Expanding the mutation spectrum in ICF syndrome: Evidence for a gender bias in ICF2.

BACKGROUND: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare, genetically heterogeneous, autosomal recessive disorder. Patients suffer from recurrent infections caused by reduced levels or absence of serum immunoglobulins. Genetically, 4 subtypes of ICF syndrome have been identified to date: ICF1 (DNMT3B mutations), ICF2 (ZBTB24 mutations), ICF3 (CDCA7 mutations), and ICF4 (HELLS mutations). AIM: To study the mutation spectrum in ICF syndrome. MATERIALS AND METHODS: Genetic studies were performed in peripheral blood lymphocyte DNA from suspected ICF patients and family members. RESULTS: We describe 7 ICF1 patients and 6 novel missense mutations in DNMT3B, affecting highly conserved residues in the catalytic domain. We also describe 5 new ICF2 patients, one of them carrying a homozygous deletion of the complete ZBTB24 locus. In a meta-analysis of all published ICF cases, we observed a gender bias in ICF2 with 79% male patients. DISCUSSION: The biallelic deletion of ZBTB24 provides strong support for the hypothesis that most ICF2 patients suffer from a ZBTB24 loss of function mechanism and confirms that complete absence of ZBTB24 is compatible with human life. This is in contrast to the observed early embryonic lethality in mice lacking functional Zbtb24. The observed gender bias seems to be restricted to ICF2 as it is not observed in the ICF1 cohort. CONCLUSION: Our study expands the mutation spectrum in ICF syndrome and supports that DNMT3B and ZBTB24 are the most common disease genes.

B-cell subsets in patients with transient hypogammaglobulinemia of infancy, partial IgA deficiency, and selective IgM deficiency.

BACKGROUND: The pathogenesis of some primary humoral immunodeficiencies, such as transient hypogammaglobulinemia of infancy (THI) and immunoglobulin (Ig) A deficiency, remains unknown and can render diagnosis problematic. OBJECTIVE: In the present study, we used flow cytometry to analyze peripheral blood B-cell subsets in patients with THI and unclassified hypogammaglobulinemia (UCH), partial IgA deficiency, and selective IgM deficiency. METHODS: The study population comprised 41 patients with hypogammaglobulinemia (THI, 18; UCH, 23), 16 patients with partial IgA deficiency, and 16 patients with selective IgM deficiency who were admitted to Ankara University Department of Pediatric Immunology-Allergy between January 2010 and April 2011, as well as 29 healthy controls. B-cell subsets were examined according to the EUROclass classification. RESULTS: Age at diagnosis in the hypogammaglobulinemia group ranged between-14 months and 13 years (median, 26 months). Naive B-cell percentages were significantly higher and activated B-cell values lower in the THI patients than in the UCH patients and age-matched healthy controls. Nonswitched (IgM+CD27+IgD+) memory B-cell values were found to be significantly lower in patients with selective IgM deficiency than in healthy controls. No significant differences in B-cell subsets were found in patients with partial IgA deficiency. CONCLUSIONS: Previous reports show that reduced class-switched memory B cell values are associated with CVID, THI, and selective IgA deficiency. Our findings did not support these reports. Furthermore, we observed that naive B cell values were higher in patients with THI. A maturation defect could play a role in the pathogenesis of THI.

Bacille Calmette-Guérin lymphadenitis and recurrent oral candidiasis in an infant with a new mutation leading to interleukin-12 receptor beta-1 deficiency.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome characterized by predisposition to infections caused by weakly virulent mycobacteria, such as those in bacille Calmette-Guérin (BCG) vaccine and environmental mycobacteria. Salmonellosis has been reported in almost half of affected patients. Patients are also vulnerable to Mycobacterium tuberculosis infection. Several other infectious diseases may occur, albeit rarely. Mucocutaneous candidiasis is more common. Interleukin-12 receptor beta1 (IL-12Rbeta1) deficiency is the most frequent genetic cause of MSMD. Here, we describe an infant with a single episode of BCG lymphadenitis who also suffered from recurrent oral candidiasis. Genetic analysis revealed a new homozygous mutation (64+1G>T) in the IL12RB1 gene that caused complete IL-12R1beta1 deficiency. IL-12Rbeta1 deficiency should be considered in patients with BCG infection, even in those who experience a single episode of BCG lymphadenitis or recurrent mucocutaneous candidiasis. Every attempt should be made to heighten awareness in countries where BCG vaccination is performed.

CD27 expression on lymphocyte and sCD27 levels in children with asthma

Background: CD27, a lymphocyte specific member of the Tumour Necrosis Factor- Receptor (TNF-R) family is expressed on the majority of peripheral blood T cells. Activation of T cells via TCR/CD3 induces high CD27 surface expression and release of a soluble form (sCD27) of the molecule. sCD27 level increases in patients suffering from a variety of chronic inflammatory diseases. In the present study we aimed to measure both the serum sCD27 levels and CD27 expression on T cells in asthmatic patients, to evaluate the state of this molecule in allergic inflammation. Methods: Forty-three patients with asthma were included in to the study. CD27 molecule expression and soluble form of this molecule were analysed in atopic asthmatic (n:17) and non-atopic asthmatic (n:13) patients receiving inhaled corticosteroid treatment, in asthmatic patients whose treatment ceased at least for 6 months (n:13) and healthy control subjects (n:14). Results: There were no differences in the expression of CD27 molecule on peripheral blood lymphocyte nor in its soluble form sCD27 levels in sera between the atopic asthmatic and non-atopic asthmatic patients receiving ICS treatment, treatment free asthmatic patients and healthy control subjects. Conclusions: Neither the soluble form of CD27 nor its expression on T cells seem to be a reliable marker of atopic or non-atopic asthmatic inflammation

CD27 expression on lymphocyte and sCD27 levels in children with asthma.

BACKGROUND: CD27, a lymphocyte specific member of the Tumour Necrosis Factor- Receptor (TNF-R) family is expressed on the majority of peripheral blood T cells. Activation of T cells via TCR/CD3 induces high CD27 surface expression and release of a soluble form (sCD27) of the molecule. sCD27 level increases in patients suffering from a variety of chronic inflammatory diseases. In the present study we aimed to measure both the serum sCD27 levels and CD27 expression on T cells in asthmatic patients, to evaluate the state of this molecule in allergic inflammation. METHODS: Forty-three patients with asthma were included in to the study. CD27 molecule expression and soluble form of this molecule were analysed in atopic asthmatic (n:17) and non-atopic asthmatic (n:13) patients receiving inhaled corticosteroid treatment, in asthmatic patients whose treatment ceased at least for 6 months (n:13) and healthy control subjects (n:14). RESULTS: There were no differences in the expression of CD27 molecule on peripheral blood lymphocyte nor in its soluble form sCD27 levels in sera between the atopic asthmatic and non-atopic asthmatic patients receiving ICS treatment, treatment free asthmatic patients and healthy control subjects. CONCLUSIONS: Neither the soluble form of CD27 nor its expression on T cells seem to be a reliable marker of atopic or non-atopic asthmatic inflammation.

An intensive approach to the treatment of disseminated BCG infection in a SCID patient.

There is an appreciable mortality associated with BMT in patients with SCID and advanced BCG infection. We present a girl with T-B+ SCID complicated by spina ventosa and disseminated BCG osteitis after receiving a fully matched sibling marrow transplant. Considerable progression characterised by two clinical activations and multiple pleural and perivertebral abscess formations occurred with conventional anti-mycobacterial chemotherapy. She finally recovered with full immune reconstitution after BMT and intensive treatment comprising five conventional and alternative agents that she received for 36 months. No side-effects and/or complications have been seen other than hearing loss.

657del5 mutation in the NBS1 gene is associated with Nijmegen breakage syndrome in a Turkish family.

We report on a consanguineous Turkish family whose first son died of anal atresia and whose second son presented with severe pre- and post-natal growth retardation as well as striking microcephaly, immunodeficiency, congenital heart disease, chromosomal instability and rhabdomyosarcoma in the anal region. The proband was found to carry the homozygous 657del5 mutation in the NBS1 gene, which is responsible for Nijmegen breakage syndrome (NBS) in most of the Slav populations. Our family, the first diagnosed with NBS in the Turkish population, represents one of the most severely affected examples of the syndrome, with profound pre- and post-natal growth retardation associated with structural abnormalities, and expands the clinical spectrum of this rare disorder.

Natural killer cell numbers and cytotoxic activity in pediatric Hodgkin disease.

In this study peripheral blood natural killer (NK) cell activity was evaluated in 17 pediatric cases with Hodgkin disease (HD) (9 untreated, 8 in remission) and 20 age-matched healthy children. Peripheral blood CD16 and CD56 molecule expressions were also examined. No difference related to NK cell numbers and cytotoxic activity was detected at either stage of the disease. In cases in which long-term remission has been achieved (> or = 5 years) NK cell activity was slightly but not significantly increased in parallel with remission duration. Finally, no relation between NK cell activity and the etiology, prognosis, and severity of the disease has been established in children with HD.