Fc-Gamma Receptor Polymorphisms Are Associated with Susceptibility to and Recovery from Pediatric Immune Thrombocytopenia
Authors: Heitink-Polle Katja M.J. , Laarhoven Annemieke G. , Bruin Marrie C.A. , Veldhuisen Barbera , Nagelkerke Sietse Q. , Kuijpers Taco , van der Schoot C. Ellen , Vidarsson Gestur , de Haas Masja 
Published: October 2019

Introduction: Immune thrombocytopenia (ITP) in children is a rare autoimmune disorder characterized by isolated thrombocytopenia. Platelet specific autoantibodies are often present leading to accelerated clearance of opsonized platelets by Fc-gamma receptor (FcγR) bearing phagocytes, particularly in the spleen. Both activating FcγRs as well as the inhibitory FcγRIIb are subject to genetic variation that affects their function. This includes mutations resulting in loss of expression; for example only the FCGR2C*ORF with an open reading frame leads to FcγRIIc expression. On myeloid and natural killer cells, FcγRIIc expression enhances IgG-mediated activation. Similarly, functional FcγRIIb polymorphisms also exist (FCGR2B*232I/T), with the FCGR2B*232T variant being functionally impaired in downregulating activating FcγRs and the B-cell receptor. We evaluated whether FcγR polymorphisms are associated with occurrence of ITP, response to intravenous immunoglobulin (IVIg) therapy and recovery in children with newly diagnosed ITP.

Patients and methods: Children aged 3 months-16 years with newly diagnosed ITP, a platelet count below 20x109/L and with mild to moderate bleeding were included in the randomized multicenter TIKI trial (Therapy with or without IVIg for Kids with acute ITP; NTR study ID TC1563). Patients were randomized to receive either a single dose of IVIg (0.8 g/kg) or to receive careful observation and medical treatment only in case of severe bleeding. At diagnosis, blood samples were taken to perform the multiplex ligation-dependent probe amplification (MLPA) assay, assessing copy number variations and detecting all known FcγR polymorphisms.

Results: From May 2009 until May 2015, 180 newly diagnosed patients were enrolled in this part of our study. ITP patients showed an FcγR profile different from that of healthy controls, with an overrepresentation of FCGR2C*ORF (31.7% versus 19.6%, p=0.007) and its associated promoter 2B.2, a higher allele frequency of FCGR3A*158V (41.4% versus 32.8%; p=0.019), and less often FCGR3B-HNA1a (9.4% versus 18.1%, p=0.032). In the observation group (n=81), all children with complete recovery at 1 week (n=17) were homozygous for 232I in FCGR2B (p=0.016). In patients randomized to receive IVIg, complete response rate after one week was 68.4%; complete responders were either homozygous FCGR2B*232I or heterozygous FCGR2B*232I/232T. No complete responses to IVIg were seen in the three patients with the homozygous FCGR2B*232T genotype (p=0.03). In patients with a homozygous FCGR2B*232I genotype combined with the 2B.4 promoter haplotype, complete response rate was significantly higher than in patients lacking this combination (93.3% versus 64.6%, respectively; p=0.03).

Conclusion: Functional FcγR polymorphisms in FCGR2C, FCGR3A and FCGR3B genes are associated with newly diagnosed ITP in children. Furthermore, the less functional 232T-FcγRIIb isoform is associated with the lack of early recovery, either with or without IVIg treatment. FcγR profiles can be regarded as a risk factor to develop ITP during childhood. FcγR profiles are associated with the clinical course and response to IVIg treatment suggesting that determination of the FcγR profile can be of additional value in patient counselling and decision algorithms whether or not to start IVIg treatment in ITP.

Disclosures

No relevant conflicts of interest to declare.