Name: Immunodeficiency 82 with systemic inflammation | Acronym: IMD82
Alt. names: SYK-GOF

Gene: SYK | MOI: Autosomal dominant | Mechanism of action: Gain of Function

No. of cases in DB: 6 | First reported in: 2021

Last updated on: 2023-10-23 05:16:35 by Xiao P. Peng

OMIM: 619381

Orphanet: -

MONDO: 0030308

DOID: -

ClinGen:

Wang et al. (2021) identified heterozygous SYK missense mutations in 6 patients from 5 unrelated families of diverse ancestries presenting with systemic autoinflammation with CNS, GI, skin, joint, liver and/or lung involvement, as well as recurrent viral and bacterial infections also involving multiple organs (PMID: 33782605). Two patients developed diffuse large B-cell lymphoma (DLBCL) in adulthood. Labs were notable for elevated inflammatory markers, hypogammaglobulinemia, and leukocytosis with normal to decreased lymphocyte counts and skewing of lymphocyte subsets towards activated and memory phenotypes. Tissue pathology often showed lymphogranulomatous infiltrate. The authors showed that the SYK variants increased phosphorylation and enhanced downstream signaling consistent with a gain-of-function mechanism.

The authors of the paper above suggested that bone marrow transplant or use of a SYK inhibitor may help reduced inflammatory disease severity based on studies in mouse models. Rigel Pharmaceuticals' first-in-class SYK inhibitor fostamatinib is currently FDA-approved for use in adult patients with treatment-refractory chronic immune thrombocytopenia (ITP).