title: Osteogenesis imperfecta: Ultrastructural and histological findings on examination of skin revealing novel insights into genotype-phenotype correlation.
abstract: Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. Over 90% of patients with OI have a mutation in COL1A1/COL1A2, which shows an autosomal dominant pattern of inheritance. In-depth phenotyping and in particular, studies involving manifestations in the skin connective tissue have not previously been undertaken in OI. The aims of the study were to perform histological and ultrastructural examination of skin biopsies in a cohort of patients with OI; to identify common and distinguishing features in order to inform genotype-phenotype correlation; and to identify common and distinguishing features between the different subtypes of OI. As part of the RUDY (Rare Diseases in Bone, Joints and/or Blood Vessels) study, in collaboration with the NIHR Rare Diseases Translational Research Collaboration, we undertook a national study of skin biopsies in patients with OI. We studied the manifestations in the skin connective tissue and undertook in-depth clinical and molecular phenotyping of 16 patients with OI. We recruited 16 patients: analyses have shown that in type 1 collagen mutation positive patients (COL1A1/ COL1A2) (n-4/16) consistent findings included: variable collagen fibril diameter (CFD) and presence of collagen flowers. Histological examination in these patients showed an increase in elastic fibers that are frequently fragmented and clumped. These observations provide evidence that collagen flowers and CFD variability are consistent features in OI due to type 1 collagen defects and reinforce the need for accurate phenotyping in conjunction with genomic analyses.
authors: a Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust , Sheffield , UK.
authors: M
authors: M
authors: Balasubramanian
authors: a Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust , Sheffield , UK.|b National Ehlers Danlos Syndrome Diagnostic Service , Sheffield , UK.
authors: G J
authors: GJ
authors: Sobey
authors: c Electron Microscopy Unit, Department of Histopathology , Royal Hallamshire Hospital , Sheffield , UK.
authors: B E
authors: BE
authors: Wagner
authors: d Department of Histopathology , Sheffield Children's NHS Foundation Trust , Sheffield , UK.
authors: L C
authors: LC
authors: Peres
authors: a Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust , Sheffield , UK.|b National Ehlers Danlos Syndrome Diagnostic Service , Sheffield , UK.
authors: J
authors: J
authors: Bowen
authors: b National Ehlers Danlos Syndrome Diagnostic Service , Sheffield , UK.
authors: J
authors: J
authors: Bexon
authors: e Department of Academic Rheumatology, Nuffield Department of Orthopaedics, Rhuematology & Musculoskeletal Sciences , University of Oxford , Oxford , UK.
authors: M K
authors: MK
authors: Javaid
authors: f Academic Unit of Child Health , University of Sheffield , Sheffield , UK.
authors: P
authors: P
authors: Arundel
authors: f Academic Unit of Child Health , University of Sheffield , Sheffield , UK.
authors: N J
authors: NJ
authors: Bishop
mesh_terms: D000293:Adolescent; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D024042:Collagen Type I / Q000235:genetics* / Q000648:ultrastructure; D000090602:Collagen Type I, alpha 1 Chain; D004252:DNA Mutational Analysis; D004547:Elastic Tissue / Q000648:ultrastructure; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D012867:Skin / Q000648:ultrastructure*
chemical_list: C000601279:COL1A2 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain
keywords: COL1A1/COL1A2; collagen fibril diameter; collagen flowers; elastic fibers; electron microscopy; osteogenesis imperfecta; type 1 collagen