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

Abstract

BackgroundFibrodysplasia 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.MethodsAll 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.ResultsFindings from 114 subjects (age range 4 to 56\u2009years) were evaluated. While subject age was significantly (p\u2009<\u20090.0001) correlated with increased CAJIS (r\u2009=\u20090.66) and FOP-PFQ scores (r\u2009=\u20090.41), the estimated mean increases per year (based on cross-sectional average changes over time) were small (0.47\u2009units and 1.2%, respectively). There was also a significant (p\u2009<\u20090.0001) correlation between baseline age and HO volume (r\u2009=\u20090.56), with an estimated mean increase of 25,574\u2009mm3/year. There were significant (p\u2009<\u20090.0001) correlations between the objective assessment of HO volume and clinical assessments of CAJIS (r\u2009=\u20090.57) and FOP-PFQ (r\u2009=\u20090.52).ConclusionsBased 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 registrationThis study (NCT02322255) was first posted on 23 December, 2014.