Caffey Disease is a Type I Collagenopathy

Caffey disease (OMIM 114000), also known as infantile cortical hyperostosis, is characterized by spontaneous episodes of subperiosteal new bone formation typically involving the diaphyses of long bones, mandible, and clavicles in young children. It is associated with acute inflammation of soft tissues and can lead to profound alterations in the shape and structure of affected bones. It often exhibits an autosomal dominant pattern of inheritance with substantial variation in severity.

A group headed by Jüppner undertook genome-wide linkage studies to map the Caffey disease gene locus in 3 unrelated families. Their search led them to chromosome 17q21 and eventually—to their surprise—to the COL1A1 locus, which encodes the α 1 chain of type I collagen. Affected individuals in all 3 families had the identical mutation: an arginine to cysteine substitution at position 836 (R836C) placing it in the carboxy portion of the triple helical domain of the collagen molecule. About one-fifth of family members in whom the mutation was detected had no clinical features consistent with previous reports of reduced penetrance for the condition.

Mutations of the COL1A1 are typically associated with osteogenesis imperfecta (OI) and, to a lesser extent, with Ehlers-Danlos syndrome (EDS). The affected members of these families did not display clinical signs of OI. They lacked gray-blue sclerae, dentinogenesis imperfecta, premature hearing loss, and short stature. Although bone fractures were relatively common in one family, they were considered within the range of normal. One affected member in this family had normal bone densitometry studies.

Schematic illustrating normal and exuberant bone formation. (A) Representation of a growing bone. Growth in length is achieved by endochondral bone formation adding cancellous bone in the metaphyseal area. Gain in diameter comes from subperiosteal new bone apposition by intramembranous bone formation. The periosteum is an envelope of fibrous connective tissue that is wrapped around diaphyses. The size of the marrow cavity is controlled by a combination of bone apposition and resorption at the endocortical surface. (B and C) In ICH/Caffey disease, hyperostosis develops by exacerbated subperiosteal intramembranous bone formation triggered by local inflammation (left side of B and C). In the remodeling phase, the excess of bone tissue is resorbed either at the endocortical surface, leading to an expansion of the marrow cavity and a more persistent deformity (right side of B), or at the exocortical surface, with no effect on the size of the marrow cavity (right side of C). Reprinted with permission Glorieux F. J Clin Invest. 2005;115:1142-1144. Copyright ©2005. ASCI. All rights reserved.

Several affected family members had joint hypermobility and abnormally soft and hyperextensible skin suggestive of mild EDS. Electron microscopy of a skin biopsy from one of these patients revealed that collagen fibrils varied more in size and shape and were less densely packed than normal. Collagen biosynthetic studies of fibroblasts from this patient showed abnormalities consistent with the presence of cysteine residues in the mutant type I collagen chains.

Perhaps most interesting, as addressed by both Gensure et al and in an accompanying comment by Glorieux,¹ is how one explains the episodic nature of this condition by a mutation in an extremely abundant structural protein present in bone and neighboring tissues (Figure). Although both raise several interesting possibilities, they also conceded that the question remains open and will require further investigation.

Editor’s Comment: It was not surprising to learn that OI and some forms of EDS are allelic disorders given the overlap in some of their features. However, it is surprising to find Caffey disease in this group. Even though there appears to be some clinical overlap with mild EDS, the inflammatory and episodic nature of Caffey disease makes it quite distinct. As both Gensure and Glorieux¹ point out, some of the differences in clinical phenotype may be due to the fact that the mutation reported here does not involve a glycine residue as do most OI mutations. Collagen glycine mutations are thought to disrupt the formation and stability of the collagen triple helix, which is responsible for the structural properties of collagen. The Caffey disease mutation affects an arginine residue, which interestingly has been reported in 2 unrelated patients with classic EDS. As both also note, administration of prostaglandin E to infants with congenital heart disease sometimes causes local hyperostosis similar to episodes of Caffey disease, raising the possibility that this substance somehow mediates the pathologic events. If so, it remains to be determined how abnormal type I collagen sets the stage for inflammation and reactive bone formation.


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