Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva

Abstract

Background: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic ossification of skeletal muscle and soft connective tissues. The disorder is caused by a recurrent missense mutation in the glycine-serine activation domain of activin A receptor type I, a bone morphogenetic protein (BMP) type-I receptor, in all classically affected individuals. Osteochondromas of the proximal part of the tibia are benign osteochondral neoplasms or orthotopic lesions of skeletal remodeling associated with dysregulated BMP signaling and have been considered an atypical feature of fibrodysplasia ossificans progressiva, but they may be underdiagnosed because of their often asymptomatic nature. The purpose of the present study was to determine the prevalence and characteristics of proximal tibial osteochondromas in individuals who have fibrodysplasia ossificans progressiva.

Methods: Over a period of thirty months, we evaluated all patients with new and established fibrodysplasia ossificans progressiva for the presence of proximal tibial osteochondromas on the basis of medical history, physical examination, and radiographic studies. We quantified the prevalence of osteochondromas and characterized the types of osteochondromas to identify relevant trends.

Results: Ninety-six patients (including fifty-two female patients and forty-four male patients) with fibrodysplasia ossificans progressiva were evaluated on the basis of a history and physical examination. Plain radiographs were available for sixty-seven patients. Ninety percent of all patients had osteochondroma of the proximal part of the tibia. These lesions usually were asymptomatic, most commonly were bilateral, and typically were located at the pes anserinus. Seventy-five percent of the lesions were pedunculated, and 25% were sessile.

Conclusions: Proximal tibial osteochondromas are a common phenotypic feature of fibrodysplasia ossificans progressiva, a finding that expands the recognized consequences of recurrent activating mutations in activin A receptor type I to include not only congenital skeletal malformations and heterotopic skeletogenesis but also benign osteochondral neoplasms or orthotopic lesions of skeletal modeling. The present study provides insight into the genetic basis of osteochondroma formation in patients with fibrodysplasia ossificans progressiva and possibly into that of more common conditions in which these lesions occur.

Fig. 1

Lateral photograph (A) and anteroposterior radiograph (B) showing a typical anteromedial proximal tibial osteochondroma in a sixteen-year-old patient with fibrodysplasia ossificans progressiva. The lesion appears as a hard, fixed, nontender mass.

Fig. 2

Anteroposterior radiographs of the proximal parts of the right tibiae in two patients with fibrodysplasia ossificans progressiva. In our patients with fibrodysplasia ossificans progressiva, most osteochondromas were pedunculated (A), although some appeared sessile (B). These radiographs show osteochondromas (arrows) composed of cortical and medullary bone that is continuous with the underlying native osseous cortex and medullary canal.

Fig. 3

Hypothetical model of the molecular pathogenesis of osteochondromas in multiple hereditary exostoses and fibrodysplasia ossificans progressiva. A, Multiple hereditary exostoses is a condition caused by mutations within the EXT family of genes, leading to deficient biosynthesis of heparan sulfate proteoglycans (HSPGs), hyperactivity of Indian hedgehog (Ihh), and a proposed resulting dysregulation of the BMP/Ihh/PTHrP feedback loop in the growth plate and perichondrium. Fibrodysplasia ossificans progressiva is caused by a mutation in the gene encoding ACVR1, a bone morphogenetic protein type-I receptor, leading to abnormal BMP signaling and a proposed dysregulation of the BMP/Ihh/PTHrP feedback loop in the growth plate and perichondrium. The model proposes that the BMP/Ihh/PTHrP regulatory loop is the common signaling pathway in the pathogenesis of osteochondromas in the two genetic diseases. B, Normal regulation of the BMP/Ihh/PTHrP pathway. Arrows signify stimulation, and lines ending in bars signify inhibition. C, Abnormal signaling pathways in multiple hereditary exostoses and fibrodysplasia ossificans progressiva. For multiple hereditary exostoses, abnormal EXT1/2 (EXT1/2*) leads to deficient synthesis of heparan sulfate proteoglycans (HSPGs*), resulting in increased Ihh and BMP activity via diminished inhibition (unbolded lines and bars). For fibrodysplasia ossificans progressiva, constitutively active ACVR1 (ACVR1^*) is postulated to cause hyperstimulation of Ihh (left bolded arrow) and, subsequently, of PTHrP (right bolded arrow). In both multiple hereditary exostoses and chicken models having fibrodysplasia ossificans progressiva-like features, hyperactive Ihh results in abnormalities in the regulation of chondrocyte differentiation and leads to osteochondroma formation.

Fig. 3

Hypothetical model of the molecular pathogenesis of osteochondromas in multiple hereditary exostoses and fibrodysplasia ossificans progressiva. A, Multiple hereditary exostoses is a condition caused by mutations within the EXT family of genes, leading to deficient biosynthesis of heparan sulfate proteoglycans (HSPGs), hyperactivity of Indian hedgehog (Ihh), and a proposed resulting dysregulation of the BMP/Ihh/PTHrP feedback loop in the growth plate and perichondrium. Fibrodysplasia ossificans progressiva is caused by a mutation in the gene encoding ACVR1, a bone morphogenetic protein type-I receptor, leading to abnormal BMP signaling and a proposed dysregulation of the BMP/Ihh/PTHrP feedback loop in the growth plate and perichondrium. The model proposes that the BMP/Ihh/PTHrP regulatory loop is the common signaling pathway in the pathogenesis of osteochondromas in the two genetic diseases. B, Normal regulation of the BMP/Ihh/PTHrP pathway. Arrows signify stimulation, and lines ending in bars signify inhibition. C, Abnormal signaling pathways in multiple hereditary exostoses and fibrodysplasia ossificans progressiva. For multiple hereditary exostoses, abnormal EXT1/2 (EXT1/2*) leads to deficient synthesis of heparan sulfate proteoglycans (HSPGs*), resulting in increased Ihh and BMP activity via diminished inhibition (unbolded lines and bars). For fibrodysplasia ossificans progressiva, constitutively active ACVR1 (ACVR1^*) is postulated to cause hyperstimulation of Ihh (left bolded arrow) and, subsequently, of PTHrP (right bolded arrow). In both multiple hereditary exostoses and chicken models having fibrodysplasia ossificans progressiva-like features, hyperactive Ihh results in abnormalities in the regulation of chondrocyte differentiation and leads to osteochondroma formation.

Fig. 3

Hypothetical model of the molecular pathogenesis of osteochondromas in multiple hereditary exostoses and fibrodysplasia ossificans progressiva. A, Multiple hereditary exostoses is a condition caused by mutations within the EXT family of genes, leading to deficient biosynthesis of heparan sulfate proteoglycans (HSPGs), hyperactivity of Indian hedgehog (Ihh), and a proposed resulting dysregulation of the BMP/Ihh/PTHrP feedback loop in the growth plate and perichondrium. Fibrodysplasia ossificans progressiva is caused by a mutation in the gene encoding ACVR1, a bone morphogenetic protein type-I receptor, leading to abnormal BMP signaling and a proposed dysregulation of the BMP/Ihh/PTHrP feedback loop in the growth plate and perichondrium. The model proposes that the BMP/Ihh/PTHrP regulatory loop is the common signaling pathway in the pathogenesis of osteochondromas in the two genetic diseases. B, Normal regulation of the BMP/Ihh/PTHrP pathway. Arrows signify stimulation, and lines ending in bars signify inhibition. C, Abnormal signaling pathways in multiple hereditary exostoses and fibrodysplasia ossificans progressiva. For multiple hereditary exostoses, abnormal EXT1/2 (EXT1/2*) leads to deficient synthesis of heparan sulfate proteoglycans (HSPGs*), resulting in increased Ihh and BMP activity via diminished inhibition (unbolded lines and bars). For fibrodysplasia ossificans progressiva, constitutively active ACVR1 (ACVR1^*) is postulated to cause hyperstimulation of Ihh (left bolded arrow) and, subsequently, of PTHrP (right bolded arrow). In both multiple hereditary exostoses and chicken models having fibrodysplasia ossificans progressiva-like features, hyperactive Ihh results in abnormalities in the regulation of chondrocyte differentiation and leads to osteochondroma formation.