SOCS1 Haploinsufficiency Presenting As Incidental Refractory Thrombocytopenia in a Pediatric Patient with Inflammatory Symptoms and History of Sars Cov-2 Infection

ABSTRACT

BACKGROUND: Immune thrombocytopenia purpura (ITP) has a complex pathogenesis and may be a primary diagnosis or secondary to an underlying condition 1. Evaluation for underlying diagnoses in patients presenting with atypical features of classic ITP is key, as this can impact treatment decisions, therapy response, and prognosis. Genetic variants that predispose patients to ITP are especially important to investigate as patients may be at risk for additional autoimmune phenomenon or malignancy. The SARS CoV-2 pandemic has added further complexity as reports suggest the infection can lead to autoimmunity in those with genetic predispositions 2,3. Loss of the suppressor of cytokine signaling 1 (SOCS1) function has been described to manifest with autoinflammatory syndrome, with or without immunodeficiency 4,5. Reports of autoimmunity developing in patients with SOCS1 haploinsufficiency after SARS CoV-2 infection are documented, including multi-system inflammatory syndrome (MIS-C) 2. A proposed mechanism of this virus-triggered autoimmunity includes a transient innate and adaptive immunodeficiency 3. This raises the question whether patients harboring genetic variants with risk of autoimmunity are placed at an even higher risk for ITP in the wake of SARS-CoV2 infection. CASE PRESENTATION We present a 6-year-old female with isolated thrombocytopenia of 4,000/uL identified during evaluation for severe arthralgias unresponsive to corticosteroid treatment (maximum dose 1mg/kg/day) over a 6-month period. Laboratory results at presentation were consistent with ITP, including presence of platelet autoantibodies. Evaluation revealed hypocellularity for age (~50%) on bone marrow evaluation as well as elevated IgE (2080 kU/L), with IgA, IgM, and IgG levels within reference range. She had a remote history of SARS CoV-2-like illness and SARS CoV-2 antibodies were found present in serologic assay, without a history of vaccination. Genetic testing, including chromosomal microarray from peripheral blood and marrow, was included in the diagnostic workup given concern for a history of developmental delays with macrocephaly and necessity to rule-out malignancy with the patient noted to have a 5 mega-base deletion at 16p13.2p13.11, which includes the SOCS1 gene. Comprehensive next generation sequencing for additional immune dysregulation/primary immunodeficiency associated variants was unremarkable. Functional studies of surface expression of interferon-inducible genes (CD169 (SIGLEC-1)) and STAT1 phosphorylation via analysis of CD14+ monocytes revealed excess interferon signaling previously described in patients with SOCS1 haploinsufficiency (Figure 1). Measurements of B-cell-activating factor were also found to be extremely elevated at 6432 pg/mL. The patient's ITP course was complicated by hematuria, melena and refractory platelet response to first line therapy consisting of intravenous immunoglobulin 1 g/kg x2 doses and 2 mg/kg/day prednisolone. She required escalation to high dose methylprednisolone (30mg/kg), rituximab 375 mg/m 2/weekly x4 doses, and concurrent romiplostim (2 doses) for control of thrombocytopenia and bleeding manifestations. Her rheumatologic symptoms subsided with initiation of corticosteroids, and she has subsequently completed a prolonged corticosteroid taper. She currently has a normal platelet count with non-steroidal anti-inflammatory therapy utilized for arthralgia management with plan to transition to JAK inhibition for maintenance therapy. CONCLUSION: This case highlights the potential impact of investigating for susceptibility genes for ITP with consideration for broader testing including targeted next generation sequencing panels or microarray analysis in patients with atypical ITP presentations or response to therapy, as knowledge of this patient's underlying genetics led to earlier treatment and use of alternative agents. Additionally, the case adds the novel finding of bone marrow hypocellularity to the clinical phenotype of SOCS1 haploinsufficiency, as this has not yet been reported and contributes to the literature on the relationship of autoimmunity and SARS CoV-2 infections in patients with predisposing genetic variants. [Formula presented] Disclosures Walkovich Horizon Pharmaceuticals Honoraria, Membership on an entity's Board of Directors or advisory committees;Pharming Honoraria, Membership on an entity's Board of Directors or advisory committees;Swedish Orphan Biovitrum AB (Sobi) Consultancy, Honoraria;X4 Pharmaceuticals Other Local PI for clinical trial involving mavorixafor and patients with neutropenia.