Paget Disease of Bone Harboring Bone Metastatic Neuroendocrine Cancer: A Case Report.

In this case report, we describe an uncommon case of neuroendocrine cancer of unknown origin began with cauda equina syndrome in a patient affected by Paget disease of bone (PDB). A 76-year-old man with diagnosis of PDB, without history of pain or bone deformity, developed sudden severe low back pain. Bone alkaline phosphatase was increased and MRI and whole-body scintigraphy confirmed the localization of the disease at the third vertebra of the lumbar spine. Treatment with Neridronic Acid was started, but after only 2 weeks of therapy anuria and bowel occlusion occurred together with lower limb weakness and walking impairment. Cauda equina syndrome consequent to spinal stenosis at the level of L2-L3 was diagnosed after admission to Emergency Department and the patient underwent neurosurgery for spinal medulla decompression. The histologic results showed a complete subversion of bone structure in neoplastic tissue, consistent with metastatic neuroendocrine carcinoma of unknown origin. In conclusion, low back pain in the elderly may require deep investigation to individuate rare diseases. In asymptomatic patients with apparently stable PDB, the sudden appearance of pain or neurologic symptoms may alert the clinician for the possibility of other superimposing diseases, like bone metastases.

Osteocytes and Paget's Disease of Bone.

PURPOSE OF REVIEW: To describe the contributions of osteocytes to the lesions in Paget's disease, which are characterized by locally overactive bone resorption and formation. RECENT FINDINGS: Osteocytes, the most abundant cells in bone, are altered in Paget's disease lesions, displaying increased size, decreased canalicular length, incomplete differentiation, and less sclerostin expression compared to controls in both patients and mouse models. Pagetic lesions show increased senescent osteocytes that express RANK ligand, which drives osteoclastic bone resorption. Abnormal osteoclasts in Paget's disease secrete abundant IGF1, which enhances osteocyte senescence, contributing to lesion formation. Recent data suggest that osteocytes contribute to lesion formation in Paget's disease by responding to high local IGF1 released from abnormal osteoclasts. Here we describe the characteristics of osteocytes in Paget's disease and their role in bone lesion formation based on recent results with mouse models and supported by patient data.

Adolescent-onset multisystem proteinopathy due to a novel VCP variant.

Valosin-containing protein (VCP) pathogenic variants are the most common cause of multisystem proteinopathy presenting with inclusion body myopathy, amyotrophic lateral sclerosis/frontotemporal dementia, and Paget disease of bone in isolation or in combination. We report a patient manifesting with adolescent-onset myopathy caused by a novel heterozygous VCP variant (c.467G > T, p.Gly156Val). The myopathy manifested asymmetrically in lower limbs and extended to proximal, axial, and upper limb muscles, with loss of ambulation at age 35. Creatine kinase value was normal. Alkaline phosphatase was elevated. Electromyography detected mixed low amplitude, short duration and high amplitude, long duration motor unit potentials. Muscle biopsy showed features of inclusion body myopathy, which in combination with newly diagnosed Paget disease of bone, supported the VCP variant pathogenicity. In conclusion, VCP-multisystem proteinopathy is not only a disease of adulthood but can have a pediatric onset and should be considered in differential diagnosis of neuromuscular weakness in the pediatric population.

VCP activator reverses nuclear proteostasis defects and enhances TDP-43 aggregate clearance in multisystem proteinopathy models.

Pathogenic variants in valosin-containing protein (VCP) cause multisystem proteinopathy (MSP), a disease characterized by multiple clinical phenotypes including inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (FTD). How such diverse phenotypes are driven by pathogenic VCP variants is not known. We found that these diseases exhibit a common pathologic feature: ubiquitinated intranuclear inclusions affecting myocytes, osteoclasts, and neurons. Moreover, knock-in cell lines harboring MSP variants show a reduction in nuclear VCP. Given that MSP is associated with neuronal intranuclear inclusions comprised of TDP-43 protein, we developed a cellular model whereby proteostatic stress results in the formation of insoluble intranuclear TDP-43 aggregates. Consistent with a loss of nuclear VCP function, cells harboring MSP variants or cells treated with VCP inhibitor exhibited decreased clearance of insoluble intranuclear TDP-43 aggregates. Moreover, we identified 4 compounds that activate VCP primarily by increasing D2 ATPase activity, where pharmacologic VCP activation appears to enhance clearance of insoluble intranuclear TDP-43 aggregate. Our findings suggest that VCP function is important for nuclear protein homeostasis, that impaired nuclear proteostasis may contribute to MSP, and that VCP activation may be a potential therapeutic by virtue of enhancing the clearance of intranuclear protein aggregates.

Enterococcus faecalis causes osteitis deformans in aGolden Lancehead snake (Bothrops insularis): a case report / Enterococcus faecalis causa osteíte deformante em uma serpente Jararaca-ilhoa (Bothrops insularis): relato de caso

Osteitis deformans (Paget's disease) is a chronic bone disorder characterized by excessive osteoclast-mediated bone resorption followed by new bone formation. The present paper reports this condition in an 18-year-old captive golden lancehead (Bothrops insularis) from Brazil. This patient initially exhibited anorexia and swelling in the middle third of the spine associated with locomotor disability. For diagnosis, radiography, ultrasound, computed tomography, cytology, and microbiological culture were performed. Diagnostic imaging showed bone changes, vertebral fusion, and bone proliferation. Cytology revealed blood cells how toxic heterophiles, reactive monocytes, young red blood cells, and polychromasia compatible with an infectious process. A bacterial culture identified an ampicillin-susceptible strain of Enterococcus faecalis. Antibiotic treatment was promptly started, but the snake died 25 days later. Histopathologically, the bone tissue showed a generalized thickening of the vertebral trabeculae. For the first time, the presence of E. faecalisassociated with the development of osteitis deformans in snakes was presented.(AU)

Osteíte deformante (Doença de Paget) é um distúrbio ósseo crônico caracterizado por reabsorção óssea excessiva mediada por osteoclastos, seguida por nova formação óssea. O presente trabalho relata essa condição em uma serpente jararaca-ilhoa (Bothrops insularis) do Brasil de 18 anos. O paciente apresentou inicialmente anorexia e um inchaço no primeiro terço médio da coluna associado com a incapacidade locomotora. O diagnóstico foi estabelecido com o apoio de radiografia, ultrassonografia, tomografia computadorizada, citologia e cultura microbiológica. O diagnóstico por imagem mostrou alterações ósseas, fusão de vértebras e proliferação óssea. A citologia mostrou células sanguíneas como heterófílos tóxicos, monócitos reativos, células sanguíneas jovens e policromasia compatíveis com um processo infeccioso. A cultura bacteriana identificou uma cepa de Enterococcus faecalis suscetível à ampicilina. O tratamento com antibióticos foi iniciado imediatamente, mas a serpente morreu 25 dias depois. Histopatologicamente, o tecido ósseo mostrou um espessamento generalizado das trabéculas vertebrais. Portanto, foi demonstrado pela primeira vez a presença de E. faecalis associada ao desenvolvimento de osteíte deformante em uma serpente.(AU)

La importancia del compromiso vertebral en la enfermedad de Paget / Vertebral compromised in Paget's disease

La enfermedad ósea de Paget (EP) se caracteriza por un trastorno focal de esqueleto, inicialmente determinado por una excesiva resorción del hueso y una subsiguiente formación exagerada, adoptando finalmente una configuración histológica típica denominada "en mosaico". Macroscópicamente el hueso se deforma y sus diámetros se agrandan, resultando un hueso de mayor tamaño, muy vascularizado y de estructura desordenada. La anormalidad parece estar en la regulación de los osteoclastos, que están aumentados en número y tamaño. La ubicación más frecuente es el esqueleto axial, especialmente la pelvis, el sacro, la columna lumbar y el cráneo. En nuestra población de pacientes con EP detectamos un compromiso vertebral en el 47% de los pacientes que habíamos calificado previamente con monostóticos y en el 36.8% de los pacientes con EP poliostótica. El compromiso vertebral puede afectar la médula espinal por compromiso de la circulación, generando cuadriparesia o paraparesia, dependiendo del nivel vertebral afectado. La hipótesis sugerida de dicha afectación es el robo o atrapamiento vascular. Esto explica la importancia de medicar tempranamente a los pacientes con compromiso vertebral, ya que estos problemas neurológicos revierten drásticamente con el hoy simple y adecuado tratamiento médico de la EP.

Imagen por resonancia magnética de la cadera / MRI of the hip

Se analizan la anatomía y algunas de las manifestaciones patológicas de la articulación de la cadera en la Imagen por Resonancia Magnética, entre las que se destacan la osteoartropatía degenerativa, la enfermedad de Paget, la necrosis avascular, la artritis reumatoide y los tumores, haciendo notar la utilidad de la Radiología convencional y las aportaciones adicionales que da la IRM al diagnóstico.

Avaliaçäo por imagem da doença de paget do osso / The role of imaging in Paget's disease of the bone

Resumo: Os autores procuram demonstrar o valor dos diversos métodos de imagem no diagnóstico da doença de Paget (DP) nos ossos, dando aos seus aspectos comuns, incomuns e complicaçöes . Foram revisados 89 casos da DP no arquivo de ensino do Centro Radiológico de Brasília; destes, 78 foram estudados isoladamente por radiografias convencionais, 9 por tomografia computadorizada, 2 ressonância magnética e 4 pela combinaçäo por mais de um método. Os sinais radiográficos mas comumente observados foram: reabsorçäo óssea em cunha, trabeculado grosseiro ao longo da linha de "stress", espessamento da cortical e aumento de volume ósseo. As principais complicaçöes encontradas foram: fraturas patológicas, doença articular degenerativa e transformaçäo sarcomatosa. Na DP näo-complicada do esqueleto periférico, o estudo radiológico convencional é suficiente para o diagnóstico. Para a avaliaçäo das complicaçöes ou das manifestaçöes da DP no esqueleto axial, métodos multiplanares de imagem devem tambem ser empregados.