Clinical characteristics of 10 Chinese patients with melorheostosis and identification of a somatic MAP2K1 variant in one case.

BACKGROUND: Melorheostosis (MEL) is an exceptionally rare sclerosing bone dysplasia with asymmetrically exuberant bone formation and soft tissue lesions in a segmental distribution. We aimed to summarize the clinical characteristics of Chinese MEL patients and identify their pathogenic cause. METHODS: In total, 10 Chinese MEL patients were recruited, and clinical manifestations and radiological characteristics were recorded. Sanger sequencing of the LEMD3 gene was performed on peripheral blood samples of all patients, while the exome sequencing of matched peripheral blood, melorheostotic bone, and skin lesion samples was conducted on one patient who provided affected bone and skin tissues. Micro-computed tomography (micro-CT) was also used to scan the melorheostotic bone tissue. RESULTS: We found the average age of the 10 MEL patients was 29.5 years (range 11-40 years), and the major symptoms were bone pain, restricted movement, and bone deformity. The lesions sites were mainly located in femur (8/10), tibia (8/10), fibula (6/10), and foot (7/10), the next was pelvis (4/10), and the last were patella (1/10), hand (1/10) and spine (1/10). Radiological examinations showed a mixture of hyperostosis consisting of classic "dripping candle wax," "osteoma-like," or "myositis ossificans-like" patterns in most patients. No germline pathogenic variants in the LEMD3 gene were found in all patients, but a disease-causing somatic variant of MAP2K1 (c.167A > C, p.Gln56Pro) was detected in melorheostotic bone from one patient. Moreover, the micro-CT analysis showed increased porosity in the melorheostotic bone with somatic MAP2K1 variant. CONCLUSION: This is a summary of the clinical characteristics of Chinese MEL patients and we first identify the somatic MAP2K1 variant in Chinese patients. Our findings validate the molecular genetic mechanism of MEL and broaden its phenotype spectrum in the Chinese population.

Osteoblast Dysfunction in Non-Hereditary Sclerosing Bone Diseases.

A review of the available literature was performed in order to summarize the existing evidence between osteoblast dysfunction and clinical features in non-hereditary sclerosing bone diseases. It has been known that proliferation and migration of osteoblasts are concerted by soluble factors such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), bone morphogenetic protein (BMP) but also by signal transduction cascades such as Wnt signaling pathway. Protein kinases play also a leading role in triggering the activation of osteoblasts in this group of diseases. Post-zygotic changes in mitogen-activated protein kinase (MAPK) have been shown to be associated with sporadic cases of Melorheostosis. Serum levels of FGF and PDGF have been shown to be increased in myelofibrosis, although studies focusing on Sphingosine-1-phosphate receptor was shown to be strongly expressed in Paget disease of the bone, which may partially explain the osteoblastic hyperactivity during this condition. Pathophysiological mechanisms of osteoblasts in osteoblastic metastases have been studied much more thoroughly than in rare sclerosing syndromes: striking cellular mechanisms such as osteomimicry or complex intercellular signaling alterations have been described. Further research is needed to describe pathological mechanisms by which rare sclerosing non hereditary diseases lead to osteoblast dysfunction.

Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-ß/SMAD pathway.

Melorheostosis is a rare sclerosing dysostosis characterized by asymmetric exuberant bone formation. Recently, we reported that somatic mosaicism for MAP2K1-activating mutations causes radiographical "dripping candle wax" melorheostosis. We now report somatic SMAD3 mutations in bone lesions of four unrelated patients with endosteal pattern melorheostosis. In vitro, the SMAD3 mutations stimulated the TGF-ß pathway in osteoblasts, enhanced nuclear translocation and target gene expression, and inhibited proliferation. Osteoblast differentiation and mineralization were stimulated by the SMAD3 mutation, consistent with higher mineralization in affected than in unaffected bone, but differing from MAP2K1 mutation-positive melorheostosis. Conversely, osteoblast differentiation and mineralization were inhibited when osteogenesis of affected osteoblasts was driven in the presence of BMP2. Transcriptome profiling displayed that TGF-ß pathway activation and ossification-related processes were significantly influenced by the SMAD3 mutation. Co-expression clustering illuminated melorheostosis pathophysiology, including alterations in ECM organization, cell growth, and interferon signaling. These data reveal antagonism of TGF-ß/SMAD3 activation by BMP signaling in SMAD3 mutation-positive endosteal melorheostosis, which may guide future therapies.

Bone Features of Unaffected Skeletal Sites in Melorheostosis: A Case Report.

BACKGROUND: Melorheostosis is a rare sporadic sclerosing bone dysplasia, which commonly affects appendicular skeleton with bone hyperostosis and soft tissues sclerosis; fragility fractures are rare in melorheostotic patients. We investigated bone features at unaffected sites in a postmenopausal woman with melorheostosis of the right lower limb and with a fracture of the melorheostosis-free T11 vertebral. METHODOLOGY: Melorheostotic lesions were evaluated by plain radiography, magnetic resonance of the right lower limb, and whole-body bone scintigraphy. Dual X-ray absorptiometry, trabecular bone score, and quantitative computed tomography were performed to investigate unaffected bone sites. Biochemical assessment of bone metabolism was obtained. RESULTS: Dual X-ray absorptiometry was indicative of normal mineralization at femoral sites and osteopenia at lumbar spine (T-score -1.1), which was confirmed by spinal quantitative computed tomography (volumetric bone mineral density 89 mg/cm3). Trabecular bone score suggested only mildly altered bone microarchitecture (1.304, normal values >1.350). Bone markers were consistent with high bone turnover. Causes of secondary osteoporosis or alterations in bone metabolism were excluded. Zoledronic acid induced a reduction in bone turnover markers after 6 months without significant changes in clinical features. CONCLUSIONS: Fragility fractures at apparently unaffected sites may occur in adults with melorheostosis, in absence of significant demineralization diagnosed by dual X-ray absorptiometry, trabecular bone score, and quantitative computed tomography, which may underestimate the fracture risk in this set of patients. Treatment with zoledronate could be considered also to prevent fragility fractures.

Melorheostosis: A Clinical, Pathologic, and Radiologic Case Series.

Melorheostosis is a rare sclerosing bone disease characterized by excessive cortical bone deposition that is frequently on the differential diagnosis for bone biopsies. Although the radiologic pattern of "dripping candle wax" is well known, the pathologic findings have been poorly defined. Here, we comprehensively describe the histology of melorheostosis in 15 patients who underwent bone biopsies. Common histologic findings included: dense cortical bone (73.3%), woven bone (60%), and hypervascular features and increased porosity (66.7%). One third of the patients (5/15) also had prominent cement lines. Multiple patients had >1 histologic pattern (ie, dense cortical bone and hypervascularity). Overall, this study suggests that melorheostosis exists with several histologically distinct patterns. When confronted with a case of suspected melorheostosis, the clinical pathologist should use the histologic features common to melorheostotic lesions presented here in conjunction with the patient's clinical presentation and radiographic findings to arrive at a diagnosis. An illustrative case is presented.

Melorheostosis with an associated para-articular enhancing soft tissue mass.

Melorheostosis is a rare non-hereditary sclerosing bone dysplasia which predominantly affects the appendicular skeleton. Although melorheostosis is typically recognized as an osseous lesion, associated soft-tissue components have been reported. Advanced imaging with MRI may allow for more complete evaluation of these soft tissue components; however, there is little information regarding their MRI characteristics which may lead to confusion with malignant processes. We present a case of melorheostosis in a 32-year-old woman with an associated paraarticular enhancing soft tissue mass and emphasize discriminating this from soft tissue sarcoma.

Osteoma-like melorheostosis: a rare type of skeletal dysplasia depicted on FDG PET/CT.

Melorheostosis, also known as Leri's disease, is a rare benign form of mesodermal mixed sclerosing bone dysplasia. We report the unusual case of a 14-year-old boy with melorheostosis in the lower extremity that went undiagnosed due to concurrent Ewing sarcoma in the opposite limb, confounding the findings for metastatic disease. The diagnosis was made on FDG PET/CT when the patient presented for post Ewing sarcoma treatment follow-up. The different types of melorheostosis as well as the challenge of diagnosing this rare entity are discussed in this report.

Distinct Clinical and Pathological Features of Melorheostosis Associated With Somatic MAP2K1 Mutations.

Melorheostosis is a rare hyperostotic disease of the long bones classically characterized by a "dripping candle-wax" radiographic appearance. We recently described somatic activating mutations in MAP2K1 as a cause of melorheostosis. Here, we report distinguishing characteristics of patients with MAP2K1-positive melorheostosis. Fifteen unrelated patients with radiographic appearance of melorheostosis underwent paired biopsies of affected and unaffected bone for whole-exome sequencing, histology, and cell culture. Eight patients with mutations in MAP2K1 in affected bone were compared to the seven MAP2K1-negative patients to identify distinguishing characteristics. Patients with MAP2K1-positive melorheostosis had a distinct phenotype with classic "dripping candle-wax" appearance on radiographs (p = 0.01), characteristic vascular lesions on skin overlying affected bone (p = 0.01), and higher prevalence of extraosseous mineralization and joint involvement (p = 0.04 for both). Melorheostotic bone from both MAP2K1-positive and MAP2K1-negative patients showed two zones of distinct morphology-an outer segment of parallel layers of primary lamellar bone and a deeper zone of intensely remodeled highly porous osteonal-like bone. Affected bone from MAP2K1-positive patients showed excessive osteoid (p = 0.0012), increased number of osteoblasts (p = 0.012) and osteoclasts (p = 0.04), and increased vascularity on histology in comparison to paired unaffected bone which was not seen in affected bone in most MAP2K1-negative patients. The identification of a distinct phenotype of patients with MAP2K1-positive melorheostosis demonstrates clinical and genetic heterogeneity among patients with the disease. Further studies are needed to better understand the underlying pathophysiology and associated skin findings. © 2018 American Society for Bone and Mineral Research.

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.

Somatic activating mutations in MAP2K1 cause melorheostosis.

Melorheostosis is a sporadic disease of uncertain etiology characterized by asymmetric bone overgrowth and functional impairment. Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected, but not unaffected, bone of eight unrelated patients with melorheostosis. The activating mutations (Q56P, K57E and K57N) cluster tightly in the MEK1 negative regulatory domain. Affected bone displays a mosaic pattern of increased p-ERK1/2 in osteoblast immunohistochemistry. Osteoblasts cultured from affected bone comprise two populations with distinct p-ERK1/2 levels by flow cytometry, enhanced ERK1/2 activation, and increased cell proliferation. However, these MAP2K1 mutations inhibit BMP2-mediated osteoblast mineralization and differentiation in vitro, underlying the markedly increased osteoid detected in affected bone histology. Mosaicism is also detected in the skin overlying bone lesions in four of five patients tested. Our data show that the MAP2K1 oncogene is important in human bone formation and implicate MEK1 inhibition as a potential treatment avenue for melorheostosis.

Melorheostosis: a Rare Sclerosing Bone Dysplasia.

PURPOSE OF REVIEW: Melorheostosis is a rare sclerosing bone dysplasia that affects both cortical bone and adjacent soft tissue structures in a sclerotomal distribution. In this review, we describe the natural history, radiological features, proposed pathogenesis, and management options for this debilitating condition. RECENT FINDINGS: 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.

Melorheostosis with recurrent soft-tissue components: a histologically confirmed case.

Melorheostosis is a very rare disorder characterized by irregular cortical thickening seen on radiographs. In this paper, we present a case of melorheostosis with microscopically confirmed soft-tissue components. The patient was a 51-year-old man who complained of severe pain in the lateral aspect of his right knee. The excision of an ossified soft-tissue lesion relieved intractable pain that had lasted 20 years. Microscopically, the cortex of the affected fibula was composed of thick compact bone and the soft-tissue component consisted of dense compact bone without endochondral ossification. The presence of soft-tissue osseous nodules around the joints is one of the specific conditions for melorheostosis and should be differentiated from synovial chondromatosis. The ossified soft-tissue lesion in our patient is to our knowledge the first reported case of the histologically confirmed soft-tissue component of melorheostosis, which differs from that of synovial chondromatosis.

Arthroscopic findings in melorheostosis.

Melorheostosis is a rare dysplastic bone formation disease that can also affect the joints. We present a case of a patient with knee pain that was radiographically diagnosed as melorheostosis because of "dripping wax" image. An exploratory arthroscopy was made. In the joint, we found hyperplasic synovial tissue and an increased retropatellar Hoffa pad, which was surrounding an intra-articular ossification resulting from the disease. This was removed and led to a clinical and functional improvement.

Melorheostosis and central giant cell granuloma of the mandible in a 15-year-old girl.

Melorheostosis is a nonhereditary bone dysplasia primarily affecting the appendicular skeleton. Because clinical and histologic features are often nonspecific, the diagnosis is often based on the radiographic presentation. Involvement of the craniofacial skeleton is rare. We describe a case of a 15-year-old girl with appendicular and craniofacial melorheostosis with adjacent central giant cell granuloma. We discuss the possible significance of this previously unreported finding.

Melorheostosis of the ulna.

Melorheostosis is a rare osteosclerotic bone dysplasia. It is usually characterized by dull and aching pain, reduced joint motion and contractures. Classic radiograph findings are of undulating cortical hyperostosis along the length of the bone, simulating a "dripping candlewax appearance". We report two cases of melorheostosis of the ulna bone, diagnosed 6 years apart in two different females in their early 20s. Both the patients presented with the characteristic features of dull and aching pain in the forearm and were treated conservatively. However, we misdiagnosed the first case as bone malignancy and subjected the patient to a biopsy. For the second case, with hindsight we made the correct diagnosis based only on the classic clinical history and radiographs. We believe that the discussion of a misdiagnosed case of melorheostosis with salient findings may be important for clinicians and orthopedicians in day-to-day clinical practice.

Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis.

Mutations in the LEMD3 gene were recently incriminated in Buschke-Ollendorff syndrome (BOS) and osteopoikilosis, with or without melorheostosis. The relationship of this gene with isolated sporadic melorheostosis is less clear. We investigated LEMD3 in a two-generation BOS family showing an extremely variable expression of the disease, in a sporadic patient with skin features of BOS, and in an additional subject with isolated melorheostosis. We identified two different mutations, both resulting in a premature stop codon, in the two cases of BOS. The mutation (c.2564G>A) reported in the familial case is novel, while that observed in the sporadic case (c.1963C>T) has been previously reported in an American woman with osteopoikilosis and melorheostosis who had a family history of isolated osteopoikilosis. The search for mutations in DNA extracted from the peripheral blood, as well as skin and bone biopsies of the patient with melorheostosis failed to identify any pathogenic change. Our results further expand the LEMD3 mutation repertoire, corroborate the extreme interfamilial and intrafamilial clinical variability of LEMD3 mutations, and underline the lack of a clear phenotype-genotype correlation in BOS. The present study supports the general conclusion that LEMD3 mutations do not contribute to isolated sporadic melorheostosis. The genetic or epigenetic influences that are responsible for the development of melorheostosis require further investigation.

Craniofacial melorheostosis.

Melorheostosis is a rare benign disease of cortical bone most frequently presenting as peripheral hyperostosis with a characteristic "melting wax" appearance on conventional radiographs. The disease most frequently affects the appendicular skeleton and is seen only rarely in the craniofacial bones. We discuss a case of melorheostosis in the nasal cavity and skull base with an atypical radiographic appearance and suggest findings that may differentiate craniofacial melorheostosis from more common entities in this region.