The phenotype and genotype of fibrodysplasia ossificans progressiva in China: a report of 72 cases

Abstract

Fibrodysplasia ossificans progressiva, an ultra-rare and disabling genetic disorder of skeletal malformations and progressive heterotopic ossification (HO), is the most catastrophic condition of skeletal metamorphosis in humans. We studied 72 patients with FOP in China and analyzed their phenotypes and genotypes comprising the world's largest ethnically homogeneous population of FOP patients. Ninety-nine percent of patients (71/72 cases) were of Han nationality; and 1% of patients (1/72 cases) were of Hui nationality. Based on clinical examination, 92% of patients (66/72 cases) had classic FOP; 4% of patients (3/72 cases) were FOP-plus; and 4% of patients (3/72) were FOP variants. Importantly, all individuals with FOP had mutations in the protein-coding region of activin A receptor, type I/activin-like kinase 2 (ACVR1/ALK2). Ninety-seven percent of FOP patients (70/72 cases) had the canonical c.617G>A (p.R206H) mutation, while 3% of FOP patients (2/72 cases) had variant mutations in ACVR1/ALK2. Taken together, the genotypes and phenotypes of individuals with FOP from the Han nationality in China are similar to those reported elsewhere and support the fidelity of this ultra-rare disorder in the world's most highly populated nation and across wide racial, ethnic, gender and geographic distributions.

Keywords: ACVR1; ALK2; Bone morphogenetic protein; Fibrodysplasia ossificans progressiva; Heterotopic ossification.

Conflict of interest statement

Conflict of interests

None.

© 2013.

Figures

Figure 1

Representative appearance of the feet in a patient with classic FOP [ACVR1/ALK2 (R206H)]. A photograph (A1) of the feet in a 6-year-old boy with classic FOP shows bilateral hallux valgus deformity with the lack of a toe crease at the metatarso-phalangeal joints (Arrows) and incidental heterotopic ossification of a tendon in the foot (arrowheads). An Anterior-posterior radiograph of the right foot (A2) shows characteristic malformation of the great toe (arrow) with incidental heterotopic bone proximally in a tendon (arrowheads).

Figure 2. Characteristic and common-variable features of classic FOP [ACVR1/ALK2 (R206H)]

(A) Lateral radiograph of the cervical spine in a 22-year-old male FOP patient shows heterotopic bone in the nuchal ligament (arrow) and posterior orthotopic fusion of the facet joints of several cervical vertebrae (arrowheads). (B) Photograph (B1) and anterior-posterior radiograph (B2) of the chest of a 16-year-old girl with classic FOP showing subcutaneous bands of heterotopic bone (arrows) in the back. (C) Photograph of the back of a 5-year-old girl with classic FOP showing two prominent subcutaneous flare-ups (arrows). (D) Anterior-posterior radiograph of the pelvis in a 29-year-old female with classic FOP showing mature heterotopic ossification bridging the left hip (arrow) and more proximally about both the left and right pelvis, as well as intra-articular synovial osteochondromatosis of right hip (arrowheads). The patient also has characteristic femoral necks that are short and broad. (E) Anterior-posterior radiographs of the knees in a 22-year-old male with classic FOP showing a large sessile osteochondroma of the left proximal medial tibia and small pedunculated osteochondroma of the right distal femur (arrows). Additionally, there are prominent areas of heterotopic bone about both knees.