Increased Bleeding Tendency in a Patient with Caffey Disease Due to a COL1A1 Mutation and a Defect in Platelet Morphology and Function.
Authors: Freson Kathleen , Labarque Veerle , Thys Chantal , Wittevrongel Christine , De Vos Rita , Farndale Richard , Van Geet Chris 
Published: April 2020

Abstract
Caffey disease or infantile cortical hyperostosis is characterized by hyperirritability, acute inflammation of soft tissues, and profound alterations of the shape and structure of particularly the long bones. This autosomal dominant disorder in 4 unrelated families is caused by a similar missense mutation (R836C) in the gene for the alpha1 chain of type I collagen (COL1A1; Gentile et al, JCI, 2005). The precise link between this mutation and either the localized inflammation problems or the originally described thrombocytosis and easy bruising associated with Caffey disease (Lorber et al, 1979) was not evidenced. In the present study, we studied the platelets from a 6-year-old girl with Caffey disease due to a de novo COL1A1 R836C mutation because of her increased bleeding tendency. Apart from the typical skeletal deformities she also presented with easy bruising. This COL1A1 mutation modulates normal megakaryopoiesis since the patient presented with a relatively high number of platelets (+/−450.000/mL) and a decreased MPV (7-8 fL). All other hematological parameters were normal. Electron microscopy further revealed platelets with a proliferation of the dense tubular system, a pronounced open canalicular system and a reduced number of often smaller dense granules. Platelet ATP secretion was reduced after stimulation with 5 mg/ml Horm collagen (2 mM: nl 3-7 mM). The PFA100 response with either collagen/epinephrine or collagen/ADP was within the normal range. Aggregation studies were suggestive for a selective impairment of platelet activation to collagen since the patient platelets showed a reduced and retarded response towards Horm Collagen, convulxin and the collagen related peptide (CRP-XL) but a normal aggregation with ADP, U46019 and arachidonic acid. Membrane glycoprotein (GP) profiling by flow cytometry showed a normal antibody binding to integrin beta3, integrin alpha2beta1 and GPVI. Since R to C amino acid substitutions in COL1A1 are associated with an increased disulfide crosslinking within mutant collagen fibers (Gentile et al, JCI, 2005) but also with other cysteine-containing proteins as integrins, we hypothesized that the platelet integrins might be triggered when mature megakaryocytes are in contact with the collagen type I of the extracellular matrix of the patients bone marrow. Immunoblot analysis of platelet lysates from the patient indeed showed the presence of a 190 kDa COL1A1 band, which could not be detected in control samples. In addition, beta1 integrin could be co-immunoprecipitated with an anti-COL1A1 antibody in platelet lysates from the patient. Further studies are needed to determine whether this COL1A1 R836C binding to platelet collagen receptors is responsible for the defective collagen signaling in this patient by receptor desensitization. In conclusion, we here present the first collagen type I mutation that leads to a defective platelet ultra structure and function.