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Molecular Genetics & Genomic Medicine Oct 2022Melorheostosis (MEL) is an exceptionally rare sclerosing bone dysplasia with asymmetrically exuberant bone formation and soft tissue lesions in a segmental distribution....
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.
Topics: Bone and Bones; China; Humans; MAP Kinase Kinase 1; Melorheostosis; Exome Sequencing; X-Ray Microtomography
PubMed: 36004822
DOI: 10.1002/mgg3.2043 -
Bone Reports Dec 2022Loss-of-function mutations in cause Loeys-Dietz syndrome type 3 (LDS3), a rare autosomal-dominant connective tissue disorder characterized by vascular pathology and...
Loss-of-function mutations in cause Loeys-Dietz syndrome type 3 (LDS3), a rare autosomal-dominant connective tissue disorder characterized by vascular pathology and skeletal abnormalities. Dysregulation of TGF-β/SMAD signaling is associated with abnormal skeletal features and bone fragility. To date, histomorphometric and ultrastructural characteristics of bone with mutations have not been reported in humans and the exact mechanism by which mutations cause the LDS3 phenotype is poorly understood. Here, we investigated bone histomorphometry and matrix mineralization in human bone with a mutation and explored the associated cellular defect in the TGF-β/SMAD pathway . The index patient had recurrent fractures, mild facial dysmorphism, arachnodactyly, pectus excavatum, chest asymmetry and kyphoscoliosis. Bone histomorphometry revealed markedly reduced cortical thickness (-68 %), trabecular thickness (-32 %), bone formation rate (-50 %) and delayed mineralization. Quantitative backscattered electron imaging demonstrated undermineralized bone matrix with increased heterogeneity in mineralization. The patient's mutation (c.200 T > G; p.I67S), when expressed from plasmid vectors in HEK293 cells, showed reduced phosphorylation and transcription factor activity compared to normal control and SMAD3 (p.S264Y), a gain-of-function mutation, somatic mosaicism of which causes melorheostosis. Transfection study of the patients' SMAD3 (p.I67S) mutation displayed lower luciferase reporter activity than normal SMAD3 and reduced expression of TGF-β signaling target genes. Patient fibroblasts also demonstrated impaired SMAD3 protein stability. Osteoclastogenic differentiation significantly increased and osteoclast-associated genes, including (encoding TRAP), , and , were up-regulated in CD14 (+) peripheral blood mononuclear cells (PBMCs) with the SMAD3 (p.I67S) mutation. Upregulation of osteoclastogenic genes was associated with decreased expression of TGF-β signaling target genes. We conclude that bone with the SMAD3 (p.I67S) mutation features reduced bone formation, and our functional studies revealed decreased SMAD3 activation and protein stability as well as increased osteoclastogenesis. These findings enhance our understanding of the pathophysiology of LDS3 caused by mutations. Emerging therapies targeting in the TGF-β/SMAD pathway also raise hope for treatment of LDS3.
PubMed: 35874167
DOI: 10.1016/j.bonr.2022.101603 -
Journal of Musculoskeletal & Neuronal... Jun 2022Buschke-Ollendorff syndrome (BOS) is a rare, usually benign, autosomal dominant genetic disease affecting about 0.005% globally. BOS commonly manifests with asymptomatic...
Buschke-Ollendorff syndrome (BOS) is a rare, usually benign, autosomal dominant genetic disease affecting about 0.005% globally. BOS commonly manifests with asymptomatic connective tissue nevi, sometimes with sclerotic bone lesions like osteopoikilosis or melorheostosis. However, BOS may develop severe, symptomatic complications that require surgical intervention. Here we report a 9-year-8-month girl presenting with multiple nonpruritic, nonpainful skin plaques scattered around the trunk, buttocks, and bilateral legs. She had a history of right varus foot with inadequate plantar flexion. Upon visiting, obvious leg length discrepancy (LLD) was noted. Lesional biopsy revealed increased fibroblasts within dermal collagen bundles. Verhoeff-van Gieson stain revealed scattered foci of thickened elastic fibers between collagen fibers, especially in the mid-dermis. Radiographic examination of the lower extremities showed multiple small, round-to-oval shaped, radiopaque spots on the pelvic bones, femurs, tibiae, and both feet. Hyperostosis along the long axis with "dripping candle wax" appearance was characteristic of osteopoikilosis and melorheostosis. Genetic analysis showed heterozygous point mutation in exon 1 of LEMD3 gene (c.1323C>A, p.Y441X), confirming diagnosis of BOS. Sequential and epiphyseodesis were performed to correct LLD with a favorable outcome at 2-year follow-up. BOS associated with severe bone abnormalities is rare, but orthopedic surgical intervention can provide satisfactory outcome.
Topics: Child; Collagen; Female; Humans; Leg; Melorheostosis; Osteopoikilosis; Skin Diseases, Genetic
PubMed: 35642708
DOI: No ID Found -
Journal of Orthopaedic Case Reports Sep 2021Melorheostosis is a rare sclerosing bone disease characterized by linear hyperostotic bone dysplasia with its radiological appearance as melting candle wax dripping by...
INTRODUCTION
Melorheostosis is a rare sclerosing bone disease characterized by linear hyperostotic bone dysplasia with its radiological appearance as melting candle wax dripping by its side. It usually affects long bones, especially the lower limb. The exact cause of the disease has not been clearly explained though many theories are available. It is insidious in onset and symptoms being pain, deformity, and joint stiffness. Although there is no definitive treatment, the administration of bisphosphonates dramatically reduces pain and improves the patient clinically.
CASE REPORT
We described a case of a 28-year-old female who presented with a history of pain and swelling in her left leg for the past 2 years. The onset of complaints was insidious. On physical examination, there was tender swelling over the shaft of the tibia with irregular borders. Knee and ankle range of movements were normal. Radiographs showed hyperostosis of the proximal two-thirds of the tibia of the left leg with a flowing candle wax appearance. The patient was treated with a single dose of intravenous zolendronic acid and physical therapy. The patient had dramatic alleviation of pain without the need for any further treatment till 1 year follow-up.
CONCLUSION
Although there is no specific treatment available for this disease, the intravenous infusion of zolendronic acid has dramatically improved the patient clinically.
PubMed: 35415166
DOI: 10.13107/jocr.2021.v11.i09.2436 -
PM & R : the Journal of Injury,... May 2023Melorheostosis is a rare bone disorder with limited literature that describes the effect of this disease on functional and motor abilities. As part of a natural history... (Observational Study)
Observational Study
INTRODUCTION
Melorheostosis is a rare bone disorder with limited literature that describes the effect of this disease on functional and motor abilities. As part of a natural history study, four outcome measures were administered to better understand the burden this disease has on a person's ability to engage in basic and instrumental activities of daily living.
OBJECTIVE
To investigate the relationship between functional engagement, fatigue, and motor ability in patients with melorheostosis.
DESIGN
Cross-sectional data gathered from a longitudinal natural history observational study.
SETTING
Rehabilitation department within a single institution.
PARTICIPANTS
Forty-seven adult volunteers with melorheostosis were enrolled. Two participants were removed for failure to meet diagnosis eligibility. Thirty patients had lower extremity (LE) osteosclerotic bone lesions, 14 had upper extremity (UE) lesions, and one had lesions in both UEs and LEs.
INTERVENTIONS
Not applicable.
MAIN OUTCOME MEASURES
Activity Card Sort, Second Edition (ACS); Multi-Dimensional Fatigue Inventory; Lower Extremity Functional Scale; Upper Extremity Functional Index.
RESULTS
On the ACS, high-demand leisure (HDL) activities were the least retained (p < .001). Of the activities rated most important, HDL activities were the most likely to have been given up (27%). General fatigue (μ = 11.8) and physical fatigue (μ = 11.0) were the two most limiting fatigue constructs. There were moderate negative correlations with HDL activities compared to physical fatigue (r = -0.524, p < .001) and reduced activity fatigue (r = -0.58, p = .001). LE lesions had a large effect on completing LE tasks (d = 0.95) and UE lesions had a medium effect on completing tasks involving the UE (d = 0.69).
CONCLUSIONS
Patients with melorheostosis experience fatigue and low engagement in HDL activities. The results of this study underscore the importance of acknowledging activity domain, fatigue constructs, and lesion location to support and provide targeted evidence-based rehabilitative therapy.
CLINICAL TRIAL REGISTRATION NUMBER
NCT02504879.
Topics: Adult; Humans; Activities of Daily Living; Cross-Sectional Studies; Fatigue; Lower Extremity; Melorheostosis; Upper Extremity
PubMed: 35403375
DOI: 10.1002/pmrj.12817 -
Journal of Clinical Imaging Science 2022Melorheostosis is a rare bone dysplasia of unknown etiology with an incidence of 0.9 cases per million. It typically affects the upper or lower limbs and can cause...
Melorheostosis is a rare bone dysplasia of unknown etiology with an incidence of 0.9 cases per million. It typically affects the upper or lower limbs and can cause severe deformity and functional impairment. Diagnosis is radiological and is often described as a "flowing candle wax" appearance on the radiograph. Treatment is individualized depending on the site and severity of symptoms. We report a rare case of spinal melorheostosis. We demonstrate the imaging features of melorheostosis on CT and MRI. We discuss the classification, genetics, and management of this condition.
PubMed: 35251764
DOI: 10.25259/JCIS_202_2021 -
The Journal of Investigative Dermatology Sep 2022Melorheostosis is a rare sclerosing bone disease with associated vascular abnormalities in skin and bone, which is caused by somatic mosaic single nucleotide variations...
Melorheostosis is a rare sclerosing bone disease with associated vascular abnormalities in skin and bone, which is caused by somatic mosaic single nucleotide variations in the MAP2K1 gene, which encodes MAPK/extracellular signal‒regulated kinase (ERK) kinase 1. However, disease pathogenesis is poorly understood. Using patient-derived cells, we found that affected skin fibroblasts carrying the single nucleotide variations have increased activation of ERK1/2, which results in increased expression and secretion of proangiogenic factors, including VEGF. VEGF secretion was strongly reduced in affected cells after treatment with MAPK/ERK kinase 1 inhibitor trametinib. Treatment of healthy endothelial cells on matrigel with conditioned medium from affected fibroblasts induces the adoption of a proangiogenic phenotype. Direct coculture of fibroblasts and endothelial cells further shows that both secreted factors and extracellular matrix are capable of inducing a proangiogenic phenotype in healthy endothelial cells. Blocking VEGF with bevacizumab reduces the proangiogenic effect of affected fibroblasts in both the matrigel and direct coculture angiogenesis models, indicating that elevated VEGF secretion is a key mediator of increased angiogenesis in melorheostosis tissue. In conclusion, this work identifies the role of several important molecular mediators in the pathogenesis of melorheostosis, including MAPK/ERK kinase 1, phosphorylated ERK1/2, and VEGF, all of which have clinically available pharmacologic inhibitors, which could be further explored as therapeutic targets.
Topics: Endothelial Cells; Fibroblasts; Humans; Melorheostosis; Neovascularization, Pathologic; Nucleotides; Vascular Endothelial Growth Factor A
PubMed: 35189151
DOI: 10.1016/j.jid.2022.02.006 -
RoFo : Fortschritte Auf Dem Gebiete Der... Apr 2022
Topics: Bone Neoplasms; Diagnosis, Differential; Humans; Melorheostosis; Young Adult
PubMed: 34933351
DOI: 10.1055/a-1656-9987 -
International Journal of Molecular... Jul 2021A review of the available literature was performed in order to summarize the existing evidence between osteoblast dysfunction and clinical features in non-hereditary... (Review)
Review
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.
Topics: Animals; Bone Morphogenetic Proteins; Fibroblast Growth Factors; Humans; MAP Kinase Signaling System; Melorheostosis; Osteoblasts; Platelet-Derived Growth Factor; Sphingosine-1-Phosphate Receptors
PubMed: 34360745
DOI: 10.3390/ijms22157980 -
Journal of Orthopaedic Case Reports Apr 2021Melorheostosis is a rare benign bone condition characterized by excessive segmental sclerosis of cortical bone being reminiscent of dripping candle wax. It typically...
INTRODUCTION
Melorheostosis is a rare benign bone condition characterized by excessive segmental sclerosis of cortical bone being reminiscent of dripping candle wax. It typically affects the long bones and can cause impingement and nerve compression syndromes that may require surgical treatment.
CASE REPORT
We report the case of a 49-year-old male patient with a 12-month history of the left-sided knee pain and a concomitant limitation of his left knee flexion to 90 degree. Radiographic and magnetic resonance imaging revealed the typical radiographic appearance of melorheostosis with an extraosseous lesion in the fossa intercondylaris femoris being causative for the limited knee range of motion. Following the resection of the extraosseous part of the lesion through a direct open approach, the patient is pain free with a maximum of 110 degree knee flexion at 12-month follow-up.
CONCLUSION
Melorheostosis can present with manifold clinical manifestations that potentially require surgical treatment. Even in patients with a challenging localization of extraosseous lesions, a good to excellent functional outcome is possible.
PubMed: 34327164
DOI: 10.13107/jocr.2021.v11.i04.2146