Spinal Melorheostosis: A Rare Presentation.

CASE: A 22-year-old female patient was referred to the orthopaedic department for further examination after a radiopaque area was observed in the T6 vertebra in her chest radiograph. Computed Tomography (CT) showed a sclerotic mass with smooth borders, involving the entire body of the T6 vertebra, left posterior elements, posterior of the rib past the left zygapophyseal joint, and a "flowing candle wax" image toward the T7 vertebra. Spinal melorheostosis was considered radiologically in the patient, but malignancy could not be completely excluded. Thereupon, open biopsy was performed under general anesthesia. CONCLUSION: Spinal melorheostosis is a rare condition. Histological examination should be considered in cases where the diagnosis remains suspicious after clinical and radiological evaluations.

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.

Open Excision of Olecranon Melorheostosis to Relieve Elbow Extension Block.

We report a 34-year-old man who presented with hyperostosis of his right elbow associated with an inability to fully extend his elbow. The radiographic assessment revealed a classical dripping candle wax appearance of his proximal ulna suggestive of melorheostosis. Computed tomography was performed to identify the impingement point and aid in surgical planning. A targeted open excision biopsy via a Boyd incision was performed to excise the exophytic component that was causing the functional block. After surgery, he achieved full elbow extension and was able to return to his usual activity.

Displasia ósea esclerosante en paciente adulto sin diagnóstico previo: presentación de un caso / Bone sclerosing dysplasia in an adult patient without previous diagnosis: a case report

La displasia ósea esclerosante es una afectación en el desarrollo intrínseco del esqueleto, por alteración en la formación y modelado del hueso, que lleva a una excesiva acumulación ósea con un aumento de la densidad (esclero-sis). Existen varios tipos y todos ellos son de origen genético. Presentamos el caso de una paciente de 37 años que llega a la consulta sin diagnóstico previo, por dolor en miembros inferiores de larga evolución con reagudizaciones, asociado a deformidad e impotencia funcional, que cedía parcialmente con analgésicos comunes. (AU)

Bone sclerosing dysplasia is an affectation of the intrinsic development of the skeleton by an alteration in bone formation and modeling. It causes excessive bone accumulation with an increase in density (sclerosis). There are several types of bone sclerosing dysplasia. They are of genetic origin. We report here a 37 year-old patient without a previous diagnosis of sclerosing bone dysplasia who was seen in the clinic for pain in the lower limbs associated with bone deformity with only partial response to analgesics. (AU)

Meralgia Paresthetica Caused by Melorheostosis Affecting the Ipsilateral Ilium: A Case Report.

CASE: A 51-year-old woman presented with a 2-month history of pain in the right thigh. Radiography and computed tomography of the pelvis showed cortical hyperostosis of the right ilium. She was diagnosed with meralgia paresthetica (MP) caused by melorheostosis involving the right ilium. After 6 weeks of conservative management, an operation was performed for the persisting pain. At the 1-year follow-up, no findings of recurrence were observed clinically and radiographically. CONCLUSION: MP, caused by proximal irritation of the lateral femoral cutaneous nerve, can occur because of melorheostosis, which is a rare condition.

A multi-omics approach expands the mutational spectrum of MAP2K1-related melorheostosis.

Melorheostosis is a very rare sclerosing bone dysplasia characterized by asymmetrical and progressive cortical hyperostosis, usually with involvement of soft tissues surrounding the lesions. Recently Kang et al. identified somatic mosaicism for variants (p.Gln56Pro, p.Lys57Asn, or p.Lys57Glu) in the negative regulatory domain of MAP2K1, resulting in increased ERK1/2 signalling in affected tissues. In our study, we employed several sequencing technologies to unravel genetic variants (only present in affected tissues) from four sporadic melorheostosis patients. In the exome of two patients, we identified the same variants (p.K57N and p.K57E) as previously described by Kang et al. WGS and RNAseq analysis in a third patient demonstrated the presence of a novel variant (p.Cys121Ser) in the catalytic domain of MAP2K1. In addition, gene set enrichment analysis of the transcriptome data demonstrated upregulation of proliferative pathways. Interestingly, increased proliferation of MAP2K1 p.Lys57Asn-positive osteoblasts has been reported by Kang et al. The variants located in the hotspot region of the negative regulatory domain as well as this newly identified p.Cys121Ser variant have all been classified as MAP2K1 variants that can constitutively activate the downstream effector Erk. Finally, in a fourth patient with classical radiographic features of melorheostosis, no pathogenic variants could be identified in MAP2K1 or the other candidate genes for melorheostosis (SMAD3; LEMD3; KRAS). In conclusion, our study strongly suggests that not only somatic variants in the regulatory domain of MAP2K1 but also in the catalytic domain can cause melorheostosis. Our observations confirm that mutations in MAP2K1 are a major cause of melorheostosis and also suggest further locus heterogeneity for this disorder.

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.

Asociación de aneurismas aórtico y viscerales con lesiones óseas / Association of aortic and visceral aneurysms with bone lesions

Paciente de 22 años con rigidez congénita de miembro superior izquierdo y hallazgos en angio TAC de pseudocoartación aórtica y aneurismas a varios niveles (aorta ascendente, cayado aórtico, arteria mesentérica superior, mesentérica inferior, renales segmentarias, aorta abdominal y arteria hipogástrica izquierda). Presenta imagen en "gota de cera" en radiografía de pelvis y en angio RM destacan lesiones esclerosas poliostóticas y malformación arteriovenosa en partes blandas de cadera izquierda. No se realiza estudio genético por la negativa del paciente

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