A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders

Endocrine and Pediatric Endocrine Units, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 06/2005; 115(5):1250-7. DOI: 10.1172/JCI22760
Source: PubMed


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.

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Available from: Robert Gensure, Jan 28, 2014
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    • "It has been suggested that early onset of fetus ICH is usually lethal because of massive hepatic myeloid hyperplasia resulting in enlarged liver, ascites, anasarca, and pulmonary hypoplasia [32]. However, mutational analysis of COL1A1 gene in two fetuses manifesting ICH characteristics disclosed a wild genotype [18]. Kamoun-Goldrat et al. [21] reported an ICH fetus terminated at 30 weeks after a diagnosis of severe osteogenesis imperfecta. "
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    ABSTRACT: Infantile cortical hyperostosis (ICH, OMIM 114000) is a rare familial disorder which affects infants. It spontaneously heals in the first years of life. The disease is characterized by regressive subperiosteal hyperosteogenesis mainly affecting long bones, mandible, clavicles, and ribs which are remarkably swollen and deformed on X-rays. But it is also important to take into consideration the autosomal dominant pattern of inheritance to detect it. In 2005 Gensure et al. detected 3040C → T mutation in COL1A1 gene in three unrelated ICH families. Four generations of patients belonging to the same family were examined in our study. Molecular testing has now disclosed a pathogenic mutation in nine of them. The patients spontaneously recovered. Although our paper shows a distinct correlation between R836C mutation and ICH, there is a certain interindividual and intra-familial variability.
    Preview · Article · May 2011 · European Journal of Pediatrics
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    • "It has been suggested, that infantile cortical hyperostosis is closely associated with a mutation in COL1A1, the gene encoding the alpha chain of type I collagen. Of the 24 affected members of a family segregating Caffey disease in which Gensure et al [9] identified an R836C mutation in the COL1A1 gene, only 19 (79%) had experienced an episode of cortical hyperostosis and 5 (21%) obligate carriers had not, consistent with reduced penetrance. Skull base sclerosis/thickening was not a feature in the above-mentioned reports. "
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    ABSTRACT: Infantile cortical hyperostosis is characterised by hyperirritability, acute inflammation of soft tissue, and profound alterations of the shape and structure of the underlying bones, particularly the long bones, mandible, clavicles, or ribs. We report on a clinical case of a 3-months-old baby girl of non-consanguineous parents. Multiple long bone swellings were the motive of referral to our department for clinical evaluation. Radiographic documentation was consistent with infantile cortical hyperostosis (Caffey disease). Interestingly, skull base sclerosis associated with excessive thickening was the most unusual malformation. We report a baby with mixed endochondral and intramembraneous ossification defects. Bone dysplasias, mucopolysaccharidoses, and metabolic diseases are a group of disorders that cause abnormal growth, density, and skull base shape. Skull base sclerosis/thickening is a well-known malformation in connection with other forms of sclerosing bone disorders such as dysosteosclerosis, frontometaphyseal dysplasia, and progressive diaphyseal dysplasia with skull base involvement. It is noteworthy that our present patient had an unusually sclerosed/thickened skull base. Narrowing of skull foramina due to sclerosis of skull base is likely to result in cranial nerves deficits. In this baby, the pathology has been judged to be the result of child abuse and it is not, in this case considerable harm to his parents, and the doctor-parent relationship was the outcome.
    Full-text · Article · Mar 2009 · Cases Journal
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    • "However, as this patient had showed only non-painful curved forearms and hallux valgus since infancy, the diagnosis is dubious. Then, all the patients certainly having ICH phenotype in two previous reports (Gensure et al. 2005; Suphapeetiporn et al. 2007) and the current study carried the same c.3040C [ T mutation in COL1A1. It is interesting to note that only a single mutation of this large gene causes a specific ICH phenotype. "
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    ABSTRACT: Infantile cortical hyperostosis (ICH) is characterized by spontaneous episodes of subperiosteal new bone formation in the long bones, mandible, and clavicle during infancy. A heterozygous missense mutation, c.3040C>T (p.R1014C), in the type I collagen α1 chain gene (COL1A1) was reported in families with the autosomal dominant form of ICH. We examined six consecutive cases of ICH from five unrelated families and their parents. The mutation was identified in all patients and two parents tested. Our result supported that ICH is caused by the single mutation in COL1A1 with incomplete penetrance.
    Full-text · Article · Aug 2008 · Journal of Human Genetics
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