Clinical Characteristics, Management, and Hematopoietic Cell Transplantation of Patients with TLR8 Gain-of-Function Open Access

• TLR8 GOF is an X-linked dominant disease that should be considered in both male and female patients with cytopenia and immune dysregulation.

• Patients with TLR8 GOF are refractory to medical management and should be considered for allogeneic HCT.

TLR8 gain-of-function (GOF) somatic variants were recently identified as causing severe neutropenia, lymphoproliferation, and immune dysregulation. We report the expanded clinical and laboratory phenotype and management of 10 patients, including the original cohort of 6 male patients. We identify the first female patient with TLR8 GOF who presented during infancy with pure red cell aplasia due to a germline TLR8 variant, and two new disease-causing somatic variants in male patients. Eight patients had somatic mosaicism with peripheral blood variant allele fractions of 7-26% and age of disease onset of 9 months to 28 years. All patients had neutropenia, most with severe neutropenia refractory to medical therapy. Anemia and thrombocytopenia were common. Bone marrow characteristically demonstrated severe myeloid hypoplasia and activated T-cell infiltrates and/or aggregates. An increased number of large granular lymphocytes (LGLs) were identified in five patients. Seven patients underwent allogeneic hematopoietic cell transplantation (HCT). High rates of post-HCT cytopenia of unclear etiology and graft-versus-host disease were observed. Five are surviving at 1 to 3 years post-HCT with full donor myeloid and T-cell chimerism and resolution of disease phenotype. The two patients who presented during childhood and did not undergo HCT ultimately died from disease. In conclusion, TLR8 GOF is an X-linked dominant disorder that should be considered in male and female patients with cytopenia, particularly severe neutropenia, lymphoproliferation with immune dysregulation, increased LGLs, and new to this cohort, red cell aplasia. Disease is refractory to medical management, and curative, allogeneic HCT should be considered early after diagnosis. (NCT04339777)