Caffey disease: New perspectives on old questions

Abstract

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 of I collagen. However, the functional link between this mutation and the underlying pathogenetic mechanisms still remains elusive. First, 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 second, the contribution of the structural and inflammatory components 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.

Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction

“…In contrast, periosteal lamellar bone deposition occurs much more slowly, in agreement with a progression of melorheostotic lesions over years . Periosteal new bone formation is often viewed as a physiological response to focal insults or systemic condition such as infections, hemorrhages, inflammations (periostitis), osteonecrosis, tumor processes, and malign neoplasms such as Ewing's sarcoma or Caffey's disease . In fact, so‐called “periosteal reactions” occur widely and represent a rather nonspecific mechanism to maintain bone strength, counteracting the effects of cortical lysis or endocortical bone loss by forming a bridge over damaged cortical area .…”

“…(44,46,47) Periosteal new bone formation is often viewed as a physiological response to focal insults or systemic condition such as infections, hemorrhages, inflammations (periostitis), osteonecrosis, tumor processes, and malign neoplasms such as Ewing's sarcoma or Caffey's disease. (13,(48)(49)(50)(51) In fact, so-called "periosteal reactions" occur widely and represent a rather nonspecific mechanism to maintain bone strength, counteracting the effects of cortical lysis or endocortical bone loss by forming a bridge over damaged cortical area. (13) Activating MAP2K1 mutations lead to highly proliferative osteoblasts, poor matrix mineralization, accelerated bone remodeling, and highly increased osteoclastogenesis.…”

Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs

“…The structure of connective tissues includes collagens, proteoglycans, and non-collagenous proteins, as well as enzymes that are necessary for precise extracellular matrix assembly and degradation. Mutations in genes encoding these distinct components of the matrix result in similar phenotypes [28]. The triple-helical domain in collagen proteins consists of a Gly-X-Y repeating motif that is essential for the helix folding [29].…”

Unusual findings on infantile cortical hyperostosis: A case report

“…The laboratory tests do not help in diagnosis . Its etiology is uncertain, but recently has been speculated an autosomal dominant mutation (Arg to Cys substitution (R836C) in the α1(I) chain of type I collagen), with variable penetrance . In most cases, however, it should be sporadic …”