Expanding the Phenotype: New Variant in the IL1RN-Gene Associated with Late Onset and Atypical Presentation of Dira

Jasmin B. Kuemmerle-Deschner¹, Konstanze Hoertnagel², Susanne Schlipf³, Sandra Hansmann⁴, Toni Hospach⁵, Ilias Tsiflikas⁶, Xiao Liu⁷, Susanne Benseler⁸ and Alexander Weber⁷, ¹Department of Pediatrics, Division of Rheumatology, University Hospital Tuebingen, Germany, Tuebingen, Germany, ²Praxis für Humangenetik Tübingen,Tuebingen, Germany, Tuebingen, Germany, ³Kinderarztpraxis Dr. Lakner, Schwäbisch Gmünd, Germany, Schwäbisch Gmünd, Germany, ⁴Department of Pediatrics, Division of Pediatric Rheumatology, University Hospital Tuebingen, Tuebingen, Germany, Tuebingen, Germany, ⁵Pediatrics, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany, ⁶Division of Pediatric Radiology, Department of Radiology, University Hospital Tuebingen, Germany, Tuebingen, Germany, ⁷Department of Immunology, University of Tübingen, Tübingen, Germany, Tuebingen, Germany, ⁸Rheumatology, Department of Paediatrics, Alberta Children's Hospital, University of Calgary, Alberta, Canada, Calgary, AB, Canada

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Autoinflammatory Disease, Biologic agents, genetic disorders and phenotypes, IL-1

Session Information

Date: Tuesday, October 23, 2018

Session Title: 5T105 ACR Abstract: Innate Immunity (2850–2855)

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Deficiency of the Interleukin-1 receptor antagonist (DIRA) is an autoinflammatory disease of infancy characterized by severe systemic inflammation with bone and skin involvement. This is a report of a novel variant in the IL1RN-gene associated with late onset and atypical phenotype of DIRA.

Methods: A 3 year-old Caucasian boy presented with recurrent monthly episodes of fever and fatigue, associated with lymphadenopathy, pericarditis, pleuritis, pancreatitis, and arthritis involving sacroiliac, hip, knee and ankle joints in the absence of skin involvement. Symptoms had started at age one and progressed over time to life-threatening episodes requiring intensive care. Throughout, ESR, CRP, SAA, S100A8/9, leukocytes, and platelets were highly elevated. Treatment with colchicine and steroids improved symptoms; however, did not prevent flares. Genetic testing did not identify known pathogenic variants of immune deficiencies and AIDs including DITRA.

Results: Whole exome sequencing detected a novel homozygous stop variant c.62C>G; p.Ser21* in the ILRN gene (NM_173842.2). Mother, father and brother were heterozygous for the same variant. In addition, three variants of unknown significance were identified in the patient’s PCGF5, CPA1 and SPTA1 genes. Functional studies revealed marginally low secretion of IL-1RA from unstimulated leucocytes and after stimulation with IL-1β and LPS, confirming the disease-causing nature of the variant. IL-1 inhibition with anakinra at 2 mg/kg/d was started resulting in complete resolution of clinical symptoms, inflammatory markers and signs of inflammation on MRI. Intolerance to daily sc injections prompted a switch to canakinumab at 4 mg/kg/4 weeks. However, canakinumab did not prevent significant disease flares including new bone inflammation. Re-start of anakinra resulted in recapture of disease control.

Conclusion: This is the first report of the novel c.62C>G; p.Ser21* variant in the IL1RN-gene resulting in late onset DIRA with prominent systemic and bone/joint inflammation. DIRA should be considered in older children even in the absence of skin disease.

Disclosure: J. B. Kuemmerle-Deschner, Novartis, 2,Novartis, SOBI, 5; K. Hoertnagel, None; S. Schlipf, None; S. Hansmann, None; T. Hospach, None; I. Tsiflikas, None; X. Liu, None; S. Benseler, None; A. Weber, None.

To cite this abstract in AMA style:

Kuemmerle-Deschner JB, Hoertnagel K, Schlipf S, Hansmann S, Hospach T, Tsiflikas I, Liu X, Benseler S, Weber A. Expanding the Phenotype: New Variant in the IL1RN-Gene Associated with Late Onset and Atypical Presentation of Dira [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/expanding-the-phenotype-new-variant-in-the-il1rn-gene-associated-with-late-onset-and-atypical-presentation-of-dira/. Accessed May 16, 2022.

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