Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes

Abstract

Background Fibrodysplasia Ossificans Progressiva (FOP; OMIM#135100) is an ultra-rare, severely disabling genetic disease characterized by congenital malformation of the great toes and progressive heterotopic ossification (HO) in muscles, tendons, ligaments, fascia, and aponeuroses often preceded by painful, recurrent soft tissue swelling (flare-ups). The formation of HO leads to progressive disability, severe functional limitations in joint mobility, and to a shortened life-span. In this prospective natural history study, we describe the baseline, cross-sectional disease phenotype of 114 individuals with FOP. Methods All subjects underwent protocol-specified baseline assessments to determine their disease status. Cross-sectional analyses were performed using linear regression in which functional evaluations (Cumulative Analogue Joint Involvement Scale [CAJIS] and the FOP-Physical Function Questionnaire [FOP-PFQ]) and the burden of HO as measured by low-dose whole body CT (volume of HO and number of body regions with HO) were assessed. Results Findings from 114 subjects (age range 4 to 56 years) were evaluated. While subject age was significantly ( p < 0.0001) correlated with increased CAJIS ( r = 0.66) and FOP-PFQ scores ( r = 0.41), the estimated mean increases per year (based on cross-sectional average changes over time) were small (0.47 units and 1.2%, respectively). There was also a significant ( p < 0.0001) correlation between baseline age and HO volume ( r = 0.56), with an estimated mean increase of 25,574 mm 3 /year. There were significant ( p < 0.0001) correlations between the objective assessment of HO volume and clinical assessments of CAJIS ( r = 0.57) and FOP-PFQ ( r = 0.52). Conclusions Based on the cross-sectional analysis of the baseline data, functional and physical disability as assessed by CAJIS and the FOP-PFQ increased over time. Although longitudinal data are not yet available, the cross-sectional analyses suggest that CAJIS and FOP-PFQ are not sensitive to detect substantial progression over a 1- to 2-year period. Future evaluation of longitudinal data will test this hypothesis. The statistically significant correlations between HO volume and the functional endpoints, and the estimated average annual increase in total HO volume, suggest that the formation of new HO will be measurable over the relative short-term course of a clinical trial, and represents an endpoint that is clinically meaningful to patients. Trial registration This study ( NCT02322255 ) was first posted on 23 December, 2014. Electronic supplementary material The online version of this article (10.1186/...

Patients with ACVR1R206H mutations have an increased prevalence of cardiac conduction abnormalities on electrocardiogram in a natural history study of Fibrodysplasia Ossificans Progressiva

“…Figure 2 shows the QRS duration in our NHS cohort plotted by age and the criteria threshold for IVCD by age [ 8 ], as well as the CAJIS total score by age. As expected, there was a positive correlation between age and CAJIS, a pattern consistent with previously published results [ 7 ] [ 13 ]. These data suggest that a majority of participants under the age of 18 years in our NHS cohort have some form of IVCD (60.3%) based on the published age-dependent criteria [ 8 ] and is likely the reason individuals with conduction abnormalities recorded lower CAJIS scores.…”

“…Baseline and year-1 follow up data collected from the Natural History Study of Fibrodysplasia Ossificans Progressiva (NHS; clinicaltrials.gov #NCT02322255), sponsored by Clementia, an Ipsen company, were utilized for this study [ 7 ]. The NHS is an ongoing 3-year longitudinal study that includes sites in Buenos Aires, Argentina (20 subjects); Brisbane, Australia (6 subjects); Paris, France (15 subjects); Genoa, Italy (14 subjects); Stanmore, United Kingdom (17 subjects); Philadelphia, Pennsylvania, United States (22 subjects); and San Francisco, California, United States (20 subjects).…”

“…The lead center for this ECG study was the University of California at San Francisco (IRB approval number: 14–13854). More details regarding the recruitment protocol and cohort characteristics are described separately [ 7 ].…”

“…The NHS protocol included on-site ECGs, clinical exams (described below), and whole body imaging at baseline and yearly thereafter [ 7 ]. Participants without ECG data or with mis-positioned leads were excluded from our analysis (2 participants without ECG data and 6 participants with mis-positioned leads).…”

“…To better define the potential cardiovascular complications that may be found in patients with FOP, we examined the baseline and 12 month follow up ECGs of 114 patients with classical FOP enrolled in the ongoing PVO-1A-001 Natural History Study of Fibrodysplasia Ossificans Progressiva (NHS) [ 7 ]. This dataset allowed use to systematically examine the electrocardiography results from patients with FOP, and to correlate our findings with other clinical end points.…”