Background/Purpose: Tyrosine-protein kinase Lyn is a Src-family tyrosine kinase expressed by hematopoietic and non-hematopoietic cell types. Phosphorylation of a tyrosine residue at position 508 renders the molecule inactive. In a mouse model, amino acid modification Y508F causes severe anemia, autoimmune glomerulonephritis and positive ANA (Lyn^up/up mice) but the human phenotype and its role in human disease remain unkonwn. We characterize the clinical phenotype and cellular function of mutant Lyn kinase in two patients with systemic inflammation and vasculitis both presenting with a de novo germline mutation at the regulatory tyrosine residue 508 in LYN.

Methods:  Patients were clinically evaluated, records were reviewed, WES (Illumina HiSeq2000 platform) of the de novomutations were confirmed by Sanger sequening. B and T lymphocyte and monocyte immunophenotyping were performed through flow cytometry.

Results: The de novo mutations in LYN leads to a premature stop-codon at p.Y508* which removes 5 terminal amino acid residues (pt.1) 1 and revealed the missense p.Y508F that was studied in the lyn up/up mice (pt.2). The clinical features of both patients included perinatal-onset of systemic inflammation. Patient 1 presented with hydrops fetalis, requiring an intra-utero blood transfusion and post partum, purpuric skin rash, hepatosplenomegaly, periorbital erythema and testicular pain and swelling with increased CRP. Cytopenias including anemia, and thrombocytopenia required a splenectomy at the age of 9mo. Post-splenectomy development of chronic leukocytosis and thrombocytosis with persistent anemia and Increased liver enzymes led to a liver biopsy at age 23 mo showing a periportal lymphocytic infiltrate, vanishing bile duct disease and evidence of periportal bridging fibrosis. A skin biopsy confirmed neutrophilic small vessel vasculitis and low titer circulating autoantibodies (positive ANA, anti-Sm, anti-SSA, anti-phospholipids and anti-mitochondrial antibodies). Initiation of prednisone and IVIG infusions led to some improvement but prednisone could not be weaned. Pt. B lymphocytes showed constitutive phosphorylation of Lyn and a significantly diminished frequency of immature B cell populations in peripheral blood and in bone marrow. Reduced B cell activation in response to IgM stimulation compared to healthy controls was observed. The tyrosine kinase inhibitor dasatinib normalized lyn phosphorylation in pt B cells and was initiated with significant clinical and laboratory response. Patient 2 presented with a generalized purpuric skin rash and recurrent episodes of fevers since his first hours of life. Other symptoms included abdominal and testicular pain, headaches, conjunctival erythema, arthralgias, oral ulcers and fatigue. The recurrent symptoms have responded to short courses of oral steroids. He had a partial response to colchicine, no response to anakinra and tocilizumab and was recently started on etanercept.

Conclusion: We identified activating mutations in Lyn kinase gene (LYN) as cause for a novel immunedysregulatory syndrome presenting with neonatal-onset of fever, small vessel neutrophilic vasculitis and systemic inflammation.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/mutations-in-the-tyrosine-protein-kinase-lyn-cause-an-early-onset-neutrophilic-vasculitis-syndrome/