Clinical phenotype and functional analysis of a rare XIAP/BIRC4 mutation.

X-linked lymphoproliferative syndromes (XLP) are rare primary immunodeficiencies. Mutations within the XIAP/BIRC4 gene characterize XLP type 2 and cause XIAP deficiency. We present the case of a 5-year-old boy with a novel mutation of the XIAP/BIRC4 gene and describe the immunological phenotype for the first time. We characterized the distinct immunological phenotype and evaluated the family history accordingly.

X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis.

X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.

From neonates to adolescents--the diagnostic significance of pitted erythrocytes in hyposplenic and asplenic children.

BACKGROUND: Splenic function may be reduced or absent in a range of medical conditions in childhood, most prominently in homozygous sickle cell disease, celiac disease, or after total or partial splenectomy. In neonates and patients with malignant disease, transient hyposplenia has been reported as well. A simple method with reliable reference values is required to determine a patient's splenic function and thereby assess the risk of systemic infection. PATIENTS: Pitted erythrocytes (pitE) were determined semi-quantitatively in patients up to 20 years of age. This included splenectomized individuals, patients at risk for hyposplenia (homozygous sickle cell anemia (HbSS), leukemia, nephroblastoma and Hodgkin's disease after irradiation, patients after stem cell transplantation (SCT)), term and preterm neonates, and 90 controls (0-20 years of age, no neonates). METHOD: A capillary blood sample was diluted in buffered glutaraldehyde. PitE were scored using differential interference contrast microscopy with Nomarski optics. RESULTS: PitE were <2% in all controls regardless of age, in splenectomized individuals >18%. In patients with HbSS, pitE scores ranged from 6.2 to 44%. Scores did not exceed 2% in patients after SCT, irradiation, or during chemotherapy for leukaemia. In term neonates, pitE were increased in the perinatal period only. The elevation in preterm neonates persisted up to 2 months after birth. CONCLUSION: Serial measurement of pitE can be used to accurately and reliably assess splenic function in children. Except for neonates, pitE are consistently <2% in healthy individuals. For clinical purposes, the degree of hyposplenia can be determined to give an estimation of the risk of severe infection, e.g. in patients with HbSS or after partial splenectomy.

Resistance to cytarabine and gemcitabine and in vitro selection of transduced cells after retroviral expression of cytidine deaminase in human hematopoietic progenitor cells.

Overexpression of the detoxifying enzyme cytidine deaminase (CDD) renders normal and leukemic hematopoietic cells resistant to cytarabine (1-beta-D-arabinofuranosylcytosine), and studies on murine cells have suggested transgenic CDD overexpression as a way to reduce the substantial myelotoxicity induced by the deoxycytidine analogs cytarabine and gemcitabine (2',2'-difluorodeoxycytidine). We now have investigated CDD (over-)expression in the human hematopoietic system. Retroviral gene transfer significantly increased the resistance of CDD-transduced cord blood and peripheral blood-derived progenitor cells for doses ranging from 20-100 nM cytarabine and 8-10 nM gemcitabine. Protection was observed for progenitors of erythroid as well as myeloid differentiation, though the degree of protection varied for individual drugs. In addition, significant selection of CDD-transduced cells was obtained after a 4-day culture in 30-100 nM cytarabine. Thus, our data demonstrate that overexpression of CDD cDNA results in significant protection of human progenitors from cytarabine- as well as gemcitabine-induced toxicity, and allows in vitro selection of transduced cells. This strongly argues for a potential therapeutic role of CDD gene transfer in conjunction with dose-intensive cytarabine- or gemcitabine-containing chemotherapy regimen.