Primary Combined Immunodeficiency Research Articles

Clinical case of hereditary thrombocytopenia in a 6 year old child with primary combined immunodeficiency condition

Clinical case of hereditary thrombocytopenia in a 6 year old child with primary combined immunodeficiency condition

CXCR4 WHIM syndrome is a cancer predisposition condition for virus-induced malignancies.

Warts, hypogammaglobulinaemia, infections and myelokathexissyndrome (WHIMS) is a rare combined primary immunodeficiency caused by the gain of function of the CXCR4 chemokine receptor. We present the prevalence of cancer in WHIMS patients based on data from the French Severe Chronic Neutropenia Registry and an exhaustive literature review. The median follow-up of the 14 WHIMS 'patients was 28.5 years. A central review and viral evaluation of pathological samples were organized, and we conducted a thorough literature review to identify all reports of WHIMS cases. Six French patients were diagnosed with cancer at a median age of 37.6 years. The 40-year risk of malignancy was 39% (95% confidence interval [CI]: 6%-74%). We observed two human papillomavirus (HPV)-induced vulvar carcinomas, three lymphomas (two Epstein-Barr virus [EBV]-related) and one basal cell carcinoma. Among the 155 WHIMS cases from the literature, 22 cancers were reported in 16 patients, with an overall cancer 40-year risk of 23% (95% CI: 13%-39%). Malignancies included EBV-associated lymphoproliferative disorders and HPV-positive genital and anal cancers as in the French cohort. Worldwide, nine cases of malignancy were associated with HPV and four with EBV. Immunocompromised WHIMS patients appear to be particularly susceptible to developing early malignancy, mainly HPV-induced carcinomas, followed by EBV-related lymphomas.

Periodontal disease in patients with WHIM syndrome.

WHIM (warts, hypogammaglobulinaemia, infections and myelokathexis) syndrome is a rare combined primary immunodeficiency disease caused by gain-of-function (GOF) mutations in the chemokine receptor CXCR4 and includes severe neutropenia as a common feature. Neutropenia is a known risk factor for periodontitis; however, a detailed periodontal evaluation of a WHIM syndrome cohort is lacking. This study aimed to establish the evidence base for the periodontal status of patients with WHIM syndrome. Twenty-two adult WHIM syndrome patients and 22 age- and gender-matched healthy volunteers (HVs) were evaluated through a comprehensive medical and periodontal examination. A mouse model of WHIM syndrome was assessed for susceptibility to naturally progressing or inducible periodontitis. Fourteen patients with WHIM syndrome (63.6%) and one HV (4.5%) were diagnosed with Stage III/IV periodontitis. No WHIM patient presented with the early onset, dramatic clinical phenotypes typically associated with genetic forms of neutropenia. Age, but not the specific CXCR4 mutation or absolute neutrophil count, was associated with periodontitis severity in the WHIM cohort. Mice with a Cxcr4 GOF mutation did not exhibit increased alveolar bone loss in spontaneous or ligature-induced periodontitis. Overall, WHIM syndrome patients presented with an increased severity of periodontitis despite past and ongoing neutrophil mobilization treatments. GOF mutations in CXCR4 may be a risk factor for periodontitis in humans.

Outcome of BCG Vaccination in ADA-SCID Patients: A 12-Patient Series.

Vaccination with Bacillus Calmette-Guérin (BCG) can be harmful to patients with combined primary immunodeficiencies. We report the outcome of BCG vaccination in a series of twelve patients affected by adenosine deaminase deficiency (ADA-SCID). BCG vaccination resulted in a very high incidence of complications due to uncontrolled replication of the mycobacterium. All patients who developed BCG-related disease were treated successfully and remained free from recurrence of disease. We recommend the prompt initiation of enzyme replacement therapy and secondary prophylaxis to reduce the risk of BCG-related complications in ADA-SCID patients.

Severe CD8+ T Lymphopenia in WHIM Syndrome Caused by Selective Sequestration in Primary Immune Organs.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is an ultra-rare combined primary immunodeficiency disease caused by heterozygous gain-of-function mutations in the chemokine receptor CXCR4. WHIM patients typically present with recurrent acute infections associated with myelokathexis (severe neutropenia due to bone marrow retention of mature neutrophils). Severe lymphopenia is also common, but the only associated chronic opportunistic pathogen is human papillomavirus and mechanisms are not clearly defined. In this study, we show that WHIM mutations cause more severe CD8 than CD4 lymphopenia in WHIM patients and WHIM model mice. Mechanistic studies in mice revealed selective and WHIM allele dose-dependent accumulation of mature CD8 single-positive cells in thymus in a cell-intrinsic manner due to prolonged intrathymic residence, associated with increased CD8 single-positive thymocyte chemotactic responses invitro toward the CXCR4 ligand CXCL12. In addition, mature WHIM CD8+ T cells preferentially home to and are retained in the bone marrow in mice in a cell-intrinsic manner. Administration of the specific CXCR4 antagonist AMD3100 (plerixafor) in mice rapidly and transiently corrected T cell lymphopenia and the CD4/CD8 ratio. After lymphocytic choriomeningitis virus infection, we found no difference in memory CD8+ T cell differentiation or viral load between wild-type and WHIM model mice. Thus, lymphopenia in WHIM syndrome may involve severe CXCR4-dependent CD8+ T cell deficiency resulting in part from sequestration in the primary lymphoid organs, thymus, and bone marrow.

Circulating B-Cell Precursor Cells As Potential Diagnostic and Therapeutic Biomarker in Patients with WHIM Syndrome

Background Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a combined immunodeficiency caused in most known cases by gain-of-function mutations in the CXCR4 gene. The wide spectrum of multisystem clinical presentations, often with incomplete penetrance and expressivity, can pose a diagnostic challenge. WHIM syndrome has historically been a clinicopathologic diagnosis, with myelokathexis being the pathognomonic feature of WHIM. As genetic testing is becoming readily available, sequencing of the CXCR4 gene is often used to confirm a clinical suspicion of WHIM syndrome by finding genetic variants. There is a need for additional easily accessible and noninvasive biomarkers for diagnosing WHIM syndrome. We hypothesize that B-cell compartment might also show pathognomonic features of WHIM syndrome. Patients and Methods We analyzed peripheral blood B-cell subsets in 13 patients diagnosed with WHIM syndrome from 8 families with pathogenic CXCR4 mutations using 9-multicolor flow cytometry after informed consent approval. Samples from 2 patients who received plerixafor were collected at baseline before and after treatment. The duration of treatment was approximately 6 months. Results Using multicolor flow cytometry, we analyzed circulating B-cell subsets (CD10,CD19,CD21,CD27,CD38,IgA,IgD,IgG and IgM) in 13 patients (pediatric, n=7; adult, n=6) with WHIM syndrome (9 patients with p.Arg334Stop mutation, 2 patients with p.Val320Glufs*23 mutation, 1 patient with p.Ser338Stop mutation, and 1 patient with p.Ser346Stop mutation). We observed severe peripheral B-cell lymphopenia, accompanied by the presence of a consistent and specific scarce CD19+CD10+CD38+IgM-IgD-CD21-CD27- B-cell subpopulation. A B-cell subpopulation with an equivalent marker expression pattern was not found in healthy controls (n=50) or in non-WHIM disease controls (n=20). The rare B-cell population found in WHIM syndrome was further characterized as belonging mostly to the pre-B-cell stage revealed by intracellular expression of IgM, CD179a (VpreB chain), and CD179b (lambda 5). The presence of these early B-cell precursors was independent of age and was stable over time in patients with WHIM syndrome. The number of these peripheral B-cell precursors found specifically in patients with WHIM syndrome was greatly reduced when the patients were treated with granulocyte colony-stimulating factor (G-CSF) or plerixafor; counts of the precursor cells returned to baseline after the patients discontinued plerixafor treatment. Conclusions Taken together, we identify a unique CD19+CD10+CD38+IgM-IgD-CD21-CD27- B-cell subpopulation in patients with WHIM syndrome that might be used as a noninvasive biomarker to help identify patients with this rare primary combined immunodeficiency. In addition, these circulating B-cell precursors may be used to monitor response to therapy in patients with WHIM syndrome. The observed impact of G-CSF on the B-cell precursor population may be attributed to downregulation of CXCL12/CXCR4, which influences myelokathexis and impairs egression of the precursor population from the bone marrow but needs further experimental validation.

Role of innate errors of immunity in the group of children with fatal outcomes during the first year of life

In the modern world, inborn errors of immunity (IEIs), or primary immunodeficiencies (PIDs), are among of the main causes of childhood disability and mortality, determining the demographic state of mankind not only at present, but also in the future. In the Sverdlovsk Region over the past 5 years, there were about 30% of children who died from severe combined primary immunodeficiency. This retrospective study is devoted to the study of the nosological profile of mortality in the children with immune-dependent disorders in the Sverdlovsk Region, as well as to assess information significance of extrachromosomal circular DNA molecules (TREC and KREC) analysis. Some anamnestic data on the course of prenatal period in the current and previous pregnancies were considered the signs of suggested diagnosis of primary immunodeficiencies, i.e., threats of pregnancy loss at the early terms, documented cases of early childhood death, persistent viral and bacterial infections in the mother, complicated course of pregnancy in the mother, as well as some clinical manifestations, including fungal-bacterial sepsis, generalized viral infection, repair disorders, reduced physiological tolerance accompanied by autoimmune organ damage and uncontrolled systemic inflammation. The study demonstrated a wide range of nosological entities of innate errors of immunity in the structure of early childhood mortality, including both classical forms of primary immunodeficiencies and the disorders not directly related to innate errors of immunity, but those showing phenotypically pronounced immunodeficiency and their immediate role in statistical deviations. Among the main criteria that may presume possible presence of an immune-dependent pathology in the early neonatal period we considered the molecular markers of naive T and B cells (TREC and KREC, respectively) revealed in 70% of the cases studied, with, at least, one of these indexes found to be reduced. It is important to understand that primary immunodeficiencies are not as rare as previously thought. Therefore, it is necessary to carry out timely and high-quality diagnostics, in order to avoid unavoidable deaths.

Clinical case of primary combined immunodeficiency. Chronic mucocutaneous candidiasis in a 5-year-old girl

Clinical case of primary combined immunodeficiency. Chronic mucocutaneous candidiasis in a 5-year-old girl

M189 DOCK8 DEFICIENCY PRESENTING AS MULTIFOCAL EBV-ASSOCIATED SMOOTH MUSCLE TUMORS

DOCK8 deficiency is a combined primary immunodeficiency (PID) that causes autosomal recessive hyper-IgE syndrome and is characterized by recurrent infections, atopy, and risk of autoimmunity and malignancy.[1] We report a case of EBV-associated smooth muscle tumors secondary to DOCK8 deficiency requiring allogeneic bone marrow transplant.

Clinical Manifestations and Outcomes of Activated Phosphoinositide 3-Kinase δ Syndrome from the USIDNET Cohort

Activated phosphoinositide 3-kinase δ syndrome is a combined primary immunodeficiency characterized by gain-of-function mutations in PIK3CD and PIK3R1. Activated phosphoinositide 3-kinase δ syndrome demonstrates a large range of phenotypes including respiratory and herpesvirus infections, lymphadenopathy, autoimmunity, and developmental delay. To describe clinical phenotypes and disease outcomes of a large activated phosphoinositide 3-kinase δ syndrome cohort from the United States Immunodeficiency Network Registry. A total of 38 patients were enrolled in the United States Immunodeficiency Network Registry, and 2 additional patients were obtained from the Clinical Immunology Division at Mount Sinai Hospital. Each patient's demographic characteristics, disease complications, genetic studies, laboratory data, therapeutic interventions, and clinical outcomes were reviewed. There was a high frequency of respiratory infections (70.0% pneumonia) and herpesvirus infections (37.5%). Bronchiectasis was observed in 45.0% of patients. Lymphadenopathy was common (52.5%), and 12.5% of patients developed lymphoma. Neurological and developmental findings were common: 20.0% had developmental delay, 15.0% had seizures, and 10.0% had dysmorphic features. Asthma was more common in PIK3CD compared with PIK3R1 patients (63.6% vs 14.3%). More subjects with PIK3CD had CD3 lymphopenia compared with the PIK3R1 cohort. Seven patients underwent hematopoietic stem cell transplantation. One patient died from infectious complications. This is the first cohort comparing clinical manifestations in PIK3CD and PIK3R1 patients from the USIDNET Registry. Similar frequencies of respiratory and herpesvirus infections, lymphadenopathy, and developmental delay were observed compared with previous cohort studies. However, a higher frequency of asthma and CD3 lymphopenia in the PIK3CD cohort compared with the PIK3R1 cohort was observed.

Characteristics of a group of patients with WHIM syndrome

WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis) is a rare combined primary immunodeficiency. Here we describe 10 Russian patients with WHIM syndrome that were followed in the Dmitry Rogachev National Medical Research Center оf Pediatric Hematology, Oncology and Immunology. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Neutropenia and lymphopenia were observed in all 10 patients, hypogammaglobulinemia – in 7/10 patients. In all cases bone marrow analysis demonstrated myelokathexis features (cytoplasmic vacuolization in neutrophils and eosinophils, hyperlobulated pyknotic nuclear lobes connected by long thin strands, hypogranular and hypersegmented neutrophils). All patients were treated with granulocyte colony-stimulating factor and intravenous immunoglobulin. In 3/10 poor disease control was an indication to perform HSCT. In 2 of 3 patients HSTC was successful and all symptoms of the disease resolved. In conclusion, the diagnosis of WHIM syndrome must be considered in patients with early onset of neutro- and lymphopenia in conjunction with morphological features of myelokathexis. Treatment of this disease is still a challenging problem.

The First Iranian Cohort of Pediatric Patients with Activated Phosphoinositide 3-Kinase-δ (PI3Kδ) Syndrome (APDS)

ABSTRACT Background Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently defined combined primary immunodeficiency disease (PID) characterized by recurrent respiratory tract infections, lymphoproliferation, autoimmunity and lymphoma. Gain-of-function mutations in PIK3CD and loss-of-function of PIK3R1 genes lead to APDS1 and APDS2, respectively. Methods Demographic, clinical, immunological and genetic data were collected from medical records of 15 pediatric patients, who were genetically identified using the whole-exome sequencing method. Results Fifteen patients (6 APDS1 and 9 APDS2) were enrolled in this study. Recurrent respiratory tract infections followed by lymphoproliferation and autoimmunity were the most common manifestations (86.7%, 53.3% and 26.7%, respectively). Five patients (33.3%) had a Hyper-IgM-syndrome-like immunoglobulin profile. In the APDS1 group, splice site and missense mutations were found in half of the patients and the C-lobe domain of PIK3CD was the most affected region (50%). In the APDS2 group, splice site mutation was the most frequent mutation (77.8%) and the inter-SH2 domain was the most affected region of PIK3R1 (66.7%). Mortality rate was significantly higher in APDS2 group (P = .02) mainly due to chronic lung infections. Conclusion Respiratory tract infections and humoral immunodeficiency are commonly the most important complication in pediatric APDS patients, and they can be fatal by ultimately causing catastrophic damage to the structure of lungs. Hence, physicians should be aware of its significance and further work-up of patients with recurrent respiratory tract infections especially in patients with lymphoproliferation. Moreover, delineation of genotype-phenotype associations with disease severity could be helpful in the timely application of appropriate management and patients’ survival.

Indicative to the use of leukocyte dialysate extract in clinical practice

Experience in the use of factor transfer in medicine is more than 60 years, and begins with the proposal of F. Lawrence in 1955 to use dialysed leukocyte blood extract to transfer antitumor immunity from the immunized body to non-immune.Preparations of immune extract of leukocyte dialysate are an important component of modern science about transfer factors. It is a highly active multicomponent immunobiological agent of natural origin, containing more than 200 low molecular weight peptides, which are components of the immune system of the human body, mainly – products of synthetic activity of CD8+ cytotoxic T-lymphocytes.This biological preparation has immunosubstitutional, immunizing and immunomodulatory biological properties, which are implemented inseparably from each other, providing known anti-infectious, pro-/antiinflammatory, tolerogenic, immunoactivating and antitumor therapeutic effects.The drug based on the immune extract of leukocytes dialysate is included in the modern international protocols for the treatment of primary immunodeficiency – hereditary skin and mucous candidiasis. In addition, at the moment there are at least 30 more indications with varying degrees of evidence for the clinical use of such transfer factors in immunology, infectology, allergology, rheumatology and oncology.The main immunomodulatory effect of the drug is associated with increased functioning of T-helpers type 1 by stimulating the production of cytokines interleukin-2 and gamma-interferon, which leads to the potentiation of cellular immune response. This immunomodulatory effect can be explained by the efficacy of transfer factor in some cellular and combined primary and secondary immunodeficiencies, chronic infections caused by intracellular microorganisms, and various malignancies. The reciprocal decrease in functional activity of T-helpers type 2 leads to attenuation of atopic allergic reactions and some types of autoimmunity, which explains moderate success of transfer factor in allergology and rheumatology.

Improved transplant survival and long-term disease outcome in children with MHC class II deficiency

AbstractMHC class II deficiency is a rare, but life-threatening, primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor. We analyzed the outcome of 25 patients with MHC class II deficiency undergoing first HCT at Great North Children's Hospital between 1995 and 2018. Median age at diagnosis was 6.5 months (birth to 7.5 years). Median age at transplant was 21.4 months (0.1-7.8 years). Donors were matched family donors (MFDs; n = 6), unrelated donors (UDs; n = 12), and haploidentical donors (HIDs; n = 7). Peripheral blood stem cells were the stem cell source in 68% of patients. Conditioning was treosulfanbased in 84% of patients; 84% received alemtuzumab (n = 14) or anti-thymocyte globulin (n = 8) as serotherapy. With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008 (n = 19; P = .003). For HCT after 2008, OS according to donor was 100% for MFDs and UDs and 85% for HIDs (P = .40). None had grade III-IV acute or chronic graft-versus-host disease. Latest median donor myeloid and lymphocyte chimerism were 100% (range, 0-100) and 100% (range, 64-100), respectively. Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n = 14) compared with posttransplant disease controls (P = .01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity. Changing transplant strategy in Great North Children's Hospital has significantly improved outcomes for MHC class II deficiency.

Diagnosis and treatment of acute lymphoblastic leukemia in a patient with niimegen syndrome first diagnosed in adulthood

Background. Nijmegen breakage syndrome is a rare hereditary autosomal recessive disorder characterized by microcephaly, combined primary immunodeficiency, sensitivity to radioactive radiation and liability to tumours of various nature (in particular, those developing in the lymphatic tissue). This syndrome is part of a group of diseases characterized by chromosomal instability. This disease develops as a result of mutations in the NBS1 gene, which is responsible for repairing DNA double-stranded breaks.Aim. To describe a clinical case of the diagnosis and treatment of T-cell acute lymphoblastic leukemia in a patient with Nijmegen syndrome, which was first diagnosed in adulthood.General findings. A clinical case of the diagnosis and treatment of Nijmegen syndrome in a young man with de novo T-cell acute lymphoblastic leukemia is presented. The difficulty of early diagnosis of hereditary genetic syndromes is demonstrated. The genetic character of such conditions is revealed over time, when children and young adults begin to develop long-term complications, in particular tumours of various origins. Early detection of hereditary genetic syndromes in children is of great importance.

Hematopoietic Cell Transplantation for MHC Class II Deficiency.

Major histocompatibility complex (MHC) class II deficiency is a rare and fatal primary combined immunodeficiency. It affects both marrow-derived cells and thymic epithelium, leading to impaired antigen presentation by antigen presenting cells and delayed and incomplete maturation of CD4+ lymphocyte populations. Affected children are susceptible to multiple infections by viruses, Pneumocystis jirovecii, bacteria and fungi. Immunological assessment usually shows severe CD4+ T-lymphocytopenia, hypogammaglobulinemia, and lack of antigen-specific antibody responses. The diagnosis is confirmed by absence of constitutive and inducible expression of MHC class II molecules on affected cell types which is the immunologic hallmark of the disease. Hematopoietic cell transplantation (HCT) is the only established curative therapy for MHC class II deficiency but it is difficult as affected children have significant comorbidities at the time of HCT. Optimization organ function, implementing a reduced toxicity conditioning regimen, improved T-cell depletion techniques using serotherapy and graft manipulation, vigilant infection surveillance, pre-emptive and aggressive therapy for infection and newer treatments for graft-versus-host disease have improved the transplant survival for children with MHC class II deficiency. Despite persistent low CD4+ T-lymphopenia reported in post-HCT patients, transplanted patients show normalization of antigen-specific T-lymphocyte stimulation and antibody production in response to immunization antigens. There is a need for a multi-center collaborative study to look at transplant survival of HCT and long-term disease outcome in children with MHC class II deficiency in the modern era of HCT.

Metabolomics Distinguishes DOCK8 Deficiency from Atopic Dermatitis: Towards a Biomarker Discovery.

Bi-allelic mutations in the dedicator of cytokinesis 8 (DOCK8) are responsible for a rare autosomal recessive primary combined immunodeficiency syndrome, characterized by atopic dermatitis, elevated serum Immunoglobulin E (IgE) levels, recurrent severe cutaneous viral infections, autoimmunity, and predisposition to malignancy. The molecular link between DOCK8 deficiency and atopic skin inflammation remains unknown. Severe atopic dermatitis (AD) and DOCK8 deficiency share some clinical symptoms, including eczema, eosinophilia, and increased serum IgE levels. Increased serum IgE levels are characteristic of, but not specific to allergic diseases. Herein, we aimed to study the metabolomic profiles of DOCK8-deficient and AD patients for potential disease-specific biomarkers using chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS). Serum samples were collected from DOCK8-deficient (n = 10) and AD (n = 9) patients. Metabolomics profiling using CIL LC-MS was performed on patient samples and compared to unrelated healthy controls (n = 33). Seven metabolites were positively identified, distinguishing DOCK8-deficient from AD patients. Aspartic acid and 3-hydroxyanthranillic acid (3HAA, a tryptophan degradation pathway intermediate) were up-regulated in DOCK8 deficiency, whereas hypotaurine, leucyl-phenylalanine, glycyl-phenylalanine, and guanosine were down-regulated. Hypotaurine, 3-hydroxyanthranillic acid, and glycyl-phenylalanine were identified as potential biomarkers specific to DOCK8 deficiency. Aspartate availability has been recently implicated as a limiting metabolite for tumour growth and 3HAA; furthermore, other tryptophan metabolism pathway-related molecules have been considered as potential novel targets for cancer therapy. Taken together, perturbations in tryptophan degradation and increased availability of aspartate suggest a link of DOCK8 deficiency to oncogenesis. Additionally, perturbations in taurine and dipeptides metabolism suggest altered antixidation and cell signaling states in DOCK8 deficiency. Further studies examining the mechanisms underlying these observations are necessary.

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.

Treatment approaches to hyper-IgE syndrome: a clinical case report

The hyper-IgE syndrome with dominant-negative mutations in signal transducer and activator of transcription 3 (STAT3) gene is a combined primary immunodeficiency characterized by severe bacterial infections (skin and lungs with bullae formation), characteristic phenotype, serum IgE elevation, eosinophilia, as well as connective tissue, and bone anomalies. Patients also have high risk of cancer. STAT3 is a transcription factor important for the JAK/STAT signaling pathway, which plays the key role in the synthesis of cytokines, hormones, and bioactive agents. Hyper-IgE syndrome therapy includes antimicrobial prophylaxis, immunoglobulin replacement, and use of bisphosphonates. Hematopoietic stem cell transplantation is an alternative way for the disease treatment. Here we describe a patient with severe autosomal dominant hyper-IgE-syndrome with thte loss-of-function mutation in the STAT3 gene. Patient's parents agreed to use personal dats and photos in research and publications.

Особенности лечения интерстициальной лимфоцитарной болезни легких у пациентов с синдромами иммунной дизрегуляции: клинический пример

Immune dysregulation syndromes (CTLA4 and LRBA deficiency) belong to the combined primary immunodeficiencies with defective tolerance due to lack of T regulatory lymphocytes function and resulting autoimmune complications. One of them is interstitial lymphocytic lung disease (ILLD), caused by pathologic bronchi-associated lymphoid tissue hyperplasia, progressive loss of lung function and decreased life expectancy. ILLD diagnosis is based on pathomorphological lung changes and radiologic symptoms. Targeted therapy with Abatacept in patients with immune dysregulation syndromes provides control of the autoimmune complications, including ILLD and is well tolerated. Here we demonstrate two cases of patients with immune dysregulation syndromes and ILLD treated with Abatacept.