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An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation.

July 30, 2015 By Manish Butte

An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation.

J Allergy Clin Immunol. 2015 Jul 25;

Authors: Le Guen T, Touzot F, André-Schmutz I, Lagresle-Peyrou C, France B, Kermasson L, Lambert N, Picard C, Nitschke P, Carpentier W, Bole-Feysot C, Lim A, Cavazzana M, Callebaut I, Soulier J, Jabado N, Fischer A, de Villartay JP, Revy P

Abstract
BACKGROUND: Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear. Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities.
OBJECTIVES: We sought to characterize the underlying genetic cause of this syndrome.
METHODS: We performed genome-wide homozygosity mapping, followed by whole-exome sequencing.
RESULTS: Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain. Remarkably, during the course of our study, the patient recovered a normal immunohematologic phenotype. Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell.
CONCLUSIONS: We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects. In addition, we describe one of the few examples of spontaneous in vivo genetic cure of a human immunodeficiency.

PMID: 26220525 [PubMed – as supplied by publisher]

Efficacy of subcutaneous immunoglobulins in primary immunodeficiency with Crohn's-like phenotype: report of a case.

July 30, 2015 By Manish Butte

Efficacy of subcutaneous immunoglobulins in primary immunodeficiency with Crohn’s-like phenotype: report of a case.

Eur Rev Med Pharmacol Sci. 2015 Jul;19(14):2641-2645

Authors: Sanges M, Spadaro G, Miniero M, Mattera D, Sollazzo R, D’Armiento FP, De Palma GD, Pecoraro A, Borrelli F, Genovese A, D’Arienzo A

Abstract
Common variable immune deficiency (CVID) is the most frequent primary immunodeficiency in adults. In CVID, the prevalence of gastrointestinal manifestations ranges between 2 and 50% with a complication-related morbidity second only to that of the respiratory tract. In some cases, clinical and endoscopic features are undistinguishable from those of inflammatory bowel disease (IBD). We describe the case of a 28-year-old man in which a diagnosis of Crohn’s disease was firstly suspected. Subsequently, a diagnosis of Crohn’s-like disease in a patient with CVID was made and a replacement therapy with human normal immunoglobulin intravenously was started. Unfortunately, serum IgG levels remained below 2.0 g/l in pre-infusional controls with persistence of gastrointestinal symptoms and malnutrition despite anti-inflammatory therapy (mesalazine, corticosteroids). Then, the patient began treatment with human normal immunoglobulins administered subcutaneously. The follow-up visits showed a progressive increase in serum IgG. Moreover, the patient reported improvement of gastrointestinal symptoms with reduction of diarrhoea, and laboratory tests showed a progressive and significant improvement. We confirm that therapy with subcutaneously administered immunoglobulins is safe and effective. In addition, our observations indicate that, for patients with CVID and enteropathic complications, replacement therapy with subcutaneous IgG may be the treatment of choice.

PMID: 26221895 [PubMed – as supplied by publisher]

Hyper-IgE syndromes: recent advances in pathogenesis, diagnostics and clinical care.

July 30, 2015 By Manish Butte

Hyper-IgE syndromes: recent advances in pathogenesis, diagnostics and clinical care.

Curr Opin Hematol. 2015 Jan;22(1):12-22

Authors: Farmand S, Sundin M

Abstract
PURPOSE OF REVIEW: This review provides an overview on recent data regarding pathogenesis, diagnostics and clinical care of hyper-IgE syndromes (HIES). HIES are a group of primary immunodeficiencies with overlapping and distinct features, most frequently caused by deficiency in signal transducer and activator of transcription 3 (STAT3) or dedicator of cytokinesis 8 (DOCK8).
RECENT FINDINGS: Particular progress has been made in deciphering the relevance of STAT3 and DOCK8 for B-cell, T-cell and natural killer-cell immunity as well as in understanding allergic features. Multisystemic features of STAT3-deficient HIES, for example, recurrent fractures and osteopenia, a high degree of vasculopathy and brain white matter hyperintensities, have been thoroughly characterized. IgG replacement may add to the clinical care in STAT3-deficient HIES. In DOCK8-deficient HIES, the high morbidity and deaths in early age seem to justify allogeneic hematopoietic stem cell transplantation. New HIES entities have also been reported.
SUMMARY: The recent advances expand our understanding of HIES, and improve the diagnostics and clinical care. Yet, more research is required to fully elucidate the specific infection susceptibilities and lung complications, particularly in STAT3-deficient HIES. Future studies also need to focus on clinical care and treatment of nonimmunologic features of HIES, as well as on exploring curative treatments.

PMID: 25469836 [PubMed – indexed for MEDLINE]

Leukocyte adhesion deficiency type III: clinical features and treatment with stem cell transplantation.

July 29, 2015 By Manish Butte

Leukocyte adhesion deficiency type III: clinical features and treatment with stem cell transplantation.

J Pediatr Hematol Oncol. 2015 May;37(4):264-8

Authors: Stepensky PY, Wolach B, Gavrieli R, Rousso S, Ben Ami T, Goldman V, Rozovsky K, Hanna S, Etzioni A, Weintraub M

Abstract
Leukocyte adhesion deficiency type III (LADIII) is an autosomal recessive disorder that presents with a severe leukocyte adhesion defect and a Glanzmann-type thrombocytopathy. Hematopoietic stem cell transplantation (HSCT)–the only definitive treatment for LADIII–appears to have a high rate of complications. In this study, we describe a new group of patients with LADIII, highlighting further clinical and immunologic aspects of this disease, and reevaluating the effectiveness of HSCT for its treatment. The patients had clinical and laboratory findings consistent with LADIII. Molecular analysis confirmed the presence of a mutation in the kindlin-3 gene. HSCT was carried out in 3 patients and was successful in 2. The diagnosis of LADIII should be considered in all patients who present with recurrent infections and a bleeding diathesis, regardless of the leukocyte count. LADIII is a primary immune deficiency, which can be successfully corrected by bone marrow transplantation if applied early in the course of the disease using appropriate conditioning.

PMID: 25072369 [PubMed – indexed for MEDLINE]

Eosinophilia Associated with Disorders of Immune Deficiency or Immune Dysregulation.

July 27, 2015 By Manish Butte

Eosinophilia Associated with Disorders of Immune Deficiency or Immune Dysregulation.

Immunol Allergy Clin North Am. 2015 Aug;35(3):523-544

Authors: Williams KW, Milner JD, Freeman AF

Abstract
Increased serum eosinophil levels have been associated with multiple disorders of immune deficiency or immune dysregulation. Although primary immunodeficiency diseases are rare, it is important to consider these in the differential diagnosis of patients with eosinophilia. In this review, the clinical features, laboratory findings, diagnosis, and genetic basis of disease of several disorders of immune deficiency or dysregulation are discussed. The article includes autosomal dominant hyper IgE syndrome, DOCK8 deficiency, phosphoglucomutase 3 deficiency, ADA-SCID, Omenn syndrome, Wiskott-Aldrich syndrome, Loeys-Dietz syndrome, autoimmune lymphoproliferative syndrome, immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, Comel-Netherton syndrome, and severe dermatitis, multiple allergies, and metabolic wasting syndrome.

PMID: 26209898 [PubMed – as supplied by publisher]

Should mild hypogammaglobulinemia be managed as severe hypogammaglobulinemia? A study of 389 patients with secondary hypogammaglobulinemia.

July 25, 2015 By Manish Butte

Should mild hypogammaglobulinemia be managed as severe hypogammaglobulinemia? A study of 389 patients with secondary hypogammaglobulinemia.

Eur J Intern Med. 2014 Nov;25(9):837-42

Authors: Blot M, Boyer P, Samson M, Audia S, Devilliers H, Leguy V, Berthier S, Besancenot JF, Lorcerie B, Lakomy D, Bonnotte B

Abstract
BACKGROUND: Although secondary hypogammaglobulinemia is more frequent than primary hypogammaglobulinemia, its etiology and management are poorly described, particularly for mild hypogammaglobulinemia.
METHODS: This retrospective observational study included all adult patients with a gammaglobulin level <6.4g/L on serum electrophoresis identified at Dijon teaching hospital between April and September 2012. Clinico-biological features, etiologies and infectious complications were collected at inclusion and compared between group 1 (gammaglobulin <5g/L, severe hypogammaglobulinemia), and group 2 (gammaglobulin <6.4 and ≥5g/L, mild hypogammaglobulinemia).
RESULTS: Among the 4011 serum electrophoreses, 570 samples from 389 patients had gammaglobulin levels below 6.4g/L: 156 (40%) in group 1 and 233 (60%) in group 2. Mean age±SD was 67 (15) years, and sex ratio was 1.04 (M/F) with no difference between the two groups. An etiology was identified in 79% and 58% of patients in groups 1 and 2, respectively (p<0.0001). The main etiologies were similar in both groups and included malignant hemopathy treated with cytostatic agents (n=129, 33%), smoldering or newly-diagnosed hemopathy without treatment (n=49, 13%) and immunosuppressive treatment (n=91, 23%). The incidence of hypogammaglobulinemia-related infections was 22/100/year, with no significant difference between the two groups (p=0.17). Vaccination coverage against pneumococcus was 33%, and higher in group 1 (46% vs. 24%; p<0.0001). When no cause was known at inclusion, an etiology was discovered in 22/130 patients (17%), 11 in each group.
CONCLUSIONS: Though mild hypogammaglobulinemia does not meet the classical criteria for hypogammaglobulinemia (<5g/L), the etiology and infectious risk are similar. It therefore requires investigation and vaccination.

PMID: 25307285 [PubMed – indexed for MEDLINE]

A case of Griscelli syndrome.

July 25, 2015 By Manish Butte

A case of Griscelli syndrome.

Dermatol Online J. 2014 Nov;20(11)

Authors: Kerketta JA, Lodh M, Mandal K

Abstract
A hallmark of Griscelli syndrome, a rare autosomal recessive disorder, is hair hypopigmentation characterized by a silver-gray sheen and the presence of large clusters of pigment unevenly distributed in the hair shaft. Either a primary neurological impairment or immune abnormalities are associated with this phenotype. We report the case of a 10-year-old child of consanguineous parents. He presented with abdominal pain and fever and was noted to have silvery hair, eyelashes, and eyebrows. Bone marrow studies indicated hemophagocytosis, whilst microscopic examination of the hair showed irregular agglomerations of pigment in hair shafts. The prognosis, treatment, and genetic counseling needs differ considerably among the various forms of Griscelli Syndrome.

PMID: 25419745 [PubMed – indexed for MEDLINE]

Effects of tDCS-induced motor cortex modulation on pain in HTLV-1: a blind randomized clinical trial.

July 25, 2015 By Manish Butte

Effects of tDCS-induced motor cortex modulation on pain in HTLV-1: a blind randomized clinical trial.

Clin J Pain. 2014 Sep;30(9):809-15

Authors: Souto G, Borges IC, Goes BT, de Mendonça ME, Gonçalves RG, Garcia LB, Sá KN, Coutinho MR, Galvão-Castro B, Fregni F, Baptista AF

Abstract
OBJECTIVE: We aimed to evaluate the effects of transcranial direct current stimulation (tDCS) on chronic pain in human T-lymphotropic virus type I-infected patients.
MATERIALS AND METHODS: This is a sham-controlled randomized clinical trial. Twenty participants were randomized to receive active or sham anodal tDCS over the primary motor cortex (M1), with 2 mA, 25 cm electrodes, for 20 minutes on 5 consecutive days. Pain intensity was measured at baseline and after each day of treatment using a Visual Analog Scale. Associated factors such as pain components description, pressure pain threshold, and Timed Up and Go task were also assessed.
RESULTS: Mild adverse events were reported by 100% of patients in the tDCS group and 90% in the sham group. Comparison of daily Visual Analog Scale pain scores from both groups demonstrated a significant effect for the factor Time (P<0.001), but not for Group (P=0.13) or Time×Group interaction (P=0.06). There were 8 (80%) responders (reduction of 50% or more in pain intensity) in the tDCS group and 3 (30%) in the sham group (P=0.03). Both groups demonstrated improvements for most associated factors evaluated. However, there was no difference in between-groups comparison analyses.
CONCLUSIONS: The analysis of the main outcomes in this study did not demonstrate a significant advantage of anodal tDCS applied to M1 in patients with human T-lymphotropic virus type I and chronic pain in comparison with sham tDCS, although secondary analysis suggests some superiority of active tDCS over sham. The large placebo effect observed in this study may explain the small differences between sham versus active tDCS.

PMID: 24300224 [PubMed – indexed for MEDLINE]

Small Bowel Bacterial Overgrowth in Children: A Comprehensive Review.

July 22, 2015 By Manish Butte

Small Bowel Bacterial Overgrowth in Children: A Comprehensive Review.

J Pediatr Gastroenterol Nutr. 2015 Jul 20;

Authors: Sieczkowska A, Landowski P, Kamińska B, Lifschitz C

Abstract
OBJECTIVES: To perform a comprehensive review of the pathogenesis, available diagnostic procedures, prevalence, clinical manifestations and consequences of small bowel bacterial overgrowth (SBBO) as well as treatment options in the pediatric population.
METHODS: A literature search including MEDLINE, PubMed and Web of Science databases was performed.
RESULTS: SBBO is found in a varierty of childhood conditions in which the normal homeostatic mechanisms restricting bacterial colonization in the small bowel are disturbed by congenital or acquired anatomical abnormalities, diminished gastric acid secretion, congenital alteration of intestinal motility or acquired small bowel diseases, or other chronic disorders including primary or acquired immunodeficiency. Data show that SBBO may be an under-recognized cause of pediatric morbidity. Although several diagnostic tests for SBBO determination are available, each has its drawbacks and limitations. Indeed, there is still no “gold standard’ for SBBO diagnosis in the pediatric population. Due to lack of established guidelines and very few published interventional studies that assess the effectiveness of SBBO therapy, treatment of children with SBBO remains empiric and comprises antibiotic or probiotic therapy.
CONCLUSIONS: Further research is needed to determine the clinical impact of SBBO and to establish diagnostic and therapeutic guidelines applicable to children.

PMID: 26196206 [PubMed – as supplied by publisher]

Exome Sequencing Analysis Reveals Variants in Primary Immunodeficiency Genes in Patients With Very Early Onset Inflammatory Bowel Disease.

July 21, 2015 By Manish Butte

Exome Sequencing Analysis Reveals Variants in Primary Immunodeficiency Genes in Patients With Very Early Onset Inflammatory Bowel Disease.

Gastroenterology. 2015 Jul 16;

Authors: Kelsen JR, Dawany N, Moran CJ, Petersen BS, Sarmady M, Sasson A, Pauly-Hubbard H, Martinez A, Maurer K, Soong J, Rappaport E, Franke A, Keller A, Winter HS, Mamula P, Piccoli D, Artis D, Sonnenberg GF, Daly M, Sullivan KE, Baldassano RN, Devoto M

Abstract
BACKGROUND & AIMS: Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed ≤5 y of age, frequently presents with a different and more severe phenotype than older-onset IBD. We investigated whether patients with VEO-IBD carry rare or novel variants in genes associated with immunodeficiencies that might contribute to disease development.
METHODS: Patients with VEO-IBD and parents (when available) were recruited from the Children’s Hospital of Philadelphia from March 2013 through July 2014. We analyzed DNA from 125 patients with VEO-IBD (ages 3 weeks to 4 y) and 19 parents, 4 of whom also had IBD. Exome capture was performed by Agilent SureSelect V4, and sequencing was performed using the Illumina HiSeq platform. Alignment to human genome GRCh37 was achieved followed by post-processing and variant calling. Following functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency <0.1%, and scaled combined annotation dependent depletion scores ≤10. We focused on genes associated with primary immunodeficiencies and related pathways. An additional 210 exome samples from patients with pediatric IBD (n=45) or adult-onset Crohn’s disease (n=20) and healthy individuals (controls, n=145) were obtained from the University of Kiel, Germany and used as control groups.
RESULTS: Four-hundred genes and regions associated with primary immunodeficiency, covering approximately 6500 coding exons totaling > 1 Mbp of coding sequence, were selected from the whole exome data. Our analysis revealed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19.
CONCLUSIONS: In an exome sequence analysis of patients with VEO-IBD and their parents, we identified variants in genes that regulate B- and T-cell functions and could contribute to pathogenesis. Our analysis could lead to the identification of previously unidentified IBD-associated variants.

PMID: 26193622 [PubMed – as supplied by publisher]