Format

Send to

Choose Destination
Orphanet J Rare Dis. 2019 May 3;14(1):98. doi: 10.1186/s13023-019-1068-7.

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

Author information

1
Department of Medicine, Mayo Clinic, Rochester, MN, USA. pignolo.robert@mayo.edu.
2
Departement de Genetique, Institut IMAGINE and Hôpital Necker-Enfants Malades, Paris, France.
3
Institute of Health and Biomedical Innovation (IHBI), Translational Research Institute, Princess Alexandra Hospital, Queensland University of Technology (QUT), Queensland, Australia.
4
Pediatric Rheumatology Section, Department of Pediatrics, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
5
Unit of Rare Diseases, Department of Pediatrics, Giannina Gaslini Institute, Genoa, Italy.
6
Division of Endocrinology and Metabolism, the UCSF Metabolic Bone Clinic, the Institute of Human Genetics, and the UCSF Program in Craniofacial Biology, Department of Medicine, University of California-San Francisco, San Francisco, California, USA.
7
Centre for Metabolic Bone Disease, Royal National Orthopaedic Hospital, Stanmore, UK.
8
Departments of Medicine and Orthopaedic Surgery, The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
9
Clementia Pharmaceuticals Inc, Newton, MA, USA.
10
Departments of Orthopaedic Surgery & Medicine, The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. frederick.kaplan@uphs.upenn.edu.

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 mm3/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.

KEYWORDS:

Clinical trial endpoints; Cross-sectional analysis; Disease progression; Fibrodysplasia Ossificans Progressiva; Heterotopic ossification; Natural history

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center