Abstract
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.
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Acknowledgements
We thank the patient’s family for their cooperation. We thank the Care-for-Rare Foundation and the DAAD for supporting the study.
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R.M.-R., A.R., A.L. and A.J.S. designed, performed, and analyzed experiments; I.S. and C.K. conducted WES study and analyzed the results; J.J. diagnosed imaging and reviewed manuscript; S.I., A.A. and R.S. followed, diagnosed, and treated the patient; R.M.-R., A.J.S. and R.S. drafted the manuscript and supervised the experiments.
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Merdler-Rabinowicz, R., Grinberg, A., Jacobson, J.M. et al. Fetuin-A deficiency is associated with infantile cortical hyperostosis (Caffey disease). Pediatr Res 86, 603–607 (2019). https://doi.org/10.1038/s41390-019-0499-0
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DOI: https://doi.org/10.1038/s41390-019-0499-0
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