Background/Purpose: Cryopyrin associated periodic syndrome (CAPS) is an autosomal dominant autoinflammatory disease caused by mutations in NLRP3. CAPS comprises 3 clinical phenotypes of increasing severity: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), neonatal onset multisystem inflammatory disease (NOMID). CAPS is characterized by early onset systemic inflammation and neutrophilic urticaria (NOMID, MWS, FCAS), cochlear inflammation with hearing loss (NOMID, MWS), and central nervous system inflammation (NOMID). Although all patients had clinical features of CAPS, we aimed to identify additional Mendelian diagnoses that may explain phenotypic variability not attributable to CAPS.

Methods: CAPS patients and their parents, when available, had whole exome sequencing (WES) performed at the NIAID Centralized Sequencing Initiative (CENSEQ). Chromosomal microarray analysis (CMA) was performed in selected cases. Patients were evaluated for investigation of clinical phenotypic features not associated with CAPS.

Results: Of the 11 CAPS patients analyzed, 4 (36.4%) had a Mendelian genetic diagnosis in addition to CAPS. Patient 1 is a 10-year-old female with a somatic mutation in NLRP3 (p.G307C, ˜15% mosaicism) and classic NOMID manifestations responsive to anti-IL-1 therapy. She was noted to have developmental delay, upslanting palpebral fissures and sparse eyebrows, which were explained by CMA findings compatible with 12q21.2q22 deletion syndrome (1). Patient 2 is a 10-year-old female with a germline NLRP3 mutation (p.E304K), clinical features of FCAS/MWS and response to anti IL-1. She presented clinodactyly, scoliosis, and broad great toes. Height was between the 5^th and 10^th percentile.  WES revealed a novel heterozygous variant in NPR2 (p.M1?), gene associated with autosomal dominant epiphyseal chondrodysplasia (OMIM#615923). Patient 3 is an 8-year-old female with a germline NLRP3 mutation (p.N479K) and a NOMID phenotype, treated with anakinra with resolution of inflammation but no benefit on growth. She presented brachydactyly, a round face and a broad nasal bridge. WES showed a novel heterozygous variant in FBN1 (p.L2626V), gene associated with several musculoskeletal syndromes, including Marfan syndrome (OMIM#154700), geleophysic dysplasia 2 (OMIM#614185) and Weill-Marchesani syndrome (OMIM#608328). Patient 4 is a 19-year-old male with a germline mutation in NLRP3 (p.G326E) and a clinical picture of NOMID, requiring high doses of canakinumab. WES showed a novel heterozygous variant (p.M274R) in NLRC4 (OMIM#616050).

Conclusion: Of 11 CAPS patients with pathogenic NLRP3 mutation, 4 had a secondary genetic diagnosis, which explained clinical features that were not attributable to CAPS.  Our data suggest that further genetic testing should be considered to explain “phenotypic variability”.

References

1. Oliveira R, Pereira C, Melo JB, Mesquita S, Venâncio M, Carreira IM, Saraiva J. 12q21.2q22 deletion: a new patient. Am J Med Genet A. 2015 Aug;167A(8):1877-83.

Funding & Disclaimer
Funding for this study was provided in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

« Back to 2019 ACR/ARP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/multiple-genetic-diagnoses-in-a-cohort-of-patients-with-cryopyrin-associated-periodic-syndrome-caps/