Rare case of ACTH-independent Cushing syndrome: diagnostic challenges and management

To describe the clinical course, diagnosis, and management of a rare pediatric case of ACTH-independent Cushing syndrome (CS), associated with developmental delay.

A three-year-old boy with global developmental delay, was referred for evaluation of rapid weight gain over the preceding three months, accompanied by increased body hair, a moon-shaped face, and sleep disturbances. Biochemical testing revealed undetectable ACTH levels and elevated cortisol levels, leading to the diagnosis of ACTH-independent CS. Abdominal magnetic resonance imaging demonstrated adrenal asymmetry, with a larger left adrenal gland, and further investigation using PET scan excluded the presence of adrenal adenomas/carcinomas. The patient was initially treated with metyrapone, which effectively reduced cortisol levels. However, after two months, a left adrenalectomy was performed. Pathological examination confirmed micronodular non-pigmented adrenal hyperplasia. One year later, cortisol levels increased again with undetectable ACTH, prompting the re-initiation of metyrapone. Due to intolerance to this medication, osilodrostat, an off-label treatment, was introduced. At the time of follow-up, 15 months after initiation of osilodrostat, both serum and urinary cortisol levels remained within normal ranges, ACTH levels remained undetectable, and the clinical symptoms of CS were well controlled.

This case underscores the diagnostic and therapeutic challenges associated with rare pediatric cases of ACTH-independent CS. The treatment course, which included metyrapone, adrenalectomy, and off-label use of osilodrostat, resulted in significant improvement in cortisol control and clinical symptoms. Ongoing genetic analysis is being conducted to explore potential underlying genetic factors contributing to the patient's non-pigmented micronodular adrenal hyperplasia and developmental delay.