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Journal of Bone and Mineral Research :... May 2019Melorheostosis is a rare non-hereditary condition characterized by dense hyperostotic lesions with radiographic "dripping candle wax" appearance. Somatic activating... (Clinical Trial)
Clinical Trial
Melorheostosis is a rare non-hereditary condition characterized by dense hyperostotic lesions with radiographic "dripping candle wax" appearance. Somatic activating mutations in MAP2K1 have recently been identified as a cause of melorheostosis. However, little is known about the development, composition, structure, and mechanical properties of the bone lesions. We performed a multi-method phenotype characterization of material properties in affected and unaffected bone biopsy samples from six melorheostosis patients with MAP2K1 mutations. On standard histology, lesions show a zone with intensively remodeled osteonal-like structure and prominent osteoid accumulation, covered by a shell formed through bone apposition, consisting of compact multi-layered lamellae oriented parallel to the periosteal surface and devoid of osteoid. Compared with unaffected bone, melorheostotic bone has lower average mineralization density measured by quantitative backscattered electron imaging (CaMean: -4.5%, p = 0.04). The lamellar portion of the lesion is even less mineralized, possibly because the newly deposited material has younger tissue age. Affected bone has higher porosity by micro-CT, due to increased tissue vascularity and elevated 2D-microporosity (osteocyte lacunar porosity: +39%, p = 0.01) determined on quantitative backscattered electron images. Furthermore, nano-indentation modulus characterizing material hardness and stiffness was strictly dependent on tissue mineralization (correlation with typical calcium concentration, CaPeak: r = 0.8984, p = 0.0150, and r = 0.9788, p = 0.0007, respectively) in both affected and unaffected bone, indicating that the surgical hardness of melorheostotic lesions results from their lamellar structure. The results suggest a model for pathophysiology of melorheostosis caused by somatic activating mutations in MAP2K1, in which the genetically induced gradual deterioration of bone microarchitecture triggers a periosteal reaction, similar to the process found to occur after bone infection or local trauma, and leads to an overall cortical outgrowth. The micromechanical properties of the lesions reflect their structural heterogeneity and correlate with local variations in mineral content, tissue age, and remodeling rates, in the same way as normal bone. © 2018 American Society for Bone and Mineral Research.
Topics: Adult; Bone Density; Female; Humans; MAP Kinase Kinase 1; Male; Melorheostosis; Middle Aged; Models, Biological; Mutation; Periosteum; X-Ray Microtomography
PubMed: 30667555
DOI: 10.1002/jbmr.3656 -
Journal of Radiology Case Reports Nov 2018Melorheostosis is a benign hyperostotic disease of the peripheral skeleton, rarely involving the axial skeleton. This disease is associated with ossified and...
Melorheostosis is a benign hyperostotic disease of the peripheral skeleton, rarely involving the axial skeleton. This disease is associated with ossified and non-ossified soft tissue masses surrounding the joints. We report the case of a 28-year-old male who presented to an orthopedic clinic with a chronic history of right leg pain. Radiological evaluation using X-ray, computed tomography, and magnetic resonance imaging showed features consistent with that of melorheostosis. Recognition of this entity by clinicians can avoid unnecessary investigations and biopsy.
Topics: Adult; Anti-Inflammatory Agents; Diagnosis, Differential; Humans; Leg; Magnetic Resonance Imaging; Male; Melorheostosis; Tomography, X-Ray Computed
PubMed: 30647832
DOI: 10.3941/jrcr.v12i11.3539 -
Journal of Orthopaedic Case Reports 2019Melorheostosis is a rare bone dysplasia. It is mainly a radiographic diagnosis with distinct findings of endosteal or periosteal sclerosis along the axis of long bones,...
INTRODUCTION
Melorheostosis is a rare bone dysplasia. It is mainly a radiographic diagnosis with distinct findings of endosteal or periosteal sclerosis along the axis of long bones, resembling the flowing wax. It is usually polyostotic and monomelic. Clinical manifestations are pain, limitation of joint movements, deformities, and contractures. Leg length discrepancy may be found, usually the affected limb being shorter.
CASE PRESENTATION
We present an adolescent boy, with melorheostosis of the lower limb. The affected limb was longer with equally divided discrepancy of the femur and tibia. There were no another symptoms. After a thorough investigation, we performed epiphysiodesis both medial and lateral of the distal femoral and proximal tibial growth plate, using8eight plates. At the end of the growth, there was almost complete equalization of the length of his lower limbs.
CONCLUSION
Melorheostosis may be present with leg length discrepancy leg length discrepancy, with an exception, being that the affected limb is longer. Epiphysiodesis with eight plates is an effective method of limb length equalization.
PubMed: 32547993
DOI: 10.13107/jocr.2019.v09.i05.1508 -
Nucleic Acids Research Dec 2018Receptor-regulated SMAD (R-SMAD: SMAD1, SMAD2, SMAD3, SMAD5 and SMAD8) proteins are key transcription factors of the transforming growth factor-β (TGF-β) superfamily...
Receptor-regulated SMAD (R-SMAD: SMAD1, SMAD2, SMAD3, SMAD5 and SMAD8) proteins are key transcription factors of the transforming growth factor-β (TGF-β) superfamily of cytokines. MAN1, an integral protein of the inner nuclear membrane, is a SMAD cofactor that terminates TGF-β superfamily signals. Heterozygous loss-of-function mutations in MAN1 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. MAN1 interacts with MAD homology 2 (MH2) domains of R-SMAD proteins using its C-terminal U2AF homology motif (UHM) domain and UHM ligand motif (ULM) and facilitates R-SMAD dephosphorylation. Here, we report the structural basis for R-SMAD recognition by MAN1. The SMAD2-MAN1 and SMAD1-MAN1 complex structures show that an intramolecular UHM-ULM interaction of MAN1 forms a hydrophobic surface that interacts with a hydrophobic surface among the H2 helix, the strands β8 and β9, and the L3 loop of the MH2 domains of R-SMAD proteins. The complex structures also show the mechanism by which SMAD cofactors distinguish R-SMAD proteins that possess a highly conserved molecular surface.
Topics: Amino Acid Motifs; Animals; Computer Simulation; Crystallography, X-Ray; Cytokines; DNA Mutational Analysis; DNA-Binding Proteins; HEK293 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Membrane Proteins; Mutation; Nuclear Envelope; Nuclear Proteins; Phosphorylation; Protein Binding; Protein Domains; Signal Transduction; Smad1 Protein; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta
PubMed: 30321401
DOI: 10.1093/nar/gky925 -
International Journal of Surgery Case... 2018Elbow stiffness is a common condition that affects the quality of life of patients. Melorheostosis of the elbow associated with elbow stiffness is extremely rare.
INTRODUCTION
Elbow stiffness is a common condition that affects the quality of life of patients. Melorheostosis of the elbow associated with elbow stiffness is extremely rare.
PRESENTATION OF CASE
We report the case of a 28 yr old male who presented with elbow stiffness which occurred within one year without prior history of trauma or infection. The patient had decrease in range of motion together with progressive worsening pain that forced him to seek medical attention.
DISCUSSION
There is no standard treatment for melorheostosis, and management plans must be made on an individual patient basis. The aims of treatment are pain relief and maintaining function.
CONCLUSION
Debridement arthroplasty is safe and effective in treating elbow stiffness associated with Melorheostosis.
PubMed: 30312962
DOI: 10.1016/j.ijscr.2018.09.009 -
Journal of Medical Case Reports Sep 2018A 20-year-old Danish woman with melorheostosis in her right femoral shaft and disabling pain in the affected area, whose symptoms did not in the long term respond to...
BACKGROUND
A 20-year-old Danish woman with melorheostosis in her right femoral shaft and disabling pain in the affected area, whose symptoms did not in the long term respond to zoledronic acid, experienced continuous remission of pain after treatment with denosumab. To the best of our knowledge, this is the first case report on denosumab treatment for melorheostosis.
CASE PRESENTATION
Radiologic findings and bone biopsy showed irregular cortical hyperostosis in the right femoral shaft with increased tracer uptake on Tc-bone scan. The diagnosis of melorheostosis was made based on the radiological findings. There was a good initial response to zoledronic acid administration, but after relapse of pain, the second and third administrations had a poor effect. As a second line of treatment denosumab was administered at 8-week intervals, the frequency was based on our patient's symptoms and on biochemical markers of bone turnover.
CONCLUSION
This is the first report indicating that denosumab has a place in the treatment of melorheostosis when the effect of bisphosphonate treatment is insufficient.
Topics: Bone Density Conservation Agents; Denosumab; Female; Humans; Melorheostosis; Radiography; Recurrence; Tomography, X-Ray Computed; Young Adult
PubMed: 30257703
DOI: 10.1186/s13256-018-1820-y -
Bone Dec 2018Melorheostosis (MEL) is a rare disease of high bone mass with patchy skeletal distribution affecting the long bones. We recently reported somatic mosaic mutations in...
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.
Topics: Adult; Aged; Animals; Bone and Bones; Cell Proliferation; Clone Cells; Humans; Melorheostosis; Mice; Middle Aged; Tomography, X-Ray Computed; United States
PubMed: 30218789
DOI: 10.1016/j.bone.2018.09.005 -
Journal of Bone and Mineral Research :... Jan 2019Melorheostosis is a rare hyperostotic disease of the long bones classically characterized by a "dripping candle-wax" radiographic appearance. We recently described... (Clinical Trial)
Clinical Trial
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.
Topics: Adult; Aged; Bone and Bones; Female; Humans; MAP Kinase Kinase 1; Male; Melorheostosis; Middle Aged; Mutation; Osteoblasts; Skin; Exome Sequencing
PubMed: 30138550
DOI: 10.1002/jbmr.3577 -
Radiology Case Reports Aug 2018Melorheostos is a rare sclerosing bone dysplasia, characterized by cortical and medullary hyperostosis with typical "dripping candle wax" appearance, usually involving...
Melorheostos is a rare sclerosing bone dysplasia, characterized by cortical and medullary hyperostosis with typical "dripping candle wax" appearance, usually involving the long bones. Here, we present a case of melorheostosis of a rib, incidentally discovered in an asymptomatic adult patient.
PubMed: 29997717
DOI: 10.1016/j.radcr.2018.06.006 -
Nature Communications Apr 2018Melorheostosis is a sporadic disease of uncertain etiology characterized by asymmetric bone overgrowth and functional impairment. Using whole exome sequencing, we...
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.
Topics: Bone Morphogenetic Protein 2; Bone and Bones; Calcification, Physiologic; Cell Differentiation; Cell Proliferation; Gene Expression Regulation; Humans; MAP Kinase Kinase 1; Melorheostosis; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mosaicism; Mutation; Osteoblasts; Osteogenesis; Primary Cell Culture; Signal Transduction; Skin; Exome Sequencing
PubMed: 29643386
DOI: 10.1038/s41467-018-03720-z