Fibrodysplasia ossificans progressiva: current concepts from bench to bedside

Abstract

Heterotopic ossification (HO) is a disorder characterised by the formation of ectopic bone in soft tissue. Acquired HO typically occurs in response to trauma and is relatively common, yet its aetiology remains poorly understood. Genetic forms, by contrast, are very rare, but provide insights into the mechanisms of HO pathobiology. Fibrodysplasia ossificans progressiva (FOP) is the most debilitating form of HO. All patients reported to date carry heterozygous gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1). These mutations cause dysregulated bone morphogenetic protein (BMP) signalling, leading to HO at extraskeletal sites including, but not limited to, muscles, ligaments, tendons and fascia. Ever since the identification of the causative gene, developing a cure for FOP has been a focus of investigation, and studies have decoded the pathophysiology at the molecular and cellular levels, and explored novel management strategies. Based on the established role of BMP signalling throughout HO in FOP, therapeutic modalities that target multiple levels of the signalling cascade have been designed, and some drugs have entered clinical trials, holding out hope of a cure. A potential role of other signalling pathways that could influence the dysregulated BMP signalling and present alternative therapeutic targets remains a matter of debate. Here, we review the recent FOP literature, including pathophysiology, clinical aspects, animal models and current management strategies. We also consider how this research can inform our understanding of other types of HO and highlight some of the remaining knowledge gaps.

Fibrodysplasia Ossificans Progressiva: A Challenging Diagnosis

“…Specifically, it has been shown that activin A, which is expressed by innate immune system cells, plays an important role in both promoting and resolving inflammation, particularly by blocking ACVR1 WT signaling. Activin A is effectively perceived as a BMP ligand by ACVR1 R206H leading to downstream BMP signaling via SMAD1/5/9(8), thus responding to activins A, AB, AC, and B, to which the wild-type ACVR1 is unresponsive [6]. The penetrance of the ACVR1/ALK2 gene mutations is complete, and they usually arise de novo [7].…”

“…Although the FOP phenotype is extremely consistent and easily recognizable when fully expressed, early diagnosis still presents a challenge to physicians. According to the registry of the International FOP Association (IFOPA), the mean age at which the first symptoms occur is 5.4 years, while the mean age of FOP diagnosis is 7.5 years [6]. Almost all patients with FOP are typically born with various types and degrees of congenital great toe malformations, such as bilateral hallux valgus malformation with the lack of a toe crease at the metatarsophalangeal joints, and, in some cases, macrodactyly.…”

“…Debilitating effects of FOP start to become life-threatening when involvement of the intercostal muscles, costovertebral joints and thoracic paravertebral soft tissue occurs, resulting in thoracic insufficiency syndrome. Patients eventually die because of cardiorespiratory complications, such as pneumonia or right-sided heart failure, and have a median life span of around 40 years [6].…”

“…According to clinical presentation, patients with the classic FOP phenotype, who represent about 92% of cases and all have the canonical ACVR1/ALK2 gene c.617G>A (p.R206H) mutation, show both the typical congenital malformations of the great toe and progressive HO with other common but variable features of FOP such as tibial osteochondromas, conductive hearing impairment, age-depended increased risk of hypercalciuria-related nephrolithiasis, sparse hair and eyebrows, and neuroimaging abnormalities especially involving the pontine region [6]. Additional findings, often related to specific ACVR1/ALK2 mutations, are summarized in Table 1.…”

“…As to prenatal testing, fetal ultrasound may identify a hallux valgus deformity as early as gestational week 23 [26]. If an ACVR1/ALK2 gene pathogenic variant is identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing is feasible [6].…”