Adrenal Cushing's syndrome: diagnosis and management in a 10-year-old boy with Carney complex.

in Hormone research in paediatrics by Domenico Corica, Cecilia Lugarà, Jerome Bertherat, Eric Pasmant, Mariella Valenzise, Giorgia Pepe, Francesco Ferraù, Salvatore Cannavò, Tommaso Aversa, Malgorzata Gabriela Wasniewska

TLDR

  • This study is about a boy who was very overweight and had trouble growing. He was diagnosed with a rare condition called Cushing's Syndrome, which is caused by a problem with the adrenal gland. The study found that the boy's condition was caused by a genetic mutation and that he responded well to treatment with a medicine called metyrapone. The study also found that medical treatments may be helpful in managing this condition, but more research is needed to understand how to best treat it.

Abstract

ACTH-independent Cushing's 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 an autosomal-dominantly inherited genetic syndrome, usually due to pathogenic variants of the PRKAR1A (regulatory subunit R1A of the protein kinase A) gene. 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). A 10-year-old boy first came to our Outpatient clinic due to severe obesity. During the first three months of follow-up the height growth rate was normal, but the response to dietary-behavioural indications was poor in term of weight loss. Later, 10 months after the last evaluation, there was evidence of significant worsening of obesity, growth failure, arterial hypertension and the occurrence of red skin 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 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. Considering the association between ACTH-independent hypercortisolism and PPNAD, a genetic investigation was performed, which found a pathogenic variant of the PRKAR1A gene. Patient started, and well tolerated, therapy with metyrapone during a two-year follow-up. The clinical picture has slightly improved, cortisoluria returned and remains within normal limits, but ACTH suppression persists. 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 bilateral adrenalectomy. However, further studies 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.

Overview

  • The study focuses on a 10-year-old boy with severe obesity and growth failure, who was diagnosed with ACTH-independent Cushing's Syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD) and Carney complex (CNC).
  • The methodology used for the experiment includes a series of endocrinological tests, imaging studies, and genetic testing to diagnose the condition and determine the best course of treatment. The study aims to investigate the clinical and biochemical effects of 2-year medical treatment with metyrapone in a paediatric patient with PPNAD-related hypercortisolism.

Comparative Analysis & Findings

  • The study found that the patient's response to dietary-behavioral indications was poor in terms of weight loss, and there was evidence of significant worsening of obesity, growth failure, arterial hypertension, and red skin striae at the trunk and root of the limbs. The circadian rhythm of cortisol, ACTH, and cortisoluria were suggestive of ACTH-independent hypercortisolism. Adrenal ultrasound and computer tomography initially indicated the presence of a nodule or hyperplasia of the medial arm of the left adrenal gland, but magnetic resonance imaging showed a significant increase in the global dimensions of the adrenals with a bilateral micronodular appearance. Genetic testing found a pathogenic variant of the PRKAR1A gene, which is associated with PPNAD-related hypercortisolism. The patient started therapy with metyrapone, which improved the clinical picture, but ACTH suppression persists. The study suggests that medical therapies may play a role in reducing the need for bilateral adrenalectomy, but further studies are needed to clarify this aspect. In cases of CS due to PPNAD in which medical therapy was the initial approach, metyrapone may have to be discontinued in favor of another approach, including surgery.

Implications and Future Directions

  • The study highlights the importance of identifying the underlying cause of hypercortisolism in children with severe obesity and growth failure, as it can have significant implications for their health and well-being. The study also suggests that medical therapies may play a role in managing hypercortisolism in PPNAD, but further research is needed to determine the most effective and safe approaches. The study also highlights the need for more research on the management of hypercortisolism in PPNAD, especially in the pediatric field, where data are scarce. Future studies should focus on developing more effective and personalized treatment approaches for PPNAD-related hypercortisolism, taking into account the individual patient's genetic, clinical, and endocrinological characteristics.
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