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Centrum für Chronische Immundefizienz - CCI


Short information

Patients with deficiency of the X-linked inhibitor of apoptosis (XIAP) were initially identified among patients with X-linked lymphoproliferative disease (XLP) but normal sequence in SH2D1A, defective in XLP-1 (Rigaud et al. Nature 2006). XIAP deficiency is therefore frequently referred to as XLP-2. Since the initial report, it has been debated whether XIAP deficiency is correctly classified as XLP. While both diseases predispose to EBV-induced hemophagocytic lymphohistiocytosis (HLH), XIAP deficient patients do apparently not share the risk of XLP-1 patients to develop lymphoma and hypogammaglobulinemia appears less frequent (Pachlopnik-Schmid et al. Blood 2011, Marsh et al. Blood 2010). Based on the common observation of HLH in the reported cohorts, Marsh et al. proposed to re-classify XIAP deficiency as X-linked familial hemophagocytic lymphohistiocytosis (FHL). However, findings in single patients suggest that mutations in BIRC4 may also have to be considered in other conditions such as inflammatory bowel and liver disease (Pachlopnik-Schmid et al. Worthey et al.). We therefore screen patients for XIAP deficiency in a wider clinical context. The spectrum of clinical features we are interested in includes boys affected by inflammatory bowel disease (e.g. Crohn-like disese), unexplained splenomegaly with and without hypogammaglobulinemia, periodic fevers or prolonged mononucleosis. Boys with HLH are enrolled in cooperation with the German HLH reference center in Hamburg

HLH Study

We offer both flow cytometric based screening for protein expression in PBMC and functional analysis (activation induced cell death – AICD and L18MDP stimulation of monocytes). In cooperation with Mads Gyrd-Hansen (Copenhagen) individual patients are investigated further for the molecular consequence of their mutation. Aim of the study is to investigate the function of XIAP and how it regulates the immune response to bacteria and viruses. By obtaining detailed information about what happens to the XIAP protein when it is mutated and how this affects the processes in which XIAP functions, we hope to obtain understanding of what goes “wrong” in the immune cells. On the long run, this can reveal which processes in the cell could be targeted to counterbalance the defects caused by XIAP mutations for future treatment.


  1. Steele CL , Doré M , Ammann S , Loughrey M , Montero A , Burns SO , Morris EC , Gaspar B , Gilmour K, Bibi S , Shendi H , Devlin L , Speckmann C , Edgar DM, X-linked Inhibitor of Apoptosis Complicated by Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) and Granulomatous Hepatitis. J Clin Immunol. 2016 Oct; 36(7):733-8. doi: 10.1007/s10875-016-0320-3. Epub 2016 Aug 5
  2. Christiansen M , Ammann S , Speckmann C , Mogensen TH, XIAP deficiency and MEFV variants resulting in an autoinflammatory lymphoproliferative syndrome. BMJ Case Rep. 2016 Sep 28; 2016. pii: bcr2016216922. doi: 10.1136/bcr-2016-216922
  3. Dziadzio M , Ammann S, Canning C, Boyle F, Hassan A, Cale C, Elawad M, Fiil BK, Gyrd-Hansen M, Salzer U, Speckmann C, Grimbacher B, Symptomatic males and female carriers in a large Caucasian kindred with XIAP deficiency. J Clin Immunol. 2015 Jul; 35(5):439-44. doi: 10.1007/s10875-015-0166-0. Epub 2015 May 6
  4. S. Ammann, R. Elling, M. Gyrd-Hansen, G. Dückers, R. Bredius, S.O. Burns, et al., A new functional assay for the diagnosis of X-linked inhibitor of apoptosis (XIAP) deficiency, Clin Exp Immunol. (2014) n/a–n/a. doi:10.1111/cei.12306.
  5. C. Speckmann, S. Ehl, XIAP deficiency is a mendelian cause of late-onset IBD, Gut. (2013) gutjnl–2013–306474. doi:10.1136/gutjnl-2013-306474.
  6. C. Speckmann, K. Lehmberg, M.H. Albert, R.B. Damgaard, M. Fritsch, M. Gyrd-Hansen, et al., X-linked inhibitor of apoptosis (XIAP) deficiency: The spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis, Clin Immunol. 149 (2013) 133–141. doi:10.1016/j.clim.2013.07.004.
  7. R.B. Damgaard, B.K. Fiil, C. Speckmann, M. Yabal, U.Z. Stadt, S. Bekker-Jensen, et al., Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling, EMBO Mol Med. (2013). doi:10.1002/emmm.201303090.


To enroll patients or in case of clinical questions please contact

Dr. med. Carsten Speckmann



Prof. Dr. med. Stephan Ehl




Center for Chronic Immunodeficiency (CCI)
at Center for Translational Cell Research (ZTZ)

Breisacher Str. 115

D-79106 Freiburg