title: Cerebroretinal microangiopathy with calcifications and cysts: characterization of the skeletal phenotype.
abstract: Cerebral cysts and calcifications with leukoencephalopathy and retinal vascular abnormalities are diagnostic hallmarks of cerebroretinal microangiopathy with calcifications and cysts (CRMCC). Previous studies have suggested that skeletal involvement is also common, but its characteristics remain unknown. This study aimed to assess the skeletal phenotype in CRMCC. All Finnish patients with features consistent with CRMCC and for whom radiographs were available were included. Clinical information pertinent to the skeletal phenotype was collected from hospital records, and all plain radiographs were reviewed for skeletal features. Bone mineral density (BMD) was measured by DXA. In one patient, bone biopsies were obtained for bone histology and histomorphometric analyses. The LRP5 gene was analyzed for mutations by direct sequencing. Our results show that the skeletal phenotype in CRMCC includes (1) compromised longitudinal growth pre- and postnatally, (2) generalized osteopenia or early onset low turnover osteoporosis with fragility fractures, and (3) metaphyseal abnormalities that may lead to limb deformities such as short femoral neck or genua valga. DXA measurements in three patients showed low BMD, and bone biopsies in the fourth patient with pathological fractures and impaired fracture healing showed low-turnover osteoporosis, with reduced osteoclast and osteoblast activity. Direct sequencing of all LRP5 coding exons and exon-intron boundaries in six patients with CRMCC revealed no putative mutations. We conclude that the CRMCC-associated bone disease is characterized by low BMD and pathological fractures with delayed healing, metaphyseal changes, and short stature pre- and postnatally. LRP5 is not a disease-causing gene in CRMCC.
authors.affiliation: Helsinki Medical Imaging Center, Helsinki University Hospital, Finland. sanna.toiviainen-salo@fimnet.fi
authors.forename: Sanna
authors.initials: S
authors.lastname: Toiviainen-Salo
authors.forename: Tarja
authors.initials: T
authors.lastname: Linnankivi
authors.forename: Anne
authors.initials: A
authors.lastname: Saarinen
authors.forename: Mervi K
authors.initials: MK
authors.lastname: Mäyränpää
authors.forename: Riitta
authors.initials: R
authors.lastname: Karikoski
authors.forename: Outi
authors.initials: O
authors.lastname: Mäkitie
mesh_terms: D015519:Bone Density; D001851:Bone Diseases, Metabolic / Q000503:physiopathology; D001842:Bone and Bones / Q000000981:diagnostic imaging; D002114:Calcinosis / Q000473:pathology*; D020863:Central Nervous System Cysts / Q000473:pathology*; D004252:DNA Mutational Analysis; D005387:Finland; D006130:Growth Disorders / Q000503:physiopathology; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics; D056784:Leukoencephalopathies / Q000473:pathology*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011859:Radiography; D012171:Retinal Vessels / Q000002:abnormalities*; D013577:Syndrome
chemical_list: D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5