title: A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders.
abstract: Infantile cortical hyperostosis (Caffey disease) is characterized by spontaneous episodes of subperiosteal new bone formation along 1 or more bones commencing within the first 5 months of life. A genome-wide screen for genetic linkage in a large family with an autosomal dominant form of Caffey disease (ADC) revealed a locus on chromosome 17q21 (LOD score, 6.78). Affected individuals and obligate carriers were heterozygous for a missense mutation (3040Ctwo head right arrowT) in exon 41 of the gene encoding the alpha1(I) chain of type I collagen (COL1A1), altering residue 836 (R836C) in the triple-helical domain of this chain. The same mutation was identified in affected members of 2 unrelated, smaller families with ADC, but not in 2 prenatal cases and not in more than 300 chromosomes from healthy individuals. Fibroblast cultures from an affected individual produced abnormal disulfide-bonded dimeric alpha1(I) chains. Dermal collagen fibrils of the same individual were larger, more variable in shape and size, and less densely packed than those in control samples. Individuals bearing the mutation, whether they had experienced an episode of cortical hyperostosis or not, had joint hyperlaxity, hyperextensible skin, and inguinal hernias resembling symptoms of a mild form of Ehlers-Danlos syndrome type III. These findings extend the spectrum of COL1A1-related diseases to include a hyperostotic disorder.
authors.affiliation: Endocrine and Pediatric Endocrine Units, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gensure
authors.forename: Outi
authors.initials: O
authors.lastname: Mäkitie
authors.forename: Catherine
authors.initials: C
authors.lastname: Barclay
authors.forename: Catherine
authors.initials: C
authors.lastname: Chan
authors.forename: Steven R
authors.initials: SR
authors.lastname: Depalma
authors.forename: Murat
authors.initials: M
authors.lastname: Bastepe
authors.forename: Hilal
authors.initials: H
authors.lastname: Abuzahra
authors.forename: Richard
authors.initials: R
authors.lastname: Couper
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: David
authors.initials: D
authors.lastname: Sillence
authors.forename: Leena
authors.initials: L
authors.lastname: Ala Kokko
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.forename: William G
authors.initials: WG
authors.lastname: Cole
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
mesh_terms: D001842:Bone and Bones / Q000503:physiopathology*; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D020405:Dermis / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D005360:Fibula / Q000000981:diagnostic imaging; D006239:Haplotypes; D006801:Humans; D006958:Hyperostosis, Cortical, Congenital / Q000235:genetics / Q000503:physiopathology*; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D011859:Radiography; D013977:Tibia / Q000000981:diagnostic imaging
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain