gms | German Medical Science

Case: A 3 year old boy of German non consanguineous family with relapsing episodes of severe autoinflammation (spiking fever, transient exanthema, hepatosplenomegaly, hyperferritinemia > 27.500µg/l, LDH >3.500 U/ml, S100 > 8.700 ng/ml) was initially suspected for systemic onset of Juvenile idiopathic arthritis (SoJIA), even though the patient was thrombocytopenic (95/nl).

Methods: X-linked inherited AID respectively PID was suspected, when the younger brother became ill with identical symptoms two years later.

Results: normal findings for: Immunoglobulins; Complement and FACS of peripheral blood. BM aspirate: increased Granulopoesis, reduced erythropoesis, no hemophagocytosis. Due to a positive family history the patients were screened for X-linked lymphoproliferative disease – XLP. Flow cytometry detected normal SAP expression but absent XIAP expression in the patients’ lymphocytes. Mutation analysis of XIAP/BIRC4 identified a missense mutation in Exon 7(p.Cys484Ser), coding for a highly conserved amino acid. Functional relevance of the mutation was confirmed by absence of TNFa response after L18-MDP stimulation of monocytes, reflecting impaired NOD2 signaling

Conclusion: XIAP might present with severe symptoms reminiscent of AID. This increasing clinical observation in XIAP-deficient patients points towards roles of XIAP beyond the control of EBV associated HLH and lymphoproliferation - in line with recent molecular evidence that the molecule is critically involved in regulation of inflammatory responses. Thus, XIAP screening should be considered in a wide range of immune dysregulatory disorders, including SoJIA.