Symptomatic males and female carriers in a large Caucasian kindred with XIAP deficiency.

PURPOSE: X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was originally described in male patients with X-linked lymphoproliferative syndrome type 2 (XLP2). Recent observations have highlighted a critical role of XIAP for the regulation of NOD2 signaling and are probably the molecular basis for increasingly recognized further immune dysregulatory symptoms of XIAP deficient patients, such as inflammatory bowel disease (IBD). We describe a large Caucasian family in which IBD and erythema nodosum (EN) also manifested in female carriers of XIAP mutations. METHODS: Clinical data and laboratory findings including flow cytometric analysis of XIAP protein expression and sequencing of the BIRC4 gene. NOD2 signaling was investigated by determination of TNFα production in monocytes upon L18-MDP stimulation in vitro. RESULTS: The BIRC4 nonsense mutation p.P225SfsX226 was identified as the genetic cause of XIAP deficiency in our family. Surprisingly, clinical symptoms were not restricted to male patients, but also occurred in several female carriers. The most severely affected carrier demonstrated random X-inactivation, leading to a significant expression of mutated XIAP protein in monocytes, and consequently to impaired NOD2 responses in vitro. CONCLUSION: Our report provides further evidence that clinical symptoms of XIAP deficiency are not restricted to male patients. Random X-inactivation may be associated with EN and mild IBD also in female carriers of BIRC4 mutations. Analysis of the X-inactivation pattern reflected by XIAP protein expression can identify such carriers and the analysis of NOD2 signaling by flow cytometry can confirm the functional significance. XIAP expression patterns should be investigated in female patients with a family history of EN and/or IBD.

Stem cell transplantation with reduced-intensity conditioning for hemophagocytic lymphohistiocytosis.

Allogeneic stem cell transplantation (SCT) is curative for hemophagocytic lymphohistiocytosis (HLH). However, patients frequently have significant morbidity before transplantation and there is high transplant-related mortality (TRM). Because first-degree HLH is caused by immune dysregulation, a reduced-intensity conditioned (RIC) regimen might be sufficient for cure while decreasing the TRM. Twelve patients with HLH underwent RIC SCT from a matched family/unrelated or haploidentical donor. Eleven were conditioned with fludarabine/melphalan with additional busulphan for haploidentical grafts. One received fludarabine and 2-Gy total body irradiation (TBI). All patients showed engraftment at a median of 14 days. Nine of 12 (75%) are alive and in complete remission (CR) a median of 30 months (range, 9-73 months) after SCT. Two patients died from pneumonitis and one from hepatic rupture. Four patients developed acute graft-versus-host disease (GVHD) and 3 have chronic GVHD. Three of 9 survivors have mixed chimerism but remain free of disease. In summary, RIC compares favorably to conventional SCT with long-term disease control in surviving patients despite a significant incidence of mixed chimerism.