Hereditary multiple exostoses

Hereditary multiple exostoses (HME), also known as hereditary multiple osteochondromas, is a rare bone condition characterised by multiple bony growths or osteochondromas (benign cartilage-capped bone tumours that grow outward from the metaphysis of long bones).

Clinical features of HME are variable. They include:

• multiple exostoses (osteochondromas);
• possible reduction in skeletal growth;
• pain;
• restricted joint movement;
• short stature; and
• bony deformity.

Radiographic features include:

• sessile (broad-based) or pedunculated (narrow-stalk) bony growths found on the surface of bones;
• evidence of bowing and relative shortening of long bones;
• subluxation or dislocation at affected joints (elbow, knee, ankle);
• limb length discrepancy;
• osteochondromas that are often highly irregular and can become extremely large; and
• broad hands and feet with brachydactyly (short digits).

Confirming a diagnosis of HME as opposed to other conditions causing bony overgrowths is important, as rates of malignant degeneration vary.

Medical complications may occur due to the presence of moderate to large osteochondromas. They include neurovascular compression, impingement of tendons and muscles, premature osteoarthritis, scapular winging, spinal cord compression and obstetric problems.

HME is caused by a pathogenic variant in one copy of the EXT1 or EXT2 gene.

For EXT1, found on chromosome locus 8q24.11, only a few pathogenic variants have been identified and there are several relative ‘hotspots’ for variants. For EXT2, found on chromosome locus 11p11.2, pathogenic variants are mainly located in the first eight exons and are primarily loss-of-function variants.

Sequence variants account for most cases of HME, though small deletions or duplications (of a small stretch of genetic code, for example, or copy number variants) within the gene are sometimes causative. In rare circumstances, a contiguous gene deletion syndrome (CGDS), in which several genes including EXT1 or EXT2 have been deleted, may be the underlying cause.

If the patient has intellectual disability as well as bony growths, consider undertaking a microarray looking for a CGDS. If the patient has bony overgrowths, intellectual disability, a large nose, short phalanges and/or hair anomalies, consider Langer-Giedion syndrome, a CGDS arising from deletions in the q arm of chromosome 8 that combines HME (due to an EXT1 deletion) and trichorhinophalangeal syndrome (due to a TRPS1 deletion). If the patient has bony overgrowths, intellectual disability, bilateral enlarged parietal foramina and/or other craniofacial-digital anomalies, consider Pottocki-Shaffer syndrome, a CGDS arising from deletions in the p arm of chromosome 11 that includes deletion of the EXT2 and PHF21A genes. In both the CGDS above, other genes might also be affected depending on the size of the deletion, resulting in a variable phenotype.

Targeted testing for HME is available within the National Genomic Test Directory and can also be performed as part of a broader test for skeletal dysplasias. For further information about testing, see Presentation: Clinical suspicion of hereditary multiple exostoses and Presentation: Child with suspected skeletal dysplasia.

HME is an autosomal dominant condition; however, around 10% of cases occur as a result of a de novo pathogenic variant. If a parent has HME, there is a 50% chance of another child being affected. If the parents do not have the EXT1 or EXT2 pathogenic variant detectable from a blood sample,  there would be an estimated recurrence risk for future children of 1% (due to the possibility of mosaicism in the parents).

Management of children with HME is complex and should be delivered via a multidisciplinary team, including orthopaedics, with monitoring of symptoms, musculoskeletal features, neurology and development. Monitoring of exostoses may help in early identification of malignant change.

For clinicians

• GeneReviews: Hereditary multiple osteochromas
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• Skeletal Dysplasia Group (promotes teaching and research)
• Skeletal Dysplasia Management Consortium: Best practice guidelines
• US National Library of Medicine: ClinicalTrials.gov database

For patients

• MHE Coalition