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Genetic 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; ACVR1 R375P ) responsible for a mild nonclassic fibrodysplasia ossificans progressiva (FOP) phenotype. Both families include people with the ultrarare ACVR1 R375P variant who exhibit features of FOP while other individuals currently do not express any clinical signs of FOP. Thus, the mild ACVR1 R375P variant greatly expands the scope and understanding of this rare disorder., (© 2021 Wiley Periodicals LLC.)

Clinical trials for orphan diseases are critical for developing effective therapies. One such condition, fibrodysplasia ossificans progressiva (FOP; MIM#135100), is characterized by progressive heterotopic ossification (HO) that leads to severe disability. Individuals with FOP are extremely sensitive to even minor traumatic events. There has been substantial recent interest in clinical trials for novel and urgently-needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community - considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials., (© 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Severe variants of fibrodysplasia ossificans progressiva (FOP) affect <2% of all FOP patients worldwide, but provide an unprecedented opportunity to probe the phenotype-genotype relationships that propel the pathology of this disabling disease. We evaluated two unrelated children who had severe reduction deficits of the hands and feet with absence of nails, progressive heterotopic ossification, hypoplasia of the brain stem, motor and cognitive developmental delays, facial dysmorphology, small malformed teeth, and abnormal hair development. One child had sensorineural hearing loss, microcytic anemia, and a tethered spinal cord and the other had a patent ductus arteriosus and gonadal dysgenesis with sex reversal (karyotype 46, XY female). Both children had an identical mutation in ACVR1 c.772A>G; p.Arg258Gly (R258G), not previously described in FOP. Although many, if not most, FOP mutations directly perturb the structure of the GS regulatory subdomain and presumably the adjacent αC helix, substitution with glycine at R258 may directly alter the position of the helix in the kinase domain, eliminating a key aspect of the autoinhibitory mechanism intrinsic to the wild-type ACVR1 kinase. The high fidelity phenotype-genotype relationship in these unrelated children with the most severe FOP phenotype reported to date suggests that the shared features are due to the dysregulated activity of the mutant kinase during development and postnatally, and provides vital insight into the structural biology and function of ACVR1 as well as the design of small molecule inhibitors., (© 2015 Wiley Periodicals, Inc.)

Fibrodysplasia Ossificans Progressiva (FOP) is a rare debilitating disorder characterized by congenital deformity of the great toes from infancy and postnatal heterotopic ossification. Activating mutations in the activin A receptor type 1 (ACVR1) gene are responsible for the disease. The most common allelic variant leading to FOP is c.617 G>A; p.R206H, however, other alleles have been reported with atypical phenotypes. We report 14 cases presenting to a referral institution in South India over a 3-year period. The patients were clinically diagnosed based on foot abnormality or abnormal ectopic ossification and were screened for ACVR1. The genetic analysis of ACVR1 identified the recurrent allelic variant in 12 of 14 patients. One of the remaining patients had a previously reported allele c.1067G>A; p.G356D in the 9th exon and the second allele c.983G>A; p.G328E in the 8th exon of ACVR1. The most common recurrent allele c.617 G>A; p.R206H is also the most common in Indian patients with FOP., (© 2015 John Wiley & Sons Ltd/University College London.)

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification of connective tissue that begins during the first decade of life. Our patient presented with intrauterine growth retardation, respiratory distress, neonatal onset soft tissue masses, bilateral hallux valgus, and congenital anomalies of the thyroid and uterus. She was initially diagnosed with atypical infantile myofibromatosis based on clinical and pathological findings. She underwent whole-exome sequencing (WES) as part of the FORGE study to identify the gene for infantile myofibromatosis; however a de novo dominant mutation in ACVR1 (NM&#95;001105.4:c.617G>A) revised the diagnosis to FOP. This patient highlights the utility of WES as an early diagnostic tool in the investigation of patients with unusual presentations of rare diseases, thereby providing clinicians with accurate molecular diagnoses and the opportunity to tailor clinical management to improve patient care., (© 2015 Wiley Periodicals, Inc.)

Fibrodysplasia ossificans progressiva (FOP) is a rare, congenital disorder caused by heterozygous mutation of the bone morphogenetic protein type I receptor ACVR1. Various forms of atypical FOP have recently been identified, and a novel mutation, ACVR1 (587T>C), was reported in 2011. We report on the second patient worldwide with ACVR1 (587T>C) mutation. A 22-year-old Japanese male with no family history of heterotopic ossification did not show any malformation of the great toes and showed normal development from birth to the age of 17 years, when heterotopic ossification appeared in the lumbar area. The clinical symptoms were similar to those reported previously: the delayed onset with a slower and mild clinical course and little finger camptodactyly. Gene analysis revealed that the patient was heterozygous for ACVR1 (587T>C) mutation, the same one as reported in 2011, suggesting a correlation between the location of the mutation and the clinical symptoms. This second report of ACVR1 (587T>C) mutation worldwide is particularly meaningful in that it highlights the difference between clinical symptoms of the first reported patient with ACVR1 (587T>C) mutation and those of classic FOP., (© 2013 Wiley Periodicals, Inc.)

Fibrodysplasia ossificans progressiva (FOP) causes extensive heterotopic bone formation due to heterozygous mutations in the glycine-serine activation domain of ACVR1 (ALK2), a bone morphogenetic protein type I receptor. Anecdotal observations of facial similarity have been made by clinicians and parents, but no objective quantitative analysis of the faces of FOP patients has ever been undertaken. We delineated the common facial characteristics of 55 individuals with molecularly confirmed FOP by analyzing their face signature (face shape difference normalized against age and sex matched controls) and associated face signature graphs (with face signatures as vertices and adjacency corresponding to greatest similarity). Our analysis identified 10 affected individuals whose face signature is more homogeneous than others with FOP. This distinct subgroup showed the previously identified reduced mandible as well as newly identified features: underdevelopment of the upper orbit/supra-orbital ridge; infra-orbital prominence; and, low-set ears. These findings strongly suggest that the canonical FOP mutation variably affects the postnatal morphogenesis of the normotopic cranial skeleton in the upper midface and mandible and may have important diagnostic and functional implications., (Copyright © 2012 Wiley Periodicals, Inc.)