What causes an enchondroma?

Causes of Enchondroma

Enchondromas are primarily caused by somatic mutations in IDH1 or IDH2 genes, which occur in approximately 80% of cases and lead to abnormal cartilage growth within the medullary cavity of bones. 1

Genetic and Developmental Factors

Primary Genetic Causes

• Somatic mutations: In 80% of cases, enchondromas arise from postzygotic pathogenic variants in the lesion, causing somatic mosaicism rather than constitutional alterations:
  • IDH1 mutations (most commonly at p.Arg132)
  • IDH2 mutations (most commonly at p.Arg172Ser) 1

Secondary Genetic Associations

• Germline mutations: Less commonly associated with:
  • PTHR1 (Parathyroid hormone related protein receptor) mutations 1, 2
  • Potential involvement of HIF1A, VHL, and other genes related to the hypoxia-inducible factor-1 pathway (requires further validation) 1

Developmental Origin

• Enchondromas originate from growth plate cartilage that proliferates abnormally 3
• The mutant PTHR1 receptor can constitutively activate Hedgehog signaling, which has been shown to cause enchondroma-like lesions in experimental models 2

Clinical Presentation and Distribution

Solitary vs. Multiple Lesions

• Solitary enchondromas: Most common presentation, accounting for 3-10% of all bone tumors and 12-24% of benign bone tumors 3
• Multiple enchondromas (enchondromatosis):
  • Ollier Disease: Multiple enchondromas without vascular lesions
  • Maffucci Syndrome: Multiple enchondromas with benign vascular overgrowths 1, 4

Anatomical Distribution

• Most commonly affect small bones of hands and feet 3, 5
• Less commonly found in long bones (distal femur, proximal humerus) 3
• Can involve the axial skeleton (pelvis and ribs) 1
• In long bones, typically occur in the metaphyseal region 1

Pathophysiology

The development of enchondromas involves disruption of normal chondrocyte regulation:

• Normal growth plates have tightly coupled signaling involving PTHrP and Indian hedgehog (IHH) 2
• PTHrP normally delays hypertrophic differentiation of proliferating chondrocytes 2
• IHH promotes chondrocyte proliferation 2
• Mutations (particularly in IDH1/2) disrupt this balance, leading to:
  • Abnormal proliferation of cartilage cells
  • Failure of normal terminal differentiation
  • Formation of cartilaginous lesions within the medullary cavity 1, 2

Risk Factors for Malignant Transformation

While enchondromas are benign, they can transform into chondrosarcomas:

• Solitary enchondromas: Rarely transform into malignancy 4
• Multiple enchondromas (enchondromatosis):
  • Up to 30% risk of malignant transformation in Ollier Disease and Maffucci Syndrome 1, 4
  • Higher risk in specific locations: femur, tibia, humerus, pelvis, and scapula 1
  • Transformation typically occurs at median age of 30-52 years 1, 4

Clinical Implications

• Pain at the site of a cartilaginous lesion may indicate malignant transformation 1, 4
• Lesions >3cm in size warrant closer monitoring 4
• Malignancy is extremely rare in phalanges of hands and feet 4
• Central cartilaginous lesions in long bones should be considered potentially malignant until proven otherwise 4

Monitoring Recommendations

For patients with enchondromas, especially multiple ones:

• Physical examination every 6-12 months 1, 4
• Plain radiographs of known lesions every 2-3 years 1
• Consider dedicated MRI for lesions >5-6 cm or in high-risk locations (pelvis/scapula) 1
• Whole-body MRI at diagnosis and periodically after age 20 for patients with enchondromatosis 1

Understanding the genetic basis and natural history of enchondromas is crucial for appropriate management and surveillance, particularly for patients with multiple lesions who face a significantly higher risk of malignant transformation.