Information on IMD98s

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).

Summary of clinical findings

[Considering only Definitive and Possible cases]

Rank Clinical phenotype Present Absent Unreported
1 Abnormal lymphoproliferationarrow icon 5 (99.9%) 0 (0.0%) 0 (0.0%)
2 Neutropeniaarrow icon 5 (99.9%) 0 (0.0%) 0 (0.0%)
3 Unusual infectionarrow icon 5 (99.9%) 0 (0.0%) 0 (0.0%)
4 Decreased IgG levelsarrow icon 4 (80.0%) 0 (0.0%) 1 (20.0%)
5 Thrombocytopeniaarrow icon 4 (80.0%) 0 (0.0%) 1 (20.0%)
6 Hypogammaglobulinemiaarrow icon 4 (80.0%) 0 (0.0%) 1 (20.0%)
7 Hematopoietic stem cell transplantationarrow icon 3 (60.0%) 0 (0.0%) 2 (40.0%)
8 Lymphadenopathyarrow icon 3 (60.0%) 0 (0.0%) 2 (40.0%)
9 Hepatopathyarrow icon 3 (60.0%) 0 (0.0%) 2 (40.0%)
10 Hepatosplenomegalyarrow icon 3 (60.0%) 0 (0.0%) 2 (40.0%)
11 Decreased IgM levelsarrow icon 3 (60.0%) 0 (0.0%) 2 (40.0%)
12 Autoimmunityarrow icon 3 (60.0%) 1 (20.0%) 1 (20.0%)
13 Anemiaarrow icon 3 (60.0%) 0 (0.0%) 2 (40.0%)
14 Decreased IgA levelsarrow icon 2 (40.0%) 0 (0.0%) 3 (60.0%)
15 Antineutrophil antibodiesarrow icon 2 (40.0%) 2 (40.0%) 1 (20.0%)
16 Recurrent feversarrow icon 2 (40.0%) 0 (0.0%) 3 (60.0%)
17 Reduced number of B cellsarrow icon 2 (40.0%) 0 (0.0%) 3 (60.0%)
18 Bone marrow hypocellularityarrow icon 2 (40.0%) 1 (20.0%) 2 (40.0%)
19 Agranulocytosisarrow icon 2 (40.0%) 0 (0.0%) 3 (60.0%)
20 Autoimmune antibody positivityarrow icon 2 (40.0%) 2 (40.0%) 1 (20.0%)
21 Otitis mediaarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
22 Nystagmusarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
23 Penile thrusharrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
24 (unusual) Respiratory tract infectionarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
25 Type I diabetes mellitusarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
26 Pharyngitisarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
27 Antinuclear antibodiesarrow icon 1 (20.0%) 2 (40.0%) 2 (40.0%)
28 Splenomegalyarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
29 Lymphadenitisarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
30 Endocrine system abnormalityarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
31 Autoimmune thrombocytopeniaarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
32 Autoimmune cytopeniaarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
33 Lung diseasearrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
34 Enteropathyarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
35 Fatiguearrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
36 Growth delayarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
37 Hepatic calcificationarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
38 Leukopeniaarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
39 Pneumoniaarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
40 T-cell large granular lymphocyte leukemiaarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
41 Recurrent aphthous stomatitisarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
42 Hemophagocytosisarrow icon 1 (20.0%) 0 (0.0%) 4 (80.0%)
43 Septicaemiaarrow icon 0 (0.0%) 2 (40.0%) 3 (60.0%)
Age of onset
distribution

Summary of treatment outcomes

[Considering only Definitive and Possible cases]

Treatment ⓘ Responses & clinical indications
Hematopoietic stem cell transplantation
Unspecified (3) for unspecified

5 reported cases added to GenIA

SubjectID Sex Fam.ID AD AFM Validity Country Population Reference & Pub.code
102626arrow icon M 214969tree icon 18 15 U.S.A. Filipino PMID:33512449 [Fam.1:II.1(P1)]
102630arrow icon M 214970tree icon 1 1 U.S.A. European PMID:33512449 [Fam.2:II.1(P2)]
102633arrow icon M 214971tree icon 19 7 U.S.A. European PMID:33512449 [Fam.3:II.1(P3)]
102637arrow icon M 214972tree icon 27 16 U.S.A. PMID:33512449 [Fam.4:II.2(P4)]
102641arrow icon M 214973tree icon 20 5 U.S.A. European PMID:33512449 [Fam.5:II.2(P5)]

AD: Age at genetic diagnosis; AFM: age at first manifestation; PMID: PubMed ID; GRID: GenIA reference ID (ref. not in PubMed).