Review Question - QID 219624

This 14-year-old male exhibits the classic appearance of Multiple Hereditary Exostosis (MHE) on leg-length films. Due to his history of malignant transformation, osteochondromas within the axial skeleton, and limb malalignment, a mutation of the EXT1 gene is most likely responsible for his presentation (Answer 1).

MHE is an autosomal dominant disorder characterized by multiple osteochondromas localized to the metaphyseal region of long bones, though these lesions can also be found in the axial skeleton. The genetic anomaly associated with MHE involves the EXT1 (most common), EXT2, or EXT3 genes, all of which have a prominent role in bone and cartilage formation. The mutation renders glycosyltransferases responsible for heparan sulfate synthesis at the growth plate dysfunctional. The EXT1 gene in particular has been found to portend a more severe presentation of the condition, which manifests as increased numbers of osteochondromas and in particular axial osteochondromas, ultimately bestowing a higher risk for malignant transformation to chondrosarcoma (typically low-grade). Moreover, patients have higher rates of limited mobility secondary to tissue impingement around their osteochondromas, while also exhibiting more severe degrees of limb malalignment.

Pacifici provides a review of MHE, with a particular emphasis on providing a cytogenetic analysis and how recent findings impact treatment advancements for the condition. The author highlights the EXT1 gene as the integral gene for heparin sulfate synthesis, which is why those with the mutation demonstrate a more severe expression of the condition. Ultimately, the author notes a significant degree of unknown remains concerning the pathogenesis of the condition, making the development of novel, nonsurgical therapies challenging.

Tepelenis et al. review the updated literature on MHE concerning the epidemiology, pathogenesis, clinical presentation, malignant transformation, and treatment options. They note approximately 65% of those with MHE possess EXT1 gene mutations, and 21% have EXT2 mutations. The authors also note an overall 10% rate of malignant transformation and stress paying attention to the cartilage cap thickness, with greater than 3 centimeters in children or 2 centimeters in adults suggesting malignancy. The authors conclude by recommending nonoperative treatment as the mainstay of management unless the osteochondroma is symptomatic or concerns for malignancy exist.

Mnif et al. report on an 11-year-old boy with a fibular head osteochondroma that caused a peroneal nerve palsy. The patient ultimately underwent osteochondroma resection with decompression of the nerve, which led to complete recovery. The authors recommend not delaying surgery on patients with a neurological deficit and an identifiable cause (in this case, osteochondroma).

Figure A is an AP leg-length film of an MHE patient with multiple osteochondromas throughout the pelvis and bilateral lower extremities.

Incorrect Answers:
Answers 2 & 3: while mutations in these genes do cause MHE, these patients do not exhibit as severe of a presentation as would those with mutations of the EXT1 gene.
Answers 4 & 5: these answers represent mutations in neurofibromatosis, which results in widespread neurofibromas, cafe-au-lait spots, and scoliosis, among others.