1067G > A (p.G356D). This mutation has previously been reported in other FOP variant patients [7] and [25]. The R206H mutation may cause all three clinical types of FOP including classic FOP, FOP-plus and FOP variants. In this large patient series, all classic FOP and FOP-plus patients and one FOP variant carried the R206H mutation. Two FOP variant cases had non-R206H mutations. This phenomenon is consistent with a previous report [7] which only detected

non-R206H mutations in variant FOP patients. None of the 98 unaffected controls, including parents and siblings, had mutations in ACVR1. Penetrance of the ACVR1/ALK2 mutation was 100%. The parents of the FOP patients could recall the onset and features of flare-ups in all cases. In this study, the onset of FOP was considered to be the time when the first spontaneous flare-up appeared or the first HO lesion emerged after trauma. Sixty-nine percent of patients (50/72 cases) experienced the spontaneous Selleckchem E7080 onset of flare-ups. Thirty-six percent of patients (18/50 cases) experienced the spontaneous onset of a flare-up prior to two years of age; 58% of patients (29/50 cases) experienced the spontaneous onset of a flare-up between two and ten years of age; and 6% of patients (3/50 cases) experienced the spontaneous onset of a flare-up after age 10.

There Sotrastaurin in vivo was no significant difference between male and female patient’s distributions among various onset ages (Table 2). No patient with spontaneous onset of FOP had any premonitory signs or symptoms prior to the onset of a flare-up. The signs and symptoms accompanying the onset of a flare-up were different at different anatomic sites. If the flare-up was in the head, neck or trunk, the onset was usually acute with large painless or painful soft masses appearing within twelve hours. If the flare-up involved the extremities, patients were more likely to have had focal pain with decreased range of motion as their Unoprostone initial complaint, with or without the appearance of soft tissue swelling. Fifty-two percent of patients (26/50 cases) who experienced spontaneous onset of flare-ups presented with soft tissue swellings in the occipital region. Typically, as one mass subsided,

another one emerged and sequentially spread toward the back of the neck and trunk. Most masses eventually ossified, but some resolved completely. Twenty-three of the 26 patients who had spontaneous occipital masses had radiographic evidence of HO in the occipital and posterior neck regions at the first visit to our clinic, but three of the 26 patients who had reported flare-ups in the occipital region had no radiographic evidence of HO in the occipital region, although these three patients had HO at other sites where intercurrent flare-ups had occurred. Forty percent of patients (20/50 cases) with spontaneous onset of FOP presented with soft tissue swelling or focal edema in the neck, back, trunk or shoulder, and all of the soft tissue masses become ossified.