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Cushing syndrome is a multisystem disorder resulting from prolonged exposure to excess glucocorticoid.
- Characterized by growth deceleration, truncal obesity, 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 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 help to distinguish the cause of this disorder.
- Key differences exist between children and adults in the diagnosis and management of Cushing syndrome.
- The overall incidence of Cushing syndrome is approximately 2 to 5 new cases per million people per year. Only approximately 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, there may be a male predominance.
- 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 this syndrome in children.
- The pituitary-dependent form (Cushing disease) accounts for >80% of all cases of Cushing syndrome in children >7 years of age.
- Cushing disease:
- In most cases, the genetic etiology of pituitary corticotropinomas remains unknown. In rare cases, a germline mutation in Menin (multiple endocrine neoplasia type 1 [MEN-1]) or aryl hydrocarbon receptor interaction protein (AIP) gene is found.
- Recently, somatic mutations in ubiquitin-specific protease 8 (USP8) gene, resulting in increased activity of the epidermal growth factor receptor (EGFR) signaling pathway have been found to be associated with 30% of cases of Cushing disease in pediatrics.
- Adrenal sources of Cushing syndrome:
- In very young children, Cushing syndrome is usually caused by adrenal sources.
- 10–15% of all cases of Cushing syndrome in childhood are due to ACTH-independent Cushing syndrome from unregulated secretion of cortisol from the adrenal glands.
- Adrenocortical neoplasms
- Often malignant in young children
- Primary pigmented nodular adrenocortical disease (PPNAD)
- PPNAD is a genetic disorder often associated with Carney complex and related to mutations of the PRKAR1A gene.
- Cushing syndrome in PPNAD may be cyclical and difficult to diagnose.
- 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 the most likely diagnosis is iMAD.
- 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, 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 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 ectopical ACTH, is an extremely rare cause of Cushing syndrome in children.
- 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.