aimed at improving the care of patients with Cushing’s syndrome.

Authors’ contributions

Wilfredo Antonio Rivera Martínez: Conceptualization, research, methodology, writing (original draft); Johana Ramírez: conceptualization, writing (original draft); Alejandro Román González: conceptualization, writing (referring and editing corrections); Johnayro Gutierrez Restrepo: conceptualization, writing (referring and editing corrections); Carlos Esteban Builes Montaño: Conceptualization, research, methodology, writing (original draft). All authors critically reviewed and contributed to the final version of the manuscript.

Ethical implications

This work was a systematic review, so no specific ethical considerations were identified. The study did not directly involve patients, human participants, or animals and was based exclusively on a review of scientific literature and contributions from the authors.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest

The authors declare the following conflicts of interest: CEBM has received consulting and speaking fees from Sanofi, Novo Nordisk, Novartis, Recordati Rare Diseases, Janssen, Chiesi, Abbott, and Boehringer Ingelheim and is a shareholder from Festina Lente. ARG has received consulting and speaking fees from Roche, Novo Nordisk, Knightx, PTC Therapeutics, Bayer, Amryt. The remaining authors report no conflicts of interest.

Acknowledgements

The authors assume full responsibility for the content and conclusions expressed in this manuscript.

Data statement

No data was collected in the development of this manuscript.