Multiple Hereditary Exostoses

Multiple hereditary exostoses (hereditary multiple osteochondromas) is an autosomal dominant skeletal disorder in which many osteochondromas form on the metaphyses of long bones and on flat bones, with growth disturbance and deformity. It affects about 1 in 50 000 people, with penetrance of 95 to 96%, and has a similar rate in males and females (with slightly milder disease in females).

Pathogenic variants of EXT1 (about 65%, 8q24) or EXT2 (about 30%, 11p11) are found, and the rest have no identified variant. Lesions appear before age 5 in most children, and grow with the skeleton until the physes close. By adulthood, the average patient has 15 to 20 lesions. The knee, ankle, proximal humerus, forearm, hip and scapula are common sites.

Complications:

• Forearm deformity (bowing of the radius, ulnar shortening, radial head dislocation; classified by Masada).
• Genu valgum, ankle valgus, coxa valga, short stature, limited joint motion, scapular winging.
• Nerve and vascular compression, pseudoaneurysm, bursitis, spinal canal encroachment.
• Malignant transformation to peripheral chondrosarcoma in about 1 to 5% of patients (EXT1 variants are associated with more lesions and more severe disease).

Pathophysiology.

EXT1 and EXT2 encode a heparan sulphate polymerase. Loss of both alleles in a growth plate chondrocyte (a heterozygous germline variant followed by a somatic second hit) disrupts heparan sulphate chains and changes Indian hedgehog and fibroblast growth factor signalling. A clone of cells is displaced through the perichondrial ring, so that it grows as a cartilage capped exostosis. Disturbed physeal growth explains shortening and angulation.

Hard, painless lumps near the joints, found in early childhood. Features are short stature (under the third centile in about 40%), asymmetric limb length, forearm deformity, knock knees, ankle valgus, reduced elbow supination, and joint stiffness. Pain comes from mechanical irritation, bursitis, nerve compression (peroneal nerve, ulnar nerve), or vascular compression; pain with growth of a lesion in an adult suggests malignant change.

Examine all long bones, scapulae, ribs and pelvis, limb length, alignment, forearm rotation, joint range and neurovascular state. Take a family history, since a parent is affected in most cases (about 10% are new variants).

• Radiographs: multiple sessile or pedunculated bony outgrowths with cortical and medullary continuity with the parent bone, metaphyseal widening (Erlenmeyer flask deformity), and shortened bones. Films of the knees, ankles, forearms and hips at diagnosis.
• MRI (whole body or of symptomatic lesions) shows cartilage cap thickness, bursae and nerve or vessel relationship. A cap over 1.5 cm in an adult (over 3 cm in a child), growth after maturity, or a soft tissue mass suggests chondrosarcoma.
• CT for pelvic, scapular and spinal lesions; CT angiography or ultrasound for vascular compression.
• Genetic testing of EXT1 and EXT2 confirms the diagnosis, and allows genetic counselling and family testing.

Differential diagnosis.

• Solitary osteochondroma and metachondromatosis.
• Ollier disease and Trevor disease.
• Fibrous dysplasia and multiple enchondromas.
• Parosteal osteosarcoma and peripheral chondrosarcoma.

There is no drug treatment that reduces exostoses. Management is surveillance and surgery for symptoms and deformity, in a specialist centre.

Surveillance. Yearly clinical and growth review in childhood (height, limb length, alignment, forearm rotation). In adults, review yearly and whenever a lesion grows, becomes painful, or has a cartilage cap thicker than 1.5 cm. Whole body MRI at diagnosis and when symptoms change.

Surgery.

• Excision of symptomatic exostoses (pain, nerve or vascular compression, restricted joint motion, fracture, cosmesis), at the base including the cap and perichondrium. Recurrence is about 5 to 10% in children if the physis is open, and lower after maturity. Delay until near maturity when possible.
• Forearm: excision of exostoses, ulnar lengthening, radial osteotomy, ulnar hemiepiphysiodesis, or radial head reduction for progressive bowing and dislocation, usually before the end of growth.
• Lower limb: hemiepiphysiodesis with a plate (growth modulation) at the knee or ankle for valgus, osteotomy after maturity, and lengthening for limb length difference.
• Suspected chondrosarcoma: staging and wide excision by a sarcoma team; reconstruction is planned for the growing limb.

Operative antibiotic prophylaxis. Cefazolin 2 g intravenously (3 g when weight is 120 kg or over; 30 mg/kg to a maximum of 2 g in children) within 60 minutes before incision as a single dose (repeat after 4 hours or blood loss over 1500 mL). With severe penicillin allergy, vancomycin 15 mg/kg intravenously starting 90 to 120 minutes before incision as a single dose, with levels and creatinine checked in prolonged cases.

Analgesia.

• Paracetamol 1 g orally every 6 hours as needed for up to 5 to 7 days (maximum 4 g daily; 3 g daily when weight is under 50 kg, with chronic alcohol use or hepatic impairment).
• Ibuprofen 400 mg orally every 8 hours with food for up to 5 days (maximum 1200 mg daily); avoid with eGFR under 30 mL/min/1.73 m2, peptic ulcer, heart failure or anticoagulant use.
• Children: paracetamol 15 mg/kg orally every 4 to 6 hours (maximum 75 mg/kg daily and not exceeding 4 g daily).
• Children: ibuprofen 10 mg/kg orally every 6 to 8 hours with food (maximum 40 mg/kg daily and not exceeding 2400 mg daily); both drugs for up to 5 days.

Monitoring. Wound and neurovascular check after surgery, and review at 2 weeks, 3 months and 12 months. Radiographs after growth modulation every 3 to 6 months until the angle is corrected, to avoid overcorrection. Height, limb length and function yearly. Surveillance for malignant change for life.

Referral and escalation. Refer every child with multiple exostoses to paediatric orthopaedics and clinical genetics. Urgent referral for rapid growth, new pain in an adult, a thick cartilage cap, soft tissue mass, or nerve or vascular compromise.

Special groups.

• Children: protect the physis; plan deformity correction at the best age.
• Adults: higher risk of malignant change at the pelvis, scapula and spine; investigate pain early.
• Families: genetic counselling (50% risk to each child), and prenatal or preimplantation testing where wanted.
• Pregnancy: avoid NSAIDs in the third trimester; pelvic exostoses may obstruct delivery and need obstetric review.