A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining.

Radiosensitive T-B- severe combined immunodeficiency (RS-SCID) is caused by defects in the nonhomologous end-joining (NHEJ) DNA repair pathway, which results in failure of functional V(D)J recombination. Here we have identified the first human RS-SCID patient to our knowledge with a DNA-PKcs missense mutation (L3062R). The causative mutation did not affect the kinase activity or DNA end-binding capacity of DNA-PKcs itself; rather, the presence of long P-nucleotide stretches in the immunoglobulin coding joints indicated that it caused insufficient Artemis activation, something that is dependent on Artemis interaction with autophosphorylated DNA-PKcs. Moreover, overall end-joining activity was hampered, suggesting that Artemis-independent DNA-PKcs functions were also inhibited. This study demonstrates that the presence of DNA-PKcs kinase activity is not sufficient to rule out a defect in this gene during diagnosis and treatment of RS-SCID patients. Further, the data suggest that residual DNA-PKcs activity is indispensable in humans.

Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency.

One of the severe combined immunodeficiencies (SCIDs), which is caused by a genetic defect in the signal transduction pathways involved in T-cell activation, is the ZAP70 deficiency. Mutations in ZAP70 lead to both abnormal thymic development and defective T-cell receptor (TCR) signaling of peripheral T-cells. In contrast to the lymphopenia in most SCID patients, ZAP70-deficient patients have lymphocytosis, despite the selective absence of CD8+ T-cells. The clinical presentation is usually before 2 years of age with typical findings of SCID. Here, we present three new ZAP70-deficient patients who vary in their clinical presentation. One of the ZAP70-deficient patients presented as a classical SCID, the second patient presented as a healthy looking wheezy infant, whereas the third patient came to clinical attention for the eczematous skin lesions simulating atopic dermatitis with eosinophilia and elevated immunoglobulin E (IgE), similar to the Omenn syndrome. This study illustrates that awareness of the clinical heterogeneity of ZAP70 deficiency is of utmost importance for making a fast and accurate diagnosis, which will contribute to the improvement of the adequate treatment of this severe immunodeficiency.

Parvovirus B19-induced persistent pure red cell aplasia in a child with T-cell immunodeficiency.

Persistent pure red cell aplasia can be a manifestation of parvovirus B19 infection in immunocompromised hosts. Failure of the humoral immune response to clear parvovirus B19 in such patients results in persistent pure red cell aplasia. The authors describe a child who had T-cell immunodeficiency and persistent pure red cell aplasia due to parvovirus B19 infection. Interestingly, they detected human parvovirus B19 genome by polymerase chain reaction (PCR) not in the peripheral blood, but in the bone marrow specimen of the patient. In their patient, T-cell immunodeficiency may have caused impaired B-cell activation and failure of effective humoral immune response to neutralize the virus. Additionally, before the diagnosis of pure red cell aplasia, IVIG treatment given at a dosage of 400 mg/kg/day with 3-week intervals may result in sufficient neutralization of peripheral blood parvovirus B19, whereas it may not be sufficient for the neutralization of parvovirus B19 genome in bone marrow. Thus, peripheral blood parvovirus B19 serology (IgM and IgG) and PCR were negative, whereas bone marrow aspiration sample was positive for parvovirus B19 PCR in this patient. Reticulocytopenia and severe anemia may warn the physicians of parvovirus B19 infection, especially in immunocompromised children. Diagnosis may require demonstration of absence of late erythroid precursors in the bone marrow as well as serologic testing and detection of parvovirus B19 genome by PCR in the serum and/or bone marrow samples of the patient.

Hematopoietic stem cell transplantation from a donor with Klinefelter syndrome for Wiskott-Aldrich syndrome.

WAS is a rare X-linked recessive disorder characterized by primary progressive T cell immunodeficiency, impaired antipolysaccharide antibody response, thrombocytopenia with small platelet, and eczematoid dermatitis. Untreated patients with typical WAS have poor prognosis with the major causes of death being infection, bleeding, lymphoproliferative disorders, and malignancy. Due to the increased risk of infectious and hemorrhagic episodes the best results with HSCT are achieved in patients less than five yr of age and are recommended as early as possible. Here, we report a three-yr-old boy with WAS who underwent UCB and BMT from his genotypically identical brother with Klinefelter syndrome.

A novel mutation leading to a deletion in the SH3 domain of Bruton's tyrosine kinase.

X-linked agammaglobulinemia (XLA) is a primary B cell immunodeficiency disorder, caused by a defect in the Bruton tyrosine kinase (BTK) gene. Here, we describe a novel four base pair mutation (838delGAGT) in intron 9 of the BTK gene leading to the skipping of exon 9 in a 2.5-year-old boy with this disorder.

Trimethoprim-sulfamethoxazole induced prolonged hypoglycemia in an infant with MHC class II deficiency: diazoxide as a treatment option.

Hyperinsulinemic hypoglycemia associated with trimethoprim-sulfamethoxazole (TMP-SMX) has generally been reported in adults who had renal impairment or in patients with AIDS using high dose TMP-SMX. We present a 5 month-old infant with immunodeficiency due to major histocompatibility complex class II expression defect, developing hypoglycemic convulsion on the third day of high dose TMP-SMX administration. High insulin and C-peptide levels were documented at the time of hypoglycemia. To overcome hypoglycemia while TMP-SMX tapered off, diazoxide was administered which resolved hypoglycemia in 2 months.

Presentation of interleukin-12/-23 receptor beta1 deficiency with various clinical symptoms of Salmonella infections.

Clinical disease caused by weakly pathogenic mycobacterial species, Mycobacterium bovis Bacille Calmette-Guérin (BCG) and non-tuberculous environmental mycobacteria (EM), which is known as Mendelian susceptibility to mycobacterial disease (MSMD), is a rare entity defined recently. Infections with the more virulent Mycobacterium species, M. tuberculosis, may have largely gone unnoticed in these patients due to early death. Mutations in five proteins (IFNgammaR1, IFNgammaR2, IL-12/IL-23Rbeta1, IL-12/IL-23p40 and STAT1) have been found in MSMD. These patients are prone to surprisingly few other infectious diseases mainly to salmonellosis. Here we present three IL-12/IL-23Rbeta1 deficient patients from three different families and with different genetic mutations, who presented exclusively with Salmonella infections. Bacteremia and lymph node involvement were common clinical expressions. Leukocytoclastic vasculitis developed in one of these patients. Two patients were not inoculated with BCG, the third patient did not develop BCG infection although BCG vaccine had been given twice at ages of 1 and 7 years. All three patients responded well to antibiotic treatment. In conclusion, patients with chronic, recurrent or complicated Salmonella infections should be screened for MSMD, particularly for IL-12/IL-23p40/IL-12R/-23Rbeta1 deficiency. Conversely, in patients with genetic IL-12/-23Rbeta1 deficiency a full evaluation for Salmonella infection is required. IL-12/IL-23p40/IL-12R/IL-23Rbeta1 deficiency seem to be underdiagnosed in patients with salmonellosis, and since such patients need prolonged therapy, diagnosis is important.

Long-term survival in severe combined immune deficiency: the role of persistent maternal engraftment.

Two siblings with severe combined immune deficiency, one with maternal engraftment and detectable immunologic functions who was alive at the age of 8 years are presented. Both patients had the same JAK3 gene mutation, suggesting that maternal engraftment may result in immune competence leading to long-term survival in patients with severe combined immune deficiency.

Thrombocytopenia and emperipolesis in a patient with hepatitis a infection.

lmmune thrombocytopenia is a benign, self-limiting disease in children, responding well to treatment and generally associated with viral infections. A 13-year-old girl was admitted to a hospital with the epistaxis and purpura after an attack of jaundice 6 weeks before. The diagnosis of hepatitis A virus (HAV)-induced thrombocytopenia was made. Furthermore, erythrophagocytosis by megakaryocytes was demonstrated in the bone marrow of the patient. Although hematologic complications following hepatitis B and C viruses are commonly reported, the association of hepatitis A virus and thrombocytopenia has rarely been described.

Antibody response to a seven-valent pneumococcal conjugated vaccine in patients with ataxia-telangiectasia.

Immunodeficiency is a characteristic feature of ataxia-telangiectasia (A-T). Humoral immunodeficiency generally consists of hypogammaglobulinemia and impaired antibody response to bacterial and viral antigens. We previously observed defective antibody response to 23-valent pneumococcal polysaccharide vaccine (PPV) in 96% of 29 patients with A-T. In this study, we investigated the antibody response to a seven-valent pneumococcal conjugate vaccine, PCV7, in 14 patients with A-T. IgG antibody levels to four pneumococcal serotypes, 6B, 14, 19F, 23F, which were included in PCV7, were measured by ELISA in pre- and postimmunization serum samples. Antibody titers against each individual Streptococcus pneumoniae serotype was considered to be positive when serotype specific pneumococcal antibody titer was higher than 10% (>10 U/mL) of the reference plasma pool level. However, when the fold increase (FI) in postimmunization antibody titer was less than two, the subject was determined to be unresponsive to the given serotype. The values were compared with the results obtained in age- and ethnic-matched children after one dose of PPV. Only two patients produced antibodies to one serotype each; one to serotype 19 with a fold increase of <2, and the other to serotype 23F with a fold increase of 5.7 based on the above criteria, although the differences between pre- and postvaccine antibody titers for serotypes 14, 19, and 23 appeared to be statistically significant. In conclusion, A-T patients failed to respond to one dose of PCV7 vaccine. Two or more doses of conjugated vaccine may be required to recruit the help of T lymphocytes in A-T patients.