Osteochondromas in fibrodysplasia ossificans progressiva: a widespread trait with a streaking but overlooked appearance when arising at femoral bone end

Abstract

Metaphyseal bony outgrowths are a well-recognized feature of fibrodysplasia ossificans progressiva (FOP) phenotype, but its genuine frequency, topographic distribution, morphological aspect, and potential implications are not fully established. To better ascertain the frequency and characteristics of osteocartilaginous exostoses in FOP disease, we conducted a cross-sectional radiological study based on all the traceable cases identified in a previous comprehensive national research. Metaphyseal exostoses were present in all the 17 cases of FOP studied. Although most often arising from the distal femoral (where metaphyseal exostoses adopt a peculiar not yet reported appearance) and proximal tibial bones, we have found that they are not restricted to these areas, but rather can be seen scattered at a variety of other skeletal sites. Using nuclear magnetic resonance imaging, we show that these exophytic outgrowths are true osteochondromas. As a whole, these results are in agreement with data coming from the literature review. Our study confirms the presence of metaphyseal osteochondromas as a very frequent trait of FOP phenotype and an outstanding feature of its anomalous skeletal developmental component. In line with recent evidences, this might imply that dysregulation of BMP signaling, in addition to promoting exuberant heterotopic ossification, could induce aberrant chondrogenesis and osteochondroma formation. Unveiling the molecular links between these physiopathological pathways could help to illuminate the mechanisms that govern bone morphogenesis.

Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity

“…Also evident were mild overgrowths of endogenous boney protuberances, particularly the deltoid tuberosity, which were observed in 40% of P14 Pdgfrα-R206H mice ( Figure 1C ; Table 1 ). These overgrowths were often stalk-like cartilage-capped projections that morphologically resemble the osteochondromas observed in FOP patients ( Deirmengian et al, 2008 ; Kaplan et al, 1993 ; Morales-Piga et al, 2015 ).…”

“…HO ( Figure 1I ) and osteochondromas ( Figure 1L ) were often detected at the deltoid tuberosity (also see Figure 1—figure supplement 1A–C ). Although it remains formally possible that osteochondromas progressed to HO in Pdgfrα-R206H mice, such an occurrence is rare in human FOP ( Deirmengian et al, 2008 ; Kaplan et al, 1993 ; Morales-Piga et al, 2015 ). Hence, we speculate that HO of the deltoid tuberosity arises from recruitment of nearby intramuscular or intratendinous R206H-FAPs.…”

Bone morphogenetic protein receptor signal transduction in human disease

“…Also, through in vitro experiments, ALK2 mutations have been shown to enhance cell proliferation . Surprisingly, although benign osteochondromas have been reported in the majority of FOP patients , lack of oncogenic predisposition in FOP patients with identical mutations in ACVR1 suggests that the mutant ACVR1 favors tumor development initiated by Histone H3 disruptions. In sporadic colorectal cancer with a microsatellite unstable phenotype, the BMPR2 3′ untranslated region is frequently mutated .…”

Fibrodysplasia ossificans progressiva: Review and research activities in Japan

“…a), but “horn‐shaped” osteochondromas are also recognized in the distal femoral metaphyses, especially in adult patients. Abnormalities in other bones are also reported …”