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ABSTRACT: Hyponatremia is the most frequent electrolyte disorder in critically ill neurological patients. The major differential diagnoses in this situation are the syndrome of inappropriate antidiuretic hormone secretion, marked by inappropriate retention of free water, and cerebral salt wasting, characterized by excessive urinary loss of sodium and resulting in polyuria and extracellular volume contraction. Cerebral salt wasting is a syndrome of hyponatremia due to increased urine output and excessive natriuresis described in patients with central nervous system disease. Although cerebral salt wasting has been well described in neurosurgical patients, data regarding pediatric patients is sparse. We present a 34-month-old boy with lissencephaly who developed cerebral salt wasting after brain biopsy. The patient was treated with hypertonic saline and multiple antiepileptic drugs. Fludrocortisone supplementation effectively treated cerebral salt wasting.
Turkish neurosurgery 01/2010; 20(1):100-2. · 0.62 Impact Factor
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Karin R Engelhardt,
Sean McGhee,
Sabine Winkler,
Atfa Sassi,
Cristina Woellner,
Gabriela Lopez-Herrera,
Andrew Chen,
Hong Sook Kim,
Maria Garcia Lloret,
Ilka Schulze, [......],
Maria C Pietrogrande,
Mehdi Yeganeh,
Zeina Baz,
Salem Al-Tamemi,
Christoph Klein,
Jennifer M Puck,
Steven M Holland,
Edward R B McCabe,
Bodo Grimbacher,
Talal A Chatila
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ABSTRACT: The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60% to 70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was reported to have a homozygous TYK2 mutation. In the remaining patients with hyper-IgE syndrome, the genetic etiology has not yet been identified.
We aimed to identify a gene that is mutated or deleted in autosomal recessive hyper-IgE syndrome.
We performed genome-wide single nucleotide polymorphism analysis for 9 patients with autosomal-recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with 12 patients from 7 additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal-recessive hyper-IgE syndrome.
Subtelomeric biallelic microdeletions were identified in 5 patients at the terminus of chromosome 9p. In all 5 patients, the deleted interval involved dedicator of cytokinesis 8 (DOCK8), encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of patients without large deletions revealed 16 patients from 9 unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, and single exon deletions and microdeletions. DOCK8 deficiency was associated with impaired activation of CD4+ and CD8+T cells.
Autosomal-recessive mutations in DOCK8 are responsible for many, although not all, cases of autosomal-recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T-cell activation and T(h)17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE.
The Journal of allergy and clinical immunology 12/2009; 124(6):1289-302.e4. · 9.17 Impact Factor
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Ulrich Salzer,
Carla Neumann,
Jens Thiel,
Cristina Woellner,
Qiang Pan-Hammarström,
Vassilis Lougaris,
Tina Hagena,
Johannes Jung,
Jennifer Birmelin,
Likun Du, Ayse Metin,
David A Webster,
Alessandro Plebani,
Viviana Moschese,
Lennart Hammarström,
Alejandro A Schäffer,
Bodo Grimbacher
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ABSTRACT: Common variable immunodeficiency (CVID) comprises a heterogeneous group of primary antibody deficiencies with complex clinical and immunological phenotypes. The recent discovery that some CVID patients show monogenic defects in the genes encoding ICOS, TACI or CD19 prompted us to investigate several functional candidate genes in individuals with CVID.
The exonic, protein coding regions of the genes encoding: APRIL, BCMA, IL10, IL10Ralpha, IL10Rbeta, IL21, IL21R, and CCL18, were analyzed primarily in familial CVID cases, who showed evidence of genetic linkage to the respective candidate gene loci and CVID families with a recessive pattern of inheritance. Two novel SNPs were identified in exon 5 and exon 8 of the IL21R gene, which segregated with the disease phenotype in one CVID family. Eleven additional SNPs in the genes encoding BCMA, APRIL, IL10, IL10Ralpha, IL21 and IL21R were observed at similar frequencies as in healthy donors.
We were unable to identify obvious disease causing mutations in the protein coding regions of the analyzed genes in the studied cohort.
BMC Immunology 02/2008; 9:3. · 2.53 Impact Factor
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ABSTRACT: Familial haemophagocytic lymphohistiocytosis (FHL) is a rare, autosomal recessive disorder. We report two newborn siblings diagnosed as FHL.
Annals of Tropical Paediatrics International Child Health 10/2007; 27(3):231-5. · 0.90 Impact Factor
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Francesco Marangoni,
Sara Trifari,
Samantha Scaramuzza,
Cristina Panaroni,
Silvana Martino,
Luigi D Notarangelo,
Zeina Baz, Ayse Metin,
Federica Cattaneo,
Anna Villa,
Alessandro Aiuti,
Manuela Battaglia,
Maria-Grazia Roncarolo,
Loïc Dupré
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ABSTRACT: A large proportion of Wiskott-Aldrich syndrome (WAS) patients develop autoimmunity and allergy. CD4(+)CD25(+)FOXP3(+) natural regulatory T (nTreg) cells play a key role in peripheral tolerance to prevent immune responses to self-antigens and allergens. Therefore, we investigated the effect of WAS protein (WASP) deficiency on the distribution and suppressor function of nTreg cells. In WAS(-/-) mice, the steady-state distribution and phenotype of nTreg cells in the thymus and spleen were normal. However, WAS(-/-) nTreg cells engrafted poorly in immunized mice, indicating perturbed homeostasis. Moreover, WAS(-/-) nTreg cells failed to proliferate and to produce transforming growth factor beta upon T cell receptor (TCR)/CD28 triggering. WASP-dependent F-actin polarization to the site of TCR triggering might not be involved in WAS(-/-) nTreg cell defects because this process was also inefficient in wild-type (WT) nTreg cells. Compared with WT nTreg cells, WAS(-/-) nTreg cells showed reduced in vitro suppressor activity on both WT and WAS(-/-) effector T cells. Similarly, peripheral nTreg cells were present at normal levels in WAS patients but failed to suppress proliferation of autologous and allogeneic CD4(+) effector T cells in vitro. Thus, WASP appears to play an important role in the activation and suppressor function of nTreg cells, and a dysfunction or incorrect localization of nTreg cells may contribute to the development of autoimmunity in WAS patients.
Journal of Experimental Medicine 03/2007; 204(2):369-80. · 13.85 Impact Factor
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ABSTRACT: 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.
Journal of Clinical Immunology 07/2004; 24(4):411-7. · 3.08 Impact Factor
