Name: Familial Behcet-like autoinflammatory disease-3 | Acronym: AIFBL3
Alt. names: Mucocutaneous ulceration, chronic

Gene: RELA | MOI: Autosomal dominant | Mechanism of action: Haploinsufficiency

No. of cases in DB: 0 | First reported in: 2017

Last updated on: 2024-05-12 04:33:48 by Xiao P. Peng

OMIM: 618287

Orphanet: -

MONDO: -

DOID: -

ClinGen:

A heterozygous RELA splice site mutation (c.559+1G>A) was found n 4 members of a family with mucocutaneous lesions, including a proband who developed early onset severe, acute ileitis [OMIM: 618287] (PMID: 28600438). Acute flares were notable for fevers, leukocytosis and elevated inflammatory markers, though immunologic evaluation was grossly normal. Patient fibroblasts showed impaired NF-κB activation downstream of TLR and TNF stimulation, followed by impaired up-regulation of antiapoptotic genes and increased stromal cell apoptosis. A de novo heterozygous nonsense mutation (c.736C>T, p.Arg246Ter) was found in a patient with ALPS-like disease featuring refractory autoimmune cytopenias, increased T cell activation and proliferation, and enhanced Th1 effector responses but without mucocutaneous ulcerations or inflammatory GI disease (PMID: 29305315). Immunophenotyping was notable for mild expansion of CD3+ double negative T cells (2.4%), increased total, activated and terminally differentiated effector CD4+ T cells, as well as reduced iTreg differentiation and intrinsic polarization towards a Th1-effector phenotype, while B cell populations and immunoglobulins were normal. Another variant (c.1044dup, p.Tyr349LeufsTer13) was identified in a family where multiple members had clinical diagnoses of Behcet's and Crohn's, some in infancy and others in adulthood. This variant resulted in premature truncation of the protein before a key phosphorylation site Ser536, leading to enhanced p65 degradation. Immunoblotting revealed significantly decreased phosphorylated populations of p65 and IκBα. The reduction in the former was thought to cause reduced heterodimer formation between p50/p65 (NFκB1/RelA). Immunophenotyping revealed decreased naïve T cells, increased memory T cells, and expanded senescent T-cell populations in one patient (P1) who also had substantially higher IL-6 and TNF-α levels post-stimulation compared with the 3 other family members tested.

Individuals can have chronic mucocutaneous ulcerations, and medical management (with a tumor necrosis factor inhibitor) has been described as beneficial. Refs. PMIDs: 28600438