Presentation: Clinical suspicion of hereditary multiple exostoses

An 11-year-old boy presents with a six-month history of unilateral elbow pain and reduced range of movement, without history of trauma. On examination, he has reduced flexion and extension at the elbow and difficulty pronating. The painful arm seems relatively shorter than the contralateral arm. Radiographs show a bony growth near the joint and another over the distal forearm.

You should consider genomic testing if your patient has features suggestive of hereditary multiple exostoses (HME) and a molecular diagnosis will contribute to clinical management or advice. Features of HME are listed below.

• Clinical features:
  • multiple exostoses (bony growths);
  • pain;
  • long bone deformity;
  • restricted joint movement;
  • growth discrepancy between bones;
  • short stature; and
  • brachydactyly.
• Radiological features:
  • sessile (broad base) or pedunculated (narrow stalk) bony growths or lesions found on the surface of bones;
  • evidence of bowing and relative shortening of long bones; and
  • subluxation or dislocation at affected joints (elbow, knee, ankle).
• A family history of similar features is often present.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provide information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• If you suspect HME in a family, the correct test to order is:
  • R390 Multiple exostoses: This includes a small panel and multiplex ligation-dependent probe amplification (MLPA).
• If you suspect the patient has HME plus additional features that suggest a contiguous gene deletion (such as intellectual disability and/or craniofacial or digital anomalies), consider requesting in addition:
  • R377 Intellectual disability (microarray only).
• If you feel there are other likely diagnoses for the presentation, you may wish to consider the following tests:
  • R104 Skeletal dysplasia: This should be considered if clinical features are indicative of a likely monogenic skeletal dysplasia. See Child with suspected skeletal dysplasia and When to suspect a skeletal dysplasia as a cause of short stature.
  • R28 Congenital malformation and dysmorphism syndromes (microarray only) or R27 Paediatric disorders: These should be considered if your patient has short stature and congenital malformations and/or dysmorphism suggestive of an underlying monogenic disorder, and targeted genomic testing is not possible.
• If a family member already has a known HME-related gene causative variant, cascade testing can be carried out to identify other affected individuals. Testing relatives when the molecular basis is confirmed in the family may not be needed unless there is a clear rationale for doing so (for example, the clinical diagnosis in the relative is in doubt, or testing the relative will lead to a clear benefit in management, like eligibility for a clinical trial). In this situation, the laboratory will test for the known familial variant only. First-degree relatives may be eligible for genomic counselling, at which point subsequent testing (R240 Diagnostic testing for known mutation(s)) can be arranged.
• R104 and R27 are large whole genome sequencing (WGS) ‘super panels’ (panels comprised of several different constituent panels forming one large panel), and requesting them currently requires authorisation from clinical genetics. As they are undertaken using WGS, you will need to:
  • complete an NHS GMS test order form with details of the affected child (proband) and their parents, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for whole genome sequencing for support in completing WGS-specific forms);
  • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
  • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• For tests that do not include WGS, including R390 and R28:
  • you can use your local Genomic Laboratory Hub test order and consent (RoD) forms; and
  • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• All the above tests are DNA based, so an EDTA sample (purple topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (green-topped tube).
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• GeneReviews: Hereditary multiple osteochondromas
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Organization for Rare Disorders: Hereditary multiple osteochondromas
• NHS England: National Genomic Test Directory
• Skeletal Dysplasia Group
• Skeletal Dysplasia Management Consortium: Publications

For patients

• MHE Coalition