# Case Report: Diverse pediatric phenotypes of RELA frameshift variants: comparison of two cases

## TL;DR

Two children with RELA gene variants showed different autoinflammatory symptoms, highlighting the variable effects of these mutations in pediatric patients.

## Contribution

This case report identifies diverse clinical manifestations of RELA frameshift variants in children and suggests the importance of RELA screening in unexplained autoinflammatory cases.

## Key findings

- Patient 1 with a RELA variant showed Behçet’s disease-like symptoms and responded to colchicine and steroids.
- Patient 2 with a different RELA variant had systemic inflammation and hearing loss, and improved with adalimumab.
- In vitro assays showed altered NF-κB signaling and gene expression in patient-derived cells.

## Abstract

Variants in RELA (which encodes the p65 subunit of NF-κB) can cause a monogenic autoinflammatory disease with clinical manifestations that range from mucocutaneous lesions (Behçet’s disease-like) to systemic inflammation. However, the diversity of the phenotype and its penetrance are uncertain.

Patient 1 (p.Asp465Thrfs14) presented with classic Behçet’s disease-like symptoms of oral and genital ulcers, fever, and elevated inflammatory markers. Colchicine (0.25 mg once daily) with low-dose glucocorticoids led to remission. Exploratory in vitro assays using murine fibroblasts indicated increased TNF-α–induced apoptosis associated with the RELA variant. Patient 2 (p.Glu495Serfs6) had no mucosal lesions but experienced recurrent high fever, hyperferritinemia, uveitis/scleritis, and progressive bilateral sensorineural hearing loss. Because IL-1 blockers were not available, we administered adalimumab as a steroid-sparing treatment. Defervescence was achieved within 6 months of adalimumab therapy, with stabilization of inflammatory markers and hearing thresholds during the entire 9-month follow-up. PBMCs from Patient 2 and the carrier mother that were stimulated by LPS had decreased induction of two genes targeted by NF-κB (BCL2A1, TRAF1), and the proband (but not the mother) had markedly increased IL-6 secretion.

C-terminal truncations in the transcriptional activation domain of RELA lead to haploinsufficiency and an inflammatory phenotype that depends on the cell type and stimulus. RELA screening should be considered in the evaluation of children with unexplained autoinflammatory presentation, even in the absence of mucosal ulceration.