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Infantile cortical hyperostosis (also known as Caffey disease) is characterized by hyperirritability, acute inflammation of soft tissues, and profound alterations of the shape and structure of the underlying bones, particularly the long bones, mandible, clavicles, or ribs. In this issue of the JCI, Gensure et al. undertook fine mapping of the genetic locus for this disease in a large kindred of individuals with the autosomal dominant form of the condition. The authors found a novel missense mutation in COL1A1, the gene encoding the α1 chain of type I collagen, in all affected individuals in 3 discrete pedigrees. This is a surprising finding, as all other reported mutations affecting the synthesis of type I collagen lead to conditions such as osteogenesis imperfecta and Ehlers-Danlos syndrome, in which quantitative or qualitative defects in type I collagen synthesis give rise to bone fragility and/or connective tissue hyperextensibility. The deleterious effect of the mutation on collagen fibril morphology is demonstrated; however, the precise functional link between the reported missense mutation and the localized inflammation and hyperostosis seen in Caffey disease awaits future studies.
Infantile cortical hyperostosis (ICH) — also referred to as Caffey or Caffey-Silverman disease — was recognized in 1945 by Caffey and Silverman (1). The condition, later shown to be transmitted as an autosomal dominant trait with incomplete penetrance, becomes clinically evident before 5–7 months of life, and the average age at onset is around 9 weeks. The initial symptom is general hyperirritability, with fever and anorexia, quickly followed by painful, firm soft-tissue swelling, particularly in the face (cheeks and jaws), the scapular region, and upper and lower limbs. It is usually self-limited, with severe symptoms lasting from 2–3 weeks to 2–3 months. The pattern of distribution of the lesions varies from patient to patient and can be symmetrical (Figure (Figure1).1). Swelling also involves underlying muscle. It is important to note that this phase of acute inflammation precedes the abnormal thickening of cortical bone (hyperostosis) that gives its name to the disease. It also subsides long before the hyperostosis resolves. Sometimes lesions recur suddenly in their original sites or in new sites, either during or after the subsidence of the swellings that appeared at the onset of the disease. This uneven protracted clinical course with unpredictable remissions and relapses is one of the most characteristic features of the condition (2).
The radiographic features of ICH evolve in stages. Hyperostoses develop on the outer cortical surface, expand, and then remodel by resorption either at the external surface or at the endocortical surface. In the latter case, there is an expansion of the medullary cavity and the cortex is thin (Figure (Figure2B).2B). Epiphyses and metaphyses are typically not involved. Tubular bones may be grossly deformed (Figure (Figure1),1), with bony bridges sometimes appearing between adjacent bones (forearm, ribs). The histology of the bone lesions has been described in detail (3). Such lesions include not only subperiosteal new lamellar bone formation but also evidence of local inflammation. Early on, foci of acute inflammation are confined in the periosteum; they then disrupt the periosteal envelope to blend with contiguous tissues (fasciae, muscle, and tendon). In the subacute phase, the periosteum reestablishes itself as an entity with a sheet of fibrous tissue under which new subperiosteal bone is formed. In the late remodeling stage, signs of inflammation disappear, and excess peripheral bone is removed.
Based on these facts, discussion of the pathophysiology of ICH naturally turns toward a mechanism likely to induce local inflammation. Such a hypothesis received strong support from a report by Ueda et al. (4) demonstrating that administration of prostaglandin E (PGE) in infants with ductus-dependent cyanotic heart disease induced a form of cortical hyperostosis that mimics ICH. Two years later, Heyman et al. (5) reported that in 5 affected children, PGE serum levels were significantly elevated and that treatment with indomethacin (an inhibitor of PGE synthesis) rapidly suppressed irritability and led to a progressive decrease in soft-tissue swelling in 6–9 days. Whether elevated PGE levels were a cause or a consequence of the lesions could not be answered. We have made the same observations in 3 patients (Glorieux et al., unpublished data).
At a time when the debate regarding how a state of acute bone and soft-tissue inflammation could be limited in time and space and yet be transmitted as an autosomal dominant trait with incomplete penetrance is at a virtual standstill comes the surprising finding reported in this issue of the JCI that ICH is closely associated with a mutation in COL1A1, the gene encoding the α1 chain of type I collagen (6). The careful and elegant work of Gensure et al. has established a strong linkage between the ICH phenotype and the COL1A1 locus on chromosome 17q21 in 3 discrete pedigrees from Australia and Canada with an autosomal dominant form of ICH. More importantly, despite the fact that the families were geographically dispersed and unrelated, it was found that all affected individuals were heterozygous for the identical mutation, a substitution of Arg by Cys at position 836 (R836C), within the helical domain of the α1 chain of type I collagen. The linkage and sequencing data are solid and convincing and represent a major step forward in the understanding of the pathology of an elusive disease.
One has to now try and understand how a point mutation in a widely distributed structural protein can initiate the cascade of inflammatory events that lead to ICH. Type I collagen, the most abundant protein present within bone, is also present in periosteum, ligaments, dermis, and tendon. It is made of a long, continuous triple helix that assembles in highly organized collagen fibrils. The fibrils have high tensile strength, which is critical for the function of bone and other tissues (7). Glycine occurs at every third residue of the triple-helical domain. Because of its small size, it packs tightly at the center of the helix and confers stability. A mutation affecting a Gly residue will thus have an impact on the conformation of the collagen molecule, its integration in the tissue (bone, skin, and tendon), and the structural qualities of the tissue. This is the case in osteogenesis imperfecta, or brittle bone disease, where most mutations within COL1A1 are glycine substitutions. The severity of the phenotype is determined in part by the pattern of inheritance, the position of the mutation in the α1 chain, and the bulkiness of the replacement residue, as it will variably compromise formation and stability of the helix.
In contrast, the R836C mutation identified by Gensure et al. (6) in these ICH patients would not be predicted to have such an effect on the collagen molecule. Why and how it would instead stimulate new bone formation through a process of inflammation has yet to be understood. There has been only one other Arg-to-Cys substitution reported in the α1 chain of type I human collagen. R134C is associated with classical Ehlers-Danlos syndrome (EDS), which is characterized by skin hyperelasticity, joint hypermobility, increased tendency to bruise, and abnormal scarring (8). Some of the clinical features of EDS are actually evident in the families with ICH studied by Gensure et al. (6), and this makes sense. But the reason why some ICH patients also develop acute bone lesions at a specific age is not clear. The authors hypothesize that periosteum is only loosely attached to the underlying bone structure in infants and that periosteum detachment (perhaps facilitated by the collagen mutation) would be the primum movens leading to increased bone formation. Such a hypothesis is not entirely consistent with the histologic studies done sequentially in cases of ICH (3), which clearly indicate that inflammation is the initial event, in agreement with the clinical and PGE-related observations. It is noteworthy that Gensure et al. found that 79% of the individuals studied who were heterozygous for the COL1A1 mutation had an episode of cortical hyperostosis, while 21% of the subjects carrying the R836C substitution do not develop disease, which confirms the clinically observed reduced penetrance at the molecular level. Many unresolved questions regarding the pathology of this disease may have to wait for the engineering of an appropriate mouse model.
In conclusion, by showing convincingly that Caffey disease is associated with a COL1A1 missense mutation, Gensure et al. (6) have once again demonstrated the power of linkage analysis. They have lifted the lid of a black box, but what is inside the box remains to be discovered.
Work in the author’s laboratory is supported by the Shriners of North America. The author wishes to thank Frank Rauch for critical reading of the manuscript.
See the related article beginning on page 1250.
Nonstandard abbreviations used: COL1A1, gene encoding the α1 chain of type I collagen; EDS, Ehlers-Danlos syndrome; ICH, infantile cortical hyperostosis; PGE, prostaglandin E.
Conflict of interest: The author has declared that no conflict of interest exists.