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 ACVR1 ^R206H 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.

Keywords: ACVR1; BMP signaling; FOP; fibrodysplasia ossificans progressiva; great toe malformation; hallux valgus; skeletal development.

FIGURE 1

The FOP great toe malformation with monophalangeal or biphalangeal hallux. (A,B) Representative control radiographs at 2 months and 8 years of age. Note the presence of three phalanges (p) in each digit except the first, which has two. (C–E) Radiographs from three FOP subjects at different ages illustrate the two major presentations of the great toe malformation: monophalangeal hallux (p2 only; C,E) and biphalangeal hallux (p1 and p2; D,E). (C) Radiograph of a subject at 4 years of age shows bilateral monophalangism, with p1 being absent in both feet. Severe hallux valgus is evident (hallux valgus angle > 15°, illustrated). By this age, ectopic ossification centers (EOC; arrowheads) have fused to the metatarsal heads. (C’) At age 14, the same subject shows large epiphyses (e) associated with the remaining phalanx, medially deviated metatarsals with malformed heads (asterisk), and laterally deviated hallucal sesamoids (s); the fibular sesamoid is clearly visible, whereas the tibial sesamoid is masked by the metatarsal. (D) Radiographs of a subject at 10 years of age showing biphalangism, with both phalanges of the first digit present in both feet. Hallux valgus is minor, consistent with other subjects with this morphological progression. This subject additionally presents with biphalangeal digits 4 and 5, though this is not considered a hallmark of FOP. (D’) At age 16, the phalanges of the first digit have completely fused, which is characteristic of biphalangeal hallux in FOP (detailed in Supplementary Figure 1). (E) One subject, imaged at 9 months of age, presents with both a proximal and distal phalanx in the left foot and only the distal phalanx in the right foot. Note the asymmetric, amorphous shape of the proximal phalanx as contrasted with the rectangular, symmetrical morphology of the proximal phalanges in A. The right foot shows more severe hallux valgus than the left, but both feet have EOCs distal and medial to the first metatarsal (arrowheads). (E’) Two years later, the EOCs have both fused to the metatarsal head. (F–H) Illustrations of the skeletal elements of the human mid- and forefoot with (F) all usual elements in adulthood (control), (G) the monophalangeal FOP phenotype, and (H) the biphalangeal FOP phenotype. Digits (d) are numbered d1 to d5 from medial to lateral and phalanges (p) are numbered proximal to distal. By X-ray, primary ossification centers (POC) of each element are visible before their respective secondary ossification centers (SOC) can be seen. Midfoot elements, including the tarsals, are included for reference and are numbered according to their respective articulating digits. Sesamoids (s) are normally associated only with the hallux but may arise at the metatarsophalangeal joints of the second and/or fifth digits. The characteristic EOC medial and distal to the metatarsal of the hallux seen in FOP patients is marked in (G,H). In (E’,H), phalanges affected by LEPB or “delta phalanx” (also see Figure 2) are labeled as Δp1.

FIGURE 2

Longitudinal epiphyseal bracket in subjects with FOP. (A) Radiograph showing longitudinal epiphyseal bracket (LEPB; ep) of the proximal phalanx (p) of the great toe in a subject with FOP. A phalanx affected by LEPB may be referred to as delta phalanx, here labeled as Δp1. An apparent ectopic ossification center (EOC) distal to the metatarsal (mt) head is present. (B) Radiograph showing compound LEPB of the proximal phalanx, with outlines for clarity in (B’). Dotted lines denote distinct osseous elements occurring in concentric hemi-circles. Age (in years) and sex (F, M) of each subject, bottom right of each panel.

FIGURE 3

Progression of the FOP great toe malformation. Radiographs from a single FOP subject with monophalangeal hallux from birth to approximately 4 years of age illustrate the persistence of hallux valgus and the progression of the ectopic ossification center (EOC; black arrowheads). (A) At birth, the EOC is evident as a miniscule, radio-positive region distal and medial to the head of the first metatarsal. (B,C) Over time, the EOC increases in size and proximity to the metatarsal, with little to no growth distally relative to the phalanx. (D) The secondary ossification center of the remaining phalanx (white arrowheads D,E) forms immediately proximal to the phalanx, distinct from the EOC. (E) Finally, bone appears to fully bridge the EOC and the metatarsal (black arrowhead), fusing them together.

FIGURE 4

Uncommon forefoot phenotypes in FOP. (A,B) Radiographs from two patients reveal osseous syndactyly (black arrowheads) between metatarsals of digits 3 and 4 (A) and among digits 3, 4, and 5 (B). White arrowheads indicate the dysmorphic metatarsal heads (all panels), corresponding to the position of the ectopic ossification center noted in nearly all subjects with FOP. In B, extra-articular HO bridges the metatarsophalangeal joint of digit 5 (black asterisk) and HO is present in d2. (C) One of two identified patients presenting with atypical proximal metatarsal growth plates in digits 2–5 (white asterisks). Age (in years) and sex (F, M) of each subject, bottom right of each panel.