Name: Immunodeficiency 98 with autoinflammation, somatic | Acronym: IMD98s
Alt. names: TLR8-GOF | TLR8 gain of function

Gene: TLR8 | MOI: Somatic | Mechanism of action: Gain of Function

No. of cases in DB: 5 | First reported in: 2021

Last updated on: 2023-03-31 by Xiao P. Peng

OMIM: 301078

Orphanet: -

MONDO: -

DOID: -

ClinGen:

Description

The somatic form of this condition has been described in 5 unrelated individuals thus far with ranges of mosaicism sufficient to cause disease between 5-30% (PMID: 33512449, 34981838). As for the patients with germline mutations, it is characterized by early onset non-malignant lymphoproliferation recurrent sinorespiratory and GI infections, multi-organ autoimmunity, and systemic inflammation. One patient developed an HLH-like diathesis, whilst another developed T-cell large granular lymphocytic (T-LGL) leukemia. Immunophenotyping is notable for elevated proinflammatory serum cytokines, activated T cells and monocytes, and evidence of T-cell dysregulation, with inverted CD4:CD8 ratios, skewed naive to memory ratio of CD4+ T cells, and increased double-negative T cells. Patients also show hypogammaglobulinemia, nonspecific auto-antibody production, and B cell maturation defects leading to reduced class-switch memory B cells. Additionally, patients have increased peripheral blood type I IFN signatures, albeit lower than for patients with primary IFNopathies. In addition, patients may show hypocellular bone marrow on biopsy pathology.

Management

Some patients received immunoglobulin replacement therapy for hypogammaglobulinemia and all patients received immunosuppression for autoimmune/autoinflammatory complications (i.e. sirolimus, rituximab, cyclosporine A, anakinra) including steroids. In general, patients with neutropenia had a poor response to therapeutic or high doses of G-CSF. Thus far, the few patients receiving hematopoietic stem cell transplant have died due to complications of disease and/or transplant (PMID: 33512449).