The nuclear factor kappa light-chain enhancer of activated B cells (NFKB1) pathway is a central regulator of inflammatory gene expression. NFKB1 haploinsufficiency can present with common variable immunodeficiency (CVID) and autoimmunity. Recent publications report patients with necrotizing soft tissue inflammation who had truncating monoallelic loss-of-function variants in NFKB1.
We present a case of a 17-year-old male who had multiple episodes of sterile inflammatory responses to surgery or trauma in addition to recurrent infections. As an infant in the neonatal intensive care unit, he developed nasal columella erosion attributed to nasal respiratory support interfaces. At 15 years old, he underwent nasal reconstruction with a right ear graft that failed by 3 months post-operatively, resulting in nasal tip collapse and obstruction. A concurrent inguinal hernia repair was complicated by fevers and a purulent yet sterile abscess at the surgical site. Eight months later, reconstruction of the full-thickness columellar defect with left ear composite cartilage and cutaneous graft was complicated by a large, nonhealing graft site skin ulcer that was unresponsive to antibiotics and a surgical washout. Biopsy of this wound showed extensive, deep dermal and subcutaneous neutrophilic inflammation without identification of microorganisms consistent with pyoderma gangrenosum. The aforementioned, in conjunction with a history of recurrent oral ulcers and a new purulent scrotal ulcer, was felt to be consistent with Behçet disease. He was treated with pulse dose corticosteroids with subsequent taper, adalimumab, methotrexate, and colchicine with subsequent skin healing. He continued to have intermittent oral ulcers, fatigue, and increased frequency of upper respiratory infections.
Given his atypical clinical picture, a primary immunodeficiency-focused genetic panel was obtained and revealed a heterozygous pathogenic truncating NFKB1 variant (c.909dup, p.Thr304Hisfs*5). Given published evidence of truncating NFKB1 variants leading to impaired autophagy and type I interferon and NLRP3 inflammasome-mediated autoinflammation, canakinumab was started, and adalimumab, methotrexate, and colchicine were discontinued. Intravenous immunoglobulin replacement was initiated due to newly identified CVID. Frequency of oral ulcers, upper respiratory infections, and fatigue improved over the subsequent four months.
This case illustrates the autoinflammatory phenotype of NFKB1 deficiency with early truncating variants and highlights the prospect of targeted, personalized immunomodulatory therapy.
