Father, daughter with Cushing’s disease share CDKN1B variant
Case report raises possible link to rare inherited MEN4 syndrome
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A father and daughter who carried the same genetic variant both developed Cushing’s disease, according to a recent report.
Both underwent pituitary surgery through the nose, called an endoscopic endonasal approach, followed by glucocorticoid replacement therapy, and both remain in biochemical remission.
Researchers still do not know whether the variant in the CDKN1B gene actually causes disease. CDKN1B has been linked to a rare inherited condition called multiple endocrine neoplasia type 4 (MEN4), which increases the risk of tumors in hormone-producing tissues, including the pituitary gland.
CDKN1B variant may be linked to Cushing’s
The case, reported in “MEN4 variant of unknown significance in two generations of patients presenting with Cushing disease” and published in JCEM Case Reports by researchers at the University of Pittsburgh, “raises the possibility that the variant could be [disease-causing].”
Cushing’s disease occurs when the body produces too much cortisol, a hormone involved in the stress response. The condition is usually caused by a tumor in the pituitary gland that releases excess adrenocorticotropic hormone (ACTH), which signals the adrenal glands to produce cortisol. While most forms of Cushing’s are sporadic, “some inherited causes include multiple endocrine neoplasia type 1 or type 4,” the researchers wrote.
Here, they report the case of a father and daughter who both developed Cushing’s disease and were found to carry the same variant in the CDKN1B gene. The genetic variant is called a “variant of unknown significance,” meaning doctors do not yet know if it causes disease. Still, the fact that both family members carried the variant and developed Cushing’s disease raises the possibility of a connection, the researchers noted.
The father first came to medical attention at age 62. He already had high blood pressure and then developed worsening type 2 diabetes and severe insomnia. Doctors noticed signs often seen in Cushing’s disease, including weight gain around the abdomen, redness of the face, and weakness in the upper arm muscles.
A computed tomography (CT) scan showed enlarged adrenal glands on both sides, a finding that can occur when cortisol remains elevated for a long time. Blood and urine tests confirmed elevated cortisol levels. Cortisol remained elevated during a dexamethasone suppression test, a test in which cortisol levels normally fall after a person takes the steroid dexamethasone. Because his cortisol did not fall as expected, the result supported abnormal cortisol production.
The doctors suspected the pituitary gland was the source of excess cortisol. An MRI scan showed a possible very small pituitary tumor, called a microadenoma. To confirm this, the doctors performed inferior petrosal sinus sampling (IPSS) to measure ACTH levels in the veins draining the pituitary gland. The results showed excess ACTH was coming from the pituitary gland.
Father achieved remission after second surgery
The patient underwent endoscopic endonasal surgery, a procedure done through the nose, to remove a pituitary microadenoma. During the first surgery, suspicious tissue from both sides of the pituitary gland was removed, but cortisol remained very high afterward, suggesting the source of excess cortisol had not been fully removed.
Three days later, he underwent a second surgery to remove more tissue on the left side of the pituitary gland. Afterward, his cortisol levels fell to very low levels, indicating that the surgery had worked. Because his cortisol levels were low after surgery, he was started on glucocorticoid replacement therapy.
Five years later, his 40-year-old daughter developed symptoms including weight gain, muscle weakness, sweating, and poor sleep. Despite major diet and exercise efforts, she gained 50 pounds. She also had high blood pressure and physical signs typical of Cushing’s disease, including a rounded face and a fat pad at the back of the neck.
Testing showed elevated cortisol levels in saliva collected late at night and in urine samples collected over 24 hours. Her dexamethasone suppression test was also abnormal, and excess cortisol was ACTH-dependent, meaning the pituitary gland was likely involved.
Unlike her father, a brain MRI did not clearly show a tumor. However, IPSS again confirmed that the source of ACTH was the pituitary gland. Because both father and daughter developed Cushing’s disease, genetic testing was performed. Both were found to carry a variant called c.280 C>T (p.P94S) in the CDKN1B gene.
Daughter also improved after pituitary surgery
The daughter also underwent endoscopic endonasal surgery. After the first procedure, her cortisol did not decrease enough, so a second procedure was performed four days later on the right side of the pituitary gland. Afterward, her cortisol fell to low levels, indicating remission. Pathology did not identify an adenoma in the tissue removed. She also received temporary glucocorticoid replacement therapy and was able to stop it six months later.
Both patients remain in biochemical remission, meaning that laboratory tests continue to show no evidence of recurrent Cushing’s disease. They continue regular follow-up, and so far neither has developed other tumors commonly linked to MEN4.
“This case report describes [two] related patients who presented with Cushing disease and were successfully treated with pituitary surgery, resulting in biochemical remission. Both were found to carry the same CDKN1B variant, the gene responsible for MEN4, suggesting a possible causative relationship,” the researchers wrote.
The daughter’s own daughter is being checked for premature adrenarche — when signs such as pubic or armpit hair and body odor develop earlier than expected due to early production of adrenal hormones called androgens — although genetic testing has not yet been performed, the researchers noted.
