SAT0200 UNUSUAL SYSTEMIC LUPUS ERYTHEMATOSUS/SJOEGREN'S SYNDROME PHENOTYPE IN A PATIENT WITH A TNFAIP3 GENE MUTATION
Authors: Kerstin Nott, Yvonne Glackin, Stephen D. Marks, Paul Brogan, Sandrine Compeyrot-Lacassagne
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Mono-allelic mutation in tumor necrosis factor alpha induced protein 3 (<i>TNFAIP3</i>) has been found to cause haploinsufficiency of A20 protein, the cause of an early-onset auto inflammatory disease resembling Behcets's disease (BD). Single nucleotide polymorphism in <i>TNFAIP3</i> may also contribute to susceptibility to systemic lupus erythematosus (SLE). Several mutations in <i>TNFA1P3</i> have been shown to be disease-causing, including a single case with heterozygous mutation in the <i>TNFAIP3</i> gene for c.811C&gt;T; p.(arg271*) with a BD-like phenotype. <h3>Objectives</h3> To report the case of a child with heterozygous mutation <i>TNFAIP3</i> (c.811C&gt;T; p.(arg271*) with an unusual SLE/SS (Sjoegren syndrome) phenotype, thus expanding the phenotype associated with this mutation; and describe the disease course and treatment <h3>Methods</h3> Clinical details were retrospectively collated using routine clinical records. The molecular cause of the phenotype was investigated using a targeted gene next generation sequencing (NGS) panel (the vasculitis and inflammation panel, VIP). Confirmation of findings detected by NGS were confirmed using conventional Sanger sequencing in the index case and subsequently in the parents. <h3>Results</h3> A 4yr old Caucasian female presented with a 2-year history of photosensitive malar rash, mouth ulcers, hair loss, arthralgia, livedo reticularis, cervical lymphadenopathy and hepatosplenomegaly. Laboratory tests revealed anemia, raised inflammatory markers and hypocomplementemia; RF, ANA and anti Ro positivity, raised C1q antibodies and low C1Q level. 7 out of 11 classification criteria for SLE were met and treatment with hydroxychloroquine was commenced. Subsequently she developed blepharitis, acute anterior uveitis, chilblains and discoid skin lesions. Azathioprine and oral steroids were added. Due to young age at disease onset, NGS screening was performed and revealed heterozygous mutation in <i>TNFAIP3</i> c.811C&gt;T; p.(Arg271*). Screening of both parents revealed the same mutation in the mother, who is asymptomatic. The child further developed Raynaud's and underwent renal biopsy for intermittent proteinuria which revealed ISN/RPS Class III and V lupus nephritis. Azathioprine was switched to mycophenolate mofetil. One year later her skin symptoms continue to improve, uveitis is in remission and her renal function is normal. Prednisolone was tapered off. <h3>Conclusion</h3> We further expand the phenotype associated with mutation in the <i>TNFAIP3</i>; the c.811C&gt;T; p.(arg271*) variant previously described as the cause of a BD-like-phenotype, in our case caused an auto immune disease with severe SLE/SS phenotype. This variant also demonstrated variable penetrance in our pedigree, since the mother harbours the same variant but remains asymptomatic. Thus, the genetic cause of monogenic lupus continues to expand, and the distinction between autoinflammatory and autoimmune disease is less clear-cut than first thought. <h3>References</h3> [1] Aeschlimann, F. A., &amp; Laxer, R. M. (2018). Haploinsufficiency of A20 and other paediatric inflammatory disorders with mucosal involvement. Curr Opin Rheumatol, 30(5), 506-513. [2] Liu, X., Qin, H., Wu, J., &amp; Xu, J. (2018). Association of TNFAIP3 and TNIP1 polymorphisms with systemic lupus erythematosus risk: A meta-analysis. Gene, 668, 155-165. [3] Zhou, Q., Wang, H., Schwartz, D. M., Stoffels, M., Park, Y. H., Zhang, Y., . . . Aksentijevich, I. (2016). Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet, 48(1), 67-73. <h3>Disclosure of Interests</h3> Kerstin Nott: None declared, Yvonne Glackin: None declared, Stephen D Marks Grant/research support from: chief investigator and principal investigator for pharma sponsored randomised controlled trials in children from Astellas and Novartis but receive no money personally as the income goes directly to our institutions., Paul Brogan Grant/research support from: SOBI, Novartis, Roche, Novimmune, Chemocentryx, Consultant for: Roche, SOBI, Speakers bureau: SOBI, Roche, Novartis, UCB, Sandrine Compeyrot-Lacassagne Grant/research support from: Abbvie