Cushing’s Syndrome Treatment Preceded Cushing’s Disease Diagnosis

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by Margarida Maia |

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A woman developed Cushing’s disease years after she had received successful treatment for Cushing’s syndrome, as described in a recent case report.

“Our case illustrates that both [forms of Cushing’s] may develop in a single individual even without evidence for a common genetic background,” its authors wrote.

The study, “Case report: consecutive adrenal Cushing’s syndrome and Cushing’s disease in a patient with somatic CTNNB1, USP8, and NR3C1 mutations,” was published in the journal Frontiers in Endocrinology.

Cushing’s syndrome occurs when the levels of the hormone cortisol in the body are too high. Cushing’s disease — a form of Cushing’s syndrome — occurs when the brain’s pituitary gland makes too much adrenocorticotropic hormone (ACTH), a hormone that drives the adrenal glands sitting atop the kidneys to produce and release cortisol. This excessive production of ACTH by the pituitary gland is usually driven by the presence of a tumor.

Cushing’s syndrome occurring at the same time as Cushing’s disease or in the same person is rare, but has been reported.

Now, a team of researchers in Germany presented the case of a woman who was cured from adrenal Cushing’s syndrome four years before being diagnosed with Cushing’s disease.

The woman was 49 when she first visited the hospital in March 2014 with complaints of recurrent belly pain and irregular, heavy menstrual bleeding. MRI scans revealed the presence of a lesion on her left adrenal gland, measuring about 4 cm in diameter. The doctor suspected it was a cortisol-producing adrenal tumor, and referred the patient to another clinic, where she was seen in January 2015.

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She had muscle weakness, a lack of energy (asthenia), and high blood pressure, for which she was taking anti-hypertensive medication. She also had excessive fat around the waist (central obesity), excessive hair growth in the face and other parts of the body (hirsutism), violaceous stretch marks (striae rubrae), redness in the face (facial plethora), thinning of the skin (skin atrophy), and multiple bleeds outside blood vessels (hematomas). All these are typical symptoms of Cushing’s syndrome.

Laboratory testing revealed she had high levels of cortisol in the blood, saliva, and urine. The levels of ACTH were toward the low end of the normal range. Based on these findings, doctors diagnosed the patient with ACTH-independent Cushing’s syndrome.

One month later, the woman underwent an adrenalectomy to surgically remove the left adrenal gland, and cortisol levels dropped. For three months, she took cortisol replacement therapy to correct cortisol levels.

Two years after the operation, all clinical symptoms had eased. Blood pressure returned to normal and the patient no longer needed any medication.

However, starting in April 2018, the woman reported symptoms suggestive of recurrent Cushing’s syndrome and she resumed treatment with anti-hypertensive medication to lower her blood pressure.

Laboratory testing revealed higher-than-normal levels of both cortisol and ACTH. A pituitary MRI scan revealed the presence of a microadenoma (a tiny benign tumor) measuring about a half-millimeter in diameter as the source of excessive ACTH production. Based on these findings, physicians diagnosed her with Cushing’s disease.

In June 2019, the woman underwent a transsphenoidal adenomectomy to remove the pituitary microadenoma. Again, she needed cortisol replacement therapy to correct cortisol levels until her body was able to produce the hormone naturally.

To understand whether there was a genetic basis for the occurrence of both Cushing’s syndrome and Cushing’s disease in the same patient, researchers performed whole exome sequencing using tumor and blood samples to search for genetic mutations. (The exome is the part of the genome — the set of all human genes — that contains instructions to make proteins.)

They found no germline mutations — those arising from genetic changes in a reproductive cell (either the egg or sperm) that can be incorporated into the DNA of every cell in the body of the offspring.

However, in the adrenal tumor, they found a mutation in CTNNB1, the gene carrying instructions to make beta-catenin — a protein that plays a role in tumor development.

In the pituitary microadenoma, they found a mutation in USP8, the gene containing instructions to make ubiquitin-specific peptidase 8 — a protein involved in a process that allows cells to destroy and recycle malformed proteins. There also was a mutation in NR3C1, the gene carrying instructions to make the glucocorticoid receptor — the protein that binds cortisol and other glucocorticoids. All three mutations had been reported previously as pathogenic, or disease-causing.

“We performed whole exome sequencing of both [tumors] and could clearly demonstrate that they are genetically distinct,” the researchers wrote.

“The extremely rare event of recurrent hypercortisolism [higher-than-normal cortisol levels] due to different subtypes of [Cushing’s syndrome] must be taken into account if corresponding (but unexpected) findings are observed during follow-up,” they concluded.

In March 2021, the woman had no signs or symptoms of Cushing’s.