SAT0200 UNUSUAL SYSTEMIC LUPUS ERYTHEMATOSUS/SJOEGREN'S SYNDROME PHENOTYPE IN A PATIENT WITH A TNFAIP3 GENE MUTATION

Abstract

Background Mono-allelic mutation in tumor necrosis factor alpha induced protein 3 (TNFAIP3) 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 TNFAIP3 may also contribute to susceptibility to systemic lupus erythematosus (SLE). Several mutations in TNFA1P3 have been shown to be disease-causing, including a single case with heterozygous mutation in the TNFAIP3 gene for c.811C>T; p.(arg271*) with a BD-like phenotype. Objectives To report the case of a child with heterozygous mutation TNFAIP3 (c.811C>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 Methods 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. Results 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 TNFAIP3 c.811C>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. Conclusion We further expand the phenotype associated with mutation in the TNFAIP3; the c.811C>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.