DESCRIPTION

Cushing syndrome is a multisystem disorder resulting from prolonged exposure to excess glucocorticoid.

• Characterized by growth deceleration, truncal obesity, change in facial appearance, characteristic skin changes, muscle weakness, and hypertension
• Most common cause in childhood is exogenous glucocorticoid administration.
• Endogenous Cushing syndrome may be caused by adrenocorticotropic hormone (ACTH)-secreting tumor of the pituitary gland (Cushing disease), ectopic secretion of ACTH, or ACTH-independent secretion of glucocorticoids by the adrenal glands.
• Accurate diagnosis and classification of Cushing syndrome in children is crucial to prevent long-term morbidity and guide appropriate therapeutic intervention.
• In endogenous Cushing syndrome, the hypothalamic-pituitary-adrenal axis has lost its ability to self-regulate due to excessive secretion of either ACTH or cortisol and loss of the negative feedback function.
• Diagnostic tests are essential to distinguish the etiology.
• There are key differences between children and adults in the diagnosis and management of Cushing syndrome.

EPIDEMIOLOGY

• The overall incidence of Cushing syndrome is approximately 2 to 5 new cases per million people per year. Only ~10% of the new cases each year occur in children.
• In older children with Cushing syndrome, there is a female-to-male predominance, whereas in younger children, male predominance has been reported.
• Exogenous Cushing syndrome caused by chronic administration of glucocorticoids (by any route) or, more rarely, by administration of ACTH (e.g., for infantile seizures) is the most common cause of pediatric Cushing syndrome.
• The pituitary-dependent form (Cushing disease) accounts for >80% of all cases of endogenous Cushing syndrome in children >7 years of age. The incidence of Cushing disease in pediatrics is one twentieth of that seen in the adult population.

ETIOLOGY

• Exogenous steroids: Iatrogenic Cushing syndrome is the most common cause in pediatrics. Cushing syndrome can be caused by chronic systemic, topical, or intranasal steroid use, or ACTH use.
• Cushing disease:
  • In most cases, the genetic etiology of pituitary corticotropinomas remains unknown. Rare germline mutations in Menin (multiple endocrine neoplasia type 1 [MEN-1]) or aryl hydrocarbon receptor interaction protein (AIP) gene have been described.
  • Somatic mutations in ubiquitin-specific protease 8 (USP8) gene, resulting in increased activity of the epidermal growth factor receptor (EGFR) signaling pathway, are associated with 30% of cases of Cushing disease in pediatrics.
• Adrenal endogenous Cushing syndrome:
  • In very young children, this form of Cushing syndrome is usually caused by adrenocortical hyperplasia.
  • 10–15% of all cases of endogenous Cushing syndrome in childhood are due to ACTH-independent unregulated secretion of cortisol from the adrenal glands.
  • Adrenocortical neoplasms
    • Often malignant in young children
    • Pure cortisol-secreting adrenocortical neoplasms are rare.
    • Most adrenocortical tumors cause virilization and mixed hormone secretion.
  • Primary pigmented nodular adrenocortical disease (PPNAD)
    • PPNAD is a genetic disorder often associated with Carney complex and related to PRKAR1A gene mutations.
    • Cushing syndrome in PPNAD may be cyclical and difficult to diagnose.
    • The overall size of the adrenals is not increased. Nodules may be seen on magnetic resonance imaging (MRI).
  • Isolated micronodular adrenocortical disease (iMAD)
    • If no PRKAR1A mutations are found or if the patient does not have Carney complex, and Cushing syndrome is due to bilateral adrenal hyperplasia without massive enlargement of the adrenal glands on imaging, then iMAD is the most likely diagnosis.
    • Like in PPNAD, Cushing syndrome in iMAD can be difficult to diagnose due to an often atypical and/or cyclical clinical course.
  • Massive macronodular adrenocortical disease (MMAD)
    • Another form of ACTH-independent bilateral adrenal disease seen (rarely) in children
    • Easier to diagnose due to massive enlargement of the adrenal glands on imaging studies
  • Adrenal hyperplasia and/or adenomas can also be seen in the McCune-Albright and Beckwith-Wiedemann syndromes, usually in the infantile period.
• Ectopic ACTH production accounts for <1% of the cases of Cushing syndrome in children and may be due to a variety of neuroendocrine (NE) tumors.
  • NE tumors include carcinoid tumors in the lungs (bronchi), pancreas (and other locations in the gastrointestinal tract), or thymus; medullary carcinomas of the thyroid; and pheochromocytomas, as well as small cell carcinoma of the lungs that may be seen very rarely in adolescents.
  • Other causes of ectopic ACTH secretion include infantile neuroblastomas (and related tumors) and paraneoplastic syndromes in all ages.
• Corticotropin-releasing hormone (CRH) secretion by an ectopic CRH-producing source, typically an NE tumor such as the ones producing ectopic ACTH, is an extremely rare cause of Cushing syndrome in children.