Low-level NLRP3 mosaicism in chronic urticarial lesions: extending the phenotypic spectrum of NLRP3-related disorders

Chronic urticarial lesions, a common condition of mostly unknown cause, can occur in immune dysregulation disorders such as hypocomplementaemic urticarial vasculitis syndrome (HUVS), neutrophilic urticarial dermatosis (NUD) and systemic autoinflammatory diseases (SAIDs), including Schnitzler syndrome. To identify the molecular basis of nonpruritic chronic urticarial eruptions in four unrelated patients initially diagnosed with neonatal NUD, Schnitzler syndrome, HUVS or giant-cell arteritis. Conventional next-generation sequencing (NGS) of leucocyte DNA was supplemented with high-depth NGS (> 1500×) to improve the detection of low-level mosaicism in SAID-related genes. Functional assays were performed on recombinant NLRP3 proteins to assess the impact of the identified variations on the nuclear factor-κB (NF-κB) pathway. One patient presented with persistent isolated urticarial lesions since birth, while the other three experienced late-onset skin lesions. In contrast to the initially suspected diagnoses, conventional NGS revealed NLRP3 mosaicism in two patients, with variant allele fractions (VAFs) of 5% and 11%, respectively. In the other two patients, high-depth NGS uncovered NLRP3 mosaicism with VAFs as low as 2-3%. All identified variations activated the NF-κB pathway, demonstrating a gain-of-function effect. Subsequent anti-interleukin-1 therapy led to symptom improvement for all patients. This study highlights the importance of considering NLRP3 mosaicism as an underlying pathological mechanism in chronic urticarial lesions, whether of early or late onset, and whether isolated or mimicking other conditions. As blood contains key target cells for NLRP3 inflammasome activation, even extremely low-level leucocyte mosaicism can be pathogenic. High-depth NGS-based diagnosis of NLRP3-related disorders enables timely initiation of anti-IL-1 therapy, which is crucial to preventing complications such as systemic amyloidosis.