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1.
BMC Musculoskelet Disord ; 21(1): 152, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143615

RESUMO

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by extraskeletal heterotopic ossification. It is well recognized that FOP can lead to a devastating condition of disability. However, the mortality rate of FOP patients in China and risk factors for mortality are still largely unclear. METHODS: We conducted a retrospective research on a cohort of 65 cases of FOP patients in China from 2008 to 2018. We reviewed medical records of these FOP patients to retrieve information such as date of birth/death, gender, clinical features, genotypes and biochemical parameters and analyze the correlation of these parameters with the mortality. RESULTS: 92.3% (60/65 cases) patients were classic FOP patients, 3.1% (2/65 cases) were FOP-plus and 4.6% (3/65 cases) were FOP variants. 9 cases of this cohort were dead during the ten-year period, and the overall mortality rate was 13.8%. c.617G > A mutation was confirmed in all non-survivors. In FOP patients≤18 years at diagnosis, non-survivors demonstrated significantly lower blood osteocalcin and alkaline phosphatase levels compared with survivors (P < 0.05), and spearman correlation and logistic regression analysis indicated that serum osteocalcin and alkaline phosphatase levels were negatively correlated with the mortality. Furthermore, the receiver-operating characteristic curve analysis showed serum osteocalcin had the largest area under the curve of 0.855 among four biochemical parameters, and serum osteocalcin < 65.9 ng/ml displayed a good capacity to discriminate the non-survivors from survivors in FOP patients aged 18 years and younger at diagnosis. CONCLUSIONS: Our findings showed that the mortality rate of FOP was 13.8% in China. Serum OC level was negatively correlated with the mortality in Chinese FOP patients ≤18 years at diagnosis.


Assuntos
Miosite Ossificante/epidemiologia , Miosite Ossificante/mortalidade , Ossificação Heterotópica/epidemiologia , Ossificação Heterotópica/mortalidade , Osteocalcina/sangue , Receptores de Ativinas Tipo I/genética , Adolescente , Fosfatase Alcalina/sangue , Criança , Pré-Escolar , China/epidemiologia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Mortalidade , Mutação , Miosite Ossificante/sangue , Miosite Ossificante/diagnóstico , Ossificação Heterotópica/sangue , Ossificação Heterotópica/diagnóstico , Doenças Raras/sangue , Doenças Raras/diagnóstico , Doenças Raras/epidemiologia , Doenças Raras/mortalidade , Estudos Retrospectivos
2.
Pediatr Rheumatol Online J ; 17(1): 84, 2019 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-31864380

RESUMO

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is the most catastrophic form of heterotopic ossification, due to ongoing intracellular signaling through the bone morphogenic protein pathway. The paroxysmal appearance of inflammatory lumps and elevated inflammatory markers during flares, suggest that FOP is an auto-inflammatory disease. Based on evidence, demonstrating a role for interleukin-1ß (IL-1ß) in other forms of heterotopic ossification, we hypothesized that treating FOP patients with anti-IL-1 agents could help lower the rate of FOP paroxysms and/or limit the symptoms and residual lesions. CASE PRESENTATION: A 13.5-year-old Arab boy was diagnosed with FOP. Treatment with anti-inflammatory drugs did not change the disease course. New lumps appeared in a rate of approximately one every 8 days. Treatment with the anti-IL-1 agents anakinra and canakinumab resulted in significantly lower rate of paroxysms (every 22-25 days, of which almost all involved only 2 existing lumps), as well as shorter duration. High levels of IL-1ß were found in the patient's plasma samples, collected during a paroxysm that appeared 8 weeks after the last canakinumab dose. In contrast, IL-1ß plasma levels were undetectable in the previous three plasma samples, obtained while he was treated with anti-IL-1 agents. CONCLUSIONS: Our data demonstrate the efficacy of anti-IL-1 agents in the treatment of a patient with FOP. Results showing the marked increase in IL-1ß plasma levels during a paroxysm support a role for IL-1ß in the pathogenesis of FOP and further provide the rationale for the use of anti-IL-1 agents in FOP treatment.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Interleucina-1beta/sangue , Miosite Ossificante/sangue , Adolescente , Biomarcadores/sangue , Progressão da Doença , Humanos , Interleucina-1beta/antagonistas & inibidores , Imageamento por Ressonância Magnética , Masculino , Miosite Ossificante/diagnóstico , Miosite Ossificante/tratamento farmacológico , Tomografia Computadorizada por Raios X
3.
Med Hypotheses ; 131: 109313, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443758

RESUMO

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disease caused by a mutation in the intracellular domain of the activin A receptor type I and is characterized by episodes (flare-ups) of progressive heterotopic endochondral ossification (HO) in the soft tissues. The mutation alone is not sufficient for the occurrence of HO since flare-ups are triggered by inflammation and activation of the innate immune system. A number of cellular and humoral mediators have been implicated in animal and in vitro models. Observations in humans support the inflammatory nature of the condition, but data on the involved mediators are variable. We hypothesize that for induction of flare-ups in patients with FOP increase in at least one of the pro-inflammatory cytokines is both essential and sufficient to trigger the entire process of the inflammatory cells influx resulting in the novel ectopic bone formation and we suggest that C-C motif ligand 5 (CCL5), a pro-inflammatory chemokine also known as Regulated on activation, normal T-cell expressed and secreted (RANTES), might be the key candidate. CCL5 is a chemoattractant for all cellular types implicated in HO and is produced by the cells of the tissue microenvironment at the sites of HO as well as by the pro-inflammatory cellular mediators. CCL5 induces ossification in cultured human pluripotent mesenchymal cells (hMSCs) and in the primary culture of monocytes from FOP patients (but not from their healthy relatives), stimulation with lipopolysaccharide induces CCL5 expression. Finally, in a pilot study we used a panel of 23 cytokines and chemokines to screen the plasma samples of three subjects: a female patient with FOP during a flare-up; a female patient with hyperostosis corticalis generalisata (van Buchem disease), another rare disease characterized by excessive bone formation at the sites where it regularly occurs that does not include inflammatory events; and a healthy woman without bone disorders. There appeared a rather clear-cut signal of a 2-fold higher level of CCL5 in the FOP patient vs. the healthy subject and the van Buchem patient. Evaluation of the hypothesis would require an international prospective study, with main motivation being the lack of a conclusive treatment as the major unmet need in FOP. A treatment targeting CCL5 receptor already exists and is used in HIV-infected patients.


Assuntos
Quimiocina CCL5/sangue , Terapia de Alvo Molecular , Miosite Ossificante/sangue , Ossificação Heterotópica/sangue , Quimiocina CCL5/antagonistas & inibidores , Citocinas/fisiologia , Feminino , Humanos , Inflamação , Lipopolissacarídeos/farmacologia , Células-Tronco Mesenquimais/metabolismo , Modelos Imunológicos , Monócitos/metabolismo , Miosite Ossificante/tratamento farmacológico , Miosite Ossificante/imunologia , Ossificação Heterotópica/imunologia , Osteocondrodisplasias/sangue , Células-Tronco Pluripotentes/metabolismo
4.
Am J Med Genet A ; 179(9): 1764-1777, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31240838

RESUMO

Diffuse idiopathic skeletal hyperostosis (DISH) is a disorder principally characterized by calcification and ossification of spinal ligaments and entheses. Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disabling disorder characterized by progressive ossification of skeletal muscle, fascia, tendons, and ligaments. These conditions manifest phenotypic overlap in the ossification of tendons and ligaments. We describe herein a patient with DISH, exhibiting heterotopic ossification of the posterior longitudinal ligament where clinical whole exome sequencing identified a variant within ACVR1, a gene implicated in FOP. This variant, p.K400E, is a novel variant, not identified previously, and occurs in a highly conserved region across orthologs. We used sequence-based predicative algorithms, molecular modeling, and molecular dynamics simulations, to test the potential for p.K400E to alter the structure and dynamics of ACVR1. We applied the same modeling and simulation methods to established FOP variants, to identify the detailed effects that they have on the ACVR1 protein, as well as to act as positive controls against which the effects of p.K400E could be evaluated. Our in silico molecular analyses support p.K400E as altering the behavior of ACVR1. In addition, functional testing to measure the effect of this variant on BMP-pSMAD 1/5/8 target genes was carried out which revealed this variant to cause increased ID1 and Msx2 expression compared with the wild-type receptor. This analysis supports the potential for the variant of uncertain significance to contribute to the patient's phenotype.


Assuntos
Receptores de Ativinas Tipo I/genética , Músculo Esquelético/metabolismo , Miosite Ossificante/genética , Ossificação do Ligamento Longitudinal Posterior/genética , Ossificação Heterotópica/genética , Adolescente , Adulto , Algoritmos , Simulação por Computador , Feminino , Humanos , Ligamentos Longitudinais/fisiopatologia , Masculino , Simulação de Dinâmica Molecular , Músculo Esquelético/fisiopatologia , Mutação/genética , Miosite Ossificante/sangue , Miosite Ossificante/diagnóstico por imagem , Miosite Ossificante/fisiopatologia , Ossificação do Ligamento Longitudinal Posterior/fisiopatologia , Ossificação Heterotópica/diagnóstico por imagem , Ossificação Heterotópica/fisiopatologia , Fenótipo , Transdução de Sinais/genética , Proteínas Smad/genética
5.
JCI Insight ; 3(22)2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30429363

RESUMO

BACKGROUND: Inflammation helps regulate normal growth and tissue repair. Although bone morphogenetic proteins (BMPs) and inflammation are known contributors to abnormal bone formation, how these pathways interact in ossification remains unclear. METHODS: We examined this potential link in patients with fibrodysplasia ossificans progressiva (FOP), a genetic condition of progressive heterotopic ossification caused by activating mutations in the Activin A type I receptor (ACVR1/ALK2). FOP patients show exquisite sensitivity to trauma, suggesting that BMP pathway activation may alter immune responses. We studied primary blood, monocyte, and macrophage samples from control and FOP subjects using multiplex cytokine, gene expression, and protein analyses; examined CD14+ primary monocyte and macrophage responses to TLR ligands; and assayed BMP, TGF-ß activated kinase 1 (TAK1), and NF-κB pathways. RESULTS: FOP subjects at baseline without clinically evident heterotopic ossification showed increased serum IL-3, IL-7, IL-8, and IL-10. CD14+ primary monocytes treated with the TLR4 activator LPS showed increased CCL5, CCR7, and CXCL10; abnormal cytokine/chemokine secretion; and prolonged activation of the NF-κB pathway. FOP macrophages derived from primary monocytes also showed abnormal cytokine/chemokine secretion, increased TGF-ß production, and p38MAPK activation. Surprisingly, SMAD phosphorylation was not significantly changed in the FOP monocytes/macrophages. CONCLUSIONS: Abnormal ACVR1 activity causes a proinflammatory state via increased NF-κB and p38MAPK activity. Similar changes may contribute to other types of heterotopic ossification, such as in scleroderma and dermatomyositis; after trauma; or with recombinant BMP-induced bone fusion. Our findings suggest that chronic antiinflammatory treatment may be useful for heterotopic ossification.


Assuntos
Receptores de Ativinas Tipo I/sangue , Inflamação/complicações , Miosite Ossificante/complicações , NF-kappa B/sangue , Ossificação Heterotópica/etiologia , Quimiocinas/sangue , Citocinas/sangue , Humanos , Inflamação/sangue , Macrófagos/metabolismo , Monócitos/metabolismo , Miosite Ossificante/sangue , Miosite Ossificante/imunologia , Ossificação Heterotópica/sangue , Ossificação Heterotópica/imunologia , Transdução de Sinais , Fator de Crescimento Transformador beta/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/sangue
6.
J Trace Elem Med Biol ; 39: 186-192, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27908413

RESUMO

Fibrodysplasia Ossificans Progressiva (FOP) is a rare inherited disease characterized by progressive heterotopic ossification. Disease onset, severity and symptoms vary between FOP patients, as does the frequency and activity of so-called flare-ups, during which tendons, ligaments, muscle and soft tissue are replaced by bone. Traumata, infections or other stressors are known inducers of flare-ups, and the hormone Activin A may be involved in disease activity; however, reliable biomarkers for FOP activity are missing, and the basal trace element and inflammatory state of patients are unknown. We hypothesized that FOP patients develop characteristic deficiencies in inflammation-related trace elements and display a chronically increased inflammatory cytokine level, collectively aggravating disease course and flare-up risk. Serum samples from 15 FOP patients and 25 relatives were collected under highest quality standards. Concentrations of Cu, Se and Zn were determined by total reflection X-ray fluorescence, and 27 cytokines along with Activin A by specific antibody-based techniques. Data were tested for normal distribution and analyzed by parametric or non-parametric tests. Concentrations of Se and Cu were not different between the groups, while Zn levels were slightly higher in FOP as compared to controls (1110±251 vs. 970±176ng/ml, P=0.04). The average concentrations of cytokines and Activin A were not different. When focusing on the two patients with self-reported flare-ups, again no obvious differences were noted. The cytokines Eotaxin, G-CSF, hbFGF and TNF-α were within the upper half of measured concentrations, and may warrant further longitudinal analyses. Our data do not support the hypothesis that FOP patients display a characteristic pattern of trace elements or have a generally increased tone of pro-inflammatory cytokines.


Assuntos
Citocinas/sangue , Miosite Ossificante/sangue , Oligoelementos/sangue , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
Orphanet J Rare Dis ; 8: 163, 2013 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-24131551

RESUMO

BACKGROUND: Currently, there are no effective medical treatment options to prevent the formation of heterotopic bones in fibrodysplasia ossificans progressiva (FOP). By the drug repositioning strategy, we confirmed that perhexiline maleate (Pex) potentially ameliorates heterotopic ossification in model cells and mice. Here, we conducted a prospective study to assess the efficacy and safety of Pex in the treatment of FOP patients. METHODS: FOP patients in this open-label single-center study were treated with Pex for a total of 12 months, and followed up for 12 consecutive months after medication discontinuation. The safety of the treatment was assessed regularly by physical and blood examinations. The efficacy of Pex for preventing heterotopic ossifications was evaluated by the presence of flare-ups, measurements of serum bone markers, and changes in the total bone volume calculated by the three-dimensional computed tomography (3D-CT) images. RESULTS: Five patients with an average age of 23.4 years were enrolled. Within safe doses of Pex administration in each individual, there were no drug-induced adverse effects during the medication phase. Three patients showed no intense inflammatory reactions during the study period, while two patients had acute flare-ups around the hip joint without evidence of trauma during the medication phase. In addition, one of them became progressively incapable of opening her mouth over the discontinuation phase. Serum levels of alkaline phosphatase (ALP) and bone specific ALP (BAP) were significantly and synchronously increased with the occurrence of flare-ups. Volumetric 3D-CT analysis demonstrated a significant increase in the total bone volume of Case 2 (378 cm(3)) and Case 3 (833 cm(3)) during the two-year study period. CONCLUSIONS: We could not prove the efficacy of oral Pex administration in the prevention of heterotopic ossifications in FOP. Serum levels of ALP and BAP appear to be promising biomarkers for monitoring the development of ectopic ossifications and efficacy of the therapy. Quantification of change in the total bone volume by whole body CT scanning could be a reliable evaluation tool for disease progression in forthcoming clinical trials of FOP.


Assuntos
Miosite Ossificante/tratamento farmacológico , Perexilina/análogos & derivados , Adolescente , Adulto , Fosfatase Alcalina/sangue , Feminino , Humanos , Masculino , Miosite Ossificante/sangue , Miosite Ossificante/diagnóstico por imagem , Osteocalcina/sangue , Perexilina/uso terapêutico , Radiografia , Adulto Jovem
8.
J Orthop Sci ; 8(2): 239-42, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12665965

RESUMO

Myositis ossificans is a benign heterotopic ossifying condition of soft tissues. The lesion may cause persistent functional impairment of adjacent joints. Surgical intervention is often needed to regain normal function, even though a high recurrence rate is reported. In the present case, we found that recurrent myositis ossificans could not be demonstrated by radiography during the early stage. However, ultrasonography proved to be an excellent tool for detecting early recurrence of myositis ossificans and for distinguishing the condition from extraosseous sarcomas.


Assuntos
Miosite Ossificante/diagnóstico por imagem , Fosfatase Alcalina/sangue , Traumatismos do Tornozelo/complicações , Criança , Humanos , Masculino , Miosite Ossificante/sangue , Miosite Ossificante/patologia , Miosite Ossificante/cirurgia , Recidiva , Entorses e Distensões/complicações , Tomografia Computadorizada por Raios X , Ultrassonografia
9.
Acta Orthop Belg ; 67(1): 86-9, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11284280

RESUMO

Myositis ossificans progressiva is a rare connective tissue disorder. We present here a case of myositis ossificans progressiva with some unusual presentations and associated congenital skeletal anomalies that are reported very infrequently in the literature. The case report highlights the importance of early diagnosis in a case of rapidly progressive myositis ossificans progressiva.


Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Articulação do Cotovelo/anormalidades , Miosite Ossificante/complicações , Miosite Ossificante/diagnóstico por imagem , Articulação do Ombro/anormalidades , Anormalidades Múltiplas/sangue , Anormalidades Múltiplas/genética , Adolescente , Progressão da Doença , Humanos , Masculino , Miosite Ossificante/sangue , Miosite Ossificante/genética , Radiografia
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