Expanding the Spectrum of Src-Family Kinase-Related Autoinflammatory Diseases: Monogenic Vasculitis Caused By Germline Pathogenic Variants in HCK and FGR.

The sarcoma (Src) family of non-receptor tyrosine kinases (SFKs) regulate innate immunity through their roles in signal transduction and cell migration, adhesion and proliferation. Germline pathogenic variants in this key kinase group are rare but increasingly recognised as causes of autoinflammatory disease. We identified three unrelated kindreds with SFK-associated vasculitis. In Family A, we report a child with systemic vasculitis due to a nonsense heterozygous variant in HCK (p.Y515X) who was subsequently treated with allogeneic haematopoietic stem cell transplantation (allo-HSCT), the first use of this approach in SFK-related disease. In Family B, we identified a novel HCK missense variant (p.Y522F) causing a cutaneous-limited phenotype. In Family C, we describe a large pedigree carrying a novel missense variant in FGR (p.Y523H), establishing FGR as a new cause of monogenic vasculitis. In all families, disease-onset was neonatal with vasculitic rash, variably progressing to systemic involvement including lung disease. Functional studies demonstrated reduced Hck and Fgr protein expression and enhanced p-STAT1 and p-STAT5 signalling in monocytes and lymphocytes. With striking similarities in the clinical phenotypes and underlying molecular mechanisms, these cases expand the spectrum of sarcoma (Src) family of non-receptor tyrosine kinase-associated autoinflammatory disease, and support this as a distinct group that we propose is termed the “autoinflammatory Src-opathies (sarcopathies)”.