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.

Keywords: Behcet’s Disease; NF-κB; RAID; RELA; RELA haploinsufficiency; RELA-associated inflammatory disease; autoinflammatory; mucosal ulcers.

Figure 1

Proband in each family is denoted with arrow. Individuals shaded in black carry a combination of clinical features including mucocutaneous, musculoskeletal, gastrointestinal, neurological manifestations, infections, or fever. G+ denotes individual carrying pathogenic/likely pathogenic RELA variant, G- denotes wild type RELA, individuals without ‘G’ were not sequenced. Patient (2D) in Family 2 died of lupus nephritis and is shaded in gray. Family 4: patients 1A and 3A presented with an isolated vesicular skin lesions and are shaded in dots.

Figure 2

Clinical images. (A): ulcer on tongue, F1-3B. (B): facial rash, F1-3B. (C): vesicular rash on lower abdomen, HSV negative, F4-4B. (D): vesicular rash on inner thigh, F4-4B. (E): conjunctivitis, F3-2B. (F): Skin biopsy of F2-2G, showing an ulcerated lesion covered by fibrinoleukocytic exudate. The surrounding epidermis demonstrates discrete irregular epithelial hyperplasia. The dermis presents moderate lymphoplasmacytic and histiocytic infiltrate associated with neutrophilic exudates.

Figure 3

Schematic showing domain structure and functional motifs of the transcription factor p65 protein with summary of pathogenic/likely pathogenic variants in RELA gene. Mutations reported in literature are depicted in regular font and in bold are mutations identified in our four families. Superscripted numbers correspond to the original cases listed in References.