Fetuin-A deficiency is associated with infantile cortical hyperostosis (Caffey disease)

Rona Merdler-Rabinowicz, Anna Grinberg, Jeffrey M. Jacobson, Ido Somekh, Christoph Klein, Atar Lev, Salama Ihsan, Adib Habib, Raz Somech, Amos J. Simon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background: Infantile cortical hyperostosis (ICH)/Caffey disease is an inflammatory collagenopathy of infancy, manifested by subperiosteal bone hyperplasia. Genetically, ICH was linked with heterozygosity for an R836C mutation in the COL1A1 gene. Although an autosomal-recessive trait is also suspected, it has not been proven thus far. Methods: A case of an infant male born to consanguineous parents is reported, presenting with classical findings, course, and clinical outcome of ICH. Whole-exome sequencing (WES) was performed in order to identify a possible underlying genetic defect. Results: WES analysis revealed a novel homozygous nonsense mutation in lysine 2 of fetuin-A, encoded by the ALPHA-2-HS-GLYCOPROTEIN (AHSG) gene (c.A4T; p.K2X). Fetuin-A is an important regulator of bone remodeling and an inhibitor of ectopic mineralization. By enzyme-linked immunosorbent assay (ELISA), we show a complete deficiency of this protein in the patient’s serum, compared to controls. Conclusion: A novel homozygous nonsense mutation in AHSG gene has been found in ICH patient with a typical phenotype, resulting in fetuin-A deficiency. This finding postulates an autosomal-recessive mode of inheritance in ICH, which, unlike the autosomal-dominant inheritance associated with COL1A1, is associated with AHSG and fetuin-A deficiency.

Original languageEnglish
Pages (from-to)603-607
Number of pages5
JournalPediatric Research
Issue number5
StatePublished - 1 Nov 2019


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