Cold-induced urticarial autoinflammatory syndrome related to factor XII activation

Abstract

Hereditary autoinflammatory diseases are caused by gene mutations of the innate immune pathway, e.g. nucleotide receptor protein 3 (NLRP3). Here, we report a four-generation family with cold-induced urticarial rash, arthralgia, chills, headache and malaise associated with an autosomal-dominant inheritance. Genetic studies identify a substitution mutation in gene F12 (T859A, resulting in p.W268R) which encodes coagulation factor XII (FXII). Functional analysis reveals enhanced autocatalytic cleavage of the mutated protein and spontaneous FXII activation in patient plasma and in supernatant of transfected HEK293 cells expressing recombinant W268R-mutated proteins. Furthermore, we observe reduced plasma prekallikrein, cleaved high molecular weight kininogen and elevated plasma bradykinin. Neutrophils are identified as a local source of FXII. Interleukin-1β (IL-1β) is upregulated in lesional skin and mononuclear donor cells exposed to recombinant mutant proteins. Treatment with icatibant (bradykinin-B2-antagonist) or anakinra (interleukin-1-antagonist) reduces disease activity in patients. In conclusion, our findings provide a link between contact system activation and cytokine-mediated inflammation.

Cold urticaria – What we know and what we do not know

“…Other mutations ( NLRP12, NLRC4 ) were also linked to an early‐onset cold‐induced urticarial rash and an autoinflammatory phenotype 135,136 . Cold‐induced urticarial rash can be a feature of a newly described FXII‐associated cold autoinflammatory syndrome (FACAS) associated with a substitution mutation in the F12 gene encoding the human coagulation factor XII 137 . In FACAS, cold‐induced whealing begins in infancy, occurs within 10‐30 minutes after whole‐body exposure to ambient temperatures below 15‐20°C, and may last for several hours.…”

Monogenic autoinflammatory disorders: Conceptual overview, phenotype, and clinical approach

“…Patients with very similar clinical presentations but without easily defined NLRP3 mutations may either have NLRP3 mutations that are difficult to detect due to somatic mosaicism or mutations in genes with related function including NLRP12, NLRC4, and factor 12. 48,49 For most patients with CAPS, symptoms begin within the first year of life, although rarely presentation is delayed until adulthood. Common symptoms include urticaria-like rash, fever, arthralgia, myalgia, headache, and conjunctivitis, usually in the context of persistent systemic inflammation indicated by neutrophilia and elevated acute-phase reactants.…”

Hereditary Hearing Impairment with Cutaneous Abnormalities

“…The CAPS-linked NLRP3 and NLPR12 are mainly expressed in neutrophils and chondrocytes, and gain-of-function variants lead to over-activation of the inflammasome, overstimulation of interleukin (IL)-1β receptors, and overproduction and secretion of IL-1β [ 185 , 267 , 268 ]. Following the constitutive activation of the NLRP3 inflammasome, mast cells in CAPS patients produce IL-1β, induce neutrophil migration, and promote vascular leakage independent of stimuli [ 269 ].…”