Caffey disease: New perspectives on old questions

•Caffey disease is caused by an Arg to Cys substitution (R836C) in the α1(I) chain of type I collagen.•The structural change caused by the R836C mutation may trigger collagen-dependent metabolic dysfunction of the matrix.•Abnormal COX2/PGE signaling is likely to play a role in periosteal new bone formation in Caffey disease.•Altered interplay between collagen matrix and bone formation in Caffey could provide novel insights into common disorders affecting bone metabolism.

The autosomal dominant form of Caffey disease is a largely self-limiting infantile bone disorder characterized by acute inflammation of soft tissues and localized thickening of the underlying bone cortex. It is caused by a recurrent arginine-to-cysteine substitution (R836C) in the α1(I) chain of type I collagen. However, the functional link between this mutation and the underlying pathogenetic mechanisms still remains elusive. Importantly, it remains to be established as to how a point-mutation in type I collagen leads to a cascade of inflammatory events and spatio-temporally limited hyperostotic bone lesions, and how structural and inflammatory components contribute to the different organ-specific manifestations in Caffey disease. In this review we attempt to shed light on these questions based on the current understanding of other mutations in type I collagen, their role in perturbing collagen biogenesis, and consequent effects on cell-cell and cell-matrix interactions.