CT analysis of anatomical distribution of melorheostosis challenges the sclerotome hypothesis

Melorheostosis (MEL) is a rare disease of high bone mass with patchy skeletal distribution affecting the long bones. We recently reported somatic mosaic mutations in MAP2K1 in 8 of 15 patients with the disease. The unique anatomic distribution of melorheostosis is of great interest. The disease remains limited to medial or lateral side of the extremity with proximo-distal progression. This pattern of distribution has historically been attributed to sclerotomes (area of bone which is innervated by a single spinal nerve level). In a further analysis of our study on MEL, 30 recruited patients underwent whole body CT scans to characterize the anatomic distribution of the disease. Two radiologists independently reviewed these scans and compared it to the proposed map of sclerotomes. We found that the disease distribution conformed to the distribution of a single sclerotome in only 5 patients (17%). In another 12 patients, the lesions spanned parts of contiguous sclerotomes but did not involve the entire extent of the sclerotomes. Our findings raise concerns about the sclerotomal hypothesis being the definitive explanation for the pattern of anatomic distribution in MEL. We believe that the disease distribution can be explained by clonal proliferation of a mutated skeletal progenitor cell along the limb axis. Studies in mice models on clonal proliferation in limb buds mimic the patterns seen in melorheostosis. We also support this hypothesis by the dorso-ventral confinement of melorheostotic lesion in a patient with low allele frequency of MAP2K1-positive osteoblasts and low skeletal burden of the disease. This suggests that the mutation occurred after the formation of dorso-ventral plane. Further studies on limb development are needed to better understand the etiology, pathophysiology and pattern of disease distribution in all patients with MEL.