Multiple Hereditary Exostoses

Multiple Hereditary Exostoses (MHE) is characterized by multiple osteochondromas.

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• Genetics: Autosomal dominant. EXT1 or EXT2 mutations (tumor suppressor genes).
• Incidence: 1 in 50,000.
• Pathophysiology: Loss of EXT function leads to abnormal cartilage growth at physes → osteochondromas.
• EXT1 vs EXT2: EXT1 mutations (chromosome 8) typically cause more severe phenotype than EXT2 (chromosome 11).
• Natural History: Lesions grow until skeletal maturity, then stop. Malignancy risk persists lifelong.

Osteochondroma Structure

• Cartilage-capped bony outgrowth arising from the metaphysis.
• Continuous with host bone cortex and medulla.
• Grows away from the adjacent joint (important for diagnosis).
• Cartilage cap: Normally less than 1cm in adults, greater than 2cm concerning for malignancy.

Why Deformity Occurs

• Osteochondromas at the distal ulna → ulnar shortening → radial bowing.
• Tethering effect on growth plate.
• Similar mechanism at ankle (fibular lesions) → ankle valgus.

Common Sites

• Distal femur (most common).
• Proximal tibia.
• Proximal humerus.
• Distal ulna/radius (causes forearm deformity).

The topic states that EXT1/EXT2 are "tumour-suppressor genes" encoding "heparan sulphate glycosyltransferases" and that loss of EXT function causes "abnormal cartilage growth at physes" — but the mechanism that links the gene to the lesion is worth developing, because it is the classic basic-science question for this condition.

From gene to signalling. EXT1 and EXT2 form a complex of glycosyltransferases that synthesise and elongate heparan-sulphate (HS) chains on heparan-sulphate proteoglycans. HS proteoglycans act as a scaffold that shapes the gradient and signalling of growth-plate morphogens — most importantly Indian Hedgehog (Ihh) (and also FGFs, BMPs and Wnts). In the normal physis, the Ihh/PTHrP negative-feedback loop sets the pace of chondrocyte proliferation and keeps proliferating chondrocytes in orderly longitudinal columns.

From signalling to osteochondroma. Defective HS disrupts this Ihh signalling, so chondrocytes at the periphery of the growth plate lose their normal polarity and proliferate laterally, escaping the perichondrial groove of Ranvier to form a cartilage-capped outgrowth. That osteochondroma then grows by endochondral ossification from its own cartilage cap and — because it is driven by the physis — ceases at physeal closure, exactly the natural history described above.

The tumour-suppressor (second-hit) angle. As EXT1/EXT2 are tumour suppressors, osteochondromas behave as clonal lesions arising after a somatic "second hit" (loss of the remaining wild-type EXT allele) in a cartilage-cap cell; progression to secondary peripheral chondrosarcoma involves further genetic change in that clone — the molecular basis of the lifelong transformation risk. (The general biochemistry of heparan-sulphate proteoglycans is developed in the proteoglycans-collagen topic, and the Ihh/PTHrP loop in the physis-growth-plate-anatomy topic.)

Multiple Cartilaginous Lesions:

Key Distinguishing Points:

• MHE: Metaphyseal, cortex continuous with host bone.
• Enchondromas (Ollier): Medullary, radiolucent with stippled calcifications.
• DEH (Trevor Disease): Single limb, epiphyseal involvement.
• Malignancy risk: MHE 1-5%, Ollier 25-30%, Maffucci 25-30%.

The surgical sections develop the forearm in detail, but MHE causes major lower-limb deformities that the management above does not address — and these are high-yield. They arise from osteochondromas tethering or asymmetrically loading the peri-articular physes.

The general technique of guided growth, genu valgum correction and leg-length-discrepancy management is developed in the guided-growth-angular-deformity-correction, genu-valgum-varum and limb-length-discrepancy-epiphysiodesis topics.

• Simple Excision: Early mobilization, wound care.
• Forearm Reconstruction: Splinting, protected ROM.
• Lengthening: Fixator care, daily adjustments.
• All Patients: Continue surveillance for other lesions.

• Most lesions remain benign.
• Malignant transformation: 1-5%.
• Significant deformity may limit function.

Global epidemiology

• Prevalence approximately 1 in 50,000 worldwide, with a male predominance (~1.5:1) and near-complete penetrance (~96%); roughly 10% of cases arise de novo without a family history.
• Mean number of osteochondromas per patient is 15-18; lesions appear and enlarge in the first decade and cease at physeal closure.

Consensus and society guidance (side by side)

Registry and network evidence

• No dedicated arthroplasty-style registry exists; long-term data derive from population databases (e.g. Schmale's Washington kindreds), tertiary bone-tumour registries and rare-disease networks (Orphanet, EuroBoNeT/European sarcoma networks).

High- vs limited-resource practice

• Well-resourced settings: MRI surveillance, genetic testing, guided growth (8-plates), staged forearm reconstruction and limb salvage for transformation.
• Limited-resource settings: diagnosis is clinical/radiographic; emphasis on educating patients about warning signs (new pain, growth after maturity, enlarging cartilage cap) and timely referral when malignancy is suspected, since chondrosarcoma is chemo- and radio-resistant and depends on adequate surgical margins.

• Routine surveillance imaging: No consensus on whether asymptomatic adults need scheduled whole-body MRI/screening. Some advocate baseline imaging of axial/proximal lesions (pelvis, shoulder) that are hard to monitor clinically; others rely on symptom-driven imaging and patient education. Porter's data suggest EXT1 carriers may justify more proactive screening.
• Timing of forearm reconstruction: Whether early excision and ulnar lengthening prevent radial head dislocation, versus observation until deformity declares itself, remains debated; high-quality comparative evidence is limited.
• True malignant transformation rate: Quoted figures range from 0.5% to 5%; older series likely overestimated risk through referral bias, while genotype (EXT1) and lesion location modify individual risk.
• Guided growth vs osteotomy: Optimal first-line correction of knee/ankle valgus (hemiepiphysiodesis versus corrective osteotomy) depends on remaining growth and deformity magnitude, without firm thresholds.
• Emerging medical therapy: Heparan-sulphate pathway and palovarotene-type signalling research is experimental; no disease-modifying drug is established in practice.