Clinical, biological and cytometric characteristics of two patients with a homozygous A91V PRF1 mutation

Abstract Objectives Inborn errors of immunity are rare genetic disorders that cause dysfunction of the immune system. Among these, familial haemophagocytic lymphohistiocytosis (FHL) involves defects in the perforin/granzyme pathway, which is essential for regulating immune responses. These conditions predispose individuals to haemophagocytic lymphohistiocytosis, a life‐threatening hyperinflammatory syndrome. FHL has traditionally been described in paediatric patients with a fatal outcome in the absence of early haematopoietic stem cell transplantation. However, some patients harbouring missense mutations may present with atypical or late‐onset symptoms, for which management remains unstandardised. Among these reported variants, the pathogenicity of the A91V PRF1 mutation remains the most controversial in the literature. Method We report clinical, biological and cytometric characteristics of two patients with a homozygous PRF1 A91V mutation who developed clinical features consistent with FHL2. Discussion We discuss the latest 2024 classifications to better characterise this group of disorders and their underlying genetic basis, with particular emphasis on atypical presentations and the A91V mutation, which may pose diagnostic and therapeutic challenges. Conclusion A91V PRF1 variant appears to represent a risk factor for the development of atypical FHL manifestations under divers triggers.