Junctional Epidermolysis Bullosa Linked to Homozygous Mutation in LAMC2 Gene: A Case Report With Eosinophil-Rich Inflammatory Infiltrate.

ABSTRACT: Junctional epidermolysis bullosa (JEB) is a rare, incurable, devastating, and mostly fatal congenital genetic disorder characterized by painful blistering of the skin and mucous membranes in response to minor trauma or pressure. JEB is classified roughly into 2 subtypes: JEB-Herlitz is caused by mutations on genes encoding laminin-332. The authors present a patient consulted with a suspicion of primary immunodeficiency due to skin sores that started at the age of 1 month and a history of 3 siblings who died with similar sores, who was diagnosed with JEB-Herlitz after detecting a homozygous LAMC2 gene mutation in WES analysis. Microscopic evaluation of hematoxylin and eosin-stained sections showed vesicle formation with subepidermal separation, which is accompanied by striking neutrophil and eosinophil leukocyte infiltration both in the vesicle and papillary dermis (eosinophil-rich inflammatory infiltrate). Such a histopathological finding has been rarely reported in this condition.

Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency.

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.

ST2 and Reg3α: Can they predict aGvHD, steroid refractoriness and transplant-related mortality in pediatric patients after HSCT?

BACKGROUND/AIM: There are several complications of hematopoietic stem cell transplantation. Without any doubt, most important of these is aGvHD that increases transplant-related mortality. The aim of this study is to investigate whether ST-2 and Reg3α levels measured at an early stage in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation can be individual biomarkers identifying future GvHD and predicting treatment response. MATERIALS AND METHODS: From January 2019 to January 2021, 27 patients undergoing hematopoietic stem cell transplantation for primary immunodeficiency or hematopoietic diseases formed the study group. During their follow-up, the patients were classified into two groups as those developing and those not developing aGvHD. Nineteen healthy volunteers from a similar age group who needed their blood samples drawn for other reasons and who did not have any history of chronic disease, infection or medication use formed the control group. Blood samples of patients scheduled to have allogeneic HSCT were obtained before the administration of the preparative regimen, on Day +7 post-transplant and on the day of diagnosis if they developed aGvHD. Serum samples were stored at -20ºC until the day of processing. ST2 and Reg3α levels were measured using the ELISA method. RESULTS: For patients who developed aGvHD (n = 13), ST2 levels obtained before the transplantation, on Day +7 post-transplant and on the day of aGvHD diagnosis (in patients developing GvHD) were significantly higher compared to the healthy Control Group (p-value <0.05). As regards to the samples obtained on the same days, ST2 levels did not differ significantly among patients who developed and those who did not develop GvHD (n = 14; p-value >0.05). ST2 levels of samples obtained on the days that acute skin and gastrointestinal tract GvHD developed did not differ significantly between these two groups (p-value >0.05). Reg3α levels of the pre-transplant samples, on Day +7 after the transplantation and on the day of aGvHD diagnosis did not show any difference between any of the groups (p-value >0.05). As only two patients died after transplantation, thus correlation of ST2 and Reg3α levels with transplant-related mortality could not be proven. CONCLUSION: The results of this study suggest that ST2 and Reg3α levels are neither diagnostic nor prognostic or predictive biomarkers of aGvHD, steroid resistance or transplant-related mortality in pediatric patients. This study can be regarded as a pilot study because of the small patient population; more research involving a larger patient population is required.

Scales of Magt1 Gene: Novel Mutations, Different Presentations.

Loss-of-function mutations in magnesium transporter 1 (MAGT1) gene cause X-linked magnesium deficiency with Epstein-Barr virus (EBV) infection and neoplasm (X-MEN), a disease with quite diverse clinical and immunological consequences. The phenotypic characteristics of the initially described patients included CD4+ T cell lymphopenia, immune deficiency, EBV viremia, and EBV-related lymphoproliferative disease. To date, a total of 25 patients have been reported. The spectrum of the MAGT1 defect ranges from other viral infections (HSV, VZV, CMV, MCV) and sinopulmonary bacterial infections, autoimmune diseases, non-EBV driven lymphoproliferative disease, Castleman disease, HHV8+ Kaposi's sarcoma, vasculitis (Kawasaki) to glycosylation defects in new patients. Here, we report 2 patients from two different families with novel MAGT1 mutations and different clinical features. The first patient presented with B cell lymphoma and low IgM level without recurrent infections. The second patient presented with recurrent upper respiratory tract infections, Kawasaki-like disease, hypogammaglobulinemia, and T cell lymphopenia. X-MEN disease is the first phenotype identified due to MAGT1 mutation. The identification of new mutations and atypical presentations will clarify whether there is a relationship between the genotype and the phenotype and the characteristics of the disease.

A rare case of syndromic severe congenital neutropenia: JAGN1 mutation.

BACKGROUND: Neutrophils are essential innate cells to fight bacterial and fungal pathogens. Jagunal homolog 1 (JAGN1) mutations were recently defined as rare genetic defects causing severe congenital neutropenia. JAGN1 participates in the secretory pathway and is required for granulocyte colony-stimulating factor receptormediated signalling. This gene is required for normal ultrastructure and granulation of endoplasmic reticulum of myeloid progenitor cells. Its defect is related to increased predisposition to apoptosis. In the literature, a few cases have been reported with congenital anomalies such as cardiac and renal anomalies. CASE: Here we report a patient in which JAGN1 deficiency was found after several years. Apart from syndromic facial appearance we were unable to detect any other systemic malformations. CONCLUSION: The causes of multisystemic features of mutations in JAGN1 gene remain unknown. JAGN1 mutations must be considered in patients with severe congenital neutropenia especially with facial dismorphism even in the absence of systemic manifestations.

Clinical Features and Outcomes of 23 Patients with Wiskott-Aldrich Syndrome: A Single-Center Experience

Objective: Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency characterized by microthrombocytopenia, eczema, and recurrent infections. We aimed to evaluate the clinical features and outcomes of a WAS cohort. Materials and Methods: We retrospectively evaluated the clinical courses, immunological features, treatments, and outcomes in a total of 23 WAS patients together with data related to 11 transplanted cases among them between 1982 and 2019. Results: Before admission, 11 patients (48%) were misdiagnosed with immune thrombocytopenia. WAS scores were mostly 4 or 5. Eleven patients were transplanted and they had an overall survival rate of 100% during a median follow-up period of 8.5 years (range: 8 months to 20 years). Five patients who were not transplanted died at a median of 7 years (range: 2-26 years). Nontransplanted patients had high morbidity due to organ damage, mostly caused by autoimmunity, bleeding, and infections. Two novel mutations were also defined. Conclusion: All male babies with microthrombocytopenia should be evaluated for WAS. Hematopoietic stem cell transplantation should be performed at the earliest age with the best possible donors.