Hidradenitis suppurativa as a manifestation of inborn errors of immunity

Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory disease of the follicular unit characterized by painful nodules, abscesses and draining sinuses in intertriginous regions. Once regarded as a disorder of follicular occlusion, HS is now recognized as an immune-mediated disease driven by dysregulated epithelial–innate–Th17 interactions. Follicular rupture exposes the dermis to keratin and microbial products, triggering NLRP3 inflammasome activation, and excess interleukin (IL)-1β and IL-18 release. This initiates a self-amplifying inflammatory loop involving IL-1, IL-17, and neutrophil recruitment. Neutrophil extracellular traps and proteolytic enzymes further damage the epithelium, perpetuating cycles of abscess formation and fibrosis. Impaired Notch signaling from γ-secretase dysfunction disrupts keratinocyte differentiation and antimicrobial defense, predisposing to follicular plugging and persistent inflammation.<br/>This review integrates current mechanistic insights into HS pathogenesis and outlines how similar pathways are perturbed in monogenic inborn errors of immunity and structural genodermatoses. Disorders affecting Th17 differentiation (eg, signal transducer and activator of transcription 3-hyper IgE syndrome, signal transducer and activator of transcription 1, and gain of function), neutrophil function (chronic granulomatous disease), or inflammasome regulation (PSTPIP1-associated, Mediterranean fever gene-related, and mevalonate kinase-related syndromes) exemplify how immune dysregulation can recapitulate HS pathology. Recognition of such entities has direct therapeutic relevance, guiding use of targeted agents such as IL-1, Janus kinase, or tumor necrosis factor inhibitors.