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Pediatr Rheumatol Online J. 2019 Oct 28;17(1):70. doi: 10.1186/s12969-019-0374-x.

Complexity in unclassified auto-inflammatory disease: a case report illustrating the potential for disease arising from the allelic burden of multiple variants.

Author information

1
Department of Pediatrics, The University of British Columbia Faculty of Medicine, BC Children's Hospital, 4480 Oak Street, Vancouver, BC, V6H 3V4, Canada.
2
The Division of Rheumatology at British Columbia Children's Hospital, 4480 Oak Street, Vancouver, BC, V6H 3V4, Canada.
3
Department of Microbiology and Immunology, The University of British Columbia Faculty of Science, Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
4
BC Children's Hospital Research Institute, Rm A4-145, 950 West 28th Ave, Vancouver, BC, V5Z 4H4, Canada.
5
Department of Medical Genetics, The University of British Columbia Faculty of Medicine, 4500 Oak Street, Vancouver, BC, V6H 3N1, Canada.
6
Present Address: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Postboks 4950, Nydalen, N-0424, Oslo, Norway.
7
Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Oxford Rd, Manchester, M13 9PL, UK.
8
Department of Pediatrics, The University of British Columbia Faculty of Medicine, BC Children's Hospital, 4480 Oak Street, Vancouver, BC, V6H 3V4, Canada. kbrown@bcchr.ca.
9
BC Children's Hospital Research Institute, Rm A4-145, 950 West 28th Ave, Vancouver, BC, V5Z 4H4, Canada. kbrown@bcchr.ca.

Abstract

BACKGROUND:

Despite recent advances in the diagnosis and understanding of many autoinflammatory diseases, there are still a great number of patients with phenotypes that do not fit any clinically- and/or genetically-defined disorders.

CASE PRESENTATION:

We describe a fourteen-year-old boy who presented at two and a half years of age with recurrent febrile episodes. Over the course of the disease, the episodes increased in frequency and severity, with new signs and symptoms continuing to appear. Most importantly, these included skin changes, splenomegaly and transaminitis. Only partial control of the disease was achieved with anti-IL-1 therapy. Extensive investigation showed generalized inflammation without immune deficiency, with increased levels of serum amyloid A and several pro-inflammatory cytokines including interferon-γ, as well as an increased type I interferon score. Exome sequence analysis identified P369S and R408Q variants in the MEFV innate immunity regulator, pyrin (MEFV) gene and T260 M and T320 M variants in the NLR family pyrin domain containing 12 (NLRP12) gene.

CONCLUSION:

Patients with unclassified and/or unexplained autoinflammatory syndromes present diagnostic and therapeutic challenges and collectively form a substantial part of every cohort of patients with autoinflammatory diseases. Therefore, it is important to acquire their full genomic profile through whole exome and/or genome sequencing and present their cases to a broader audience, to facilitate characterization of similar patients. A critical mass of well-characterized cases will lead to improved diagnosis and informed treatment.

KEYWORDS:

Autoinflammatory disease; Interleukin-1; MEFV; Macrophage activation syndrome; NLRP12; Periodic fever syndrome; Type I interferon score

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