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.
Highlights
Osteogenesis imperfecta (OI) and other decreased bone density disorders comprise a phenotypically diverse group of heritable bone dysplasia with increased skeletal fragility, most commonly arising from genetic defects in type IA Novel IFITM5 Variant Associated with Phenotype of Osteoporosis with Calvarial Doughnut...collagen [1]
Neither patient exhibits other OI-related extra-skeletal characteristics, neurological symptoms related to basilar invagination commonly seen in OI, or any of the hallmark features of OI type V features [8, 11]
The genetic cause was identified as mutations in the sphingomyelin synthase 2–encoding SGMS2 and consequent abnormal sphingomyelin metabolism [2]
Summary
Osteogenesis imperfecta (OI) and other decreased bone density disorders comprise a phenotypically diverse group of heritable bone dysplasia with increased skeletal fragility, most commonly arising from genetic defects in type IA Novel IFITM5 Variant Associated with Phenotype of Osteoporosis with Calvarial Doughnut...collagen [1]. In 2019, we expanded this spectrum by reporting novel genetic and phenotypic findings in a rare monogenic form of osteoporosis termed osteoporosis with calvarial doughnut lesions (OP-CDL, OMIM 126550) [2]. Depending on the type of the underlying mutation, affected individuals present with variably severe early-onset osteoporosis with spontaneous fractures and low bone mineral density (BMD) and typically without any of the classical extra-skeletal features of OI. They portray a distinctive feature of circular sclerotic cranial lesions, referred to as calvarial doughnut lesions (CDLs). Several families have been described so far—some prior to the genetic discovery—the disease is still extremely rare and its pathomechanisms incompletely understood [3,4,5]
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