1/224. A G to A transition at the last nucleotide of exon 6 of the gamma c gene (868G-->A) may result in either a splice or missense mutation in patients with X-linked severe combined immunodeficiency.We report here that a defect of the interleukin common gamma subunit (gamma c) in X-linked severe combined immunodeficiency (XSCID) previously known as a missense mutation resulted instead in exon skipping in a Japanese XSCID patient. The phenotype of the patient was consistent with that of typical XSCID, and his Epstein-Barr virus-transformed B cells accordingly entirely lacked surface expression of gamma c . On analysis by the reverse transcription-polymerase chain reaction (RT-PCR), a single but small gamma c mRNA species was detected. Exon 6, which encodes the transmembrane domain of gamma c, was skipped in the mRNA. A G to A mutation was found at the last nucleotide of exon 6 of the gamma c gene (868G-->A). The predicted consequence of the exon skipping is a frameshift resulting in a premature stop codon, and the mutated gamma c presumably loses association with the cell membrane. In XSCID, this mutation (868G-->A) is known as a missense mutation that results in R285Q [corrected]. Previously reported patients with the same mutation apparently had no aberrant or alternative splicing but did have the R285Q [corrected] exchange. Similar mutations at the last nucleotide of an outskipped exon have been reported. However, such mutations do not always cause exon skipping. Analyses of RNA structural changes induced by the mutations supported the variability of consequences of the mutations. Taken together, our findings suggest that the 868G-->A mutation of the gamma c gene may affect gamma c transcripts differently, i.e., generating missense or exon skipping, in XSCID patients with the same mutation. Patient-specific variation in splicing thus appears to occur.- - - - - - - - - - ranking = 1keywords = deficiency (Clic here for more details about this article) |
2/224. Successful human umbilical cord blood stem cell transplantation without conditioning in severe combined immune deficiency.A 2-month-old girl with severe combined immunodeficiency (SCID), presented with mild staphylococcal skin infection, lymphopenia, low T cell number, absence of B cells, high number of NK cells, and a negligible response to mitogens. Since her older brother died as a result of SCID 2 years earlier, cord blood was harvested from a sister born 2 1/2 years earlier, who was normal and fully matched both by serology and molecular typing. In view of her clinical condition and in spite of a high number of NK cells with normal activity, HUCBT without preparative conditioning was performed. No G-CSF was administered. Engraftment with mixed chimerism was evident 3 weeks post transplantation. There were no peritransplantation complications. Eighteen months post transplantation, the girl is in excellent condition, blood counts are normal, T cell engraftment is complete, B cell engraftment is proceeding gradually, and the mitogen stimulation tests are normal. Due to the unique nature of HUCB hematopoietic cells, engraftment without conditioning may be possible in patients with SCID with fully matched donors. This is the first HUCBT performed without conditioning.- - - - - - - - - - ranking = 1keywords = deficiency (Clic here for more details about this article) |
3/224. Interferon alpha treatment of molluscum contagiosum in immunodeficiency.A sister (aged 6 years) and brother (aged 8 years) presented four months apart with severe molluscum contagiosum. Both children demonstrated clinical and laboratory evidence of combined immunodeficiency. The extent of skin involvement by molluscum contagiosum precluded conventional treatment as well as intralesional interferon alpha (IFN alpha). Both subjects responded well to subcutaneous IFN alpha.- - - - - - - - - - ranking = 1keywords = deficiency (Clic here for more details about this article) |
4/224. Combined immunodeficiency associated with increased apoptosis of lymphocytes and radiosensitivity fibroblasts.Severe immunodeficiency characterized by lymphopenia was found in two siblings, one of whom was examined in detail. The calcium flux, pattern of tyrosine phosphorylation of proteins, and interleukin 2 (IL-2) production and proliferation in response to mitogens suggested that the peripheral blood T cells activated normally. The peripheral blood T cells were shown to have an activated phenotype with increased expression of CD45RO and CD95/Fas. Increased spontaneous apoptosis occurred in unstimulated lymphocyte cultures. The elevated apoptosis was not due to alterations in expression or to mutations in Bcl-2, Bcl-X(L), or Flip, nor could the spontaneous apoptosis be prevented by blocking Fas, suggesting that it was independent of Fas signaling. This is the first inherited combined immunodeficiency associated with impaired lymphocyte survival. fibroblasts derived from the patient showed appreciable radiosensitivity in clonal assays, but apoptosis was not elevated. Our results show that the fibroblasts represent a new radiosensitive phenotype not associated with cell cycle checkpoint defects, V(D)J recombination defects, or elevated chromosome breakage. We suggest that the affected gene plays a role in an undetermined damage response mechanism that results in elevated spontaneous apoptosis in lymphoid cells and radiosensitivity in fibroblasts.- - - - - - - - - - ranking = 1.2keywords = deficiency (Clic here for more details about this article) |
5/224. association of reticular dysgenesis (thymic alymphoplasia and congenital aleukocytosis) with bilateral sensorineural deafness.Reticular dysgenesis is a rare congenital disorder characterized by severe combined immunodeficiency and profound neutropenia, curable to date, only by bone marrow transplantation. This report describes the association of bilateral sensorineural deafness with this disease.- - - - - - - - - - ranking = 0.2keywords = deficiency (Clic here for more details about this article) |
6/224. Characterization of immune function and analysis of RAG gene mutations in Omenn syndrome and related disorders.Omenn syndrome was recently found to be caused by missense mutations in RAG1 or RAG2 gene that result in partial V(D)J recombination activity. Although the clinical hallmarks of the disease are well defined, there have been several cases with clinical findings similar to, but distinct from Omenn syndrome. The data on immune functions and RAG gene mutations of such cases are limited. We described five Japanese infants from four unrelated families, including two cases of Omenn syndrome and three cases of related disorders. Sibling cases with typical Omenn phenotype were found to be compound heterozygotes of R396C and L885R mutations in RAG1. The former has been reported in European cases and may constitute a hot spot. The latter is a novel missense mutation. Infants with related disorders exhibited erythroderma, eosinophilia, hypogammaglobulinaemia, decreased number of B cells and skewing to Th2, and their lymph node specimens showed architectural effacement, lymphocyte depletion and histiocytic hyperplasia, each of which is seen characteristically in Omenn syndrome. However, in these cases serum IgE levels were low or undetectable. We found no mutation in RAG genes except for a K820R substitution in RAG1, which was regarded to be a functional polymorphism, in two of these cases. Our study suggests that RAG missense mutation may be a genetic abnormality unique to Omenn syndrome with characteristic clinical and laboratory findings. Variations of Omenn syndrome, or related disorders, may represent a different type of immunodeficiency, distinct from abnormalities in lymphoid-specific recombinase activity.- - - - - - - - - - ranking = 0.2keywords = deficiency (Clic here for more details about this article) |
7/224. Unsuspected pneumocystis carinii pneumonia at presentation of severe primary immunodeficiency.BACKGROUND: pneumocystis carinii is an important pathogen in immunodeficiency but may be an unrecognised cause of respiratory compromise. OBJECTIVES: To ascertain the incidence of P carinii pneumonia (PCP) at presentation of severe combined immunodeficiency (SCID), whether it had been diagnosed, and the effect of treatment on outcome. SETTING: The supraregional paediatric bone marrow transplant unit for primary immunodeficiencies at Newcastle General Hospital. methods: Retrospective case note review of infants referred with a diagnosis of SCID from 1992 to 1998. RESULTS: Ten of 50 infants had PCP at presentation; only one was diagnosed before transfer. Eight were diagnosed by bronchoalveolar lavage and two by lung biopsy. In only one was P carinii identified in nasopharyngeal secretions. Five required ventilation for respiratory failure but all were successfully treated with co-trimoxazole and methylprednisolone with or without nebulised budesonide. Nine survived to bone marrow transplantation and four are long term survivors after bone marrow transplantation; no deaths were related to PCP. CONCLUSIONS: PCP is a common presenting feature of SCID but is rarely recognised. bronchoalveolar lavage or lung biopsy are needed for diagnosis. Treatment with co-trimoxazole is highly successful.- - - - - - - - - - ranking = 1.2keywords = deficiency (Clic here for more details about this article) |
8/224. Haemophagocytic lymphohistiocytosis in X-linked severe combined immunodeficiency.Haemophagocytic lymphohistiocytosis (HLH) is characterized by destruction of haematopoietic elements, and is associated with a variety of manifestations including immune abnormalities. We describe an infant with HLH who had no evidence of infection or malignancy. He had markedly reduced natural killer (NK) and T-cell numbers and mitogen responses, consistent with severe combined immune deficiency. Western blot and flow cytometry analyses revealed an absence of interleukin (IL)-2 receptor gamma (gamma common) chain expression and a transition (C --> T) at nucleotide 684 in the gamma common gene. This novel case highlights the need for a thorough evaluation of immunological phenotype and genotype in patients with HLH.- - - - - - - - - - ranking = 1keywords = deficiency (Clic here for more details about this article) |
9/224. Development of autologous T lymphocytes in two males with X-linked severe combined immune deficiency: molecular and cellular characterization.We report on two patients affected with severe combined immune deficiency (SCID) with an unusual immunological phenotype and a substantial number of autologous, poorly functioning T cells. Distinct mutations identified at the IL2RG locus in the two patients impaired IL-2-mediated signaling but affected T-cell lymphopoiesis differently, resulting in generation of a polyclonal or oligoclonal T-cell repertoire. These observations add to the growing complexity of the immunological spectrum of SCID in humans and indicate the need for detailed immunological and molecular investigations in atypical cases.- - - - - - - - - - ranking = 1keywords = deficiency (Clic here for more details about this article) |
10/224. Dental manifestations in severe combined immunodeficiency following bone marrow transplantation.severe combined immunodeficiency (SCID) is a rare primary immunodeficiency disorder with an estimated overall frequency of 1 in 75 000 live births. bone marrow transplantation is the only curative treatment available. Using T cell-depleted HLA non-identical bone marrow requires preconditioning with a short course of cytotoxic chemotherapy. We report severe dental developmental anomalies in three such patients under long-term follow up.- - - - - - - - - - ranking = 1.2keywords = deficiency (Clic here for more details about this article) |
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