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  • FREE ACCESS
    Lung histopathology evaluation of an X-MAID patient with a novel mutation in MSN
    LymphoSign Journal • Vol. 10 • No. 1 • pp. 1 - 6
    Background: The cell cytoskeleton is regulated by the ezrin-radixin-moesin (ERM) family of proteins, forming links between transmembrane proteins and the underlying actin cytoskeleton. Phosphorylation and activation of these proteins enable interactions with partners critically involved in shape regulation, such as actin filaments, transmembrane proteins, and scaffolding proteins. The MSN gene encodes moesin, which is ubiquitously expressed in lungs, spleen, kidney, endothelial cells of vessels, lymphocytes, and neutrophils. Deficiency or dysregulation of moesin, called X-linked moesin-associated immunodeficiency (X-MAID), is characterized by severe leukopenia affecting T cells, B cells, and neutrophils. To date, the clinical picture of patients with X-MAID is variable.Aim: We describe the presentation, immune-workup, and lung histopathology findings of a young male patient with X-MAID and multi-organ involvement, whose severe pulmonary vein stenosis necessitated a double lung transplant.Methods: A thorough review of the patient’s chart was performed.Results: The patient presented with a history of recurrent respiratory tract infections, oral thrush, and 3 major bacterial infections requiring admission and antibiotic therapy. His immune evaluation was remarkable for low T cells, and normal numbers of B and NK cells. At age 4 years he underwent a double lung transplant due to severe pulmonary vein stenosis and pulmonary hypertension. He further developed chronic kidney injury post-transplant. Clinical trio whole exome sequencing revealed a novel hemizygous variant in the MSN gene (c.278dupT; p.L93FfsX21), predicted to cause loss-of-function in moesin. Histologic evaluation of the lung tissue before transplantation identified profound abnormalities in alveoli formation.Conclusion: Patients with moesin deficiency may present during infancy or childhood with a severe form of the disease, including combined immunodeficiency with lymphopenia and neutropenia, while adults may have a milder clinical picture. The novel MSN mutation described here adds to the known spectrum of disease and highlights the non-redundant functions of moesin, particularly in the lung.Statement of Novelty: We report the first lung histopathological description of an X-MAID case, in a pediatric patient with recurrent infections, cytopenia, and autoimmunity who underwent a double lung transplant.
  • OPEN ACCESS
    Transcervical thymic biopsy in the immunodeficient child
    LymphoSign Journal • Vol. 6 • No. 4 • pp. 141 - 147
    Objective: The objectives of this study are to present a case series of immunodeficient children who underwent a transcervical thymic biopsy and to describe the transcervical approach to the thymus gland.Design: Case series.Setting: Pediatric otolaryngology practice in an academic setting.Patients: Consecutive sample of immunodeficient children (≤18 years old) who underwent thymic biopsies from 1996 to 2019 for the purpose of confirming or excluding profound T cell immunodeficiency.Intervention: Diagnostic transcervical thymic biopsy.Results: A total of 14 patients with atypical combined immunodeficiency underwent the procedure during the study period, with minimal post-operative complication. The thymus was found to be abnormal histologically in 9 children and normal in another 5 patients. In all cases, thymus morphology helped define the extent of the immunodeficiency, resulting in either supporting a decision to perform a bone marrow transplant (8 patients) or avoid this high risk procedure (3 patients).Conclusion: Thymus biopsy is helpful in the characterization of childhood immunodeficiency and provides critical information that affects the medical management. The transcervical approach to the thymus is feasible in children and can be accomplished with minimal morbidity.Statement of novelty: Biopsies of the thymus have assisted in the characterization of new entities of primary immunodeficiency.
  • OPEN ACCESS
    The effects of STAT1 dysfunction on the gut
    LymphoSign Journal • Vol. 3 • No. 1 • pp. 19 - 33
    Introduction: Mutations in the signal transducer and activator of transcription1 (STAT1) have been associated with a variety of clinical patterns. Interestingly patients with heterozygous mutations in the DNA binding domain (DBD) of STAT1 suffer acute and chronic colitis.Methods: To further analyze the role of STAT1 deficiency in intestinal inflammation, we employed protein expression analysis of total and activated STAT1 in intestinal biopsy samples from 2 patients with heterozygous mutations in the DBD of the STAT1 gene.Results: Both patients showed clinical and histological features of colitis. Total and activated STAT1 were decreased in duodenal and colonic enterocytes, and total STAT1 was found to be mislocalized in aggregates subapically. In addition, intestinal biopsy samples showed decreased numbers of lymphocytes. Patient-derived lymphoblasts demonstrated lack of viability and high susceptibility for cell death.Conclusion: STAT1 expression and distribution in the gut of patients with mutations in the DBD are abnormal, suggesting a primary role of STAT1 dysfunction in enterocytes in addition to the secondary effect of aberrant inflammation.Statement of novelty: Colitis associated with STAT1 mutations appears to have unique features distinct from typical inflammatory bowel disease.
  • OPEN ACCESS
    Atypical presentation and manifestations in X-linked agammaglobulinemia patients with novel BTK mutations
    LymphoSign Journal • Vol. 2 • No. 2 • pp. 75 - 83
    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
    Hematopoietic stem cell transplantation completely reversed colitis but not arthritis in IL-10Rα deficiency
    LymphoSign Journal • Vol. 1 • No. 2 • pp. 77 - 86
    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
    Mutations in tetratricopeptide repeat domain 7A (TTC7A) are associated with combined immunodeficiency with dendriform lung ossification but no intestinal atresia
    LymphoSign Journal • Vol. 01 • No. 01 • pp. 10 - 26
    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.
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