HEREDITARY EXOSTOSES

Hereditary Multiple Exostoses — affecting 1 in 50,000, EXT1 and EXT2 mutations cause benign osteochondromas with 2-5% risk of malignant transformation to chondrosarcoma requiring lifelong orthopedic surveillance.

Whole genome sequencing evaluates EXT1 and EXT2 — including large deletions, structural variants, and splice mutations — providing the molecular diagnosis for genotype-phenotype correlation and surveillance planning.

EXT1
EXT2

About this condition

Hereditary Exostoses — EXT1/EXT2

Hereditary multiple exostoses (HME, also MHE — multiple hereditary exostoses) is an autosomal dominant skeletal disorder caused by pathogenic variants in EXT1 (chromosome 8q24.11) or EXT2 (chromosome 11p11.2). These genes encode exostosin glycosyltransferases critical for heparan sulfate proteoglycan biosynthesis. HME causes multiple osteochondromas (cartilage-capped bony growths) predominantly affecting the metaphyses of long bones.

EXT1 mutations cause more severe disease than EXT2: more exostoses, greater deformity risk, and higher chondrosarcoma transformation risk. Overall lifetime chondrosarcoma risk is approximately 2-5%, primarily affecting the pelvis, scapula, and proximal femur. New growth, pain, or enlargement of an exostosis after skeletal maturity should prompt urgent imaging to rule out malignant transformation.

HME complications include: limb length discrepancy (up to 40% of patients), angular limb deformities, restricted joint motion, nerve compression (particularly peroneal nerve), and cosmetic concerns. Surgical excision is indicated for painful, compressive, or cosmetically unacceptable lesions. Lifelong orthopedic follow-up is required for chondrosarcoma surveillance — plain radiographs and clinical monitoring, with MRI for suspicious lesions.

Any growth, pain, or change in an exostosis AFTER skeletal maturity is a red flag for chondrosarcoma. Immediate imaging is required. This is why lifelong orthopedic monitoring is non-negotiable for HME patients.

Gene locus: EXT1 (8q24.11), EXT2 (11p11.2)

EXT1 vs EXT2 genotype predicts disease severity and chondrosarcoma risk. WGS detects all variant types including large deletions that standard sequencing may miss.

EXT1 mutations cause more severe disease with higher chondrosarcoma risk — genotype guides surveillance intensity

EXT1-associated HME has more exostoses, greater deformity, and higher malignant transformation risk compared to EXT2. Genotype-informed surveillance adjusts imaging frequency and triggers earlier orthopedic intervention for EXT1 patients.

Large EXT1/EXT2 deletions account for 10-15% of pathogenic variants — WGS captures what sequencing-only approaches miss

Approximately 10-15% of HME pathogenic variants are large deletions or exon-level rearrangements in EXT1 or EXT2. Standard coding-sequence panels may miss these without MLPA supplementation. WGS captures all variant types from a single test.

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