Case report: Rare PPNAD Cushing’s caused by gene duplication
Condition usually presents in young adults, is very rare in children
An 8-year-old girl was diagnosed with primary pigmented nodular adrenocortical disease (PPNAD), a rare genetic disorder that can cause Cushing’s syndrome, a case study reports.
Hers was the first reported case of PPNAD caused by a duplication in the PRKACA gene. according to the researchers. The girl’s case was described in the study, “A Rare Case of PRKACA Duplication–Associated Childhood-Onset Primary Pigmented Nodular Adrenocortical Disease,” published in JCEM Case Reports.
Cushing’s syndrome refers to a group of disorders marked by elevated levels of the hormone cortisol. Typical signs include excessive weight gain, fat accumulation, acne, and muscle weakness. Cushing’s disease, one of its most common forms, is caused by tumors in the pituitary gland that produce and release excessive amounts of the signaling molecule adrenocorticotropic hormone, or ACTH, which stimulates the adrenal glands to produce cortisol.
PPNAD is a potential cause of ACTH-independent Cushing’s syndrome. In it, multiple small masses, or nodules, form in the adrenal glands and cause excessive cortisol production without stimulating ACTH. It usually presents in young adults, but is exceedingly rare in children.
About 90% of PPNAD cases are associated with Carney complex (CNC), a genetic disorder marked by spotty skin pigmentation and benign tumors in multiple organs. PPNAD and CNC are linked to mutations in the PRKAR1A gene, but in rare cases, PPNAD is associated with mutations in the PRKACA gene. So far, three cases of PRKACA-linked PPNAD have been reported, one occurring in childhood.
Gene duplication confirms PPNAD diagnosis
Here, researchers in India described the case of an 8-year-old girl with PPNAD caused by a duplication in the PRKACA gene. While her first seven years were otherwise normal, she had recently begun to show signs that suggested Cushing’s syndrome, including acne, poor growth, and abnormal weight gain.
An clinic examination revealed other Cushing’s signs, including high blood pressure, a round moon face, and fat accumulating between the shoulder blades at the back of the neck. Still, there were no classical CNC signs, such as spotty skin pigmentation.
Blood tests revealed dyslipidemia, or abnormally high levels of fatty molecules in the bloodstream, and high numbers of neutrophils, a type of white blood cell. The girl’s blood sugar, liver, and kidney function tests were within normal limits, but insulin tests suggested marked insulin resistance, which occurs when the body doesn’t respond to insulin as it should.
Her blood cortisol levels were elevated in the morning, afternoon, and at midnight, and remained high after dexamethasone suppression tests. Under normal circumstances, dexamethasone, a medication that mimics cortisol, would reduce the hormone’s levels. Cortisol levels may not drop in response to dexamethasone in people with Cushing’s, however. The girl’s ACTH remained normal, findings consistent with ACTH-independent Cushing’s syndrome.
After CT and MRI scans showed no apparent abnormalities in either adrenal gland, clinicians ordered genetic testing, which revealed a duplication of PRKACA, confirming a PPNAD diagnosis.
The girl began treatment with medications to control blood pressure and underwent surgery to remove both adrenal glands. During the procedure, she received continuous infusions of hydrocortisone, which were maintained for two days. This was followed by oral hydrocortisone replacement therapy, along with oral fludrocortisone. Microscopic examination of adrenal tissue showed multiple well-defined, round-to-oval nodules consistent with PPNAD.
Seven days after the surgery, the girl’s blood pressure normalized and medications to lower it were stopped. She continued with hydrocortisone therapy and there were no signs of adrenal problems in the following five months. During this time, her acne and moon face disappeared, and her blood pressure stayed about normal. The girl continued to show signs of significant clinical recovery, as indicated by weight loss, increased height, and normalized blood insulin and fat levels.
“To the best of our knowledge, the present case is the first reported female patient with PPNAD caused by a [disease-causing] variant of PRKACA gene, presenting in the first decade of life,” the researchers wrote. “This case highlights that PPNAD caused by pathogenic PRKACA variants can manifest as an isolated condition in childhood without other features of CNC.”
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