Abstract
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which extensive heterotopic ossification (HO) begins to form during early childhood and progresses throughout life. Although HO does not occur during embryonic development, children who carry the ACVR1R206H mutation that causes most cases of FOP characteristically exhibit malformation of their great toes at birth, indicating that the mutation acts during embryonic development to alter skeletal formation. Despite the high prevalence of the great toe malformation in the FOP population, it has received relatively little attention due to its clinically benign nature. In this study, we examined radiographs from a cohort of 41 FOP patients ranging from 2 months to 48 years of age to provide a detailed analysis of the developmental features, progression, and variability of the great toe malformation of FOP, which include absent skeletal structures, malformed epiphyses, ectopic ossification centers, malformed first metatarsals and phalangeal fusion.
Highlights
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder in which extensive bone ectopically forms in soft connective tissues, such as skeletal muscle, in a process known as heterotopic ossification (HO) (Shore and Kaplan, 2010)
Inclusion criteria were as follows: a clinical diagnosis of FOP made by the presence of congenital malformations of the great toes and by progressive HO in characteristic anatomic patterns; confirmation of the diagnosis by molecular genetic analysis that identified the presence of the recurrent ACVR1 c617G>A;R206H FOP mutation (Shore et al, 2006); plain anterior-posterior (A-P) radiographs of the feet that had been obtained as part of routine clinical care
The great toe malformation of FOP has been an enigma since its first association with the disease (Rosenstirn, 1918) but has received little attention due to its benign nature relative to the extensive HO in FOP
Summary
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder in which extensive bone ectopically forms in soft connective tissues, such as skeletal muscle, in a process known as heterotopic ossification (HO) (Shore and Kaplan, 2010). The most frequently occurring mutation (∼97%) among FOP patients is ACVR1R206H (Shore et al, 2006; Kaplan et al, 2008). This and other ACVR1 mutations associated with FOP enhance signaling from this bone morphogenetic protein (BMP) type I receptor to increase activation of the downstream BMP signaling pathway (Kaplan et al, 2008; Shen et al, 2009; Allen et al, 2019). The congenital skeletal malformation most commonly associated with FOP affects the first digit of the foot ( called the great toe or hallux), with this toe angled inward (hallux valgus) (Kaplan et al, 2008).
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