Fetuin-A Deficiency is Associated with Infantile Cortical Hyperostosis (Caffey Disease)

Background: Infantile cortical hyperostosis (ICH)/Caffey disease is an inflammatory collagenopathy of infancy, manifested by bone hyperplasia. ICH is considered to have a strong genetic basis. So far, an autosomal dominant mutation in the COL1A1 gene has been reported. Whereas an autosomal recessive trait is also suspected, it has never been proven.

Methods: A case of an infant male born to consanguineous (first degree cousins) parents is reported, presenting with classical findings and course of ICH, including diagnostic imaging, response to anti inflammatory treatment and clinical outcome. Whole exome sequencing (WES) was performed in order to identify a possible underlying genetic defect.

Results - Following whole exome sequencing of this infant with ICH, we found a novel homozygous nonsense mutation in the lysine 2 of the AHSG gene (c.A4T; p.K2X). The AHSG gene encodes the protein fetuin-A, an important regulator of bone remodeling and an inhibitor of ectopic mineralization. By enzyme-linked immunosorbent assay (ELISA) we showed a complete deficiency of this protein in the patient`s serum, compared to controls.

Conclusion: We are the first to report this novel autosomal recessive mutation in the AHSG gene and ICH, proving that ICH indeed have an autosomal recessive mode of inheritance. This homozygous nonsense mutation in lysine 2 of AHSG (c.A4T; p.K2X) causes non production of fetuin-A, revealing the importance of this protein in the pathogenesis of ICH.