Saving the red baby: successful allogeneic cord blood transplantation in Omenn syndrome.

Haematopoietic stem cell transplantation is the treatment of choice for severe primary immunodeficiencies, but only has moderate prognosis in Omenn syndrome as it is complicated by highly activated Omenn T-cells resulting in delayed T-cell engraftment and a high rate of graft failure. A 6 1/2 months old patient with a previously unknown compound heterozygous defect within the RAG1 gene (R474C; R975W) underwent 8/10 HLA-matched cord blood transplantation after myeloablative conditioning. Immune reconstitution was impressive with T-, B- and NK-cells reaching the median of age-dependent reference values within twelve, four and two months respectively. With a continuous decrease of activated Omenn T-cells there was a steady increase of naive, probably thymus-derived T-cells. Polyclonal B-cell activation and hypergammaglobulinaemia disappeared with B-cell engraftment. This case emphasizes that, despite their naive status and HLA-barriers, cord blood T-cells were apparently able to achieve T-effector function resulting in the elimination of all activated Omenn T-cells.

An immunodeficiency disease with RAG mutations and granulomas.

We describe three unrelated girls who had an immunodeficiency disease with granulomas in the skin, mucous membranes, and internal organs. All three girls had severe complications after viral infections, including B-cell lymphoma associated with Epstein-Barr virus (EBV). Other findings were hypogammaglobulinemia, a diminished number of T and B cells, and sparse thymic tissue on ultrasonography. Molecular analysis revealed that the patients were compound heterozygotes for mutations in recombination activating gene 1 or 2 (RAG1 or RAG2). In each case, both parents were heterozygous carriers of a RAG mutation. The mutations were associated with reduced function of RAG in vitro (3 to 30% of normal activity). The parents and one sibling in the three families were healthy.

High nerve growth factor receptor (p75NTR) expression is a favourable prognostic factor in paediatric B cell precursor-acute lymphoblastic leukaemia.

Nerve growth factor (NGF) plays a pivotal role in cellular survival/death decisions with the low affinity receptor p75NTR predominately transmitting anti-proliferative signals. In spite of its established role in B-cell function and identification as a prognostically favourable marker in a number of malignancies, little is known about the expression pattern and prognostic significance of p75NTR in B cell precursor-acute lymphoblastic leukaemia (BCP-ALL). p75NTR expression was prospectively studied on primary ALL-blasts in a cohort of paediatric patients with common ALL (n = 86) and preB-ALL (n = 34) treated within the Co-operative study group for childhood acute lymphoblastic leukaemia (CoALL) protocol, CoALL06-97. Flow cytometric analysis showed that almost half of the patients expressed no or negligible amounts of p75NTR (<10%). The median expression in patients expressing p75NTR beyond that threshold was 49% (range 11-100%). In patients classified as low-risk at diagnosis, p75NTR expression was significantly higher than in high-risk patients (P = 0.001). Of note, p75NTR expression was lower in the 21 patients who subsequently developed relapse compared with those remaining in remission (P = 0.038). Accordingly, relapse-free survival was significantly better in patients expressing high surface p75NTR (P = 0.041). Thus, in this prospective analysis, high p75NTR expression was a strong prognostic marker that identified a group of paediatric ALL patients with favourable outcome.

Survivin and its prognostic significance in pediatric acute B-cell precursor lymphoblastic leukemia.

BACKGROUND AND OBJECTIVES: Impaired apoptosis, mediated by members of the inhibitor of apoptosis proteins (IAP) family such as survivin, is thought to contribute to leukemic cell survival. In contrast to low expression of survivin in normal differentiated adult tissues, very high levels of survivin have been described in a number of different tumors. Overexpression of survivin was found to correlate with poor prognosis in a variety of cancers including hematologic malignancies. To date, however, there is no information available on the prognostic role of survivin in pediatric precursor B-cell acute lymphocytic leukemia (BCP-ALL), the most frequent malignancy in childhood. DESIGN AND METHODS: In a retrospective study including 66 pediatric patients we analyzed the impact of survivin protein levels on outcome in BCP-ALL. RESULTS: Survivin overexpression, with an up to ten-fold increase of the normal level, was detected in 65% of the leukemic samples in contrast to negligible expression in non-malignant hematopoietic cells. Despite considerable variety of expression levels in ALL cells, there was no association of survivin levels with established risk factors. However, patients suffering relapse of disease or death had significantly higher survivin expression than those with a favorable outcome. Overexpression of survivin is a significant prognostic marker for 3 year relapse free, event-free and overall survival, again independent of the established prognostic factors in ALL, such as age and leukocyte count at diagnosis as assessed in multivariate analysis. INTERPRETATION AND CONCLUSIONS: Overexpression of survivin in BCP-ALL identifies patients with a high risk of early relapse. Upon confirmation in a prospective analysis, survivin expression may, in the future, serve to further refine treatment stratification with intensification of therapy in those patients prone to relapse.

Topical tacrolimus is effective against eczema in Wiskott-Aldrich syndrome (WAS).

UNLABELLED: The Wiskott-Aldrich syndrome is a rare X-linked immunodeficiency characterized by microplatelet thrombocytopenia and eczema. Eczema may be severe and facilitate entry of microorganism into the host. CONCLUSION: We report for the first time that eczema in infants with WAS can be effectively treated with topical ttacrolimus.

A single intravenous dose of prednisolone induces phosphatidylserine externalization, loss of surface marker expression and a 24-h net increase in human peripheral blood lymphocytes ex vivo.

To understand how corticosteroids act; a characterization of their effects on lymphocytes is necessary. The effect of in vivo corticosteroids on lymphocyte subpopulations, their surface molecules and externalization of phosphatidylserine (apoptosis) is examined. In a crossover study, a single, intravenous dose of 2 mg/kg prednisolone or saline was given to six male adult human volunteers. Blood samples were withdrawn before and 30 min, 2, 5, 23 and 29 h thereafter. Lymphocyte subsets were determined by FACS analysis. Externalization of phosphatidylserine was measured by Annexin-V; cell fragments were excluded by propidium iodide staining. Lymphocyte number decreased from 2,007 +/- 473 to 634 +/- 119 microl after 5 h and rose to 3,112 +/- 436 microl after 23 h. CD4, CD8 and B cell counts declined significantly after 5 h (P < or = 0.01). The expression of CD28 or CD95 on T cells and the natural killer cells were unaffected. There was a significant rebound of lymphocyte numbers above baseline 23 h after prednisolone. At baseline 9.9 +/- 3.8% of cells in the lymphocyte gate did not stain for CD3, CD20 or CD56 (referred to as "null cells"). 5 h after application of prednisolone, there was a significant increase of "null cells" (28 +/- 12%, P = 0.018). The percentage of phosphatidylserine positive CD4 cells rose from 8.1 +/- 3.3 to 19.8 +/- 8% after intravenous prednisolone, while the percentage of phosphatidylserine positive CD8, B and NK cells remained largely unchanged. Prednisolone induces a most significant depletion of CD4 cells, which to some degree is associated with apoptosis. The net increase of lymphocyte numbers 23 h after prednisolone application may be a beneficial late effect of a single i.v. prednisolone shot.

Delayed diagnosis and complications of Fanconi anaemia at advanced age--a paradigm.

Fanconi anaemia (FA) is a rare recessive DNA repair disorder clinically characterised by congenital malformations, progressive bone marrow failure and a high propensity for developing malignancies at an early age, predominantly acute myeloid leukaemia (AML) and squamous cell carcinoma. It is conceivable that a number of patients with hypomorphic mutations are not diagnosed as FA until severe complications in the treatment of a malignancy occur. Here, we report on a patient with FA-A, diagnosed only at the age of 49 years due to persistent pancytopenia and myelodysplastic syndrome/AML induced by a first cycle of chemotherapy for bilateral metachronic breast cancer. This exceptional case clearly demonstrates that, in instances of long-lasting mild pancytopenia or development of malignancies, especially at an unusually young age, FA should be ruled out, irrespective of the patient's age and features, especially before inflicting severe genotoxic stress.

Nuclear factor kappaB essential modulator-deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia.

BACKGROUND: Amorphic mutations in the X-linked nuclear factor kappaB essential modulator ( NEMO ) gene cause Incontinentia pigmenti, which is lethal in hemizygous male patients. Hypomorphic NEMO mutations in male patients lead to anhidrotic ectodermal dysplasia (EDA) with immunodeficiency. OBJECTIVE: To report the clinical features of a child bearing a NEMO mutation who displayed an immunodeficiency without EDA. METHODS: Documentation of clinical care, chart review, standard immunologic and microbiological laboratory techniques, mutation analysis of the NEMO gene. RESULTS: Since the age of 15 months, the patient had Mycobacterium avium disease, beginning with multiple adenitis, later followed by disseminated osteomyelitis and dermatitis. In addition, Haemophilus influenzae and Streptococcus pneumoniae infections led to bronchiectasis. An immunologic work-up revealed a low production of IFN-gamma by PBMCs associated with a hyper-IgM phenotype. Despite treatment using repeated cycles of a 4-drug antimycobacterial regimen, continuous subcutaneous IFN-gamma, repeated antibiotic treatment, and intravenous immunoglobulin substitution, the boy remained chronically ill. At the age of 12 years, the disease was complicated by severe autoimmune hemolytic anemia and eventually fatal herpes simplex virus 1 encephalitis despite high-dose acyclovir therapy. Although he did not present any sign of EDA, a novel type of disease-causing hypomorphic NEMO mutation (110-111insC in exon 2) was identified. CONCLUSION: This case demonstrates that patients hemizygous for NEMO mutations can present with an immunodeficiency without EDA. An investigation of NEMO should thus be undertaken in selected children with immunodeficiency despite the lack of EDA.

Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I.

This study describes the discovery of a new inherited disorder of glycosylation named "CDG-Ik." CDG-Ik (congenital disorder of glycoslyation type Ik) is based on a defect of human mannosyltransferase I (MT-I [MIM 605907]), an enzyme necessary for the elongation of dolichol-linked chitobiose during N-glycan biosynthesis. Mutations in semiconserved regions in the corresponding gene, HMT-1 (yeast homologue, Alg1), in two patients caused drastically reduced enzyme activity, leading to a severe disease with death in early infancy. One patient had a homozygous point mutation (c.773C-->T, S258L), whereas the other patient was compound heterozygous for the mutations c.773C-->T and c.1025A-->C (E342P). Glycosylation and growth of Alg1-deficient PRY56 yeast cells, showing a temperature-sensitive phenotype, could be restored by the human wild-type allele, whereas only slight restoration was observed after transformation with the patients' alleles.