Natural history and treatment of fibrous dysplasia of bone: a multicenter clinicopathologic study promoted by the European Pediatric Orthopaedic Society

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ABSTRACT:At a time when significant attention is devoted worldwide to stem cells as a potential tool for curing incurable diseases, fibrous dysplasia of bone (FD) provides a paradigm for stem cell diseases. Consideration of the time and mechanism of the causative mutations and of nature of the pluripotent cells that mutate in early embryonic development indicates that, as a disease of the entire organism, FD can be seen as a disease of pluripotent embryonic cells. As a disease of bone as an organ, in turn, FD can be seen as a disease of postnatal skeletal stem cells, which give rise to dysfunctional osteoblasts. Recognizing FD as a stem cell disease provides a novel conceptual angle and a way to generate appropriate models of the disease, which will continue to provide further insight into its natural history and pathogenesis. In addition, skeletal stem cells may represent a tool for innovative treatments. These can be conceived as directed to alter the in vivo behavior of mutated stem cells, to replace mutated cells through local transplantation, or to correct the genetic defect in the stem cells themselves. In vitro and in vivo models are currently being generated that will permit exploration of these avenues in depth.

Section: Riminucci Et Al P128mentioning

confidence: 99%

Section: Fibrous Dysplasia and Stem Cells P127mentioning

confidence: 99%

Section: Fibrous Dysplasia and Stem Cells P127mentioning

confidence: 99%

Section: Fibrous Dysplasia and Stem Cells P127mentioning

confidence: 99%

mentioning

confidence: 99%

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Fibrous Dysplasia as a Stem Cell Disease

Riminucci

Saggio

Robey

et al. 2006

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Constitutive Expression of GsαR201C in Mice Produces a Heritable, Direct Replica of Human Fibrous Dysplasia Bone Pathology and Demonstrates Its Natural History

Saggio

Remoli

Spica

et al. 2014

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Fibrous dysplasia of bone (FD) is a crippling skeletal disease associated with post zygotic mutations (R201C, R201H) of the gene encoding the α subunit of the stimulatory G protein, Gs. By causing a characteristic structural subversion of bone and bone marrow, the disease results in deformity, hypomineralization, and fracture of the affected bones, with severe morbidity arising in childhood or adolescence. Lack of inheritance of the disease in humans is thought to reflect embryonic lethality of germline-transmitted activating Gsα mutations, which would only survive through somatic mosaicism. We have generated multiple lines of mice that express GsαR201C constitutively and develop an inherited, histopathologically exact replica of human FD. Robust transgene expression in neonatal and embryonic tissues, and embryonic stem (ES) cells was associated with normal development of skeletal tissues and differentiation of skeletal cells. As in humans, FD lesions in mice developed only in the postnatal life; a defined spatial and temporal pattern characterized the onset and progression of lesions across the skeleton. In individual bones, lesions developed through a sequence of three distinct histopathological stages: a primary modeling phase defined by endosteal/medullary excess bone formation, and normal resorption; a secondary phase, with excess, inappropriate remodeling; and a tertiary fibrous dysplastic phase, which reproduced a full-blown replica of the human bone pathology in mice of age ≥1 year. Gsα mutations are sufficient to cause FD, and are per se compatible with germline transmission and normal embryonic development in mice. Our novel murine lines constitute the first model of FD.

Prognostic Factors From an Epidemiologic Evaluation of Fibrous Dysplasia of Bone in a Modern Cohort: The FRANCEDYS Study

Benhamou

Gensburger

Messiaen

et al. 2016

Fibrous dysplasia of bone (FD) is a rare genetic but sporadic bone disease that can be responsible for bone pain, fracture, and bone deformity. The prognosis may be difficult to establish because of the wide spectrum of disease severity. We have analyzed the data from the French National Reference center for FD. We have established a database from standardized medical records. We have made descriptive statistics of the various forms of FD and examined the prognostic factors by multivariable logistic regression analysis, with a parsimonious stepwise method. The primary outcome was a clinically relevant composite index combining bone pain (visual analogic scale >3) and/or incident fracture. In our modern cohort of 372 patients, the median age at diagnosis was 23 years. The revealing symptom (at a median age of 18 years) was bone pain in 44% of patients and a fracture in 9%, but the diagnosis was fortuitous in 25% of cases. Monostotic forms represented 58% of patients and polyostotic forms 42%. The femur was the most commonly affected bone (44% of patients), followed by the skull (38%). Twelve percent of patients had McCune-Albright syndrome (MAS). With a median duration of follow-up of 7 years among 211 patients, we observed an incidence of fracture of 17% and 51% of patients had no bone pain at the end of follow-up (with or without bisphosphonate therapy). In univariate analysis, younger age at diagnosis, renal phosphate wasting, a polyostotic form, prevalent fracture, and bisphosphonate use were significant predictors. In the multivariate model, the polyostotic form and bisphosphonate use remained significant predictors. In conclusion, in a national referral center for FD, one patient on follow-up out of six had incident fracture. A polyostotic form was the main risk factor of a poorer outcome. © 2016 American Society for Bone and Mineral Research.