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

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.

Fig. 1

Patient’s radiographic examinations. a Periosteal reaction along the entire shaft of the right humerus. b Periosteal reaction along the left clavicle, ribs, and mandible. c Periosteal reaction along the fibula. d Complete periosteal resolution of the humerus

Fig. 2

Validation to the AHSG mutation. Sanger sequencing chromatograms confirmed segregation of the identified AHSG sequence variants in the patient and his parents. The first ATG codon of the encoded fetuin-A protein and the resulted TAG termination codon are boxed in red. The mutated nucleotide is marked with a blue arrow

Fig. 3

Fetuin-A protein levels in the sera. The fetuin-A serum levels of the patient, both his parents, ten age-matched healthy infants, and nine healthy adults were measured, using the enzyme-linked immunosorbent assay kit specific to serum fetuin-A (R&D Systems, Minneapolis, MN, USA). The results are presented in μg/ml