Late-onset cryopyrin-associated periodic syndromes caused by somatic NLRP3 mosaicism — UK single center experience

Cryopyrin-associated periodic syndrome (CAPS) is caused bymutations. Recently, somaticmosaicism has been reported in some CAPS patients who were previously classified as "mutation-negative." We describe here the clinical and laboratory findings in eight British adult patients who presented with symptoms typical of CAPS other than an onset in mid-late adulthood. All patients underwent comprehensive clinical and laboratory investigations, including analysis of thegene using Sanger and amplicon-based deep sequencing (ADS) along with measurements of extracellular apoptosis-associated speck-like protein with CARD domain (ASC) aggregates. The clinical phenotype in all subjects was consistent with mid-spectrum CAPS, except a median age at disease onset of 50 years. Sanger sequencing ofwas non-diagnostic but ADS detected a somaticmutation in each case. In one patient, DNA isolated from blood demonstrated an increase in the mutant allele from 5 to 45% over 12 years. ASC aggregates in patients' serum measured during active disease were significantly higher than healthy controls. This series represents 8% of CAPS patients diagnosed in a single center, suggesting that acquiredmutations may not be an uncommon cause of the syndrome and should be sought in all patients with late-onset symptoms otherwise compatible with CAPS. Steadily worsening CAPS symptoms in one patient were associated with clonal expansion of the mutant allele predominantly affecting myeloid cells. Two patients developed AA amyloidosis, which previously has only been reported in CAPS in association with life-long germlinemutations.