Pheochromocytomas in Children

Pheocromocytoma Introduction Etiology Clinical Presentation Diagnosis Treatment Prognosis and Follow-up

Introduction to Pheochromocytomas in Children

Pheochromocytomas are rare neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla. When similar tumors occur outside the adrenal glands, they are called paragangliomas. In children, these tumors are particularly rare, accounting for about 10-20% of all pheochromocytoma cases, with an estimated incidence of 0.3 cases per million children per year.

Key points about pediatric pheochromocytomas include:

• Higher likelihood of being bilateral, multifocal, and extra-adrenal compared to adult cases
• Greater association with hereditary syndromes (up to 40% of cases)
• Generally better prognosis compared to adult cases, with lower malignancy rates
• Potential for life-threatening complications if undiagnosed or improperly managed

Understanding the unique features of pheochromocytomas in children is crucial for timely diagnosis, appropriate management, and long-term follow-up. The rarity of these tumors in the pediatric population often leads to delays in diagnosis, making awareness among healthcare providers essential.

Etiology of Pheochromocytomas in Children

The etiology of pheochromocytomas in children is complex and often involves genetic factors:

1. Genetic Causes:

Up to 80% of pediatric cases are associated with germline mutations, compared to about 30% in adults. Common genetic syndromes include:

• Multiple Endocrine Neoplasia Type 2 (MEN2):
  • Caused by RET proto-oncogene mutations
  • Associated with medullary thyroid carcinoma and hyperparathyroidism
• Von Hippel-Lindau (VHL) Syndrome:
  • VHL gene mutations
  • Associated with retinal and CNS hemangioblastomas, renal cell carcinoma
• Neurofibromatosis Type 1 (NF1):
  • NF1 gene mutations
  • Characterized by café-au-lait spots, neurofibromas, optic gliomas
• Hereditary Paraganglioma-Pheochromocytoma Syndromes:
  • Caused by mutations in SDHx genes (SDHB, SDHC, SDHD, SDHA, SDHAF2)
  • Higher risk of malignancy, especially with SDHB mutations
• Other Genetic Associations:
  • TMEM127, MAX, FH gene mutations
  • Recently identified genes: MDH2, SLC25A11, DNMT3A

2. Sporadic Cases:

• Less common in children compared to adults
• May still involve somatic mutations in the above-mentioned genes

3. Other Factors:

• Environmental Factors: Limited evidence, but some studies suggest a potential role of radiation exposure
• Developmental Factors: Theories about aberrant migration or differentiation of neural crest cells during embryogenesis

Understanding the genetic basis of pediatric pheochromocytomas is crucial for appropriate genetic counseling, screening of family members, and long-term management strategies. The high prevalence of genetic causes in children emphasizes the importance of comprehensive genetic testing in all pediatric cases.

Clinical Presentation of Pheochromocytomas in Children

The clinical presentation of pheochromocytomas in children can be variable and often differs from that in adults. Symptoms result from excessive catecholamine secretion and can be paroxysmal or sustained.

1. Common Symptoms:

• Hypertension: Often severe and sustained, can be paroxysmal
• Headaches: Usually severe and persistent
• Sweating: Profuse and often inappropriate for the environment
• Palpitations: Tachycardia or sense of forceful heartbeat
• Anxiety or Panic Attacks: Due to catecholamine surges

2. Less Common Symptoms:

• Pallor
• Nausea and vomiting
• Weight loss
• Fatigue
• Visual disturbances
• Abdominal or chest pain
• Constipation or diarrhea

3. Unique Features in Children:

• Growth and Development: Potential for growth retardation or failure to thrive
• Neurocognitive Effects: Attention deficits, behavioral changes, poor school performance
• Incidental Discovery: More common in children due to genetic screening in familial syndromes

4. Physical Examination Findings:

• Hypertension (may be severe)
• Tachycardia
• Orthostatic hypotension
• Pallor or flushing
• Café-au-lait spots or neurofibromas (in NF1)
• Retinal changes (in VHL syndrome)

5. Potential Complications:

• Hypertensive Crisis: Can lead to encephalopathy, stroke, or heart failure
• Cardiomyopathy: Due to chronic catecholamine excess
• Metabolic Effects: Hyperglycemia, lactic acidosis
• Multisystem Crisis: Severe hypertension, hyperthermia, encephalopathy

6. Asymptomatic Presentation:

A significant proportion of children, especially those identified through genetic screening, may be asymptomatic at diagnosis.

The clinical presentation of pheochromocytomas in children can be subtle and easily mistaken for more common conditions. A high index of suspicion is necessary, especially in children with sustained hypertension or a family history of related syndromes. Early recognition is crucial to prevent potentially life-threatening complications.

Diagnosis of Pheochromocytomas in Children

Diagnosing pheochromocytomas in children requires a combination of biochemical testing, imaging studies, and genetic analysis:

1. Biochemical Testing:

• Plasma Free Metanephrines:
  • First-line test, highest sensitivity and specificity
  • Includes metanephrine and normetanephrine
• 24-hour Urinary Fractionated Metanephrines:
  • Alternative to plasma testing
  • Challenging in younger children due to collection difficulties
• Plasma Catecholamines: Less sensitive and specific, affected by stress
• Chromogranin A: Can be elevated, especially in metastatic disease

2. Imaging Studies:

• CT or MRI:
  • Initial imaging modality of choice
  • MRI preferred in children due to lack of radiation exposure
• 123I-MIBG Scintigraphy:
  • Highly specific for pheochromocytoma
  • Useful for detecting metastatic disease
• 18F-FDG PET/CT:
  • Particularly useful in SDHB-related tumors
  • Higher sensitivity for metastatic disease
• 68Ga-DOTATATE PET/CT: Emerging modality with high sensitivity

3. Genetic Testing:

• Recommended for all children with pheochromocytoma
• Next-generation sequencing panels including:
  • RET, VHL, NF1, SDHx, TMEM127, MAX, FH genes
  • Consider wider panels for rarer genetic causes

4. Additional Tests:

• Echocardiography to assess for catecholamine-induced cardiomyopathy
• Ophthalmologic examination (for VHL-related retinal lesions)
• Thyroid ultrasound (in suspected MEN2)

5. Diagnostic Challenges in Children:

• Lower threshold for testing due to higher genetic predisposition
• Consideration of age-specific reference ranges for biochemical tests
• Potential need for sedation during imaging studies
• Importance of whole-body imaging due to higher rates of extra-adrenal tumors

The diagnosis of pheochromocytomas in children requires a high index of suspicion and a systematic approach. The combination of biochemical testing, appropriate imaging, and comprehensive genetic analysis is crucial for accurate diagnosis, proper management, and long-term care planning. Early involvement of a multidisciplinary team, including pediatric endocrinologists, geneticists, and specialized surgeons, is essential for optimal outcomes.

Treatment of Pheochromocytomas in Children

The treatment of pheochromocytomas in children requires a multidisciplinary approach and careful preoperative preparation:

1. Preoperative Management:

• Alpha-adrenergic blockade:
  • Phenoxybenzamine: First-line, typically started 7-14 days before surgery
  • Doxazosin: Alternative, shorter-acting
• Beta-adrenergic blockade:
  • Started after adequate alpha-blockade (usually 2-3 days before surgery)
  • Options include propranolol, atenolol, or metoprolol
• Volume expansion: To prevent postoperative hypotension
• Calcium channel blockers: Can be used as adjuncts
• Tyrosine hydroxylase inhibition: Metyrosine in select cases

2. Surgical Management:

• Laparoscopic adrenalectomy: Preferred approach for most cases
• Open surgery: For large tumors or those with concern for malignancy
• Partial adrenalectomy: Consider in bilateral cases to preserve adrenal function
• Lymph node dissection: In cases with suspected or confirmed malignancy

3. Intraoperative Considerations:

• Close monitoring of hemodynamics
• Availability of short-acting antihypertensives (e.g., sodium nitroprusside, esmolol)
• Preparation for potential hypotension after tumor removal

4. Postoperative Management:

• Monitoring for hypotension and hypoglycemia
• Gradual withdrawal of antihypertensive medications
• Assessment for residual disease (biochemical testing 2-6 weeks post-op)

5. Management of Malignant Pheochromocytomas:

• Surgical debulking: Primary treatment even in metastatic disease
• 131I-MIBG therapy: For MIBG-avid metastatic disease
• Chemotherapy: Cyclophosphamide, vincristine, and dacarbazine (CVD) regimen
• Targeted therapies: Sunitinib, everolimus (in clinical trials)
• Peptide receptor radionuclide therapy (PRRT): For somatostatin receptor-positive tumors

6. Special Considerations in Children:

• Dose adjustment of medications based on weight and age
• Consideration of fertility preservation in adolescents before certain treatments
• Psychological support for children and families throughout treatment
• Long-term follow-up for potential recurrence and monitoring of growth and development

7. Management of Associated Syndromes:

• Screening and treatment of associated tumors (e.g., medullary thyroid carcinoma in MEN2)
• Genetic counseling and testing of family members
• Regular surveillance based on specific genetic syndrome

The treatment of pheochromocytomas in children requires a carefully coordinated approach involving pediatric endocrinologists, surgeons, anesthesiologists, and oncologists. The goal is to achieve complete tumor removal while minimizing perioperative complications and preserving long-term endocrine function. Given the high rate of genetic syndromes in pediatric cases, treatment plans should also consider long-term surveillance and management of associated conditions.

Prognosis and Follow-up of Pheochromocytomas in Children

The prognosis for children with pheochromocytomas is generally favorable, but long-term follow-up is essential due to the risk of recurrence and the potential for associated genetic syndromes.

Prognosis:

• Overall survival rate is excellent, exceeding 95% in most cases
• Lower malignancy rate compared to adults (about 10% vs 10-20% in adults)
• Prognosis is poorer for malignant pheochromocytomas, especially those associated with SDHB mutations

Follow-up Care:

1. Immediate Post-treatment Period:
   • Monitor for signs of residual disease or complications
   • Biochemical testing 2-6 weeks post-surgery
   • Assess need for steroid replacement in bilateral adrenalectomy cases
2. Long-term Monitoring:
   • Annual biochemical screening (plasma or urinary metanephrines)
   • Regular blood pressure monitoring
   • Periodic imaging studies (frequency based on genetic status and initial presentation)
3. Genetic Syndrome-Specific Follow-up:
   • MEN2: Regular screening for medullary thyroid carcinoma and hyperparathyroidism
   • VHL: Monitoring for retinal angiomas, CNS hemangioblastomas, renal cell carcinoma
   • NF1: Regular dermatologic and neurologic evaluations
   • SDHx mutations: Increased vigilance for recurrent or metastatic disease
4. Growth and Development Monitoring:
   • Regular assessment of growth velocity and pubertal development
   • Monitoring of cognitive and psychosocial development
5. Cardiovascular Follow-up:
   • Echocardiography to assess for residual catecholamine-induced cardiomyopathy
   • Long-term blood pressure monitoring

Long-term Considerations:

• Risk of Recurrence: Lifelong risk, especially in hereditary cases
• Second Primary Tumors: Increased risk in genetic syndromes
• Fertility and Family Planning: Genetic counseling for affected individuals as they reach reproductive age
• Psychosocial Support: Addressing the challenges of chronic disease management and genetic predisposition

Transition to Adult Care:

• Planned transition to adult endocrinology care
• Education on long-term health implications and self-management
• Continued genetic counseling and family screening

The long-term prognosis for children with pheochromocytomas is generally good, especially with early detection and appropriate management. However, the potential for recurrence and the implications of associated genetic syndromes necessitate lifelong surveillance. A multidisciplinary approach to follow-up care, involving endocrinologists, oncologists, geneticists, and other specialists as needed, is crucial for optimizing long-term outcomes and quality of life.

External Resources

• UpToDate: Pheochromocytoma in Children
• Endocrine Society Clinical Practice Guideline on Pheochromocytoma and Paraganglioma
• Review Article: Pheochromocytoma in Children and Adolescents (PMC)
• Medscape: Pediatric Pheochromocytoma