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 (3040C→T) in exon 41 of the gene encoding the α1(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 α1(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.

Deficiency of interleukin-1-receptor antagonist syndrome: a rare auto-inflammatory condition that mimics multiple classic radiographic findings

“…However, DIRA syndrome shows no response to antibiotic therapy, and steroids have little to no impact on disease progression. The findings of diffuse periostitis involving the long bones, not present in this case but seen in 8/9 patients in Aksentijevich's report, simulate Caffey's disease although Caffey's disease is self-limited and caused by an autosomaldominant mutation of COL1A1 [3]. Furthermore, DIRA has not been shown to involve the mandible.…”

COL1A1 Mutation in an Indian Child with Caffey Disease

“…The sequencing of exon 41 of COL1A1, as described by Gensure et al, confirmed the heterozygous mutation c.3040 C>T (p.R1014C) in the proband [1]. The mother was not found to carry this mutation.…”

“…Both familial and sporadic occurrences have been reported. The familial autosomal dominant form has now been found to be a collagenopathy caused by a single heterozygous missense mutation in COL1A1 (c3040C>T; p R1014C) [1][2][3][4]. Though there are several case reports of Caffey disease from India, no data regarding their genetic mutation pattern have been published.…”

Caffey’s disease: an unusual cause for concern

“…Most cases are sporadic but an autosomal dominant inheritance with limited penetrance has been reported [3,4]. More recently, Gensure et al [5] identified a heterozygous mutation of the gene encoding for the alpha1(I) chain of type I collagen (COL1A1) on chromosome 17q in a large family with an autosomal dominant form of Caffey's disease.…”