Cushing Syndrome

Etiology and Classification

• Cushing syndrome encompasses any clinical state resulting from abnormally high blood levels of cortisol or other glucocorticoids.
• Exogenous (Iatrogenic) Cushing Syndrome: The most common cause in the pediatric population is the prolonged exogenous administration of potent glucocorticoid hormones, frequently utilized for treating lymphoproliferative disorders, asthma, or autoimmune conditions,,.
• Endogenous ACTH-Dependent Cushing Syndrome:
  • Cushing Disease: Defined strictly as hypercortisolism caused by excessive adrenocorticotropic hormone (ACTH) secretion from a pituitary adenoma,,. This is the most common endogenous cause in children older than 7 years and adolescents,. These tumors are almost exclusively microadenomas (less than 5 mm in diameter).
  • Ectopic ACTH Syndrome: A rare cause in children where ACTH is secreted by non-pituitary tumors, including neuroblastoma, Wilms tumor, islet cell carcinoma of the pancreas, thymic neuroendocrine tumors, and carcinoid tumors,,.
• Endogenous ACTH-Independent Cushing Syndrome:
  • Adrenocortical Tumors: Adrenal carcinomas and adenomas are the predominant cause of endogenous Cushing syndrome in infants and children younger than 7 years of age,. Adrenal adenomas typically secrete only cortisol, whereas carcinomas frequently co-secrete androgens, leading to pronounced virilization.
  • Primary Pigmented Nodular Adrenocortical Disease (PPNAD): A rare cause of micronodular adrenal hyperplasia characterized by small, pigmented nodules in an atrophic cortex, frequently presenting as a component of the Carney complex,,.
  • Bilateral Macronodular Adrenal Hyperplasia (BMAH): Can occur sporadically or as part of McCune-Albright syndrome, where activating somatic mutations lead to autonomous adrenal hyperfunction,,.

Genetic and Molecular Pathogenesis

• Pituitary Adenomas (Cushing Disease): While mostly sporadic, familial cases may occur due to mutations in the AIP gene (Familial Isolated Pituitary Adenoma syndrome) or the MEN1 gene. Whole-exome sequencing has identified somatic gain-of-function mutations in the USP8 gene (encoding a deubiquitinase regulating epidermal growth factor receptor turnover) in a significant proportion of ACTH-secreting microadenomas.
• Ectopic ACTH Secretion: Associated with genetic variants in the RET and MEN1 genes.
• Adrenocortical Tumors: Genetic predisposition to adrenal carcinomas includes germline mutations or loss of heterozygosity in the TP53 tumor suppressor gene (Li-Fraumeni syndrome), as well as mutations in CDKN2A, CTNNB1 (the Wnt/beta-catenin pathway), and IGF-2 overproduction associated with Beckwith-Wiedemann syndrome,. Adrenal adenomas have been linked to somatic gain-of-function mutations in PRKACA (catalytic subunit of protein kinase A) and phosphodiesterases (PDE11A, PDE8B),.
• Micronodular Hyperplasia (PPNAD): Strongly associated with inactivating mutations in the PRKAR1A gene, encoding the protein kinase A type I-alpha regulatory subunit, defining the Carney complex,.
• Macronodular Hyperplasia (BMAH): Caused by somatic activating mutations in the GNAS gene (encoding the Gs-alpha protein) in McCune-Albright syndrome, leading to ACTH-independent cAMP generation,. Other BMAH cases are linked to germline mutations in tumor suppressor genes such as ARMC5, APC, and FH, or the ectopic expression of aberrant hormone receptors (e.g., for vasopressin, serotonin, or LH/hCG) on the adrenal cortex,.

Pathophysiology of Hypercortisolism

• Glucocorticoids profoundly suppress linear skeletal growth by increasing hypothalamic secretion of somatostatin (which suppresses growth hormone and IGF-1 production) and by exerting a direct inhibitory action on the epiphyseal growth plate,.
• Direct epiphyseal effects include the inhibition of cartilage sulfation, mineralization, and cellular proliferation.
• Excess cortisol stimulates hepatic gluconeogenesis and glycogen storage while increasing peripheral insulin resistance, promoting hyperglycemia and compensatory hyperinsulinemia,.
• Glucocorticoids inhibit fibroblast proliferation, leading to cutaneous atrophy, poor wound healing, easy bruising, and the formation of classical violaceous striae.
• They alter calcium metabolism by decreasing intestinal calcium absorption and reducing renal tubular reabsorption of calcium and phosphorus, ultimately leading to significant osteopenia and osteoporosis,.

Clinical Manifestations

Growth and Metabolic Features

• The earliest, most sensitive, and most reliable clinical indicators of Cushing syndrome in children are an acceleration in weight gain combined with a simultaneous deceleration in linear growth (growth arrest),,.
• This specific pattern strongly differentiates Cushing syndrome from exogenous (nutritional) obesity, where children typically exhibit normal or accelerated linear growth and advanced skeletal maturation due to hyperinsulinism,,.
• In infants, the presentation is often dramatic, with severe generalized obesity and length falling below the third percentile.
• Centripetal fat distribution and the classic "buffalo hump" are signs of prolonged, long-standing disease; childhood obesity in Cushing syndrome is often generalized initially.
• Impaired glucose tolerance, insulin resistance, and progression to overt type 2 diabetes mellitus may occur.

Dermatologic and Physical Signs

• Facial features typically include a rounded "moon facies" with prominent cheeks and striking plethora (flushing),,.
• Cutaneous signs include severe acne, acanthosis nigricans, easy bruising, fine downy body hair, and hypertrichosis,,.
• Violaceous, wide striae are classic but are considered unusual in children under 7 years of age.

Neuropsychiatric and Systemic Features

• Glucocorticoids readily cross the blood-brain barrier; children frequently present with severe emotional lability, mood swings, fatigue, anxiety, and depression,,,.
• A distinctive psychological feature in pediatric Cushing disease is the presence of compulsive, overachieving behavioral tendencies, which contrasts with the profound depression typically seen in adults.
• Hypertension is common (present in up to 63% of pediatric cases) and can rarely precipitate congestive heart failure,.
• Severe bone demineralization leads to bone pain, pathological fractures, and nephrolithiasis,,.

Gonadal and Pubertal Abnormalities

• Delayed puberty or pubertal arrest is common due to the suppressive effects of hypercortisolism on the hypothalamic-pituitary-gonadal axis,,.
• Conversely, if the etiology is an adrenal carcinoma secreting excess androgens, the child may present with marked virilization (hirsutism, deepening of voice, clitoromegaly, premature pubarche) and paradoxically normal or accelerated linear growth,.

Diagnostic Evaluation

Step 1: Establishing the Presence of Hypercortisolism (Screening)

• Diurnal Cortisol Rhythm: The normal circadian rhythm (peak at 8 am, nadir by midnight) is obliterated. The earliest laboratory sign of Cushing disease is the persistent secretion of cortisol into the evening. A midnight sleeping plasma cortisol level > 4.4 $\mu$g/dL strongly suggests the diagnosis.
• Late-Night Salivary Cortisol: An outpatient alternative; levels > 1 ng/mL (2.8 nmol/L) at 11 pm to midnight indicate abnormal diurnal rhythm and raise high suspicion for the syndrome,.
• 24-Hour Urinary Free Cortisol (UFC): Highly reliable screening test. Normal values are generally < 70 $\mu$g/m2/day. Levels > 75 $\mu$g/m2/day, or levels greater than 3 to 4 times the upper limit of normal, are diagnostic,.
• Overnight Low-Dose Dexamethasone Suppression Test: Administration of 1 mg (or 0.3 mg/m2, or 25-30 $\mu$g/kg) of dexamethasone at 11 pm. A normal response is a suppression of plasma cortisol to < 1.8 $\mu$g/dL (or < 5 $\mu$g/dL) at 8 am the following morning. Failure to suppress indicates Cushing syndrome,,,.

Step 2: Differentiating the Etiology (ACTH Dependency)

• Plasma ACTH Levels: Simultaneous measurement of morning ACTH and cortisol.
  • An ACTH level < 5 pg/mL confirms an ACTH-independent cause (e.g., adrenal adenoma, carcinoma, or nodular hyperplasia),.
  • An ACTH level > 15 to 20 pg/mL indicates an ACTH-dependent cause (pituitary adenoma or ectopic secretion),,.
  • Extremely high ACTH levels (> 100 pg/mL) are highly suggestive of ectopic ACTH production,.
• Two-Step Dexamethasone Suppression Test: To differentiate pituitary from ectopic/adrenal sources. Patients receive low-dose (20 $\mu$g/kg/day or 30 $\mu$g/kg/day) followed by high-dose (80 $\mu$g/kg/day or 120 $\mu$g/kg/day) dexamethasone in divided doses every 6 hours for 2 days each,.
  • In Cushing disease (pituitary), cortisol and ACTH fail to suppress on the low dose but classically suppress by >50% on the high dose,.
  • In adrenal tumors and ectopic ACTH syndrome, cortisol typically fails to suppress on both the low and high doses,,.
• CRH Stimulation Test: Administration of intravenous corticotropin-releasing hormone (CRH). Patients with pituitary Cushing disease exhibit an exaggerated rise in ACTH and cortisol, whereas those with ectopic ACTH or adrenal tumors show no response,.
• Bilateral Inferior Petrosal Sinus Sampling (BIPSS): An invasive procedure utilized if MRI fails to identify a pituitary adenoma in confirmed ACTH-dependent disease. ACTH is measured in the petrosal sinuses (draining the pituitary) versus the periphery before and after CRH administration to localize an occult microadenoma or rule out an ectopic source,,,.

Step 3: Anatomic Localization (Imaging)

• Pituitary MRI: Magnetic resonance imaging with gadolinium contrast is the modality of choice for localizing ACTH-secreting pituitary microadenomas, though many tumors remain radiologically occult due to small size,.
• Abdominal Imaging: Computed Tomography (CT) or MRI of the abdomen detects virtually all adrenocortical tumors >1.5 cm and can identify bilateral macronodular or micronodular hyperplasias,,.
• Nuclear Imaging: Octreotide scintigraphy, PET, or PET-CT may be required to localize occult ectopic ACTH-secreting tumors (e.g., carcinoids).

Differential Diagnosis

• Exogenous Obesity: Children present with tall stature or accelerated growth, normal midnight salivary cortisol, and normal suppression on the low-dose dexamethasone test, despite occasionally showing mildly elevated 24-hour UFC,,.
• Primary Generalized Glucocorticoid Resistance: Caused by inactivating mutations in the glucocorticoid receptor (NR3C1). Patients present with massively elevated ACTH and cortisol levels but completely lack the classical cushingoid features (no central obesity, no striae, no growth arrest). Instead, they manifest signs of severe mineralocorticoid excess (hypertension, hypokalemia) and hyperandrogenism (precocious puberty, virilization) driven by the uninhibited ACTH stimulation of alternative steroid pathways,,.
• Non-classic Congenital Adrenal Hyperplasia: Can mimic the virilizing features of an adrenal carcinoma but is ruled out by demonstrating elevated 17-hydroxyprogesterone and normal/low cortisol.

Management

Treatment of Cushing Disease (Pituitary)

• Surgical Management: Transsphenoidal pituitary microsurgery to resect the microadenoma is the definitive treatment of choice, offering an initial remission rate of 70-98% and a long-term cure rate of 65-80%,,,.
• Postoperative Considerations: Successful resection uniformly results in transient secondary hypoadrenalism because the normal corticotrophs are chronically suppressed. Patients mandate strict physiological glucocorticoid replacement and stress dosing for 6 to 30 months until the hypothalamic-pituitary-adrenal axis fully recovers,. Final adult height may remain compromised, and growth hormone deficiency can persist, occasionally necessitating GH replacement,.
• Refractory Disease: If surgery fails or the tumor recurs, repeat transsphenoidal exploration is the first-line salvage therapy. Pituitary radiotherapy (conventional or stereotactic Gamma Knife) is highly effective but carries severe risks of subsequent panhypopituitarism (especially GH deficiency) and secondary CNS neoplasms,,.
• Bilateral Adrenalectomy: Utilized as a definitive, life-saving measure for completely refractory Cushing disease. It cures the hypercortisolism but renders the patient permanently dependent on lifelong glucocorticoid and mineralocorticoid replacement. It carries the specific risk of Nelson syndrome (development of an aggressive, hyperpigmenting ACTH-secreting pituitary macroadenoma due to loss of adrenal feedback), though this is exceptionally rare in pediatric patients.

Medical Therapy

• Medical therapy is generally reserved as a bridge to surgery, to control severe metabolic decompensation preoperatively, or as an adjunct following radiation therapy while awaiting its full effect.
• Steroidogenesis Inhibitors: Ketoconazole, metyrapone, aminoglutethimide, and etomidate (useful intravenously in acute life-threatening crises) block adrenal cortisol synthesis,,,.
• Adrenolytic Agents: Mitotane induces chemical destruction of the adrenal cortex but carries severe gastrointestinal toxicity,.
• Neuromodulators: Pasireotide (a somatostatin analog) and cyproheptadine (a serotonin antagonist) can suppress ACTH secretion in select patients,,.
• Receptor Antagonists: Mifepristone (a glucocorticoid receptor antagonist) rapidly ameliorates the clinical manifestations of hypercortisolism without lowering circulating cortisol levels,,.

Treatment of Adrenal Tumors and Hyperplasias

• Adrenal Adenoma and Carcinoma: Complete surgical resection (laparoscopic or open adrenalectomy) is mandatory. Adrenal carcinomas are highly malignant with significant recurrence rates. The contralateral adrenal gland will be profoundly suppressed, necessitating rigorous perioperative and postoperative glucocorticoid coverage to prevent a fatal Addisonian crisis.
• Nodular Hyperplasias (PPNAD and BMAH): Bilateral total adrenalectomy is the definitive treatment of choice, followed by lifelong physiologic replacement of hydrocortisone and fludrocortisone,,.