ITGB2 mutation combined with deleted ring 21 chromosome in a child with leukocyte adhesion deficiency

Leukocyte adhesion deficiency type 1(LAD-1) is a rare autosomal recessive primary immunodeficiency caused by defects in the ITGB2 gene located on chromosome 21q22. Clinically, LAD-1 patients are characterized by recurrent infections, slow wound healing and dystrophic scars after skin injuries, associated with persistent neutrophilia. The severity of symptoms is related to the level of CD11/CD18 expression on patients’ leucocytes and those with less than 1% expression treated with hematopoietic stem cell transplant (HSCT). We present a child affected by LAD-1 who received HSCT from a matched unrelated donor. Molecular analysis revealed apparent homozygosis for a point mutation in the ITGB2 gene, only the mother however was carrier of the mutation. Cytogenetic and FISH analysis showed the presence of a de-novo ring chromosome 21. Whole Genome Analysis with the Affymetrix GeneChip Human Mapping 250K NspI array confirmed in the child the presence of a de novo deletion of the chromosomal region 21q22.3-qter, where the ITGB2 gene maps. While HSCT resulted in successful engraftment and correction of the immunodeficiency, all the phenotypic features of ring (21) syndrome with a deletion of a 4.6Mb (including 69 genes) clearly remained unchange

Primary immunodeficiency

Primary immunodeficiency disorder (PID) refers to a heterogeneous group of over 130 disorders that result from defects in immune system development and/or function. PIDs are broadly classified as disorders of adaptive immunity (i.e., T-cell, B-cell or combined immunodeficiencies) or of innate immunity (e.g., phagocyte and complement disorders). Although the clinical manifestations of PIDs are highly variable, most disorders involve at least an increased susceptibility to infection. Early diagnosis and treatment are imperative for preventing significant disease-associated morbidity and, therefore, consultation with a clinical immunologist is essential. PIDs should be suspected in patients with: recurrent sinus or ear infections or pneumonias within a 1 year period; failure to thrive; poor response to prolonged use of antibiotics; persistent thrush or skin abscesses; or a family history of PID. Patients with multiple autoimmune diseases should also be evaluated. Diagnostic testing often involves lymphocyte proliferation assays, flow cytometry, measurement of serum immunoglobulin (Ig) levels, assessment of serum specific antibody titers in response to vaccine antigens, neutrophil function assays, stimulation assays for cytokine responses, and complement studies. The treatment of PIDs is complex and generally requires both supportive and definitive strategies. Ig replacement therapy is the mainstay of therapy for B-cell disorders, and is also an important supportive treatment for many patients with combined immunodeficiency disorders. The heterogeneous group of disorders involving the T-cell arm of the adaptive system, such as severe combined immunodeficiency (SCID), require immune reconstitution as soon as possible. The treatment of innate immunodeficiency disorders varies depending on the type of defect, but may involve antifungal and antibiotic prophylaxis, cytokine replacement, vaccinations and bone marrow transplantation. This article provides a detailed overview of the major categories of PIDs and strategies for the appropriate diagnosis and management of these rare disorders

A mutation in caspase-9 decreases the expression of BAFFR and ICOS in patients with immunodeficiency and lymphoproliferation

Lymphocyte apoptosis is mainly induced by either death receptor-dependent activation of caspase-8 or mitochondria-dependent activation of caspase-9. Mutations in caspase-8 lead to autoimmunity/lymphoproliferation and immunodeficiency. This work describes a heterozygous H237P mutation in caspase-9 that can lead to similar disorders. H237P mutation was detected in two patients: Pt1 with autoimmunity/lymphoproliferation, severe hypogammaglobulinemia and Pt2 with mild hypogammaglobulinemia and Burkitt lymphoma. Their lymphocytes displayed defective caspase-9 activity and decreased apoptotic and activation responses. Transfection experiments showed that mutant caspase-9 display defective enzyme and proapoptotic activities and a dominant-negative effect on wild-type caspase-9. Ex vivo analysis of the patients' lymphocytes and in vitro transfection experiments showed that the expression of mutant caspase-9 correlated with a downregulation of BAFFR (B-cell-activating factor belonging to the TNF family (BAFF) receptor) in B cells and ICOS (inducible T-cell costimulator) in T cells. Both patients carried a second inherited heterozygous mutation missing in the relatives carrying H237P: Pt1 in the transmembrane activator and CAML interactor (TACI) gene (S144X) and Pt2 in the perforin (PRF1) gene (N252S). Both mutations have been previously associated with immunodeficiencies in homozygosis or compound heterozygosis. Taken together, these data suggest that caspase-9 mutations may predispose to immunodeficiency by cooperating with other genetic factors, possibly by downregulating the expression of BAFFR and ICO

An introduction to immunology and immunopathology

In basic terms, the immune system has two lines of defense: innate immunity and adaptive immunity. Innate immunity is the first immunological, non-specific (antigen-independent) mechanism for fighting against an intruding pathogen. It is a rapid immune response, occurring within minutes or hours after aggression, that has no immunologic memory. Adaptive immunity, on the other hand, is antigen-dependent and antigen-specific; it has the capacity for memory, which enables the host to mount a more rapid and efficient immune response upon subsequent exposure to the antigen. There is a great deal of synergy between the adaptive immune system and its innate counterpart, and defects in either system can provoke illness or disease, such as autoimmune diseases, immunodeficiency disorders and hypersensitivity reactions. This article provides a practical overview of innate and adaptive immunity, and describes how these host defense mechanisms are involved in both health and illness

Clinical experience in T cell deficient patients

T cell disorders have been poorly understood until recently. Lack of knowledge of underlying molecular mechanisms together with incomplete data on long term outcome have made it difficult to assess prognosis and give the most effective treatment. Rapid progress in defining molecular defects, improved supportive care and much improved results from hematopoietic stem cell transplantation (HSCT) now mean that curative treatment is possible for many patients. However, this depends on prompt recognition, accurate diagnosis and careful treatment planning

Are all cases of paediatric essential thrombocythaemia really myeloproliferative neoplasms? Analysis of a large cohort

Sporadic essential thrombocythaemia (ET) is rare in paediatrics, and the diagnostic and clinical approach to paediatric cases cannot be simply copied from experience with adults. Here, we assessed 89 children with a clinical diagnosis of ET and found that 23 patients (258%) had a clonal disease. The JAK2 V617F mutation was identified in 14 children, 1 child had the MPL W515L mutation, and 6 had CALR mutations. The monoclonal X-chromosome inactivation pattern was seen in six patients (two with JAK2 V617F and two with CALR mutations). The other 66 patients (742%) had persistent thrombocytosis with no clonality. There were no clinical or haematological differences between the clonal and non-clonal patients. The relative proportion of ET-specific mutations in the clonal children was much the same as in adults. The higher prevalence of nonclonal cases suggests that some patients may not have myeloproliferative neoplasms, with significant implications for their treatment

A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP

A female offspring of consanguineous parents, showed features of Wiskott-Aldrich syndrome (WAS), including recurrent infections, eczema, thrombocytopenia, defective T cell proliferation and chemotaxis, and impaired natural killer cell function. Cells from this patient had undetectable WAS protein (WASP), but normal WAS sequence and messenger RNA levels. WASP interacting protein (WIP), which stabilizes WASP, was also undetectable. A homozygous c.1301C>G stop codon mutation was found in the WIPF1 gene, which encodes WIP. Introduction of WIP into the patient’s T cells restored WASP expression. These findings indicate that WIP deficiency should be suspected in patients with features of WAS in whom WAS sequence and mRNA levels are normal

Educational paper: Primary immunodeficiencies in children: a diagnostic challenge

Primary immunodeficiencies (PIDs) are characterized by an increased susceptibility to infections due to defects in one ore more components of the immune system. Although most PIDs are relatively rare, they are more frequent than generally acknowledged. Early diagnosis and treatment of PIDs save lives, prevent morbidity, and improve quality of life. This early diagnosis is the task of the pediatrician who encounters the child for the first time: he/she should suspect potential PID in time and perform the appropriate diagnostic tests. In this educational paper, the first in a series of five, we will describe the most common clinical presentations of PIDs and offer guidelines for the diagnostic process, as well as a brief overview of therapeutic possibilities and prognosis

Relevance of laboratory testing for the diagnosis of primary immunodeficiencies: a review of case-based examples of selected immunodeficiencies

The field of primary immunodeficiencies (PIDs) is one of several in the area of clinical immunology that has not been static, but rather has shown exponential growth due to enhanced physician, scientist and patient education and awareness, leading to identification of new diseases, new molecular diagnoses of existing clinical phenotypes, broadening of the spectrum of clinical and phenotypic presentations associated with a single or related gene defects, increased bioinformatics resources, and utilization of advanced diagnostic technology and methodology for disease diagnosis and management resulting in improved outcomes and survival. There are currently over 200 PIDs with at least 170 associated genetic defects identified, with several of these being reported in recent years. The enormous clinical and immunological heterogeneity in the PIDs makes diagnosis challenging, but there is no doubt that early and accurate diagnosis facilitates prompt intervention leading to decreased morbidity and mortality. Diagnosis of PIDs often requires correlation of data obtained from clinical and radiological findings with laboratory immunological analyses and genetic testing. The field of laboratory diagnostic immunology is also rapidly burgeoning, both in terms of novel technologies and applications, and knowledge of human immunology. Over the years, the classification of PIDs has been primarily based on the immunological defect(s) ("immunophenotype") with the relatively recent addition of genotype, though there are clinical classifications as well. There can be substantial overlap in terms of the broad immunophenotype and clinical features between PIDs, and therefore, it is relevant to refine, at a cellular and molecular level, unique immunological defects that allow for a specific and accurate diagnosis. The diagnostic testing armamentarium for PID includes flow cytometry - phenotyping and functional, cellular and molecular assays, protein analysis, and mutation identification by gene sequencing. The complexity and diversity of the laboratory diagnosis of PIDs necessitates many of the above-mentioned tests being performed in highly specialized reference laboratories. Despite these restrictions, there remains an urgent need for improved standardization and optimization of phenotypic and functional flow cytometry and protein-specific assays. A key component in the interpretation of immunological assays is the comparison of patient data to that obtained in a statistically-robust manner from age and gender-matched healthy donors. This review highlights a few of the laboratory assays available for the diagnostic work-up of broad categories of PIDs, based on immunophenotyping, followed by examples of disease-specific testing

Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multicentre nation-wide cohort

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusion-dependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX).We developed a multicentre follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95%CI=6.3-13.1). Multiple Cox regression analysis identified 3 key predictors: age showed a positive log-linear effect (adjusted HR for 50% increase=1.2, 95%CI=1.1-1.3, P=0.005), the serum concentration of thyrotropin (TSH) showed a positive linear effect (adjusted HR for 1 mIU/L increase=1.3, 95%CI=1.1-1.4, P