Patient’s Atypical Cushing’s Symptoms Lead to Discovery of Novel Genetic Mutations

New genetic mutations were found in a patient who exhibited atypical symptoms of Cushing’s syndrome, notably an abnormal protrusion of the eye, a case report shows.

The research, “Extensive ARMC5 genetic variance in primary bilateral macronodular adrenal hyperplasia that started with exophthalmos: a case report,” was published in the Journal of Medical Case Reports.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a disorder characterized by multiple lumps in the adrenal glands and excessive cortisol production. It is a rare cause of Cushing’s syndrome.

According to recent research, PBMAH is caused by mutations in the ARMC5 gene, which data suggest may act as a tumor suppressor.

Researchers presented the case of a 52-year-old Chinese woman who exhibited a protrusion of both eyes (exophtalmos), which was first thought to be Graves’ ophthalmopathy. An injection of triamcinolone acetonide, a corticosteroid, into the area behind the eye globe did not improve symptoms.

The patient later was diagnosed with diabetes, which was treated with insulin, and hypertension, treated with insulin and amlodipine. She also developed muscle weakness and bruised easily. She had no other relevant chronic illness or infectious disease, and did not smoke tobacco or drink alcohol.

Physical examination showed skin atrophy, moon face, buffalo hump (between the shoulders), and purplish abdominal striae (stretch marks), which researchers defined as a typical Cushingoid appearance. The patient also experienced elevated pressure inside the eye, and had edema, conjunctival congestion, and lid retraction. No liver, spleen, respiration, cardiac, abdominal, blood counts, urinary, sensory, or motor abnormalities were noted.

Biochemical evaluation showed elevated cortisol and reduced adrenocorticotropin (ACTH) levels. Administering  dexamethasone did not lower the level of cortisol. Abnormal responses of the hormone vasopressin also were detected.

A computed tomography (CT) scan of the adrenal glands showed bilateral multiple lobular masses, and an MRI of the eye orbits indicated bilateral exophthalmos with hypertrophy of the retro-orbital fat, which lines the orbit.

After PBMAH was diagnosed, the patient’s adrenal glands were removed. Pathological findings showed multiple, homogenous, golden-yellow-colored nodules on the glands.

The surgery successfully lowered the level of cortisol and increased that of ACTH. The patient began taking hydrocortisone and metformin for diabetes. After six months, her exophtlamos, blood glucose levels, and blood pressure had improved.

Genetic analysis revealed six specific ARMC5 mutations in five of the seven adrenal nodules analyzed. “All the mutations are novel and not found in available online databases,” the researchers wrote. The mutations may lead to resistance to cell death in the tumor cells, and cause an increase in the production of cortisol, they observed.

As a result of the ARMC5 mutations, gene expression (conversion of genetic information) of the messenger RNA (mRNA, which is converted from DNA in the first step of protein synthesis) was lower in the adrenal tumor samples, in comparison with normal adrenal cortex.

Overall, the study “highlights the importance of early recognition of atypical symptoms of Cushing’s syndrome such as exophthalmos, which would save the patient from harmful effects of excessive cortisol exposure,” the researchers said. Screening for ARMC5 mutations also would help improve diagnosis and genetic counseling, they said.


Common Cushing’s Treatment, Somatostatin Analogs, May Sometimes Worsen Disease Course

Doctors often prescribe somatostatin analogs to manage the hormonal imbalance that characterizes Cushing’s syndrome. However, in rare situations these medicines have paradoxically made patients worse than better.

This recently happened with a 48-year-old Spanish woman whose Cushing’s syndrome was caused by an adrenal gland tumor that was producing excess adrenocorticotropic hormone (ACTH). Her case was recently reported in the study “Ectopic Cushing’s syndrome: Paradoxical effect of somatostatin analogs,” and published in the journal Endocrinología, Diabetes y Nutrición.

Cushing’s syndrome occurs when the body produces too much cortisol. This can happen for many reasons, including an oversupply of ACTH, the hormone responsible for cortisol production, due to a tumor in the pituitary gland.

But sometimes, tumors growing elsewhere can also produce ACTH. This feature, known as ectopic ACTH secretion (EAS), may also cause ACTH-dependent Cushing’s syndrome.

Two-thirds of EAS tumors are located in the thorax, and 8 to 15 percent are in the abdominal cavity. Only 5 percent of EAS tumors are located in the adrenal gland, and up to 15 percent of EAS tumors are never detected.

Doctors usually use cortisol synthesis inhibitors such as ketoconazole or Metopirone (metyrapone) to control EAS, due to their efficacy and safety profiles. But somatostatin analogs (SSAs) such as Somatuline (lanreotide) have also been used to treat these tumors. However, these drugs produce mixed results.

The woman in the case study, reported by researchers at the University Hospital Vall d’Hebron in Barcelona, Spain, had an EAS tumor on the adrenal gland. She experienced s life-threatening cortisol and ACTH increase after receiving high-dose Somatuline.

The patient had been recently diagnosed with hypertension, and complained of intense fatigue, muscular weakness, easy bruising and an absence of menstruation. Laboratory analysis revealed that she had triple the normal levels of free cortisol in the urine, elevated levels of plasma cortisol, and high ACTH levels. In addition, her cortisol levels remained unchanged after receiving dexamethasone. The patient was therefore diagnosed with ACTH-dependent Cushing syndrome.

To determine the origin of her high cortisol levels, the team conducted magnetic resonance imaging (MRI). They found no tumors on the most common places, including the pituitary gland, neck, thorax or abdomen. However, additional evaluation detected a small alteration on the left adrenal gland, suggesting that was the source of ectopic ACTH production.

The team initiated treatment with 120 mg of Somatuline, but a week later, her condition had worsened and become life-threatening. Doctors started Ketoconazole treatment immediately, three times daily. The affected adrenal gland was surgically removed, and tissue analysis confirmed the diagnosis. The patient’s clinical condition improved significantly over the follow-up period.

“We highlight the need to be aware of this rare presentation of EAS, and we remark the difficulties of EAS diagnosis and treatment,”  researchers wrote.

The team could not rule out the possibility that the patient’s clinical development was due to the natural course of the disease. However, they believe “she had a paradoxical response on the basis of her dramatical worsening just after the SSAs administration, associated to an important rise in ACTH and UFC levels.”

For that reason, researchers think a new version of SSAs, such as Signifor (pasireotide) — which has improved receptor affinity — could provide better therapeutic response.


ACTH-producing Lung Tumors Hard to Detect, But May Be Cured with Surgery

Ectopic Cushing’s syndrome can be challenging to diagnose, especially when it comes identifying the problem source. But appropriate hormone management protocols, used in combination with advanced imaging methods, may help physicians identify ectopic ACTH-producing tumors.

The findings in a case report of a young man with ectopic Cushing’s syndrome were published in the International Journal of Surgery Case Reports, under the title “Case report: Ectopic Cushing’s syndrome in a young male with hidden lung carcinoid tumor.”

Cushing’s syndrome is caused by high amounts of glucocoticosteroids in the blood. The most common cause is a malfunction of the glands that produce these hormones. In some cases, however, the disease may be caused by tumors elsewhere in the body that have the ability to produce adrenocorticotropic hormone (ACTH).

In half of all Cushing’s patients, ectopic ACTH is produced by small lung cell carcinomas or lung carcinoids (a type of slow-growing lung cancer). But some tumors in the thymus and pancreas also have been found to produce ACTH.

Researchers at Damascus University Hospital in Syria presented the case of a 26-year-old man who had ectopic Cushing’s syndrome due to lung carcinoids.

The patient presented with increased appetite and rapid weight gain for more than a year. These were associated with headache, fatigue, proximal muscle weakness, and easy bruising. He had no family history of hormonal disorder.

Based on the initial physical and symptom evaluation, the clinical team suspected Cushing’s syndrome. Blood analysis revealed high levels of cortisol and ACTH hormones, which supported the diagnosis.

Administration of dexamethasone, a treatment used to inhibit the production of glucocoticosteroids by the pituitary gland, reduced cortisol levels within normal range, but not ACTH levels. This led to the diagnosis of ectopic Cushing’s syndrome.

The next step was to identify the tumor causing the syndrome. The team conducted imaging studies of the brain, chest, and abdomen, but found no tumor.

Because ectopic ACTH is commonly produced by lung cancers, the team then analyzed the patient’s lungs. Again, they failed to detect a tumor.

The patient was discharged with prescription of 200 mg of Nizoral (ketoconazole) once-daily, calcium, and vitamin D. After three months of treatment, he remained stable, with no evidence of symptom improvement.

At this point, the team decided to surgically remove both adrenal glands in an attempt to reduce the hormone levels. Treatment with prednisolone 5 mg and fludrocortisone 0.1 mg once daily was initiated, along with calcium and vitamin D.

Eighteen months later, the patient’s condition worsened and he required hospitalization.

Imaging tests targeting the neck, chest, and abdomen were conducted again. This time, physicians detected a 2 cm mass in the middle lobe of the right lung, which was removed surgically. Detailed analysis of the small tumor confirmed that it was the source of the excessive ACTH.

“ACTH secreting tumors can be very hard to detect,” the researchers stated. “Initial failed localization is common in ectopic ACTH syndrome and it is usually due to carcinoid.”

Cases where the ectopic ACTH production is caused by a carcinoid tumor can be challenging to diagnose because tumors are small and relatively slow-growing. Imaging data is often hard to analyze and the tumors can be confused with pulmonary vessels, the researchers explained.

“In such cases we should first aim to lower blood cortisol medically or through bilateral adrenalectomy to avoid Cushing’s complications,” which should then “be followed up through imaging studies (CT, MRI, scintigraphy or PET) to detect the tumor and resect it, which is the definitive treatment of these patients,” the researchers concluded.


Doctors Use Microwave Therapy on Cushing’s Patient Too Weak to Have Surgery

Microwave therapy improved the Cushing’s syndrome of a woman whose lungs had almost failed, allowing her to have the adrenal surgery needed to control her disease, a case study showed.

Lung infections had led to her near-respiratory failure.

Cushing’s syndrome stems from the pituitary gland producing excessive amounts of adrenocorticotropic hormone. Too much of the hormone leads to the adrenal glands generating excessive amounts of another hormone, cortisol — and that overproduction results in Cushing’s. The disease’s symptoms include increasing obesity, skin problems, muscle weakness, bone loss, fatigue, cognitive difficulties, and an inability to control emotions.

Doctors often remove patients’ adrenal glands to prevent cortisol production. But in this case, the patient was not in good enough condition to have the surgery. So doctors used microwave technology to reduce her cortisol levels to the point where surgeons could operate.

The case study, published in BMJ Case Reports, was titled “Ectopic ACTH syndrome complicated by multiple opportunistic infections treated with percutaneous ablation of the adrenal glands.

Excessive pituitary gland production of adrenocorticotropic hormone is the cause of 80 percent of Cushing’s cases.

In 5 to 10 percent of cases, a tumor in another part of the body also produces the hormone, leading to excessive amounts of it in the body. When a tumor is generating the hormone, the condition is called ectopic ACTH syndrome. The patient in the case study had ACTH syndrome.

The 63-year-old woman had complained to her family doctor about weight gain, headache, weakness, and flushing. When laboratory tests led to her being diagnosed with ectopic ACTH-dependent Cushing’s syndrome, she was admitted to a hospital’s internal medicine department.

Doctors planned surgery to remove her adrenal glands, but two days before the operation was scheduled, respiratory failure sent her to the hospital’s Intensive Care Unit. There, physicians treated her for two infections in her lungs, plus infections in her blood and urinary tract. She experienced serious medical complications while in the Intensive Care Unit.

After a month, she was in good enough condition to leave intensive chair but too frail for surgery. Instead, doctors used microwaves to destroy as much of her adrenal glands as they could.

Within two weeks, her condition was better. She had been unable to leave her hospital bed while in intensive care. After the microwave treatment, she engaged in physiotherapy that led to her being able to use a two-wheeled walker to go short distances. She could also make short excursions outside the hospital with her family.

Six months later she returned to the hospital for surgical removal of her adrenal glands.

There were no complications from the operation, and doctors discharged her two days later. Her cortisol levels have been at acceptable levels since then.

“Our experience demonstrates that percutaneous ablation is a viable alternative in patients with ectopic ACTH syndrome in whom medical therapy has failed and surgical adrenalectomy is not feasible,” the researchers wrote. “Further research comparing the efficacy and complication rates between percutaneous ablation [microwave therapy] and surgical adrenalectomy is needed.” In addition, “research is needed to determine the optimal method of percutaneous intervention,” the team wrote.


Study links genetic mutations, Cushing syndrome

Researchers have determined mutations in the gene CABLES1 may lead to Cushing syndrome, a rare disorder in which the body overproduces the stress hormone cortisol.

The National Institutes of Health study findings published in Endocrine-Related Cancer found four of the 181 children and adult patient examined had mutant forms of CABLES1 that do not respond to cortisol.

The determination proved significant because normal functioning CABLES1 protein, expressed by the CABLES1 gene, slows the division and growth of pituitary cells that produce the hormone adrenocorticotropin (ACTH).

Researchers at the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) joined scientists from other institutions in the United States, France and Canada, in the evaluation.

“The mutations we identified impair the tumor suppressor function in the pituitary gland,” Constantine A. Stratakis, the study’s senior author and director of the NICHD Division of Intramural Research, said. “This discovery could lead to the development of treatment strategies that simulate the function of the CABLES1 protein and prevent recurrence of pituitary tumors in people with Cushing syndrome.”

Cushing syndrome symptoms include obesity, muscle weakness, fatigue, high blood pressure, high blood sugar, depression and anxiety, officials said, adding excess cortisol found in the disorder can result from certain steroid medications or from tumors of the pituitary or adrenal glands.

Researchers maintain that more studies are needed to fully understand how CABLES1 suppresses tumor formation in the pituitary gland.



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