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- OPEN ACCESS
- Amit Nahum,
- David Manson, and
- Bo Ngan
X-linked agammaglobulinemia (XLA) is a rare immunodeficiency caused by defects in the Bruton tyrosine kinase (BTK) gene, characterized by impaired B-cell development, reduced immunoglobulin production, and increased susceptibility to bacterial infections at an early age. Some XLA patients show atypical presentations, with most reports concentrating on the diagnosis at a relatively old age. They presented with infections at late age or with unusual pathogens; however, other atypical manifestations have only rarely been reported.Methods: Description of patients with XLA and novel mutations in BTK who presented with atypical manifestations or developed noninfectious complications.Results: Four patients presented unique manifestations unusual for XLA. The first with Granulomatous Dermatitis, the second with acute demyelinating encephalomyelitis, the third with “Crohn's disease like” localized protein-losing enteropathy, and the last patient with idiopathic thrombocytopenic purpura, which is an unexpected finding in a patient devoid of endogenous immunoglobulins. Mutations in BTK were found in all domains of the gene; 1 resulted in a stop codon and 3 were missense mutations.Conclusions: Early recognition of atypical presentations and manifestations of patients with XLA is crucial for timely initiation of life-saving therapy, which may include anti-bacterial and anti-inflammatory treatments in addition to immunoglobulin.Statement of novelty: In this study we present unique inflammatory and autoimmune phenomenons in XLA patients that were not described previously and are somewhat unexpected. These should alert the immunologist for the possibility of XLA diagnosis. - OPEN ACCESS
- Vy H.D. Kim,
- Rae Brager,
- Julia Upton,
- Bo Ngan,
- Andrea Newell,
- Maian Roifman,
- Aleixo M. Muise,
- Susanne M. Benseler,
- Eyal Grunebaum, and
- Chaim M. Roifman
Mutations in IL-10R1, IL-10R2, and IL-10 have been identified in infants with severe colitis. The only possible hope for cure in these conditions is a hematopoietic stem cell transplantation (HSCT). We report here on a patient with IL-10R1 deficiency who suffered severe colitis and arthritis. She received a HSCT from a matched unrelated donor and her post-transplant course was uneventful. She has fully engrafted and her immune reconstitution was complete and robust. Although signs of colitis were completely resolved, arthritis was not reversed by HSCT. She continues to have joint swelling in the knees and inflammatory changes in the wrists. In conclusion, HSCT seems to have reversed colitis, but was insufficient to improve arthritis and possibly other autoimmune manifestations.Statement of novelty: This report describes a successful HSCT in severe infantile colitis caused by mutations in IL-10R1. Yet, the arthritis remains active, suggesting that conditions such as severe rheumatic disorders in childhood may not be reversed by replacement of the hematopoietic system. - OPEN ACCESS
- Bo Ngan,
- Daniele Merico,
- Nufar Marcus,
- Vy H.D. Kim,
- Julia Upton,
- Andrea Bates,
- Joanne Herbrick,
- Thomas Nalpathamkalam,
- Bhooma Thiruvahindrapuram,
- Peter Cox, and
- Chaim M. Roifman
Introduction: Genetic aberrations associated with combined immunodeficiency have been increasingly identified in the past two decades. Yet, there are still 30% of these patients with unidentified genetic cause.Methods: We employed whole genome sequencing to identify the genetic defect leading to combined immunodeficiency. Thymus, gut, and lung tissues were studied using hematoxylin and eosin staining as well as immunohistochemistry.Results: We identified 2 deleterious mutations in the TTC7A gene. Surprisingly, the patient did not have intestinal atresia but suffered repeated infections as well fatal pneumonitis. Dendriform lung ossification developed, which was unique to this case. The patient had typical presentation of combined immunodeficiency including profound lymphopenia, markedly reduced in-vitro response to mitogens, as well as low TRECS. Serum immunoglobulins were also markedly reduced.Conclusion: Mutations in the TTC7A gene can cause combined immunodeficiency with no intestinal atresia and predispose to lung ossification.Statement of novelty: TTC7A mutations can cause profound immunodeficiency without multiple intestinal atresia. We report here for the first time that this defect is associated with dendriform lung ossification. - OPEN ACCESSIntroduction: The transcription factor Signal Transducer and Activator of Transcription 1 (STAT1) is a key element in many of the signalling cascades involved in immune system function. Different mutations in STAT1 are associated with heterogeneous clinical phenotypes that range from early fatality due to overwhelming infection to limited involvement of the mucus membrane with recurrent Candida infections. Multiple genes related to immune function have been associated with the development of hemophagocytic lymphohistiocytosis (HLH), but the association between STAT1 mutation and HLH has not been described in detail.Methods: We report the genetic background of a patient with chronic mucocutaneous candidiasis (CMC) as well as an unusual clinical course.Results: In this study we describe a patient with a mutation in the STAT1 DNA-binding domain and a history of CMC who developed a refractory and fatal case of HLH despite having bone marrow transplantation.Conclusion: We describe a patient with refractory and fatal HLH who was found to have a mutation in the DNA-binding domain of STAT1.Statement of novelty: The association of chronic mucocutaneous candidiasis with HLH.
- OPEN ACCESSIntroduction: For close to half a century immunoglobulin replacement therapy has been the main therapy for patients unable to produce functioning antibodies. To date, both subcutaneous (SC) and intravenous delivery methods have been successful at effectively and safely replacing immunoglobulin. Home intravenous and SC therapy programs have been established and have gained attention, but the true motivation and frequency of switching from traditional hospital-based treatment to these alternatives remains unknown. This study aims to determine the willingness of patients in Canada to switch to a home-based gammaglobulin treatment program by quantifying related experiences and preferences.Methods: A cohort of 169 patients in Ontario currently on hospital-based intravenous immunoglobulin (IVIG) replacement therapy (referral centers or community hospitals) were sent a 2.5 page survey consisting of 25 questions. Data were collected and statistically analyzed using Fisher, χ2, and McNemar tests, where P < 0.05 was considered statistically significant.Results: Ninety-one patients responded and most agreed to consider home therapy regardless of the administration route, based on recommendations from an immunologist (IVIG, P = 0.006; SC, P < 0.001). Patients preferred switching to home IVIG rather than to SC (P = 0.01), but their concerns regarding home healthcare costs were more prominent with IVIG (P = 0.01). The main concern with current intravenous therapy was the overall loss of time (P = 0.0001), whereas for home therapy it was the loss of supervision (P = 0.0009) and possible associated costs. Patients considered home treatment more convenient, as it is less time consuming (P = 0.01), and this was perceived as an improvement in quality of life (P = 0.001). It was considered less convenient because it may be unsafe and (or) more expensive.Conclusion: This survey demonstrates that home intravenous therapy maybe the preferred option for patients with antibody deficiency in Ontario, provided this decision was supported by a specialist in the field, secured supervision was available, and it was not associated with personal expenses.Statement of novelty: The first study to examine patient willingness to try a new route of gammaglobulin administration at home.