Melorheostosis: a Rare Sclerosing Bone Dysplasia

Abstract

Since its first description in 1922, about 400 cases of melorheostosis have been reported, either as single reports or in small case series. Melorheostosis affects the appendicular skeleton more commonly than the axial skeleton and usually presents with lower limb deformity. Diagnosis is based on a combination of clinical and radiological features that help differentiate this condition from other sclerosing bone dysplasias. LEM domain-containing protein 3 (LEMD3) gene mutations have been demonstrated in several familial cases, but these have been more strongly correlated with other hereditary dysplasias, such as osteopoikilosis, and are not thought to be the causative gene for melorheostosis. The exact etiology of classic sporadically occurring melorheostosis remains unknown, with possible causes being somatic LEMD3 mutations, somatic mutations in the bone morphogenetic protein/transforming growth factor-beta pathway, mutations in multiple genes, or other non-genetic causes. Management in recent years has involved nitrogen-containing bisphosphonates in addition to traditional orthopedic surgical approaches and physical therapy. Melorheostosis may present as mixed or atypical osseous involvement in addition to the classically described "dripping candle wax" appearance of hyperostosis. Some patients may have overlap with osteopoikilosis or Buschke-Ollendorff syndrome. In the future, better characterization of genetic and developmental factors predisposing to melorheostosis may lead to the development of targeted therapy for this condition, as well as for more commonly encountered skeletal abnormalities.

Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction

“…Of note, pre‐osteoblasts and osteocytes both produce RANKL, the key protein of osteoclastogenesis; an increased ratio of RANKL/OPG transcripts was previously demonstrated in osteoblast cultures from affected bone . Taken together, our bone tissue and cell culture evaluations show very consistently that activating mutations in MAP2K1 lead to metabolically overactive bone, in terms of increased turnover and remodeling, in line with increased tracer uptake on bone scintigraphy …”

“…Melorheostosis is a rare non‐inherited dysostosis that is often described in the literature as a “sclerosing” bone dysplasia . Radiographs of melorheostosis show dense, overgrown, and expansive cortical bone.…”

“…Melorheostosis (OMIM %155950) is an extremely rare sporadic sclerotic bone dysostosis with an estimated prevalence of 1 case per million . First described in 1922 by Léri and Joanny, the disease is characterized by dense hyperostotic lesions with radiographic appearance of “dripping candle wax” affecting mostly the long bones of the lower and upper extremities and less frequently the axial or craniofacial skeleton . Melorheostosis typically manifests during childhood or adolescence and patients present first with symptoms of pain and joint stiffness, swelling, and deformity of the limb .…”

“…Therapeutic management is limited to symptomatic management of skeletal pain because there is no cure . A few reports of clinical improvement after zoledronate treatment suggest that increased osteoclastic resorption and/or angiogenesis might be involved in the pathogenesis of the disease . Beyond this, the etiology of the exuberant melorheostotic bone overgrowth is yet to be elucidated.…”

“…However, a phenotype of highly remodeled osteonal‐like bone with high osteoid formation does not per se explain the classic radiological presentation of melorheostosis of cortical hyperostosis . To obtain further insights into growth and development of the melorheostotic lesions, we now performed a multi‐method phenotype characterization of bone tissue properties by comparing affected and unaffected bone biopsy samples from six patients with confirmed MAP2K1 somatic activating mutations.…”