What are the causes of hemangiomatosis?

Causes of Hemangiomatosis

Hemangiomatosis is primarily caused by abnormal proliferation of endothelial cells and aberrant blood vessel architecture, with both genetic and environmental factors contributing to its development.

Primary Causes

Genetic Factors

• Familial clustering has been reported, though family history is present in only about 12% of cases 1
• Somatic mutations affecting vascular growth regulation pathways 1
• Von Hippel-Lindau (VHL) syndrome - an autosomal dominant disorder caused by pathogenic variants in the VHL gene that can lead to hemangioblastomas in multiple organs 1

Developmental and Placental Factors

• Placental origin theory - fetal progenitor cells arising from disruption of the placenta during gestation or birth 1
• Endothelial progenitor cells (EPCs) - clonal expansion of circulating EPCs resulting from placental hypoxia 1
• Developmental field disturbances affecting vascular formation 1

Angiogenic Dysregulation

• Increased angiogenic factors including:
  • Basic fibroblast growth factor (bFGF)
  • Vascular endothelial growth factors (VEGFs)
  • Insulin-like growth factors
  • Matrix metalloprotease 9 (MMP9) 1
• Cytokine microenvironment within hemangiomas, including TRAIL-OPG pathway 1
• Hypoxia-induced vascular responses triggering abnormal vessel growth 1

Risk Factors

Perinatal Factors

• Low birth weight - major risk factor with 25% increased risk for every 500g reduction in birth weight 1
• Prematurity - affecting 22-30% of infants weighing less than 1kg 1
• Multiple gestation pregnancy 1
• Placenta previa 1
• Preeclampsia 1

Maternal Factors

• Advanced maternal age 1
• Use of fertility drugs or erythropoietin 1
• Breech presentation 1
• First-born status 1

Types and Patterns

Localized vs. Diffuse

• Solitary hemangiomas may occur in isolation
• Diffuse neonatal hemangiomatosis involves multiple cutaneous and visceral hemangiomas 2
• Segmental hemangiomas have higher risk of visceral involvement and complications 3

Organ Distribution

• Hepatic involvement is most common in visceral hemangiomatosis (43% of cases) 3, 2
• Other common sites include:
  • Gastrointestinal tract (34%)
  • Brain (34%)
  • Mediastinum (19%)
  • Lung (15%)
  • Less commonly: pancreas, spleen, bones, kidneys 3

Associated Syndromes

PHACE(S) Syndrome

• Posterior fossa brain malformations
• Hemangiomas (typically facial)
• Arterial anomalies
• Cardiac defects and Coarctation of the aorta
• Eye abnormalities
• Sternal clefting/supraumbilical raphe (when included as PHACES) 3
• Approximately 40% of patients with segmental hemangiomas and visceral involvement meet criteria for PHACE(S) syndrome 3

Kasabach-Merritt Syndrome

• Characterized by thrombocytopenia and consumptive coagulopathy associated with hemangiomatous lesions 4, 5
• Can lead to disseminated intravascular coagulation and multiple organ failure 5

Clinical Implications

Morbidity and Mortality

• Diffuse hemangiomatosis can be life-threatening, with 25% mortality reported in infants with segmental hemangiomas and visceral involvement 3
• Most common causes of death include:
  • Gastrointestinal involvement
  • Congestive heart failure secondary to liver involvement 3
  • Multiple organ failure in rapidly progressing cases 5

Diagnostic Considerations

• MRI with and without contrast is the preferred imaging modality for detailed evaluation 6
• Differential diagnosis is crucial as management approaches differ significantly 6

Conclusion

Hemangiomatosis represents a spectrum of vascular anomalies with complex pathophysiology involving genetic predisposition, angiogenic dysregulation, and developmental factors. The condition ranges from benign, self-limiting lesions to life-threatening diffuse disease with visceral involvement. Understanding the causes and risk factors is essential for early identification, appropriate monitoring, and timely intervention in high-risk cases.