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. 2005 May;115(5):1250-7.
doi: 10.1172/JCI22760.

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

Robert C Gensure  1 , Outi Mäkitie, Catherine Barclay, Catherine Chan, Steven R Depalma, Murat Bastepe, Hilal Abuzahra, Richard Couper, Stefan Mundlos, David Sillence, Leena Ala Kokko, Jonathan G Seidman, William G Cole, Harald Jüppner
Affiliations

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

Robert C Gensure et al. J Clin Invest. 2005 May.

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.

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Figures

Figure 1
Figure 1
Radiographic features of infantile cortical hyperostosis. Radiographs of 3 affected individuals of 2 unrelated kindreds showing subperiosteal thickening of the femur, tibia, and fibula (left and upper middle panels: tibia and fibula, respectively, of twin II-1 of family 3; upper right panel: fibula of patient II-1 of family 2), and metacarpals of the left foot (lower right panel: twin II-2 of family 3). Note that the periosteum, which is normally anchored at the growth plates where it is continuous with the perichondrium, was frequently elevated circumferentially from the proximal to the distal growth plates (open arrows). The bone marrow cavities were also narrowed (filled arrows).
Figure 2
Figure 2
Haplotype analyses of families with infantile cortical hyperostosis. (A) Family 1: Fine mapping of the locus for Caffey disease on chromosome 17q21. Standard techniques were used to establish the genetic locus of the disease in a large Canadian family with ADC (7, 8). Black symbols, affected individuals; white symbols with black dot in the center, obligate carriers; white symbols, unaffected individuals; gray symbols, deceased individuals. The unaffected individual II-9, who has unaffected children and grandchildren (data not shown), was only included to deduce the haplotypes of I-1 and I-2 (indicated by italics); for LOD score calculations, his phenotype was entered as unknown. Marker D17S1795 provided a LOD score of 6.78 (maximal theoretical LOD score, 7.12). Markers D17S1868 and D17S1877 (indicated in white on a black background) define the centromeric and telomeric boundary, respectively. The disease-associated haplotype is shown by black numbers on gray; markers consistent with a recombination are shown by white numbers on black. Uninformative data and haplotypes not associated with the disease are shown by black numbers on white. A C↠T mutation at nucleotide 3040 of COL1A1 (see Figure 3) was identified by direct nucleotide sequence analysis only in affected members and obligate carriers. (B) Haplotypes of portions of the family shown in A and PCR-based confirmation of the identified mutation (see Methods). (C) Haplotypes and PCR analysis for family 2, comprising 2 affected brothers, their affected mother, and their healthy father. (D) Haplotypes and PCR analysis for family 3, comprising identical twin sisters affected by Caffey disease and their healthy parents and brother (19).
Figure 3
Figure 3
Nucleotide sequence analysis of portions of exon 41 of COL1A1 and adjacent intronic regions of an affected individual from family 1. The individual was heterozygous for the transition, which is indicated by the arrow, and the approximate location of both primers for PCR amplification is indicated by arrowheads within the schematic, partial drawing of COL1A1. Partial nucleotide sequence of wild-type and mutant (mut) exon 41 (capital letters), as well as adjacent intronic sequence (lower-case letters), along with the encoded amino acid sequence, are shown. The 3040C↠T transition (indicated by an asterisk), which alters the first nucleotide of the second-to-last codon in exon 41, is predicted to result in the substitution of an arginine (R) 836 to a cysteine (C) residue (R836C). The approximate location of the R836C mutation within the triple-helical region of the collagen fibril is schematically shown [bottom: thin lines, α1(I) chains; thick line, α2(I) chain], as is the location of the R134C mutation previously described in 2 unrelated patients with Ehlers-Danlos syndrome type I (31).
Figure 4
Figure 4
Dermal ultrastructure from proband IV-2 of family 1. (A) Ultrastructure of the extracellular matrix of the proband’s dermis (magnification, ×60,000). The collagen fibrils are more variable in shape and size and are less densely packed than in control samples. The fibrils are also larger (Caffey disease, 108 ± 15 nm; control, 91 ± 8 nm; n = 1,000; P < 0.0001). Granular material is visible in the matrix surrounding the collagen fibrils. (B) Ultrastructure of control dermis. In contrast to the proband’s dermis, the collagen fibrils in the control dermis are round, uniform in size, tightly packed, and are not surrounded by granular material.
Figure 5
Figure 5
Collagen biosynthesis by cultured fibroblasts from proband IV-2 of family 1. (A) One-dimensional gel electrophoresis of dermal and fibroblast collagens: lane 1, pepsin-solubilized collagen from normal dermis (ND); lane 2, proband fibroblast cell layer collagens; lane 3, proband medium collagens; lane 4, reduced proband fibroblast cell layer collagens; lane 5, reduced proband medium collagens; lane 6, control fibroblast cell layer collagens; lane 7, control medium collagens. All samples contained α1(I) and α2(I) monomeric chains of type I collagen. Control dermis (lane 1) contained α1(I) dimers (β11) and α1(I)/α2(I) dimers (β12) with lysine-derived cross-linkages; these cross-linkages were partially blocked with the addition of β-aminopropionitrile in all fibroblast cultures. The unreduced dermal and fibroblast culture samples contained disulfide-bonded type III collagen trimers [α1(III)3]. There was an additional protein band in the unreduced proband samples (arrowheads, lanes 2 and 3), designated β11′, which was more abundant in the cell layer than in the medium. This band migrated slightly slower than the dermal β11 dimer. The abnormal band disappeared, along with the type III collagen trimer, after reduction of disulfide bonds with DTT. (B) Two-dimensional gel electrophoresis of the proband’s fibroblast cell layer collagens. Disulfide bonds were unreduced in the first dimension and reduced with DTT in the second dimension. The abnormal protein band in A, lane 2, was dissociated by DTT into proteins, designated α1(I)′, which migrated in a similar manner to control α1(I) chains.
Figure 6
Figure 6
Voluntary subluxation of various joints in ADC patients. Photographs of 4 individuals carrying the R836C mutation (III-13, IV-2, IV-3, and IV-4 of family 1): upper left, 2 individuals with subluxation of the shoulders; lower left, 2 views of patellar subluxation; right: views of hyperextension and subluxation in the fingers and the elbow.
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