Abstract
Cryopyrin-associated periodic syndrome (CAPS) is caused by gain-of-function NLRP3 mutations. Recently, somatic NLRP3 mosaicism 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 the NLRP3 gene 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 of NLRP3 was non-diagnostic but ADS detected a somatic NLRP3 mutation 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 acquired NLRP3 mutations 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 germline NLRP3 mutations.
Highlights
Cryopyrin-associated periodic syndrome (CAPS) is a dominantly inherited autoinflammatory disease (AID) comprising three overlapping clinical entities of varying severity: familial cold autoinflammatory syndrome (FCAS) represents the mildest phenotype, Muckle–Wells syndrome (MWS) is of intermediate severity, and chronic infantile, neurological, cutaneous, and articular (CINCA) syndrome, known as neonatal-onset multisystem inflammatory disease (NOMID), is most severe [1,2,3,4,5]
CAPS is rarely considered among patients who present with compatible features in adult life [21]
Two mutations (p.A352T and p.E567K) have previously been reported in two Japanese children diagnosed with MWS associated with somatic NLRP3 mosaicism [12] and in a single heterozygous patient with CINCA-NOMID assessed in our center
Summary
Cryopyrin-associated periodic syndrome (CAPS) is a dominantly inherited autoinflammatory disease (AID) comprising three overlapping clinical entities of varying severity: familial cold autoinflammatory syndrome (FCAS) represents the mildest phenotype, Muckle–Wells syndrome (MWS) is of intermediate severity, and chronic infantile, neurological, cutaneous, and articular (CINCA) syndrome, known as neonatal-onset multisystem inflammatory disease (NOMID), is most severe [1,2,3,4,5]. We report here eight patients with somatic NLRP3 mosaicism, who presented in mid to late adulthood with symptoms consistent with CAPS None of these patients had a family history of similar illness and all had been completely healthy previously. The clinical diagnosis was not supported by Sanger sequencing; these patients subsequently underwent ADS analysis of the NLRP3 gene to investigate the possibility of mosaicism. Amplicon-based deep sequencing was performed to amplify all exons of the NLRP3 gene using specific pair primers as previously described [17]. Confirmation of AA-type amyloid deposits was sought immunohistochemically using monoclonal antibodies specific to SAA (Euro-Diagnostica) Those two patients diagnosed with AA amyloidosis underwent whole body anterior and posterior scintigraphic imaging 24 h after administration of 123I-labeled SAP using a GE Infinia Hawkeye gamma camera, as previously described. The SAP results were interpreted by a panel of physicians with experience of over 30,000 SAP scans [19]
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