The Diversity of the Clinical Phenotypes in Patients With Fibrodysplasia Ossificans Progressiva

Abstract

Background: The clinical presentation, phenotypic characterization and natural history of fibrodysplasia ossificans progressiva (FOP) are diverse and the natural history of the disease is, to a certain extent, different from one patient to another.

Methods: In a series of 11 patients (eight girls and three boys, aged 0 - 16 years), variable clinical presentations were the landmarks of these patients. At birth, all of our patients manifested short great toes in a valgus position. Marfan syndrome was the suggested diagnosis in three children aged 3 - 8 years and in two pre-adult patients. Clinical symptoms were torticollis, painful spine, and painful and marked limitation of the pelvic movements. Monophalangia associated with Marfanoid habitus was also a prevailing clinical presentation.

Results: Our results were based upon the appearance of the earliest pathologic feature of FOP in correlation with the clinical presentation. In infants (0 - 1 year), three infants showed congenital hallux valgus and stiff spine. In the pediatric group (3 - 8 years), all children showed no mutation in the fibrillin-1 (FBN1) gene. Their prime presentation was a progressive torticollis with simultaneous development of erythematous subfascial nodules, most commonly located on the posterior neck and back. In pre-adult group (10 - 16 years), four patients presented with monophalangia associated with painful movements because of the progressive heterotopic ossification of the spine and the weight bearing zones and marked elevation of alkaline phosphatase. Genetic confirmation has been performed in six patients who manifested the classical mutation of the ACVR1 gene. The rest of the patients were assessed via clinical and radiographic phenotypes.

Conclusion: The early recognition of FOP can be performed by noticing the short halluces and thumbs at early infancy and later on the high alkaline phosphatase activity in areas of heterotopic ossification. Misconception of FOP is of common practice and eventually unnecessary diagnostic biopsies might deteriorate the progression of the condition. The detection of ACVR1 gene mutation was a confirmatory procedure. Interestingly, the timing of the onset and the location of progressive heterotopic ossifications were extremely variable and confusing among our group of patients.

Keywords: ACVR1 gene mutation; Congenital hallux valgus; FBN1 gene mutation; Fibrodysplasia ossificans progressiva; Imaging; Monophalangia; Progressive joint limitations.

Figure 1

AP radiograph of a 6-month-old girl showed the characteristic shortening and broadening of the first metatarsal which was angulated medially with hypoplasia of the basal phalanx of the first toe - triangular distal phalanx. These features are the earliest in the diagnosis of FOP, making the diagnosis possible before the appearance of soft tissue calcification.

Figure 2

(a) Congenital flexion deformity of the thumbs is another clue for diagnosis. (b) Severe bilateral and symmetrical shortening of the big toes associated with flexion deformities of the second toes respectively.

Figure 3

AP thorax radiograph showed the columns and plaques of ectopic bone in a 7-year-old girl with FOP and situs inversus (note the direction of the apex of the heart). Opacities in the muscles and near the tendons insertions were encountered in all patients with progression from proximal to distal and formation of a true bony bridge between various parts of the skeleton was evident (arrows).

Figure 4

Reformatted CT scan in a 14-year-old girl showed monophalangia with subsequent development of severe shortening of the first metatarsals (secondary to abnormal fusion of the epiphyses).

Figure 5

(a) Progressive episodes of heterotopic ossifications typically lead to ankylosis of all major joints of the axial and appendicular skeleton, rendering movement impossible. AP radiograph of the knees showed a 13-year-old girl presented with progressive painful limitation of range of motion of the both knees with progressive extra-severe articular ankylosis of the left ankle joint. (b) 3D reconstruction CT scan of the pelvis of the same patient (13-year-old) showed two ossified bands originated from the posterior aspect of the right iliac bone, run downwards and where both got fused and inserted beneath the femoral neck adding extra dilemma to the patient.

Figure 6

3D reconstruction CT scan in a 16-year-old girl showed diffuse ankylosing ossification of the inferior margins of the scapulae with that of the spine. On the right side, diffuse ankylosing ossification was noted which extended from the inferior margin of the right scapula with a downward manner to cover the posterior aspect of the ribs (7 - 12) until it got ankylosed with the right margin of S1. On the left side, a longitudinal bar of ossification fused superiorly with the inferior margin of the left scapula with downward extension to involve the posterior aspect of the ribs (6 - 12) and bifurcated to two divisions: one extended upward to involve the shaft of the left humerus (arrow head) and the other branch fused with another bar of ossifcation which run in parallel to other bar, which originated from the spinous process of T11 and extended downwards to fuse with the other ossifcation bar at the level of the spinous process of L4 with eventual formation of a dreadful ankylosis (black arrow) (Fig. 3). These progressive episodes of heterotopic ossifications typically lead to dreadful ankylosis of all major joints of the axial and appendicular skeleton, rendering movement impossible, associated with marked elevation in the alkaline phosphatase level (three times greater than normal).

Figure 7

3D reconstruction CT scan of the pelvis in a 15-year-old female patient showed massive heterotopic ossification around the pelvis and the upper shaft of the left femur and the ischium pubis with eventual development of extra-articular ankyloses (firm bridging from the femur to the pelvis) associated with massive ossification of the soft tissue (i.e. heterotopic ossification formed in the soft tissues above and below the greater trochanter of the femur).