The Developmental Phenotype of the Great Toe in Fibrodysplasia Ossificans Progressiva

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which extensive heterotopic ossification (HO) begins to form during early childhood and progresses throughout life. Although HO does not occur during embryonic development, children who carry the ACVR1R206H mutation that causes most cases of FOP characteristically exhibit malformation of their great toes at birth, indicating that the mutation acts during embryonic development to alter skeletal formation. Despite the high prevalence of the great toe malformation in the FOP population, it has received relatively little attention due to its clinically benign nature. In this study, we examined radiographs from a cohort of 41 FOP patients ranging from 2 months to 48 years of age to provide a detailed analysis of the developmental features, progression, and variability of the great toe malformation of FOP, which include absent skeletal structures, malformed epiphyses, ectopic ossification centers, malformed first metatarsals and phalangeal fusion.

BMP signaling and skeletal development in fibrodysplasia ossificans progressiva (FOP)

“…Often, subjects with a proximal phalanx have longitudinal epiphyseal bracket, 94 a condition in which the secondary ossification center extends along the medial edge of the phalanx and changes its shape 95 (Figure 2B′), similar to the altered growth plate polarity in the Acvr1 R206H mouse models. Additionally, the great majority of subjects, with or without both phalanges, have a small, ectopic osseous body 93,94 . This ossicle fuses with and subsequently deforms the first metatarsal in a manner closely resembling growth plate closure and is thus hypothesized to be an ectopic secondary ossification center 94 …”

“…Additionally, the great majority of subjects, with or without both phalanges, have a small, ectopic osseous body. 94,95 This ossicle fuses with and subsequently deforms the first metatarsal in a manner closely resembling growth plate closure and is thus hypothesized to be an ectopic secondary ossification center. 95 At least 12 non-R206H mutations in ACVR1 have been associated with FOP.…”

“…94,95 This ossicle fuses with and subsequently deforms the first metatarsal in a manner closely resembling growth plate closure and is thus hypothesized to be an ectopic secondary ossification center. 95 At least 12 non-R206H mutations in ACVR1 have been associated with FOP. 24,97 Like the R206H mutation, these extremely rare 'variant' mutations enhance ACVR1-pSMAD1/5 signaling activity but show a range of signaling activity responses that may be due to specific molecular mechanisms.…”

“…This unique feature can be used as a reliable diagnostic tool to identify cases of FOP at birth, and prior to the onset of HO or confirmation by genetic testing for causative mutations in ACVR1 54 . These toe malformations are due to loss of joint function, 16 reduced lengths of the phalanges, 93 and, in roughly half of cases, failure to form the proximal phalanx (p1; Figure 2B,B′) 94 . In the other 50% of cases, subjects form both phalanges (p1 and p2) but consistently show eventual fusion of these phalanges late in adolescence 94 .…”

“…These toe malformations are due to loss of joint function, 16 reduced lengths of the phalanges, 93 and, in roughly half of cases, failure to form the proximal phalanx (p1; Figure 2B,B′) 94 . In the other 50% of cases, subjects form both phalanges (p1 and p2) but consistently show eventual fusion of these phalanges late in adolescence 94 . The progression of this fusion as observed radiographically suggests that a complete cleavage furrow in the interphalangeal joint never forms and any furrow that does form deteriorates with age, although the evolution of this phenotype over time has only been observed in a small number of FOP patients.…”