Case report: Novel variants in RELA associated with familial Behcet’s-like disease

Abstract

RELA haploinsufficiency is a recently described autoinflammatory condition presenting with intermittent fevers and mucocutaneous ulcerations. The RELA gene encodes the p65 protein, one of five NF-κB family transcription factors. As RELA is an essential regulator of mucosal homeostasis, haploinsufficiency leads to decreased NF-κB signaling which promotes TNF-driven mucosal apoptosis with impaired epithelial recovery. Thus far, only eight cases have been reported in the literature. Here, we report four families with three novel and one previously described pathogenic variant in RELA. These four families included 23 affected individuals for which genetic testing was available in 16. Almost half of these patients had been previously diagnosed with more common rheumatologic entities (such as Behcet’s Disease; BD) prior to the discovery of their pathogenic RELA variants. The most common clinical features were orogenital ulcers, rash, joint inflammation, and fever. The least common were conjunctivitis and recurrent infections. Clinical variability was remarkable even among familial cases, and incomplete penetrance was observed. Patients in our series were treated with a variety of medications, and benefit was observed with glucocorticoids, colchicine, and TNF inhibitors. Altogether, our work adds to the current literature and doubles the number of reported cases with RELA-Associated Inflammatory Disease (RAID). It reaffirms the central importance of the NF-κB pathway in immunity and inflammation, as well as the important regulatory role of RELA in mucosal homeostasis. RELA associated inflammatory disease should be considered in all patients with BD, particularly those with early onset and/or with a strong family history.

Autoinflammatory Diseases: A Review

“…Case 3 A 29-year-old Caucasian female presented with monthly oral ulcers since early childhood and vaginal ulceration at the age of 20 (19). At 25, she developed recurrent facial rashes, arthralgias, myalgias, subjective fevers (<38c) occurring every 2 months and lasting 2 weeks.…”

“…Some NFκB-opathies such as HA20 (Haploinsufficiency of A20), arise from loss of function mutations in enzymes that normally inhibit NFκB activation (37). Other examples of AIDs driven by NFκB dysregulation includes RAID, RNF31 deficiency, RIPK1 deficiency or gain-of-function, Otulipenia (FAM105B), Blau syndrome (NOD2) and CARD14-mediated pustular psoriasis (19) (38).…”

“…BD can be mimicked by mutations in genes involved in the NFκB pathway such as NFΚB1, TNFAIP3, Otulin, and RELA (86) (19). These disorders may present with mucosal ulcerations, ocular lesions, pathergy and vasculitis.…”

Type I interferon pathway in pediatric systemic lupus erythematosus

“…RELA encodes the p65 protein, a member of the NF-κB family of transcription factors. Earlier research indicated that RELA haploinsufficiency leads to chronic mucocutaneous ulceration and autoimmune hematological disorders, largely dependent on TNF [91]. However, a recent study showed that patients with RELA dominant-negative (DN) mutations exhibit clinical features similar to those of patients with RELA haploinsufficiency plus inflammatory symptoms such as periodic fever, inflammatory bowel diseases, juvenile idiopathic arthritis, and skin involvement such as erythema nodosum or pustulosis [92].…”

How to Build a Fire: The Genetics of Autoinflammatory Diseases

“…The patients' PBMCs showed impaired IL-6 secretion upon TNF stimulation, indicating defective NF-κB activation (14). Subsequently, 21 additional patients were described, including family cases with reduced penetrance (1,12,30). The phenotype of RELA haploinsufficiency is broad given the diverse function of NF-κB.…”