The Case of the Cyclical Cushing's: A Diagnostic Odyssey
"Unraveling the complexities of a rare Cushing's syndrome case involving a cyclic pattern and an unusual tumor location."
Cushing's syndrome (CS), a condition resulting from prolonged exposure to elevated levels of cortisol, presents a diagnostic puzzle when it stems from ectopic ACTH production. In these instances, tumors outside the pituitary gland secrete ACTH, the hormone that stimulates cortisol release. Identifying the source of this ectopic ACTH can be a lengthy and challenging process.
Adding another layer of complexity, some individuals with ectopic ACTH-dependent CS experience cyclical symptoms, where periods of cortisol excess alternate with periods of normal cortisol production. This cyclical pattern further complicates diagnosis and management.
This article delves into a fascinating case study of a patient with ACTH-dependent CS exhibiting a cyclical pattern and caused by an exceedingly rare tumor: a carotid glomus tumor, also known as a chemodectoma. We will explore the diagnostic hurdles, the impact of the cyclical nature of the disease, and the treatment approaches employed in this unique case.
A Rare but Significant Disorder
Cushing's syndrome is rare, with an estimated global incidence of 1.8–4.5 cases per million individuals per year and prevalence of 57–79 cases per million. OHSU reports approximately 10 to 15 new cases per million people annually in the United States, while noting that these figures may not capture all cases. Repeatedly normal urinary free cortisol results make Cushing's syndrome highly unlikely, except in uncommon cases of cyclic Cushing's syndrome.
Testing Requires Careful Interpretation
Consensus guidance emphasizes that Cushing's disease requires accurate diagnosis, appropriate treatment selection, and long-term management. Urinary free cortisol testing has limitations because values can fluctuate with renal function and hydration status. The Endocrine Society guidance also identifies a specific interpretive threshold in pregnancy: only urinary free cortisol values in the second or third trimester greater than three times the upper limit of normal indicate Cushing's syndrome.
The 1912 Beginning
Harvey Cushing described his famous patient with hypercorticism in 1912, although he initially assumed the condition was a polyglandular disorder. The condition was later named after Cushing, an eminent American neurosurgeon who described the first patients with it in that year. For almost 40 years, the underlying etiology remained disputed.
The Diagnostic Labyrinth: Unmasking the Source of ACTH
A 49-year-old Brazilian male presented with a constellation of symptoms including severe hypertension, mood swings, muscle weakness, skin darkening, and increased abdominal fat. Initial investigations pointed towards ACTH-dependent Cushing's syndrome, but the source of the excess ACTH remained elusive.
- Extensive Imaging: Chest X-rays, CT scans, and MRI of the pituitary and abdomen were initially unremarkable, except for bilateral adrenal enlargement.
- Petrosal Sinus Sampling: Bilateral simultaneous inferior petrosal sinus sampling (BIPSS) after desmopressin stimulation suggested ectopic ACTH production.
- Colonoscopies: Multiple colonoscopies were performed, revealing intestinal polyps, but no malignancy or evidence of ACTH production.
- Octreoscan: After four years of investigation, an Octreoscan finally pointed towards a neuroendocrine cervical tumor.
Treatment and Clinical Research
A 2024 review reported improvement in symptoms and comorbidities of Cushing's syndrome after treatment with levoketoconazole, including improvement in body mass index. Clinical research is also evaluating CORT125134 for the safety and efficacy of treating endogenous Cushing's syndrome. Recent consensus work from the Pituitary Society has focused on critically reviewing the diagnosis and management of Cushing's disease.
Why Misdiagnosis Persists
Cushing's syndrome results from prolonged exposure of body tissues to high cortisol levels. Its symptoms may appear distinctive, yet the condition is frequently misdiagnosed, according to a review focused on diagnostic error. Mayo Clinic likewise describes Cushing syndrome as excess cortisol over a long period, which can arise from the body producing too much cortisol.
Disease, Syndrome, and Addison’s
Cushing disease and Cushing syndrome produce the same symptoms; their difference is the cause. The Endocrine Society describes Cushing disease as a rare condition affecting 10 to 15 people per million. In contrast, Addison's disease involves too little cortisol, whereas Cushing's involves too much.
Lessons Learned: Navigating the Complexities of Ectopic ACTH Syndrome
This case underscores the diagnostic challenges posed by ectopic ACTH-dependent Cushing's syndrome, particularly when complicated by cyclical patterns. The rarity of chemodectomas as a cause of ectopic ACTH production further emphasizes the need for vigilance and comprehensive investigation.
A Pattern of Complexity
Cyclical Cushing's can make diagnosis especially difficult because cortisol excess may not be continuously visible on testing. The broader clinical picture therefore requires attention to changing symptoms, repeated evaluation, and the possibility that apparently reassuring results may not capture every phase of illness. This diagnostic uncertainty helps explain why a prolonged, multidisciplinary evaluation may be necessary.
A Growing Treatment Market
Market forecasts suggest continued expansion in therapies intended to manage and treat Cushing's syndrome. Estimates differ substantially: Coherent Market Insights values the global market at USD 1.2 billion in 2026 and projects USD 1.9 billion by 2033, while IMARC reports USD 444.8 million in 2025 and projects USD 994.9 million by 2036. These differences show that projections depend on the market definition, time frame, and methodology used.
Multisystem Consequences
Cushing syndrome can result from medications or from a tumor on the pituitary or another endocrine structure. The AACE patient guide lists weight gain, bone loss or osteoporosis, high blood pressure, high blood sugar or diabetes, infections, and loss of muscle mass among its health effects. Men may also experience reduced fertility, lower sex drive, and erectile dysfunction, underscoring the condition’s broad systemic impact.
Living Through Diagnostic Uncertainty
A 2022 clinical case report describes Cushing's disease as a therapeutic challenge and reports that morbidity and mortality remain increased even in patients who are successfully treated. Individual case accounts show how the diagnosis can be tied to a specific adrenal lesion: Minal's story describes an adrenal adenoma with a 3.5-centimeter tumor on the left adrenal gland. Together, these accounts illustrate both the medical burden of persistent disease and the personal significance of finally identifying its cause.
Clinicians should consider the possibility of cyclical Cushing's syndrome in patients with fluctuating symptoms and be aware that infections or other co-morbidities can exacerbate these cycles, potentially masking the underlying cause.
The successful identification and treatment of this patient's chemodectoma highlights the importance of persistent investigation, even when initial imaging is inconclusive. Emerging techniques like genetic profiling for SDH mutations may aid in the diagnosis and risk stratification of such tumors in the future. Ketoconazole can be used for managing the symptoms