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Cushing Syndrome

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Definition

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Etiology & Classification

1. Exogenous (Iatrogenic) — Most Common Overall

2. ACTH-Dependent (80–85% of endogenous cases)

3. ACTH-Independent (~15–20% of endogenous cases)

Pediatric note: In children under 5 years, adrenal causes (carcinoma, McCune-Albright) predominate over pituitary causes.

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Pathophysiology

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Clinical Manifestations

Table: Presenting Signs and Symptoms (Nelson 2024, Table 619.2)

In infants, generalized obesity is common and findings are more dramatic. In older children, truncal/facial obesity with relative limb sparing is typical.

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Laboratory Findings & Diagnosis

Screening Tests (require ≥2 abnormal results to confirm)

Distinguishing the Cause

1. Measure plasma ACTH (two samples)
   • ACTH <10 pg/mL → ACTH-independent → CT/MRI of adrenals
   • ACTH >20 pg/mL → ACTH-dependent → pituitary MRI + further testing
   • ACTH 10–20 pg/mL (indeterminate) → CRH stimulation test
2. High-dose dexamethasone suppression test (HDDSST): 30 μg/kg/24 hr × 2 days then 120 μg/kg/24 hr × 2 days. Suppression of cortisol with the larger dose (not smaller) = pituitary Cushing disease. ACTH-independent disease shows no suppression.
3. CRH stimulation: Patients with ACTH-dependent CS show an exaggerated ACTH and cortisol response; adrenal tumor patients show no response.
4. Bilateral Inferior Petrosal Sinus Sampling (BIPSS) after CRH stimulation: the gold standard to distinguish Cushing disease from ectopic ACTH. High petrosal:peripheral ACTH ratio confirms pituitary origin.
5. Imaging:
   • CT detects virtually all adrenal tumors >1.5 cm
   • Pituitary MRI (with gadolinium) for adenomas — but 50% of Cushing disease patients have no visible abnormality on MRI; and 10% of the general population have incidental pituitary findings

Confirmed CS → ACTH measurement
├── <10 pg/mL (ACTH-independent) → CT/MRI adrenals
│   └── Unilateral mass → adenoma/carcinoma
│   └── Bilateral → macronodular or micronodular hyperplasia
│
└── >20 pg/mL (ACTH-dependent) → Pituitary MRI + HDDSST + CRH test
    ├── Adenoma >6 mm + concordant tests → Surgery (Cushing disease confirmed)
    ├── Adenoma <6 mm or discordant tests → BIPSS
    └── Negative pituitary imaging → CT/MRI neck/chest/abdomen/pelvis + octreoscan/PET → ectopic ACTH tumor

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Differential Diagnosis

• Simple obesity: children are tall, cortisol suppresses normally with dexamethasone, nighttime salivary cortisol is normal
• Pseudo-Cushing states (may show false-positive cortisol tests): major depression, alcoholism, morbid obesity, poorly controlled diabetes
• Glucocorticoid resistance (Chrousos syndrome): elevated cortisol + ACTH without typical CS phenotype; presents with hypertension, hypokalemia, precocious pseudopuberty
• Exogenous steroid use (always exclude first with careful history)

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Treatment

Cushing Disease (Pituitary)

• Transsphenoidal pituitary microsurgery is the treatment of choice in children
  • Overall success rate: 60–98% (initial remission); long-term success 50–98%
  • Low postoperative cortisol predicts long-term remission
  • Relapse: reoperation or pituitary radiotherapy
• Pasireotide (somatostatin analog): approved for adults with persistent/recurrent disease post-surgery or surgical contraindication — inhibits ACTH secretion
• Cyproheptadine (serotonin antagonist): rarely used in children; remissions not sustained

Adrenal Causes

• Surgical resection (laparoscopic adrenalectomy where possible)
• For bilateral adrenalectomy: requires lifelong adrenal replacement therapy; risk of Nelson syndrome (~25% of adults post-bilateral adrenalectomy) — Nelson syndrome = markedly elevated ACTH with skin hyperpigmentation from unresected pituitary adenoma

Adrenal Steroidogenesis Inhibitors (preoperative or adjunct)

Postoperative Management

• Replace cortisol 10 mg/m²/24 hr in three divided doses after immediate postoperative period — until HPA axis recovers (may take up to 30 months)
• Monitor for sepsis, pancreatitis, thrombosis, poor wound healing
• Expect catch-up growth and pubertal progress, but bone density remains abnormal and adult height is often compromised
• Check for GH deficiency post-treatment and treat if present

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Genetics Summary (Fig. 619.1, Nelson 2024)

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Recent Evidence (PubMed 2024–2025)

• A 2024 systematic review and meta-analysis (PMID 38888685) addressed the challenge of differentiating true Cushing syndrome from non-neoplastic hypercortisolism (pseudo-Cushing), highlighting the diagnostic conundrum in clinical practice.
• A 2025 meta-analysis on ectopic Cushing syndrome (PMID 40455890) characterized survival probabilities — ectopic CS carries a significantly worse prognosis than pituitary or adrenal forms.
• A 2024 meta-analysis (PMID 38840128) documented a spectrum of thyroid dysfunction in CS, including suppressed TSH and altered thyroid hormone metabolism.

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