ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 944

A New Syndrome in the Spectrum of Cryopyrin-Associated Periodic Syndromes (CAPS) Caused By the Novel R918Q NLRP3 Mutation

Gineth Pinto-Patarroyo1, Daniel L. Kastner1, Andrew Griffith2, H. Jeffrey Kim2, Camilo Toro3, Ariane Soldatos4, John Butman5, Bibi Bielekova4, JaeJin Chae6, Ivona Aksentijevich1, Hal M. Hoffman7, Lori Broderick8, Tina Romeo9, Anne Jones1, Jessica Ratay2 and Susannah Wargo2, 1Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 2National Institute of Deafness and Other Communication Disorders, Bethesda, MD, 3NIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 4National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 5Diagnostic radiology department, Warren Grant Magnuson Clinical Center, Bethesda, MD, 6Inflammatory disease section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 7Pediatric Allergy, Immunology and Rheumatology, University of California at San Diego/Rady Children Hospital, La Jolla, CA, 8Pediatric allergy, Immunology and Rheumatology, University of California at San Diego/Rady Children Hospital, La Jolla, CA, 9National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords:

Session Information

Date: Sunday, November 13, 2016

Title: Miscellaneous Rheumatic and Inflammatory Diseases I

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Mutations in NLRP3 cause 3 different dominantly inherited autoinflammatory syndromes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). All three manifest urticarial rash and episodic or in some cases continuous elevation of acute phase reactants. Here we describe a novel NLRP3 mutation that has been identified in two separate families and presents with a predominantly neurological phenotype.

Methods: Two families presented to the NIH Otolaryngology Clinic with a history of sensorineural hearing loss. Patients from both families underwent genetic testing, a thorough rheumatologic evaluation, measurements of acute phase inflammatory markers, and cytokine profiling. Patients underwent evaluation by neuro-otology, MRI of the inner ear with the fluid-attenuation inversion recovery (MRI-FLAIR) protocol, and audiograms. Neurology evaluation and lumbar puncture was performed on patients with neurological symptoms. Peripheral blood leukocytes from patients and matched healthy controls were studied for constitutive NLRP3 inflammasome activation.

Results: Dideoxy sequence analysis of NLRP3 identified a heterozygous transition c.2753G>A in exon 7, predicted to result in the missense substitution p.Arg918Gln (also known as p.Arg920Gln) in the leucine rich repeat domain of the NLRP3 protein, that co-segregated with hearing loss in both families. Patients from both families had either mildly elevated or normal inflammatory markers in the peripheral blood. Affected members of the first family had no dermatologic or rheumatologic manifestations while those in the second family exhibited urticariform maculopapular rash, oral ulcers, and lymphadenopathy. MRI of the inner ear showed active and chronic inflammation in the labyrinth and cochlea of all patients, and audiograms from the second family had worsened in the last year. A member of the first family with progressive lower extremity weakness showed a strong predominance of innate immune activation, but no evidence of intrathecal activation of adaptive immunity in the cerebrospinal fluid. Patients from both families exhibited evidence of constitutive NLRP3 inflammasome activation. Based on these findings, the father and two older siblings from the second family were started on treatment with anakinra. Follow up audiograms three months after treatment was started showed improvement in all three patients. The most severely affected member of the first family was started on anakinra and within three weeks started to normalize her deep tendon reflexes.

Conclusion: The R918Q NLRP3 mutation is associated with a distinct phenotype, relative to other patients with CAPS. Nevertheless, initial data suggest a favorable response to IL-1 inhibition.

Disclosure: G. Pinto-Patarroyo, None; D. L. Kastner, None; A. Griffith, None; H. J. Kim, None; C. Toro, None; A. Soldatos, None; J. Butman, None; B. Bielekova, None; J. Chae, None; I. Aksentijevich, None; H. M. Hoffman, None; L. Broderick, None; T. Romeo, None; A. Jones, None; J. Ratay, None; S. Wargo, None.

To cite this abstract in AMA style:

Pinto-Patarroyo G, Kastner DL, Griffith A, Kim HJ, Toro C, Soldatos A, Butman J, Bielekova B, Chae J, Aksentijevich I, Hoffman HM, Broderick L, Romeo T, Jones A, Ratay J, Wargo S. A New Syndrome in the Spectrum of Cryopyrin-Associated Periodic Syndromes (CAPS) Caused By the Novel R918Q NLRP3 Mutation [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/a-new-syndrome-in-the-spectrum-of-cryopyrin-associated-periodic-syndromes-caps-caused-by-the-novel-r918q-nlrp3-mutation/. Accessed .

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