Kaplan, Frederick S

Case: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive heterotopic ossification. Scoliosis may develop and progress rapidly, especially during adolescence. We report 4 patients with FOP and scoliosis during early adolescence: A 12-year-old girl underwent T4-S2 posterior spinal fusion (PSF); another 12-year-old girl underwent T4-S2 PSF; a 13-year-old boy underwent T3-L4 PSF; and a 14-year-old girl was managed nonoperatively because the complex deformity and ankylosed shoulders could not be adequately balanced with surgery. Conclusion: In patients with FOP, surgical intervention can reduce thoracic deformity and improve pulmonary function but carries substantial risks, including heterotopic ossification.

Abstract Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. Present management summarized here is focused on early diagnosis, assiduous avoidance of injury and iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function. Twenty-one members of the International Clinical Council on FOP (ICC) and seven consultants from 15 countries, chosen for their clinical expertise in FOP, developed this summary statement. Further advances in therapeutics will be based on rigorous clinical trials to assess novel and emerging treatment and prevention strategies. A detailed and updated exploration of the topics outlined in this brief perspective can be found in “The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations” which can be found on the International Clinical Council on FOP (ICC) website (www.iccfop.org).

» Fibrodysplasia ossificans progressiva (FOP), the most severe form of heterotopic ossification (HO) in humans, may lead to severe thoracic deformity (TD) and thoracic insufficiency syndrome (TIS), the most common cause of mortality in individuals with FOP. » In this study, we examine the multiple causes of TD in FOP and propose a dynamic model for the development and evolution of TD that can be used to guide clinical care. This model posits that multiple factors, all originating from the causative gain-of-function mutation in activin receptor A, type 1, lead to TD in FOP. » Factors that lead to TD in FOP include early developmental costovertebral and facet joint arthropathy and joint ankylosis, progressive episodic flare-ups (both trauma induced or spontaneous) and subsequent HO, dysregulated soft tissue sensitivity to mechanical stimuli, growth plate dysregulation, and congenital rib fusions. These factors contribute to TD in FOP through a combination of intra-articular and extra-articular mechanisms, all amplified by growth. » Although FOP is a rare condition, it is illustrative of how a mutation in a critical receptor in the bone morphogenetic protein signaling pathway can cause a litany of musculoskeletal dysfunction that can lead to life-threatening consequences. Clinicians caring for individuals who have FOP must be aware of the occurrence, evolution, and implications of progressive TD and resultant TIS so that appropriate preventive measures such as avoidance of pulmonary infections, incentive spirometry, and diaphragmatic strengthening can be instituted.

In the introduction to his 1970 textbook BIOCHEMISTRY, Albert Lehninger wrote “Living things are composed of lifeless molecules [...]

AbstractGenetic variants are vital in informing clinical phenotypes, aiding physical diagnosis, guiding genetic counseling, understanding the molecular basis of disease, and potentially stimulating drug development. Here we describe two families with an ultrarare ACVR1 gain‐of‐function pathogenic variant (codon 375, Arginine > Proline; ACVR1R375P) responsible for a mild nonclassic fibrodysplasia ossificans progressiva (FOP) phenotype. Both families include people with the ultrarare ACVR1R375P variant who exhibit features of FOP while other individuals currently do not express any clinical signs of FOP. Thus, the mild ACVR1R375P variant greatly expands the scope and understanding of this rare disorder.

Abstract Background Genetic contributors to cardiac arrhythmias often found in cardiovascular conduction pathway and channel proteins. However, genes outside of these categories can contribute to cardiovascular conduction abnormalities. Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by large volumes heterotopic ossification caused by a highly recurrent R206H mutation in the ACVR1/Alk2 gene. This mutation produces an abnormal activation of the bone morphogenetic pathway (BMP) pathway in response to Activin A. Prior studies suggested an increased risk of cardiopulmonary complications in FOP1. We examined patients in a Natural History Study (NHS) of FOP (NCT02322255) to better understand their cardiovascular risk. Methods The NHS is an ongoing 3 year international multi-center cross-sectional study of 114 patients with FOP (ages 4–56 years) genetically verified to have the AVCR1 R206H mutation. Patients at baseline and 12 months were assessed by electrocardiogram (ECG). Abnormal lead placements were excluded. ECG readings were assessed in a central ECG laboratory. Results At baseline, 45.3% (48/106) of ECGs showed conduction abnormalities. The majority of these abnormalities were classified as nonspecific intraventricular conduction delay (37.7% of all ECGs). For patients > 18 years old, 22.7% (10/44) had conduction abnormalities, which was significantly higher than previously reported in the healthy population (5.9%; n=3978)2 (proportional t-test; p<0.00001). FOP patients < 18 years of age also had an extremely high prevalence of conduction abnormalities (60.3%, 38/61). The NHS 12-month follow up data showed similar prevalence. The high frequency of conduction abnormalities did not correlate with the presence of chest wall deformities or scoliosis, abnormal pulmonary function test results, increased cumulative analog joint involvement scale (CAJIS) scores, or abnormal echocardiograms. Conclusions Our results show that some patients with FOP may have subclinical conduction abnormalities. These ECG changes appear to be independent of chest wall deformities or scoliosis, although ectopic bone may make ECG measurement in FOP patients challenging. Though there is no reported association of FOP with clinically significant heart block to date and clinical implications for cardiovascular risk remain unclear, knowledge about these ECG changes may be important for planning clinical care and clinical trials of investigational agents in patients with FOP. Further studies of how the AVCR1 R206H activating mutation and BMP signaling changes cardiac conduction are needed to better understand the mechanistic link. References (1)Hingorani et al. Indian J Med Res. 2012; 135:322–330 (2)Kussmaul et al. Clinical Orthopaedic Related Research. 1998; 346:104–109

Abstract Background: FOP is an ultra-rare, severely disabling genetic disorder characterized by episodic flare-ups and heterotopic ossification (HO) leading to restricted movement, physical disability, and early death. FOP may initially be misdiagnosed in ~90% of individuals leading to unnecessary and often harmful interventions. Patients with FOP are diagnosed and managed by multiple specialties, including endocrinologists. Data from an ongoing, prospective, longitudinal, global, natural history study (NCT02322255) were used to investigate the progression of FOP, HO formation, and impact on physical functioning over time. We present results from the first 12 months of the 3-year study. Methods: Males and females with FOP and a documented ACVR1 R206H mutation participated. HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding the head. All imaging was interpreted at a blinded, central laboratory using pre-specified procedures. Functional outcomes were evaluated using the Cumulative Analogue Joint Involvement Scale (CAJIS; for each joint: score=0 represents <10% involvement, score=1 represents 10–90% involvement, and score=2 represents >90% ankylosed across 15 major joints; total score range 0 to 30 [higher scores indicate more severe mobility limitations]) and the FOP Physical Function Questionnaire (FOP-PFQ; percent total score). Changes from Baseline at Month 12 were evaluated for new HO volume, CAJIS, and FOP-PFQ. Results: Of 114 participants (pts) with Baseline data, 99 (4 to 56 years at enrollment; mean 17 years of age; 56% male) also had a Month 12 assessment. A total of 93 pts had evaluable WBCT scans at Baseline and Month 12 and were included in the HO analysis. In total, 40% (37/93) of pts had new HO over 12 months; the mean volume of new HO in these pts was 57,706 mm3 (SD=100,079 mm3; median=20,753 mm3; range: 522 to 438,826 mm3). Of the pts with new HO, 65% (24/37) reported at least one flare-up (mean rate of 2.3 flare-ups/year). Over 12 months, 60% (56/93) of pts did not have new HO; 43% (24/56) of them reported at least one flare-up (mean rate of 1.8 flare-ups/year). Mean changes from Baseline in CAJIS and FOP-PFQ were minimal: CAJIS: 0.6 (SD=2.4; median=1.0; n=99) and FOP-PFQ: 4.4% (SD=11.2; median=3.7%; n=90); and were similar across pts with or without new HO. Conclusions: In participants with FOP, although deterioration of physical function is expected over a patient’s lifetime, CAJIS and FOP-PFQ scores did not worsen significantly in the relative short-term of this study. However, HO volume, quantified by WBCT, increased over the course of 12 months. These results show that measuring HO may be a viable way to monitor changes in FOP over short periods of time.