Case Of Primary Immunodeficiency Research Articles

A case of primary immunodeficiency with immune dysregulation: features of clinical manifestation and diagnostic difficulties

A case of primary immunodeficiency with immune dysregulation: features of clinical manifestation and diagnostic difficulties

A case of Wiskott — Aldrich syndrome in an infant

Wiskott — Aldrich syndrome (WAS) is a rare, X-linked combined disease with immunodeficiency caused by mutations in the WAS gene that encodes the WAS protein (WASp). Manifestations range from a relatively mild form of the disease (intermittent X-linked thrombocytopenia), characterized by thrombocytopenia with or without minor immunodeficiency, to a severe form with deep immunodeficiency, episodes of bleeding, the development of autoimmunity and an increased risk of malignancy. Many patients have intermediate degrees of severity. It is precisely this heterogeneity in the clinical spectrum that makes it difficult to make a primary diagnosis of WAS. The article presents a clinical case of primary immunodeficiency detected in a 2-month-old child.

Progressive multifocal leukoencephalopathy in a patient with novel mutation in the RAC2 gene: a case report

BackgroundProgressive multifocal leukoencephalopathy is a rare demyelinating disease that is often secondary to lytic destruction of oligodendrocytes and, to a lesser extent, to astrocytes’ response to human neurotrophic John Cunningham polyomavirus. Any underlying congenital disorder of primary or secondary immunodeficiency may predispose to virus infection and possible invasion of the brain. We present the first reported case of progressive multifocal leukoencephalopathy due to a mutation in the RAC2 gene.Case presentationWe describe the case of a 34-year-old Iranian man with recurrent infections from the age of 2 years, along with other disorders such as nephritic syndrome, factor XI deficiency, and hypogammaglobulinemia. He was treated regularly with intravenous immunoglobulin from the age of 10 years with a diagnosis of common variable immune deficiency. Genetic testing confirmed a novel homozygous mutation in the RAC2 gene in the patient. Owing to the onset of neurological symptoms a few months ago, the patient was completely avaluated, which confirmed the diagnosis of PML. Despite all efforts, the patient died shortly after progression of neurological symptoms.ConclusionsAccording to previous studies, progressive multifocal leukoencephalopathy has been associated with 26 cases of primary immunodeficiency. Our patient presents a new case of primary immunodeficiency with progressive multifocal leukoencephalopathy. Accurate examination of these cases can help us to gain insight into the immune response to John Cunningham virus and better treat this potentially deadly disease.

A Multi-Omics Common Data Model for Primary Immunodeficiencies.

Primary Immunodeficiencies (PIDs) are associated with more than 400 rare monogenic diseases affecting various biological functions (e.g., development, regulation of the immune response) with a heterogeneous clinical expression (from no symptom to severe manifestations). To better understand PIDs, the ATRACTion project aims to perform a multi-omics analysis of PIDs cases versus a control group patients, including single-cell transcriptomics, epigenetics, proteomics, metabolomics, metagenomics and lipidomics. In this study, our goal is to develop a common data model integrating clinical and omics data, which can be used to obtain standardized information necessary for characterization of PIDs patients and for further systematic analysis. For that purpose, we extend the OMOP Common Data Model (CDM) and propose a multi-omics ATRACTion OMOP-CDM to integrate multi-omics data. This model, available for the community, is customizable for other types of rare diseases (https://framagit.org/imagine-plateforme-bdd/pub-rhu4-atraction).

Targeted RNAseq Improves Clinical Diagnosis of Very Early-Onset Pediatric Immune Dysregulation

Despite increased use of whole exome sequencing (WES) for the clinical analysis of rare disease, overall diagnostic yield for most disorders hovers around 30%. Previous studies of mRNA have succeeded in increasing diagnoses for clearly defined disorders of monogenic inheritance. We asked if targeted RNA sequencing could provide similar benefits for primary immunodeficiencies (PIDs) and very early-onset inflammatory bowel disease (VEOIBD), both of which are difficult to diagnose due to high heterogeneity and variable severity. We performed targeted RNA sequencing of a panel of 260 immune-related genes for a cohort of 13 patients (seven suspected PID cases and six VEOIBD) and analyzed variants, splicing, and exon usage. Exonic variants were identified in seven cases, some of which had been previously prioritized by exome sequencing. For four cases, allele specific expression or lack thereof provided additional insights into possible disease mechanisms. In addition, we identified five instances of aberrant splicing associated with four variants. Three of these variants had been previously classified as benign in ClinVar based on population frequency. Digenic or oligogenic inheritance is suggested for at least two patients. In addition to validating the use of targeted RNA sequencing, our results show that rare disease research will benefit from incorporating contributing genetic factors into the diagnostic approach.

Общая вариабельная иммунная недостаточность: сложности своевременной диагностики (клинический случай)

Common variable immunodeficiency (CVID) belongs to the group of primary immunodeficiencies with a predominant deficiency in antibody synthesis and the most common diagnosis among clinically significant cases of primary immunodeficiency in adults. The main laboratory criterion for this disease is considered to be hypogammaglobulinemia (a decrease in the level of IgG less than 4.5 g/l with a decrease in the level of IgA, with/without a decrease in the level of IgM). Clinical manifestations of CVID are diverse: infectious syndrome (chronic infections of the lower respiratory tract, sinusitis, otitis, infectious diarrhea, septic arthritis), autoimmune syndrome (cytopenias, systemic rheumatic diseases), non-infectious pathology of the gastrointestinal tract (celiac-like or IBD-like syndromes , nodular hyperplasia of the mucosa), interstitial lung diseases, pathological non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly), oncological diseases, the formation of non-caseating granulomas in the internal organs). Due to the lack of a typical clinical picture, the diagnosis of CVID in adults is often made many years late, especially if the clinical picture is dominated by non-infectious manifestations. The article presents a clinical case when the patient had recurrent lymphadenopathy as the main symptom for several years. After examination by various specialists, she was referred to an immunologist because hypoproteinemia and a sharp decrease in the gamma fraction of globulins have been revealed. An immunological study revealed agammaglobulinemia and a pronounced imbalance of T-lymphocyte subpopulations (a significant decrease in the number of CD4+ cells and an increase in CD8+ cells). The clinical significance of T-lymphocyte disorders in CVID, the need for treatment with adequate doses of intravenous immunoglobulins are discussed.

Analysis of familial cases of primary immunodeficiency in the context of genetic counseling

Primary immunodeficiencies (PID) are caused by defects in genes of immune system. The mutations may occur de novo or can be inherited. The frequency of familial PID cases varies in different populations and depends on multiple factors. The aim of this study was to analyze familial PID cases among pediatric patients from NMRCPHOI D. Rogachev. The study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI. 1075 children from 1020 families with molecular PID diagnosis were analyzed retrospectively. One hundred and forty-six children had at least one relative with the same disorder; mutations were identified in 31 PID’s genes. The frequency of familial cases was 13.6%. The proportion of families with two or more affected children was 5.4%. Patients born in a consanguineous marriage made up 3% of the observed children. Autosomal dominant PID were typical for families with affected adult relatives. Because of the high amount of familial cases, all parents of children with PID as well as adult PID patients of childbearing age should seek a familial genetic counselling immediately after the corresponding diagnosis. Patients whose PID diagnosis has not been genetically verified, should be urgently tested to find an underlying molecular genetic cause of the disease. Prenatal/preimplantation diagnostic and screening of their close relatives are very important in these families.

Створення онлайн-тесту для виявлення в дітей підозри на вроджені помилки імунітету

As of 2020, more than 400 nosologies of primary immunodeficiencies are known. For most children with this pathology, the key immunological diagnosis remains unclear due to the lack of pathognomonic symptoms, as well as low medical alertness due to the relative rarity of these diseases. Primary immunodeficiencies are not fatal if diagnosed early, moreover, they are treatable with the possibility of a full life or complete recovery. Today, information technology has become an integral part of everyday life. The ability to evaluate a clinical patient record online is a modern important step. Purpose — to create an online test, available to both physicians and patients, to detect suspicious cases of primary immunodeficiencies in children based on possible clinical manifestations. Material and methods. Collection and analysis of a child's clinical record on suspicious manifestations of primary immunodeficiency, age and gender comparisons using web technologies. (PHP, MySQL). Results. International and Ukrainian developments of clinical criteria for suspected primary immunodeficiency in a child have been transformed into an online test containing 35 clinical inquiries to a child's parents or attending physician, followed by analysis of a child's gender and age. As a result, the test user receives the result of the alertness level in terms of urgency to consult a pediatric immunologist. Conclusions. The immunological online test showed considerable interest, a high detection rate of suspicious cases of primary immunodeficiency. The test can be used with patients who come for an appointment or with hospital patients. The study was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the institution specified in the work. Informed consent was obtained from the parents of the children for the research. The authors declare no conflicts of interest. Key words: pediatric immunology, primary immunodeficiencies, online, test, clinical criteria.

Gene analysis of seven cases of primary immunodeficiency.

BackgroundPrimary immune deficiency diseases (PID) are a group of potentially serious disorders in which inherited defects in the immune system lead to increased infections. This paper explores the clinical characteristics and pathogenic gene mutation of PID.MethodsThe clinical data, clinical manifestations, and gene sequencing results of seven children were analyzed.ResultsAmong the seven children, six were male, and one was female, aged from 4 months to 13 years old. All of them had a history of repeated infection and pneumonia. High throughput sequencing (NGS) showed that the BTK gene of case 1 had c.1921c > t mutation; the BTK gene of case 2 had c.906-908del splice site mutation; the BTK gene of case 3 had c.718delg mutation; the cybb gene of case 4 had c.469c > t mutation; the IL2RG gene of case 5 had c.202g > A mutation; the STAT1 gene of case 6 had c.854a > G mutation; the case 7 had c.718delg mutation. There was c.1154c > t mutation in the STAT1 gene. Cases 1, 3, 6 and 7 were new mutations, and cases 2, 4, and 5 were inherited from mothers.ConclusionsIn clinical cases of children with recurrent infection, the immunologic index is abnormal, so we need to be highly aware of the possibility of PID, and timely high-throughput sequencing is helpful for the diagnosis.

Primary Immunodeficiency Diseases and Bacillus Calmette-Guérin (BCG)-Vaccine–Derived Complications: A Systematic Review

Bacillus Calmette-Guérin (BCG) vaccine is a live attenuated bacterial vaccine derived from Mycobacterium bovis, which is mostly administered to neonates in regions where tuberculosis is endemic. Adverse reactions after BCG vaccination are rare; however, immunocompromised individuals and in particular patients with primary immunodeficiencies (PIDs) are prone to develop vaccine-derived complications. To systematically review demographic, clinical, immunologic, and genetic data of PIDs that present with BCG vaccine complications. Moreover, we performed a meta-analysis aiming to determine the BCG-vaccine complications rate for patients with PID. We conducted electronic searches on Embase, Web of Science, PubMed, and Scopus (1966 to September 2018) introducing terms related to PIDs, BCG vaccination, and BCG vaccine complications. Studies with human subjects with confirmed PID, BCG vaccination history, and vaccine-associated complications (VACs) were included. A total of 46 PIDs associated with BCG-VAC were identified. Severe combined immunodeficiency was the most common (466 cases) and also showed the highest BCG-related mortality. Most BCG infection cases in patients with PID were reported from Iran (n= 219 [18.8%]). The overall frequency of BCG-VAC in the included 1691 PID cases was 41.5% (95% CI, 29.9-53.2; I2= 98.3%), based on the results of the random-effect method used in this meta-analysis. Patients with Mendelian susceptibility to mycobacterial diseases had the highest frequency of BCG-VACs with a pooled frequency of 90.6% (95% CI, 79.7-1.0; I2= 81.1%). Several PID entities are susceptible to BCG-VACs. Systemic neonatal PID screening programs may help to prevent a substantial amount of BCG vaccination complications.

A case of primary immunodeficiency: hyper IgM syndrome

Hyper IgM syndrome are group to disorders characterized by elevated serum level of IgM and low or absent serum levels of IgG, IgA and IgE the mechanism of HIGM is immunoglobulin Class-Switch Recombination (CSR) failure and Somatic Hyper Mutation (SHM). This diagnosis should be considered in any patient presenting with hypogammaglobulinemia, with low or absent IgG and IgA and normal or elevated IgM level. In the present case report, this was a 6-year-old male child who had history of recurrent respiratory tract infections who presented with otitis media and persistent fever spikes. Immunoglobulin studies revealed a pattern consistent with hyper IgM.

DOCK8 mutation diagnosed using whole-exome sequencing of the dried blood spot-derived DNA: a case report of an Iraqi girl diagnosed in Japan

BackgroundDedicator of cytokinesis 8 (DOCK8) deficiency (MIM #243700) is a rare disease, leads to a combined primary immunodeficiency (PID), and accounts for the autosomal recessive-hyper immunoglobulin E syndrome (AR-HIES). DOCK8 deficiency status characterizes by recurrent infections, atopy, and risk of cancer. Lymphoproliferative disease complicating PID, is difficult to diagnose. Our aim is to present a rare case of PID, and to the best of our knowledge, she is the first case of DOCK8 deficiency from Iraq. The genetic diagnosis was carried out in Japan using dried blood spot-based DNA transfer and whole-exome sequencing.Case presentationAn 11-year-old Iraqi girl, of double first-cousin-parents, had a history of severe eczema, food allergy, and repeated infections. She presented with a jaw mass, bilateral cervical and axillary lymphadenopathy, and immunoglobulin (Ig) assays of 20, 3.3 and 1.7-fold above maximum normal level for age of IgE, IgA and IgG, respectively, along with a low IgM, eosinophilia and lymphopenia. Based on the jaw mass biopsy, non-Hodgkin lymphoma was suggested in Iraq, whereas histopathological re-evaluation in Japan revealed the diagnosis of a polyclonal reactive proliferation spectrum of lymphoproliferative disorders/plasmacytic hyperplasia, complicating PID. Whole-exome sequencing supported the diagnosis of PID by identifying a homozygous DOCK8 mutation with previously reported pathogenicity (NM_203447:c.3332delT, p.Phe1113Leufs*2), that may be attributed to consanguinity.ConclusionsInternational collaboration using an effective DNA transportation technique and next-generation sequencing was the key to pinpoint the diagnosis of DOCK8 deficiency. Our case asserted that careful pathogenetic evaluation, in an advanced setting, was crucial for ruling out the neoplastic process. Pediatricians in areas with a high prevalence of consanguinity marriage should have a high index of suspicion of DOCK8 deficiency in patients with recalcitrant eczema, and frequent respiratory and skin infectious episodes.

Castleman Disease in a Patient with Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a primary immunodeficiency due to a disorder of the adaptive immune system which causes hypogammaglobulinemia and therefore an increased susceptibility to infection; noninfectious, inflammatory conditions including systemic autoimmunity and lymphoproliferative complications are also commonly associated with CVID. Castleman disease (CD) is a systemic disease clinically characterized by diffuse lymphadenopathy, splenomegaly, anemia, and systemic inflammatory symptoms. This makes CD a great mimicker of more common benign and malignant masses in the neck, chest, abdomen, and pelvis. A novel case of primary immunodeficiency (CVID) in a middle-aged woman, who developed multicentric CD (MDC) with splenomegaly, is described. The authors suggest that the onset of MCD and of the correlated splenomegaly was due to incorrect management of the hypogammaglobulinemia as immunoglobulin G (IgG) levels were not kept within normal ranges. Correct management of the hypogammaglobulinemia allowed splenectomy to be performed without any infectious surgical complications. MCD is reported for the first time in association with an adult case of CVID. The above reported case highlights the need for a timely correct diagnosis and treatment of CVID to avoid complications, which could cause recourse to splenectomy, such as in our case or development of malignancies.

Interest of immunodeficiency screening in adult after admission in medical intensive care unit for severe infection, a retrospective and a prospective study: the Intensive Care Unit and Primary and Secondary Immunodeficiency (ICUSPID) study.

Primary immunodeficiency (PID) in adults is rare and mostly revealed by infections. Adults without predisposing factors who were admitted to an intensive care unit (ICU) for infection were screened for PID. Six PID cases were diagnosed, mostly revealed by encapsulated bacterial infections. Investigation of PID after ICU discharge should be considered to improve early detection.

Аналіз обізнаності лікарів практичної медицини щодо первинних імунодефіцитів

The paper highlights the problem of delayed diagnosis of primary immunodeficiencies in children of Ukraine due to the lack of awareness and insufficient baggage of knowledge about their diagnostics by primary care physicians. The results of the questionnaire survey of doctors (general practitioners, pediatricians, therapists, and narrow pediatric specialists) of Ternopil region, Ukraine, regarding the knowledge of the immune system diseases were analyzed. The importance of early diagnostics and registration of primary immunodeficiency cases has been indicated for the timely and comprehensive therapy and prevention of severe and irreversible complications development that will significantly improve the quality of life of patients and change the attitude to primary immunodeficiencies as incurable and hopeless diseases.

P257 Primary immunodeficiency cases revealed by low trec screens in West Texas

T-cell receptor excision circles (TRECs) screening was introduced on the Texas newborn screen in 2012 to detect severe combined immunodeficiency (SCID) and other primary immunodeficiencies (PI). Examining diseases and treatment of newborns with positive TREC screens in West Texas may yield valuable information and insight into PI in the region.

All IBD is Not Necessarily Sporadic IBD; A Case of Primary Immunodeficiency Mimicking Small Bowel Crohnʼs Disease

The gastrointestinal (GI) tract is the largest immunological organ in the body. The GI tract contains majority of the lymphocytes and produces large amounts of immunoglobulin, protecting us from exposure to pathogens. There are over 150 heterogeneous primary immunodeficiencies and most of them are inherited. Immune defects can occur in the T cell line (cellular), B cell line (humoral), or both T and B cell lines. Dysfunction in immunity can lead to mucosal inflammation and GI distress. Thus, it is not uncommon for immunocompromised patients to present with GI symptoms. Immunocompetent and immunocompromised patients with gastrointestinal diseases can present with similar symptoms. However, immunocompromised patients have distinct histologic features and do not respond to conventional therapies. Therefore, it is critical for gastroenterologists to correctly diagnose and treat patients with immunodeficiency. Therapy for primary immunodeficiency: antibiotics, immunoglobulins, and rarely bone marrow transplantation. Herein, we report a 63-year-old male who was transferred from an outside hospital (OSH) for evaluation of Crohn Disease refractory to steroids and anti-TNF therapy. OSH work up revealed that this patient had recent exposure to Giardia. On admission, the patient was severely malnourished (albumin 0.9) with diffuse anasarca. He had multiple vitamin deficiencies due to malabsorption. MRE revealed active inflammatory small bowel disease. His hospital course was complicated by multiple infections, requiring intubation and broad spectrum antibiotics. Labs further revealed CD4 count 235, decreased absolute B cells, decreased immunoglobulins, decreased T regulatory cells, and absent NK function, suggestive of late onset combined immunodeficiency. His jejunal biopsies appeared similar to graft-versus-host disease. His biopsies were not consistent with Crohn Disease, lymphoma, or autoimmune enteropathy. He was started on monthly IVIG and sirolimus with partial recovery of his NK function. His infections resolved and he was discharged with TPN to rehab. Whole genomic sequencing was sent to determine a possible genetic link to his disease and is currently pending. This case demonstrates the importance of incorporating basic immunological work up in the assessment of patients with gut inflammation. It also suggests that individuals who present with an infection followed by gut inflammation may be more likely to have an immunodeficiency as opposed to sporadic IBD.

Infectious and non-infectious complications in primary immunodeficiency disorders: an autopsy study from North India

BackgroundPrimary immunodeficiency disorders (PID) include a wide spectrum of inherited disorders characterised by functional abnormalities of one or more components of the immune system. Recent updates from the genomic data...

Immune and Hematological Reconstitution after Allogenic Bone Marrow Transplantation in Tunisian Pediatric Recipients: Prospective Study and Tunisian Experience Report

AIM: A regular monitoring of the immune reconstitution mainly based on the quantitative determination of lymphocyte T subpopulation. This is prospective analysis for 1 year in Tunisian children treated with allogenic intrafamilial bone marrow transplantation. Methods: We conducted a prospective analysis for 1 year follow up enrolling 25 children treated with allogenic intrafamilial bone marrow transplantation among them two cases of Peripheral hematopoietic transplantation and placental cord blood transplantation including: aplastic anemia (6 cases), hemoglobinopathies (12 cases), myelodysplastic syndrome (1 case), 2 cases of Acute lymphocytic leukemia, a case of congenital amegacarycytosis and 3 cases of primary immunodeficiency with lack of expression of major MHC class II. All subjects received different conditioning regimens according to the indication. Our study consisted of a regular monitoring of the immune reconstitution mainly based on the quantitative determination of lymphocyte T subpopulation. So, these tests were routinely requested to 1 month, 2 months, 3 months, 6 months, 9 months and 12 months post- bone marrow transplantation. Results: The average time of engraftment was 18 days corresponding to neutrophil recovery (12-24). For the T cell recovery, a rate of CD4 + T lymphocytes > 200/ mm3 was provided within an average of 2.5 months (1-7). The average time to obtain CD8+ T lymphocytes >200 /mm3 was 2 months (1-5). The humoral immune reconstitution was made within an average of 2 months (1-4). A ratio of CD4+ / CD8+ T lymphocytes (>1) was obtained within 10 months and a half (1-24). Univaried analysis showed a significant correlation between the bone marrow sex matched and the faster reorganization of CD8 + T cells (p = 0.042). Moreover, a quantity of CD34 +> 6x 106/ kg was significantly associated with the recapture of a formula lymphocyte T CD4+ / CD8+ (> 1) (p=0.03). Conclusion: The immune recovery post bone marrow transplantation in children began with myeloid lineage then lymphoid B then lymphoid T. The inversion of the ratio CD4 +/CD8+ T lymphocytes, seemed to be influenced on the one hand by the high content of CD34 + cells in the graft as well as the type of conditioning on the other hand by the CMV infection since it accelerates significantly CD8+ T lymphocyte reconstitution.

Lymphoma Secondary to Congenital and Acquired Immunodeficiency Syndromes at a Turkish Pediatric Oncology Center

The prevalence of lymphoma in primary immunodeficiency cases and autoimmune diseases, as well as on a background of immunodeficiency following organ transplants, is increasing. The lymphoma treatment success rate is known to be a low prognosis. Our study aimed to emphasize the low survival rates in immunodeficient vs. immunocompetent lymphoma patients and also to investigate the effect of rituximab in patients with ataxia telangiectasia and other immunodeficiencies. We summarized the clinical characteristics and treatment results of 17 cases with primary immunodeficiency that developed non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) retrospectively. Seven patients were diagnosed with ataxia-telangiectasia, two with common variable immunodeficiency, two with selective IgA deficiency, one with X-related lymphoproliferative syndrome, one with Wiskott-Aldrich syndrome, one with Epstein-Barr virus-related lymphoproliferative syndrome, one with interleukin-2-inducible T-cell kinase (ITK) deficiency, and one with lymphoma developing after autoimmune lymphoproliferative syndrome (ALPS). One patient underwent a renal transplant. Of the nine males and eight females (aged 3-12years, median = 7) that developed lymphoma, seven were diagnosed with HL and ten with NHL (seven B-cell, three T-cell). The NHL patients were started on the Berlin-Frankfurt-Münster, POG9317, LMB-96, or R-CHOP treatment protocols with reduced chemotherapy dosages. HL cases were started on the doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and/or cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) protocol, also with modified dosages. Importantly, all seven cases of HL are alive and in remission, while six of the ten NHL patients have died. Primary immunodeficiency is a strong predisposing factor for developing lymphoma. Low treatment success rates relative to other lymphomas and difficulties encountered during treatment indicate that new treatment agents are needed. While some success has been achieved by combining rituximab with lymphoma treatment protocols in B-NHL cases with primary immunodeficiency, the need for new treatment approaches for these patients remains critical.