Early Clinical and Radiographic Characteristics in Fibrodysplasia Ossificans Progressiva

Abstract

Fibrodysplasia ossificans progressiva is an extremely rare and disabling genetic condition characterized by progressive heterotopic ossification of soft tissues such as muscles, ligaments, tendons, fasciae, and aponeuroses. The prevalence of fibrodysplasia ossificans progressiva is estimated to be about one in 2 million individuals1. Heterotopic ossification in fibrodysplasia ossificans progressiva usually begins in the first decade of life with the episodic development of inflammatory fibroproliferative masses in the axial skeleton. Most patients with fibrodysplasia ossificans progressiva are misdiagnosed as having soft-tissue sarcoma or aggressive juvenile fibromatosis before the definitive appearance of heterotopic ossification and undergo invasive procedures that usually lead to the acceleration of ossification2. Early correct diagnosis of fibrodysplasia ossificans progressiva is necessary to prevent additional iatrogenic harm or trauma. At the molecular level, dysregulated bone morphogenetic protein (BMP) signaling is associated with the formation of heterotopic ossification in fibrodysplasia ossificans progressiva. Patients with classical features of the disease have the same heterozygous missense mutation in the glycine-serine activation domain of activin A receptor type-I gene (ACVR1), a BMP type-I receptor3. The causative mutation of fibrodysplasia ossificans progressiva is a recurrent single-nucleotide substitution at position 617 (c.617G>A; R206H) in the ACVR1 gene, which is one of the most specific disease-causing mutations in the human genome. This mutant receptor constitutively activates BMP signaling without binding of ligands4. A unique and recurrent mutation has great relevance for diagnostic purposes in the case of fibrodysplasia ossificans progressiva. Definitive molecular diagnosis of fibrodysplasia ossificans progressiva is now available at early stages of disease development, when misdiagnosis is most likely to occur. Clinical awareness of the preosseous features of the disease is necessary for the early diagnosis of fibrodysplasia ossificans progressiva. In the present study, we describe the cases of two patients in whom fibrodysplasia ossificans progressiva …