Fibrodysplasia ossificans progressiva (FOP): watch the great toes!

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder and the most disabling condition of heterotopic (extraskeletal) ossification in humans. Extraskeletal bone formation associated with inflammation preceding the osseous conversion usually begins in the first decade, predominantly in the head, neck, and shoulders. All patients have malformed great toes. Most patients have a spontaneous mutation of the ACVR1 gene. We report a 17-year-old girl with malformed great toes who had her first episode of heterotopic ossification and impaired mobility of the left hip at the age of 13 years. No inflammatory fibroproliferative masses preceded the onset of heterotopic ossification. Radiographic studies demonstrated myositis ossificans, but failure to associate the great toe malformation with heterotopic ossification led to a failure to diagnose FOP. She underwent repeated and unnecessary operative procedures to remove a recurrent lesion. FOP was finally suspected when the great toe malformation was correlated with the trauma-induced heterotopic ossification. Genetic analysis confirmed the presence of the classic FOP mutation (ACVR1 c.617G>A; R206H). This case highlights the importance of examining the great toes in anyone with heterotopic ossification. The association of malformations of the great toe with heterotopic ossification in all cases of classic FOP will lead to prompt clinical diagnosis and the prevention of iatrogenic harm.

Figure 1

Radiographic examination of the feet reveals malformations of the first metatarsals and monophalangism of both great toes.

Figure 2

Radiographic examination of the right knee shows osteochondromas of the distal femur and proximal tibia.

Figure 3

Radiographic examination of the left hip exhibits extensive heterotopic ossification. The X-ray is taken after the third surgery and recurrence.

Figure 4

Sequencing chromatogram of the patient, showing the classic FOP mutation within the ACVR1 gene (c.617G>A; R206H). A G>A heterozygous substitution in nucleotide 617 of the protein-coding sequence of the ACVR1 gene was detected by direct DNA sequence analysis of genomic DNA. Nucleotides are represented by colored peaks in the electropherogram: A (green), C (blue), G (black), A (red). R = A/G. The mutation occurs in codon 206 (indicated by boxed area) and replaces arginine with histidine.