Rare Causes of Cushing Syndrome - An Overview

Introduction

Unusual production of a hormone called adrenocorticotropic hormone (ACTH) outside its normal place can cause Cushing's syndrome, a rare and serious hormonal condition with symptoms like weight gain and high blood pressure that can have severe health consequences. It is often caused by prolonged use of certain medications, but in some cases, it can result from tumors in the pituitary gland that produce a hormone called ACTH. This type of Cushing's syndrome is more common in women and less frequently seen in children. These rare instances typically happen in cancers like small cell lung cancer, abnormal tumors in the brain, bronchial carcinoids, or medullary thyroid cancer. While it is rare, there is an even less common situation where phaeochromocytomas are linked to this abnormal ACTH production. These rare scenarios make CS a complex and challenging endocrine disorder to understand and diagnose.

What Are the Unusual Causes of ACTH-Dependent Cushing Syndrome?

Cushing's Syndrome is when the body is exposed to high cortisol levels, a stress hormone. Various factors can cause this; some rare cases involve unusual hormone sources.

1. Ectopic Corticotroph Adenomas: Adenomas are abnormal growths of cells that produce cortisol outside the normal pituitary gland. These growths are usually found in areas like the sphenoid sinus or suprasellar region. Rare, but possibly underreported. Thought to develop from pituitary cells deposited along the route of embryonic pituitary development. Some cases were discovered after unsuccessful pituitary surgery, suggesting misdiagnosis.

2. Adenomas in the Neurohypophysis: Adenomas located in the posterior pituitary lobe are unusual. Difficult to detect through standard MRI scans. Possibly more common than initially thought, with improved detection methods.

3. Double Adenomas: Two distinct tumors in the pituitary. Usually small, making preoperative identification rare. In some cases, prolactinoma accompanies corticotroph adenoma. Origin may involve two separate monoclonal expansions of transformed pituitary cells.

4. Non-Adenohypophyseal Pituitary Tumors: Rare pituitary neoplasms with both gangliocytic and adenohypophyseal components. Often functioning, with GH (growth hormone) being the most common. Some cases of Cushing's disease were reported.

5. Ectopic CRH Syndrome: Overproduction of CRH (corticotropin-releasing hormone), a rare scenario. Only a few well-documented cases, some with simultaneous ACTH (adrenocorticotropic hormone) hypersecretion. Plasma CRH level measurement is crucial for diagnosis.

6. Other Peptides: Peptides more potent than CRH, theoretically capable of causing Cushing's syndrome. While none reported, instances like Ewings-sarcoma and brain tumors have shown CRH-like peptides associated with Cushing's syndrome. Other peptides, like bombesin-like peptides from certain tumors, may also contribute.

What Are the Unusual Causes of ACTH-Independent Cushing Syndrome?

Cushing's syndrome is a condition where the body is exposed to high levels of cortisol, leading to various symptoms. While the most common cause is a problem with the adrenal glands, there are some rare and unusual reasons for this syndrome.

1. Ectopic Adrenal Adenomas: Abnormal growths of cells producing cortisol outside the adrenal glands. Thought to arise from leftover adrenal tissue during embryonic development. It can be found anywhere along the path of adrenal and gonad development. Very rare, with around nine reported cases causing Cushing's syndrome. Identified when imaging shows normal adrenals, requiring specific scans for confirmation.

2. Bilateral Adrenal Adenomas: Approximately 10 to 15 percent of ACTH-independent Cushing's cases involve both adrenal glands. Two main conditions - ACTH-independent macronodular adrenal hyperplasia (AIMAH) and primary pigmented nodular adrenal disease (PPNAD). Less than 30 reported cases of functioning bilateral adrenal adenomas, mostly in Japanese patients. Different from AIMAH and PPNAD, often with a single nodule in each gland.

3. Cortisol Hyperreactive Syndrome: A rare condition where the body shows Cushing's symptoms despite normal or low cortisol levels. Tissues in the body become overly responsive to cortisol. Only a handful of documented cases, each with unique characteristics. Laboratory studies show increased sensitivity of cells to cortisol effects. The mechanism is not entirely clear; it may involve issues at the receptor or post-receptor level.

What Are the Medical Causes of Cushing Syndrome?

Cushing's Syndrome can also be caused by certain medications, even if they are given in small doses or through unexpected routes.

1. Topical Ophthalmic Corticosteroids: Rare cases of Cushing's syndrome have been reported in children and adolescents due to using corticosteroid eye drops. The body's heightened sensitivity to these steroids may be the reason for this unexpected response.

2. Megestrol Acetate: Used in cancer treatment and for HIV-related weight loss. Prolonged use (beyond six weeks) in some cases leads to Cushing's syndrome. While higher doses (around 1500 milligrams/day) typically cause the syndrome, lower doses (even 400 milligrams/day) have triggered similar symptoms. Research indicates megestrol acetate has cortisol-suppressing effects, resembling glucocorticoids.

3. Other Progestogens: Medroxyprogesterone acetate, another progestogen, has also been linked to clinical hypercortisolism.

4. Ritonavir and Fluticasone in HIV Treatment: HIV patients using Ritonavir and Fluticasone, even in daily doses below 1000 milligrams, can develop exogenous Cushing's syndrome. Ritonavir, an enzyme inhibitor, increases Fluticasone levels in the body, leading to Cushing-like symptoms.

What Is the Rare Case of Cushing Syndrome - Adrenal Adenoma in Infancy?

A five-month-old baby girl was brought to the pediatric clinic due to unusual weight gain and facial swelling. Born to healthy parents, her birth weight was normal, but she rapidly gained weight, reaching above the 95th percentile. The physical exam revealed typical Cushingoid features such as a round face and excess body fat.

Lab tests showed elevated cortisol levels, indicating Cushing's syndrome. Imaging revealed a tumor in her right adrenal gland. A surgical procedure successfully removed the tumor, diagnosed as an adrenal adenoma. The baby recovered well after surgery, and follow-up showed the resolution of Cushingoid features.

This rare case involved a baby with rapid weight gain and a round face due to a small tumor in the adrenal gland causing Cushing's syndrome. Surgery removed the tumor, and the baby is now doing fine.

Conclusion

Identifying the cause of Cushing's syndrome can be quite tricky for doctors. While most cases are linked to hormone imbalances caused by pituitary or adrenal tumors, there are rare situations where a different, uncommon condition might be the culprit. Recognizing these uncommon forms of Cushing's syndrome is crucial for accurate diagnosis.