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.

成骨不全症 (OI) 和其他骨密度降低的疾病包括一组具有骨骼脆弱性的遗传性疾病。最近，人们发现编码鞘磷脂合成酶 2 的SGMS2突变导致鞘磷脂代谢异常，并导致一种新形式的 OI，称为颅骨甜甜圈病变骨质疏松症 (OP-CDL)，伴有中度至重度骨骼脆性和可变颅骨肥大病变. 本研究描述了一个具有 OP-CDL 骨骼表型的日本家庭。受影响的个体具有中度严重的儿童期骨骼脆弱性，伴有多处长骨骨折、脊柱侧弯和骨骼畸形。此外，它们表现出具有中央射线可透性和外周射线不透性的多个 CDL 或颅骨肿块。然而，SGMS2测序正常。相反，全外显子组测序发现了一种新的IFITM5错义突变 c.143A>G (p.N48S)（被 ACMG 归类为 VUS）。IFITM5编码成骨细胞限制性蛋白 BRIL，其 5' UTR 区域中的复发性 c.-14C>T 突变导致 OI 型 V，这是一种与增生性愈伤组织形成和骨间膜骨化相关的独特 OI 亚型。此处描述的患者具有明显不同于 V 型 OI 的表型和颅骨肥厚性病变，以前未报道与IFITM5 相关的特征。我们的研究结果扩大了 OP-CDL 的遗传谱，表明致病性IFITM5的不同表型后果变体，并暗示 BRIL 在颅骨骨骼形成中的重要作用。