A Novel IFITM5 Variant Associated with Phenotype of Osteoporosis with Calvarial Doughnut Lesions: A Case Report

Abstract

Osteogenesis imperfecta (OI) and other decreased bone density disorders comprise a heterogeneous group of heritable diseases with skeletal fragility. Recently, it was discovered that mutations in SGMS2, encoding sphingomyelin synthetase 2, result in aberrant sphingomyelin metabolism and lead to a novel form of OI termed osteoporosis with calvarial doughnut lesions (OP-CDL) with moderate to severe skeletal fragility and variable cranial hyperostotic lesions. This study describes a Japanese family with the skeletal phenotype of OP-CDL. The affected individuals have moderately severe, childhood-onset skeletal fragility with multiple long-bone fractures, scoliosis and bone deformities. In addition, they exhibit multiple CDLs or calvarial bumps with central radiolucency and peripheral radiopacity. However, SGMS2 sequencing was normal. Instead, whole-exome sequencing identified a novel IFITM5 missense mutation c.143A>G (p.N48S) (classified as a VUS by ACMG). IFITM5 encodes an osteoblast-restricted protein BRIL and a recurrent c.-14C>T mutation in its 5' UTR region results in OI type V, a distinctive subtype of OI associated with hyperplastic callus formation and ossification of the interosseous membranes. The patients described here have a phenotype clearly different from OI type V and with hyperostotic cranial lesions, feature previously unreported in association with IFITM5. Our findings expand the genetic spectrum of OP-CDL, indicate diverse phenotypic consequences of pathogenic IFITM5 variants, and imply an important role for BRIL in cranial skeletogenesis.

The Role of Sphingolipid Metabolism in Bone Remodeling

“…In addition, others had a missense variant to enhance the rate of sphingomyelin production by blocking the export of a functional enzyme from the endoplasmic reticulum, with severe short stature, neonatal fractures, and spondylometaphyseal dysplasia. A recent case reported a family with moderately severe bone fragility and multiple sclerotic skull lesions similar to the osteogenesis imperfecta mentioned above; however, no pathogenic variant was found in SGMS2 ( Makitie et al, 2021 ). Knocking down the SMS2 suppressed TRAP-positive multinucleated cells’ formation through co-culture of bone marrow cells and osteoblasts, which indicated that knockdown of SMS2 inhibits osteoclastogenesis through decreasing RANKL expression in primary osteoblasts of mice ( Yoshikawa et al, 2019 ).…”

A Patient with Bone Fragility, Multiple Fractures, Osteosarcoma, and the Variant c.143A>G in the IFITM5 Gene: A Case Report

“…However, two other variants have been published to be related to OI in this same gene: the c.119C> T (p.S40L) 6 and, the recently described c.143A>G (p.N48S). 7 The latter was reported in a mother and her daughter with a novel form of OI named osteoporosis with calvarial doughnut lesions (OP-CDL) that present with skeletal fragility, multiple fractures (especially long bones), scoliosis, bone deformities, and sclerotic skull lesions; a phenotype different from those arising from the classical (c.-14C> T) variant. 7 This variant, c.143A>G, was also found in our patient, and as reported it was associated with a deleterious effect by the predicting algorithms such as SIFT, PROVEAN, and the CADD score.…”

“…6 Recently, a third variant, c.143A>G (p.N48S), was described in the IFITM5 gene, leading to a phenotype different from the one seen in type V, with fish-scale pattern in lamellar bone, osteoporosis, and calvarial doughnut lesions. 7 The disorders caused by variants in the IFITM5 gene are rare, with the most common (c.-14C> T) variant described in approximately 150 cases up to 2019, 8 which made the description of the patients bearing variants in this gene of particular interest for physicians. 9 Here we described a Colombian male patient diagnosed with osteogenesis imperfecta with the heterozygous variant c.143A>G (p.N48S) in the IFITM5 gene.…”

The Osteogenesis Imperfecta Type V Mutant BRIL/IFITM5 Promotes Transcriptional Activation of MEF2, NFATc, and NR4A in Osteoblasts

“…The only dominant OI types not caused by mutations in COL1 genes harbor mutations in the interferon induced transmembrane protein 5 gene (IFITM5 hereafter designated BRIL (bone-restricted Ifitm-like)). There have been five genetic variants in BRIL reported so far: c.-14C>T (p.M1ext-5) [4,5] in OI type V; c.119C>T (p.S40L) [6,7] and c.119C>G (p.S40W) [8,9] in atypical type VI; and the following two most recent that have not yet been classified (c.143A>G (p.N48S) [10] and c.-9C > A (p.M1ext-3) [11]).…”