Cushing’s syndrome seen in newborn with rare genetic disorder

MAS is caused by a GNAS gene mutation; affects bones, skin, endocrine systems

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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An infant naps on her back.

A newborn girl with a rare genetic disorder called McCune-Albright syndrome (MAS) developed Cushing’s syndrome, according to researchers in Turkey.

While Cushing’s syndrome in the context of MAS is linked to a poor prognosis, no specific guidelines exist for diagnosing and treating these rare cases. The newborn’s condition improved following an adrenalectomy, a surgery to fully or partially remove the adrenal glands, which are responsible for producing cortisol.

The girl’s case was described in “Case Report: Severe McCune–Albright syndrome presenting with neonatal Cushing syndrome: navigating through clinical obstacles,” published in Frontiers in Endocrinology.

MAS is a rare disorder caused by a mutation in the GNAS gene and affects bones, skin, and endocrine (hormone-producing) systems. In rare cases, endocrine dysfunction associated with MAS manifests as Cushing’s syndrome, a condition marked by excess cortisol levels.

Cushing’s can be driven by the excessive production of adrenocorticotrophic hormone (ACTH) in the pituitary gland, which instructs the adrenal glands atop the kidneys to produce more cortisol. This specific form of the syndrome is known as Cushing’s disease. Other types of the syndrome are independent of ACTH.

Cushing’s syndrome enhances MAS symptoms, which may include bone scarring, café-au-lait skin patches, and excessive levels of certain hormones. It is linked to poorer outcomes. While Cushing’s as a manifestation of MAS resolves naturally in about a third of newborns, 20% face worse outcomes. No guidelines regarding diagnosis, treatment, or follow-up of these patients have been published.

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Diagnosis of MAS, ACTH-independent Cushing’s syndrome

Researchers in Turkey described the rare case of a newborn girl with Cushing’s due to MAS and her course of treatment.

The girl, who was born small for her gestational age, was admitted to the neonatal intensive care unit on the day after her birth due to respiratory distress. Blood work revealed elevated levels of liver enzymes, a sign of liver damage.

She was initially diagnosed with a possible generalized infection and was given into-the-vein antibiotics, which resolved her respiratory distress and lowered her liver enzyme levels.

She was discharged after completing the antibiotic regimen, but hospitalized again four days later after her health deteriorated.

A physical examination revealed a round face with unusual features that included a long space between the nose and upper lip and an abnormally small mandible. She had café-au-lait patches at the front and back of the trunk and on her genitalia, and excessive hair growth on her forehead and extremities.

Her reflexes were low and she showed signs of heart malfunction. Blood work confirmed impaired kidney and liver function, along with elevated cortisol levels, which failed to drop after an overnight high-dose dexamethasone suppression test, which is generally used to confirm elevated cortisol and determine its source. It measures cortisol levels in the morning after patients take a dexamethasone tablet, a corticosteroid that normally blocks its production. The test causes cortisol to drop in people with Cushing’s disease, but not in those with ACTH-independent forms of Cushing’s syndrome.

The baby’s clinical manifestations along with lab findings led to a diagnosis of ACTH-independent Cushing’s syndrome and MAS.

Removal of adrenal glands

The girl had several complications related to excess cortisol and was medicated accordingly. Since elevated cortisol levels can suppress the immune system, she was given preventive treatment for Pneumocystis jirovecii, a common cause of pneumonia in immunosuppressed patients.

Ultrasounds showed her adrenal glands were enlarged, which was later confirmed by MRI. Alterations in the kidneys and enlargement of the heart’s left left ventricle were also observed.

She started treatment with metyrapone, a cortisol-lowering medication marketed under the name Metopirone, on the 25th day after her birth. A 300 mg dose lowered her high blood sugar and blood pressure. She was discharged after 13 days on metyrapone.

The dose was adjusted based on cortisol blood levels in regular follow-up visits, but complete cortisol suppression wasn’t achieved even when it was increased to 1,850 mg a day over six months.

The baby continued to lose bone mass, had a persistent enlargement of the heart’s left ventricle, and was lagging behind in her rate of growth. At nine months, she had surgery to remove her right adrenal gland and partially remove her left one.

Despite treatment, she developed adrenal insufficiency, a condition wherein the adrenal glands fail to produce enough steroid hormones, particularly cortisol. She was treated with a high dose of glucocorticoids for two months and remains on glucocorticoid maintenance therapy.

After surgery, her liver function and heart tests showed improvements and her cortisol levels were markedly reduced. The GNAS mutation was confirmed with a biopsy of the excised adrenal glands and a molecular analysis.

“We suggest that in neonatal [Cushing’s syndrome] due to MAS, initial very high serum cortisol levels, like our case, may be a negative prognostic factor both for spontaneous resolution and clinical response to medical treatment,” the researchers wrote. “High index of suspicion for MAS in a neonate with extensive café-au-lait macules and symptoms of hypercortisolism is the key for early recognition and intervention.”