Toll-like receptor 8 gain-of-function (TLR8 GOF) is a recently described inborn error of immunity caused by activating mutations in Tlr8. Pathogenic variants lead to constitutive signaling in myeloid cells and downstream overproduction of proinflammatory cytokines. Clinical features include recurrent infections, autoimmune cytopenias, lymphoproliferation, neutropenia, bone marrow failure, and hypogammaglobulinemia, although the full clinical spectrum and optimal management remain incompletely defined.
An 8-year-old male presented with pancytopenia following respiratory syncytial virus and Mycoplasma pneumoniae infection. Laboratory evaluation revealed elevated inflammatory markers (ferritin 4,021 ng/mL, soluble IL-2 receptor 15,628 U/mL, and CXCL9 83,818 pg/mL). Bone marrow biopsy demonstrated hemophagocytic forms consistent with hemophagocytic lymphohistiocytosis (HLH). A targeted sequencing panel identified a maternally inherited hemizygous TLR8 variant of uncertain significance (VUS) (c.1299G>C; p.Leu433Phe). Functional studies confirmed gain-of-function activity, although of lesser magnitude than in previously reported pathogenic variants. The patient’s mother, a carrier of the variant, had a history of adult-onset autoimmune hemolytic anemia. Immunophenotyping in the patient revealed hypogammaglobulinemia, B and natural killer (NK) cell lymphopenia, and absent class-switched memory B cells. He clinically improved with corticosteroids and etoposide, but persistent CXCL9 elevation prompted transition to emapalumab, which led to normalization of inflammatory markers as a bridge to planned hematopoietic stem cell transplantation.
This case illustrates several important aspects of TLR8 GOF–associated disease. It highlights the value of genomic evaluation in HLH, where identifying underlying immune-dysregulation disorders can direct management and impact decisions on transplantation. In this patient, functional studies were essential for confirming the pathogenicity of a TLR8 variant initially classified as a VUS, thereby expanding the recognized clinical phenotype of TLR8 GOF to include HLH. The attenuated functional effect of this variant may explain the later onset compared with previously reported germline cases presenting in infancy. The mother’s history of autoimmune cytopenia supports variable expressivity in heterozygous females, which is increasingly recognized, with two additional cases now identified independently. Finally, this is the first reported use of emapalumab for TLR8 GOF–associated HLH, suggesting that IFNγ blockade may serve as a rational targeted therapy and bridge to definitive therapy with transplantation.
