IFITM5 pathogenic variant causes osteogenesis imperfecta V with various phenotype severity in Ukrainian and Vietnamese patients

Abstract

Background Osteogenesis imperfecta (OI) covers a spectrum of bone fragility disorders. OI is classified into five types; however, the genetic causes of OI might hide in pathogenic variants of 20 different genes. Often clinical OI types mimic each other. This sometimes makes it impossible to identify the OI type clinically, which can be a risk for patients. Up to 90% of OI types I–IV are caused by pathogenic variants in the COL1A1/2 genes. OI type V is caused by the c.-14C > T pathogenic variant in the 5′UTR of the IFITM5 gene and is characterized by hyperplastic callus formation and the ossification of interosseous membranes. Results In the current study, we performed IFITM5 5′UTR region mutational analysis using Sanger sequencing on 90 patients who were negative for COL1A1 / 2 pathogenic variants. We also investigated the phenotypes of five patients with genetically confirmed OI type V. The proportion of OI type V patients in our cohort of all OI patients was 1.48%. In one family, there was a history of OI in at least three generations. Phenotype severity differed from mild to extremely severe among patients, but all patients harbored the same typical pathogenic variant. One patient had no visible symptoms of OI type V and was suspected to have had OI type IV previously. We also identified a case of extremely severe hyperplastic callus in a 15-year-old male, who has hearing loss and brittleness of teeth. Conclusions OI type V is underlined with some unique clinical features; however, not all patients develop them. The phenotype spectrum might be even broader than previously suspected, including typical OI features: teeth brittleness, bluish sclera, hearing loss, long bones deformities, and joint laxity. We suggest that all patients negative for COL1A1 / 2 pathogenic variants be tested for the presence of an IFITM5 pathogenic variant, even if they are not expressing typical OI type V symptoms. Further studies on the pathological nature and hyperplastic callus formation mechanisms of OI type V are necessary.

Heterotopic Ossification of the Elbow: A Literature Review

“…Other studies in the literature confirm this is a common clinical finding [37][38][39]. Other common clinical findings that might point to OI as a diagnosis include teeth brittleness, bluish sclera, hearing loss, long bone deformities, and joint laxity [37].…”

“…Clinical symptoms may once again vary widely but in a study of 13 patients with a molecularly confirmed mutation in the IFITM5 gene, 12 presented with interosseus radioulnar membrane ossification of the proximal forearm [36]. Other studies in the literature confirm this is a common clinical finding [37][38][39]. Other common clinical findings that might point to OI as a diagnosis include teeth brittleness, bluish sclera, hearing loss, long bone deformities, and joint laxity [37].…”

Osteogenesis imperfecta type 1 with an incidental finding of bilateral radioulnar synostosis

“…Type III and Type IV OI are moderately severe forms of the condition with variable phenotype in terms of the fracture history and stature. Type V OI is classified by the presence of interosseous membrane calcification, which results in limited supination and pronation (1)(2)(3)(4).…”

“…OI is a genetic condition, with most patients being affected by variants in genes known to be involved in the production or processing of type 1 collagen (1,5). The genes most commonly associated with this are COL1A1 and COL1A2, which follows an autosomal dominant (AD) pattern of inheritance (1,4,5). Over time, the number of genes recognised as part of OI has increased, including autosomal recessive variants (2,5).…”

“…Over time, the number of genes recognised as part of OI has increased, including autosomal recessive variants (2,5). Some cases of type II OI can be accounted for by recessive genes such as CRTAP/ P3H1/ PPIB and a recurrent variant in IFITM5 has been associated with Type V OI (1)(2)(3)(4)(5). The treatment of OI relies on a multidisciplinary approach with bisphosphonates being the mainstay in terms of medical management (5).…”