Recurrent Demyelinating Episodes as Sole Manifestation of Inherited CD59 Deficiency

Defects in the regulatory components of the complement system can lead to inflammatory diseases. We present a patient who had four episodes of demyelination in the central nervous system as the only manifestation of inherited CD59 deficiency. Relapsing encephalopathy partially responsive to intravenous immunoglobulin and steroid treatments on the background of parental consanguinity suggested an inherited immune dysregulation. Next generation sequencing revealed homozygous mutation in the CD59 gene, confirmed by lack of CD59 expression on flow cytometry. Inherited CD59 deficiency is a rare autosomal recessive condition characterized by chronic hemolysis, recurrent strokes, and relapsing peripheral demyelinating neuropathy mimicking Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy. Recurrent central nervous system demyelinating episodes as the only manifestation has not been reported to date in inherited CD59 deficiency. This entity should be considered in the differential diagnosis of patients with early-onset recurrent neurological diseases with central or peripheral origin

In case of recurrent wheezing and bronchiolitis: Think again, it may be a primary immunodeficiency

Background: Wheezing, starting early in life, is a heterogeneous medical condition caused by airway obstruction due to different underlying mechanisms. Primary immunodeficiencies are also among the risk factors that cause wheezing and recurrent bronchiolitis. ADA deficiency is a primary immunodeficiency, also a rare metabolic disease associated with multisystemic clinical findings. Objective: This report will be helpful for adressing the importance of thinking primary immunodeficiency in case of wheezing and recurret bronchiolitis. Methods: The patient was diagnosed by using a targeted next generation sequencing PID panel. Lymphocyte subsets were measured by flow-cytometry. Results: Here we present an infant with ADA deficiency who admitted with wheezing and recurrent bronchiolitis as the first presentation. He was found to have wheezing, relative CD4+ T cell deficiency, and prolonged neutropenia. Conclusion: Primary immunodeficiencies including ADA deficiency should be considered in infants with wheezing, recurrent bronchiolitis, lymphopenia and neutropenia

Differential diagnosis of primary immunodeficiency in patients with BCGitis and BCGosis: A single-centre study

BCG infections occur more frequently in patients with underlying primary immunodeficiency disease (PIDD). In this study, we aimed to evaluate the ratio of PIDD in the patients with BCG infections. Patients with BCG infections were analyzed in a tertiary referral centre in the 2015-2020 period. Forty-seven patients with BCGitis/BCGosis were evaluated; thirty-four (72.3%) had BCGitis, and 13 (27.7%) had BCGosis. Common tissue and organs affected are lymph nodes (57.4%), skin and subcutaneous tissue (48.9%), lungs (23.4%) and liver (17%). PIDD was shown in 26 patients (55.3%), including 92.3% of patients with BCGosis and 41.2% of patients with BCGitis. Ten patients had Mendelian susceptibility to Mycobacterial disease (MSMD) (21.2%), six had predominantly antibody deficiency (PAD) (12.7%), five had severe combined immunodeficiency (SCID) (10.6%), three had CGD (6.3%), and two had CID (4.2%). Mortality was reported in two patients (4.2%) with CID (ZAP70 deficiency (n = 1) and PIK3R1 deficiency (n = 1)). Parental consanguinity (84%), axillary lymphadenopathy (65%), mycobacterial lung disease (42%), hepatomegaly (30%) and growth retardation (19%) were significantly high in patients with PIDD diagnosis. Isolated vaccination site infection was also recorded in patients with PIDD (CID (n = 1), SCID (n = 1), PAD (n = 5)). BCG vaccination should be planned with caution for the cases with suspected PIDD. This study indicates that almost all patients (92.3%) with BCGosis and one in every two patients (41.2%) with BCGitis have an underlying PIDD. Parental consanguinity, axillary lymphadenopathy, mycobacterial lung disease, hepatomegaly and growth retardation (19%) are important clinical features in the differential diagnosis of PIDD

A Patient With AIRE Mutation Who Presented With Severe Diarrhea and Lung Abscess

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (polyglandular endocrinopathy type 1) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene (AIRE). The major clinical features of APECED are hypoparathyroidism, adrenal insufficiency (Addison disease), and chronic mucocutaneous candidiasis. This disease is also associated with multiple other and uncommon autoimmune (autoimmune hepatitis, autoimmune enteropathy, atrophic gastritis with or without pernicious anemia, gonadal failure, diabetes mellitus, hypothyroidism, functional hyposplenism), ectodermal (alopecia and vitiligo), and inflammatory (intestinal lung disease, nephritis) features. Here, we report a case of a 13-year-old Turkish boy who presented wih enteropathy and lung abscess. Molecular genetic analysis demonstrated a homozygous frameshift mutation (p.Asp70fs, c.208_209insCAGG) in exon 2, in AIRE gene. APECED may present with severe, life-threatening infections due to functional hyposplenism. Multidisciplinary approach, careful follow-up, and molecular genetic studies are needed

Clinical and laboratory findings in patients with leukocyte adhesion deficiency type I: A multicenter study in Turkey

Leukocyte adhesion deficiency type I is a rare primary immunodeficiency disorder characterized by mutations in the ITGB2 gene encoding CD18. We present clinical and immunological features of 15 patients with leukocyte adhesion deficiency type 1 (LAD-1). Targeted next-generation sequencing was performed with either a primary immunodeficiency gene panel comprising 266 genes or a small LAD-panel consisting of five genes for genetic analysis. To measure the expression level of integrins on the leukocyte surface, flow cytometry analysis was performed. The median age of the patients at diagnosis was 3 (1–48) months. Eleven (73%) of the 15 patients had a LAD-1 diagnosis in their first 6 months and 14 (93%) patients had consanguineous parents. Delayed separation of the umbilical cord was present in 80% (n = 12) of the patients in our cohort, whereas omphalitis was observed in 53% (n = 8) of the patients. Leukocytosis with neutrophil predominance was observed in 73% (n = 11) patients. Nine distinct variants in the ITGB2 gene in 13 of the 15 patients with LAD-1 were characterized, two of which (c.305_306delAA and c.779_786dup) are novel homozygous mutations of ITGB2. Four unrelated patients from Syria had a novel c.305_306delAA mutation that might be a founder effect for patients of Syrian origin. Four (27%) patients underwent hematopoietic stem cell transplantation. Two patients died because of HSCT complications and the other two are alive and well. Early differential diagnosis of the patients is critical in the management of the disease and genetic evaluation provides a basis for family studies and genetic counseling

Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency.

Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5-7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis