Abstract
Introduction: Adrenocorticotropic hormone (ACTH)-independent Cushing syndrome (CS) is very rare condition in children. Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of CS, which in most cases occurs in the context of Carney complex (CNC). CNC is a rare autosomal-dominantly inherited genetic syndrome, usually due to pathogenic variants of the PRKAR1A (regulatory subunit R1A of the protein kinase A) gene located at 17q22-24. The clinical picture is characterized by spotty skin pigmentation, cardiac, cutaneous, and mammary myxomas, melanocytic schwannomas, endocrinopathies, and tumours of the endocrine glands (mostly adrenal, pituitary, and thyroid). Case Presentation: A 10-year-old boy first came to our outpatient clinic due to severe obesity. During the first 3 months of follow-up, the height growth rate was normal, but the response to dietary-behavioural indications was poor in terms of weight loss. Later, 10 months after the last evaluation, there was evidence of significant worsening of obesity, growth failure (growth velocity 0.7 cm/year), arterial hypertension, and the occurrence of violaceous striae at the trunk and root of the limbs. Endocrinological causes of obesity associated with growth failure were investigated. The circadian rhythm of cortisol, ACTH, and cortisoluria were suggestive of ACTH-independent hypercortisolaemia. Iatrogenic causes were ruled out. Adrenal ultrasound and computer tomography scan were performed, which initially indicated the presence of a nodule or hyperplasia of the medial arm of the left adrenal gland. Conversely, magnetic resonance imaging showed a significant increase in the global dimensions of the adrenals with a bilateral micronodular appearance. In light of the association between ACTH-independent hypercortisolism and bilateral micronodular adrenal hyperplasia, a genetic investigation was performed, which found a pathogenic variant of the PRKAR1A gene. The patient was begun on treatment with metyrapone which was well tolerated over a 2-year period. The clinical picture has slightly improved, cortisoluria returned and remains within normal limits, but ACTH suppression persists. Conclusion: This is the first report on the clinical and biochemical effects of 2-year medical treatment with metyrapone of PPNAD-related hypercortisolaemia in a paediatric patient with CNC. Currently, there are no established protocols for the management of hypercortisolism in PPNAD and data are scarce, especially in the paediatric field. Medical therapies may play a role in reducing the need, at least initially, for patients to undergo bilateral adrenalectomy. However, further studies on larger case series are needed to clarify this aspect. In cases of CS due to PPNAD in which medical therapy was the initial approach, in the absence of clear clinical, auxological, and biochemical improvements, metyrapone may have to be discontinued in favour of another approach, including surgery.
