What are the treatment recommendations for pediatric patients diagnosed with Cushing's syndrome?

Treatment Recommendations for Pediatric Cushing's Syndrome

Surgical resection of the ACTH-secreting tumor is the first-line treatment for pediatric Cushing's syndrome, with medical therapy reserved for preparation for surgery or while awaiting response to radiotherapy. 1

Diagnostic Approach

1. Clinical Presentation:

   • Key finding: Lack of height gain with concurrent weight gain (most common presentation in children) 1
   • Growth pattern changes make CS easier to detect in children compared to adults 1
   • Central obesity, facial plethora, and purple striae 2
   • Virilization from adrenal androgens may lead to early pubarche and accelerated skeletal maturity 1

2. Diagnostic Testing:

   • Document hypercortisolism with at least two of the following tests:
     • 24-hour urinary free cortisol (UFC)
     • Late-night salivary cortisol (LNSC)
     • Overnight 1 mg dexamethasone suppression test (DST) 1, 2
   • Measure ACTH to distinguish ACTH-dependent from ACTH-independent causes 2
   • Note: The Dex-CRH test is not useful in children 1
   • In children over age 6, Cushing's disease (pituitary cause) is most common
   • In children under age 6, adrenal causes are more common 1

Treatment Algorithm

First-Line Treatment

• Surgical resection of the ACTH-secreting tumor 1
• Refer to multidisciplinary centers of excellence with pediatric endocrinologists and specialized neurosurgery units 1
• Unlike in adults, thromboprophylaxis should NOT be routinely used due to bleeding risk; reserve for selected pediatric patients 1

Second-Line Options

1. Radiotherapy when surgery is not possible or unsuccessful 1

2. Medical Therapy (limited role in pediatrics):

   • Use only for:
     • Normalizing cortisol levels in preparation for surgery
     • While awaiting biochemical response to radiotherapy 1
   • Options:
     • Ketoconazole or metyrapone (monitor morning cortisol for response) 1
     • Metyrapone (800-1,200 mg/day initially, maintenance 400-800 mg/day in 2-3 divided doses) 1
     • Note: Pasireotide is not recommended in children 1
     • Osilodrostat is under investigation in a phase II trial (NCT03708900) 1

3. Bilateral adrenalectomy:

   • Reserve only for:
     • Severe refractory Cushing's disease
     • Life-threatening emergencies 1
   • Caution: Nelson syndrome (corticotroph tumor progression) appears more frequent in children than adults 1

Post-Treatment Management

Immediate Post-Treatment Care

• Adrenal function typically recovers within approximately 12 months 1
• Evaluate for GH deficiency by 3-6 months postoperatively 1

Growth and Development Monitoring

• GH replacement:

  • Test for GH deficiency soon after definitive therapy (within 3 months) 1
  • Promptly initiate GH replacement if deficient (0.025 mg/kg/day) 1
  • GH ensures adequate final height, but obesity may not fully reverse 1
  • Consider combining with gonadotropin-releasing hormone analogue therapy to delay puberty and epiphyseal closure 1

• Monitor pubertal progression:

  • Many children with Cushing's disease have disturbed timing or progression through puberty 1
  • May require sex steroid replacement to enhance growth velocity 1

Long-term Follow-up

• Assess for recurrence with 6-monthly:
  • Clinical examination
  • 24-hour UFC
  • Electrolytes
  • Morning serum cortisol for at least 2 years 1
• Annual clinical assessment lifelong 1
• Consider bone mineral density assessment prior to adult transition 1
• Monitor for psychiatric and neurocognitive co-morbidities 1

Common Pitfalls and Caveats

1. Diagnostic challenges:

   • Endogenous CS is extremely rare before age 18, leading to delayed diagnosis 1
   • Proper sequence of testing is essential; improper testing stems from lack of understanding of HPA axis physiology 3

2. Treatment considerations:

   • Medical therapies have significant limitations in children:
     • Metyrapone: Can cause hirsutism and advanced bone age with prolonged use 1
     • Ketoconazole: Requires liver function monitoring due to hepatotoxicity 1

3. Post-treatment complications:

   • Pituitary hormone deficiencies are common after surgical or radiotherapeutic cure 1
   • GH deficiency is the most frequent pituitary deficit 1
   • After radiotherapy, additional anterior pituitary deficiencies (TSH and permanent ACTH deficits) can develop 1
   • Cerebral atrophy may reverse after treatment, but cognitive function may paradoxically decline 1

4. Genetic considerations:

   • Screen for germline mutations in MEN1, RET, AIP, PRKAR1A, CDKN1B, DICER1, SDHx, and CABLES1 when there is family history or signs suggestive of genetic syndrome 1

By following this structured approach to diagnosis and treatment, pediatric patients with Cushing's syndrome can achieve optimal outcomes with minimized long-term complications.