Fibrodysplasia ossificans progressiva is an extremely rare and disabling genetic condition characterized by progressive heterotopic ossification of soft tissues such as muscles, ligaments, tendons, fasciae, and aponeuroses. The prevalence of fibrodysplasia ossificans progressiva is estimated to be about one in 2 million individuals1. Heterotopic ossification in fibrodysplasia ossificans progressiva usually begins in the first decade of life with the episodic development of inflammatory fibroproliferative masses in the axial skeleton. Most patients with fibrodysplasia ossificans progressiva are misdiagnosed as having soft-tissue sarcoma or aggressive juvenile fibromatosis before the definitive appearance of heterotopic ossification and undergo invasive procedures that usually lead to the acceleration of ossification2. Early correct diagnosis of fibrodysplasia ossificans progressiva is necessary to prevent additional iatrogenic harm or trauma.
At the molecular level, dysregulated bone morphogenetic protein (BMP) signaling is associated with the formation of heterotopic ossification in fibrodysplasia ossificans progressiva. Patients with classical features of the disease have the same heterozygous missense mutation in the glycine-serine activation domain of activin A receptor type-I gene (ACVR1), a BMP type-I receptor3. The causative mutation of fibrodysplasia ossificans progressiva is a recurrent single-nucleotide substitution at position 617 (c.617G>A; R206H) in the ACVR1 gene, which is one of the most specific disease-causing mutations in the human genome. This mutant receptor constitutively activates BMP signaling without binding of ligands4. A unique and recurrent mutation has great relevance for diagnostic purposes in the case of fibrodysplasia ossificans progressiva. Definitive molecular diagnosis of fibrodysplasia ossificans progressiva is now available at early stages of disease development, when misdiagnosis is most likely to occur. Clinical awareness of the preosseous features of the disease is necessary for the early diagnosis of fibrodysplasia ossificans progressiva.
In the present study, we describe the cases of two patients in whom fibrodysplasia ossificans progressiva was genetically confirmed before the appearance of heterotopic ossification and demonstrate the clinical and radiographic features of systemic skeletal abnormalities. Father-to-son transmission was confirmed in the case of one of our patients; to our knowledge, this case represents the first reported instance of familial fibrodysplasia ossificans progressiva in Japan. Our study provides important information on the early clinical signs and symptoms of fibrodysplasia ossificans progressiva. The patients and their parents were informed that data concerning the cases would be submitted for publication, and they consented.
Case 1. A ten-month-old boy was referred to our hospital with bilateral valgus deformity of the great toe. The patient's father also had had bilateral hallux valgus and had undergone corrective osteotomies at the age of three years. At the age of seven years, the father had had resection of a soft-tissue mass on the left posterolateral part of the neck. At the age of twelve years, the father had been diagnosed with fibrodysplasia ossificans progressiva on the basis of the clinical course, including progressive spinal deformity and joint contractures in the extremities due to heterotopic ossification. At the age of thirty-two years, the father was confirmed to have fibrodysplasia ossificans progressiva on the basis of genetic testing (617G>A; R206H in the ACVR1 gene).
The patient, the first child for his parents, was delivered by cesarean section at thirty-eight weeks of gestational age because of breech presentation. He had an uneventful perinatal and postnatal clinical course with normal developmental milestones. Physical examination revealed no abnormal findings except for bilateral valgus deformity of the great toe (Fig. 1, A) and mild stiffness of the neck, especially in extension. A full radiographic skeletal survey demonstrated various malformations in the feet, hands, spine, and extremities. Hallux valgus was associated with the extra ossification center in the distal end of the first metatarsal bone and marked hypoplasia of the proximal phalanx (Fig. 1, B). Shortening of the first metacarpal and the proximal phalanx of the thumbs was noted (Fig. 2, A). In the cervical spine, enlarged posterior elements, including pedicles, laminae, and spinous processes, were seen (Fig. 3, A). Neither cartilaginous fusions of the posterior elements of the cervical vertebrae nor inflammatory processes in the posterior part of the neck were detected with magnetic resonance imaging (MRI) at the age of 1.5 years (data not shown). The femoral neck was broad, and an osteochondroma-like spur was seen in the proximal part of the left femur (Fig. 4, A). Faint osseous protrusions were found on the proximal-medial side of the tibia bilaterally (Fig. 4, C). Genomic DNA was obtained from the oral mucosa, and sequencing analysis demonstrated the presence of the same heterozygous single-nucleotide change (617G>A; R206H) in ACVR1 as had been demonstrated in his father.
Photographs and anteroposterior radiographs of the left foot of the first patient (Case 1) at the age of eleven months (A and B) and the second patient (Case 2) at the age of 7.1 years (C and D), demonstrating marked hallux valgus. Note the extra ossification center of the first metatarsal and hypoplasia of the proximal phalanx in the first patient (Case 1) (B). In contrast, monophalanx of the great toe and deformity of the distal end of the first metatarsal were observed in the second patient (Case 2) (D).
Anteroposterior radiographs of the left hand of the first patient (Case 1) at the age of eleven months (A) and the second patient (Case 2) at the age of 8.4 years (B), showing shortening of the first metacarpal. The thumb of the second patient (Case 2) appears as a monophalanx associated with a cone-shaped epiphysis of the proximal phalanx and a fused epiphysis of the distal phalanx (B).
Lateral radiographs of the cervical spine of the first patient (Case 1) at the age of eleven months (A) and the second patient (Case 2) at the age of 7.6 years (B), demonstrating hypertrophy of the laminae and spinous processes of the cervical vertebrae. Complete osseous fusions in facet joints and spinous processes were evident between C5/C6 and C7/T1 in the second patient (Case 2) (B).
Anteroposterior radiographs of the lower limb of the first patient (Case 1) at the age of eleven months (A and C) and the second patient (Case 2) at the age of 7.1 years (B and D). Note apparent coxa valga and broad femoral necks with the osteochondroma-like spurs in the metaphysis of the proximal part of the femur (A and B). Faint osseous protrusions are seen bilaterally on the metaphysis of the proximal part of the tibia (arrows) in the first patient (Case 1) (C), whereas multiple osteochondroma-like lesions are seen bilaterally at the medial side of the proximal part of the tibia in the second patient (Case 2) (D).
Case 2. A seven-year-old boy without any remarkable family history was referred to our hospital for genetic testing for fibrodysplasia ossificans progressiva. He was born as a low-birth-weight baby by means of cesarean section because of preterm rupture. Bilateral valgus deformity of the great toe was evident from birth. He had been repeatedly examined by several orthopaedists because of the hallux valgus but was never suspected as having fibrodysplasia ossificans progressiva. At the age of six years, the patient was referred to another physician, who made a provisional diagnosis of fibrodysplasia ossificans progressiva on the basis of the congenital malformations of the great toes and stiffness of the neck. The clinical course was unremarkable during follow-up periods.
Physical examination revealed remarkable bilateral shortening and valgus deformity of the great toe (Fig. 1, C). Although the range of motion of the upper and lower extremities was normal, neck motion was limited in all planes. The radiographic characteristics were similar to but more severe than those in the first patient (Case 1). He had monophalanx of the great toes, marked hallux valgus, and deformity of the distal end of the first metatarsal (Fig. 1, D), corresponding in position to the extra ossification center in the first patient (Case 1). The first metacarpals were extremely short, the epiphysis and metaphysis of the proximal phalanx of the thumb were deformed, and the thumb appeared to be a monophalanx as the ossification centers within the interphalangeal joint were very close together (Fig. 2, B). The posterior elements of the cervical spine were extremely hypertrophic, with fusions in facet joints and ligamentum interspinales between C5/C6 and C7/T1 (Fig. 3, B). The femoral necks were broad, with osteochondroma-like lesions hanging from the medial aspect of the proximal metaphysis, and bilateral distal femoral and proximal tibial osteochondromas were obvious (Fig. 4, B and D). Genomic DNA was extracted from peripheral blood, and sequencing analysis confirmed the same mutation (617G>A; R206H) in the ACVR1 gene.