Academic literature on the topic 'Clinical immunology; Genotype; Immunologic deficiency syndromes'

Monogenic autoinflammatory diseases (mAIDs) are inherited errors of innate immunity characterized by systemic inflammation recurring with variable frequency and involving the skin, serosal membranes, synovial membranes, joints, the gastrointestinal tube, and/or the central nervous system, with reactive amyloidosis as a potential severe long-term consequence. Although individually uncommon, all mAIDs set up an emerging chapter of internal medicine: recent findings have modified our knowledge regarding mAID pathophysiology and clarified that protean inflammatory symptoms can be variably associated with periodic fevers, depicting multiple specific conditions which usually start in childhood, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndrome, and mevalonate kinase deficiency. There are no evidence-based studies to establish which potential genotype analysis is the most appropriate in adult patients with clinical phenotypes suggestive of mAIDs. This review discusses genetic and clinical hints for an ideal diagnostic approach to mAIDs in adult patients, as their early identification is essential to prompt effective treatment and improve quality of life, and also highlights the most recent developments in the diagnostic work-up for the most frequent hereditary periodic febrile syndromes worldwide.

Abstract Haploinsufficiency of the hematopoietic transcription factor GATA2 underlies monocytopenia and mycobacterial infections; dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency; familial myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML); and Emberger syndrome (primary lymphedema with MDS). A comprehensive examination of the clinical features of GATA2 deficiency is currently lacking. We reviewed the medical records of 57 patients with GATA2 deficiency evaluated at the National Institutes of Health from January 1, 1992, to March 1, 2013, and categorized mutations as missense, null, or regulatory to identify genotype-phenotype associations. We identified a broad spectrum of disease: hematologic (MDS 84%, AML 14%, chronic myelomonocytic leukemia 8%), infectious (severe viral 70%, disseminated mycobacterial 53%, and invasive fungal infections 16%), pulmonary (diffusion 79% and ventilatory defects 63%, pulmonary alveolar proteinosis 18%, pulmonary arterial hypertension 9%), dermatologic (warts 53%, panniculitis 30%), neoplastic (human papillomavirus+ tumors 35%, Epstein-Barr virus+ tumors 4%), vascular/lymphatic (venous thrombosis 25%, lymphedema 11%), sensorineural hearing loss 76%, miscarriage 33%, and hypothyroidism 14%. Viral infections and lymphedema were more common in individuals with null mutations (P = .038 and P = .006, respectively). Monocytopenia, B, NK, and CD4 lymphocytopenia correlated with the presence of disease (P < .001). GATA2 deficiency unites susceptibility to MDS/AML, immunodeficiency, pulmonary disease, and vascular/lymphatic dysfunction. Early genetic diagnosis is critical to direct clinical management, preventive care, and family screening.

Abstract Introduction Stomatocytes in peripheral blood are pathognomonic findings in multiple conditions along with hemolysis and reticulocytosis, often suggestive of erythrocyte membrane transport defects. These uncommon disorders are usually difficult to diagnose due to a wide range of overlapping phenotypes and a perception of stomatocytes being artefacts. Genes involved in these disorders are multiple (RHAG,SLC4A1, ABCG5, ABCG8, PIEZO1,KCNN4, ABCB6, SLC2A1 etc) rendering Sanger sequencing costly and labor intensive. Phenotypes vary from transfusion-dependent anemia to compensated hemolysis. Methods Seventeen patients were encountered in 12 families and enrolled in this study. Majority of the cases showed the presence of significant numbers of red blood cells showing stomatocytes with or without thrombocytopenia. Various hematological, biochemical and molecular tests were used to exclude thalassemia syndromes and hemoglobinopathies, glucose-6-phosphate dehydrogenase (G6PD) deficiency, autoimmune hemolytic anemia, hereditary spherocytosis (HS) and pyruvate kinase deficiency. Genomic DNA was extracted by the QIAamp DNA Blood Midi Kit and quantified on NanoDrop 2000 spectrophotometer and QubitFluorometer. DNA libraries were prepared using Illumina's custom panels (TruSight One Sequencing Panel and TruSeq Custom Amplicon v1.5) and sequenced on a MiSeq Sequencing System. MiSeq Reporter and VariantStudio were used for analysis, classification, and reporting of variants. Variants which were predicted pathogenic by in silico analysis using PolyPhen-2, SIFT, PROVEAN (http://provean.jcvi.org/), Mutpred (http://mutpred.mutdb.org/) and Human Splicing Finder as indicated, were subjected to Sanger sequencing in the patient and family members (where available). Results Of these 17 patients, 10 patients in 6 families were diagnosed to have Mediterranean stomatocytosis/ macrothrombocytopenia. All had the presence of stomatocytes along with macrothrombocytopenia, short stature, continuous abdominal discomfort and marked pleiotropic effects in different cases. This is a syndromic form of stomatocytosis and defects in ABCG5/ABCG8 genes were found and showed an autosomal recessive inheritance pattern. One case did not show any mutation. This number of cases suggests that this disorder is not rare in India and is probably underdiagnosed as patients have mild or moderate anemia and are often misdiagnosed as cases with HS. One of the patients also had coinheritance of G6PD deficiency (G6PD Kerela Kalyan). Patients with Mediterranean stomatocytosis/macrothrombocytopenia are advised to take sterol-absorption inhibitor 'ezetimibe' to reduce sterol accumulation. We also found 2 unrelated patients with stomatocytosis, reticulocytosis and splenomegaly with overhydrated hereditary stomatocytosis (OHSt) and pathogenic mutation in RHAG gene was found in both of them. The pattern of inheritance is sporadic or autosomal dominant. Splenectomy was deferred in a patient with OHSt as postsplenectomy thrombotic complications are known to occur and is contraindicated. Four patients in 3 families were found to have mutations in PIEZO1 gene which translates to red cell membrane mechanosensitive cation channel protein, causing xerocytosis/dehydrated hereditary stomatocytosis and 3 patients had severe anemia and were transfusion dependent. One patient showed the presence of stomatocytes and macrothrombocytopenia was found to have probably disease causing variant in SLC2A1 gene. She was incidentally undergoing treatment for infertility when the stomatocytosis was noted. Conclusions Stomatocytic disorders appear to be underdiagnosed in India which is compounded by the protean clinical manifestations, milder phenotypes, low index of suspicion and non-availability of molecular confirmation. Astute phenotype characterization is critical as it will help in establishing the causality of the variants identified and appropriate genetic counseling. Recently NGS for hemolytic anemias has led to rapid molecular characterization and accurate phenotypic correlation. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 2128 Clinical phenotype in β-thalassemia syndromes is determined by the degree of chain imbalance. An increase in γ-globin production will compensate for the absent or deficient β-globin synthesis and will result in the amelioration of the chain imbalance, and hence an improvement in clinical features. The known genotypes of δβ-thalassemia are associated with an increase in Hb F production, which results in the amelioration of the clinical presentation. Most δβ-thalassemias result from deletions that remove the δ- and β-globin genes, (δβ)0 with a compensatory increase in γ-globin (Hb F) expression. We report an unusual case of homozygous δ0β+ thalassemia that provides interesting insights into increased γ-globin expression and the regulation of β-globin gene expression. An 8-year old boy of African ancestry presented with lifelong jaundice and pallor. He also experienced episodes of worsening symptoms. He exhibited frontal bossing, pale mucosa, scleral icterus, and moderate splenomegaly. He was known to have G6PD deficiency and was suspected of having additional erythrocyte pathology. The CBC revealed a Hb of 8.7, Hct 26.4, MCV 64.7, WBC 10,700, platelets 283,000, reticulocytes 2.2%, and total bilirubin 5.3. Hemoglobin analysis by HPLC and IEF revealed HbA 13.4%, Hb F 86.6%, and no additional components. Alpha thalassemia −3.7kb deletion was not detected. Globin chain analysis revealed α, β, Gγ and AγI chains. DNA analysis revealed a novel Senegalese-type deletion of the beta and delta genes, resulting in a delta0 beta+ thalassemia. The subject's parents who were both from the same small village in Niger had normal hematology values. Their hemoglobin analyses revealed Hb A 94. 8%, Hb A2 2.0%, Hb F 3.2% and Hb A 93.5%, Hb A2 2.1%, Hb F 4.5% in the father and mother, respectively. They were both heterozygous for the delta-beta deletion identified in their son. DNA analysis revealed a breakpoint in the delta gene at nucleotides 54755–54760 and a breakpoint in the beta gene at nucleotides 62153– 62158 [GenBank Ref ID: HUMHBB] with a 5 nucleotide “CAACA” bp region overlapping area. The subject, who is homozygous for the identified deletions, has a clinical phenotype of thalassemia intermedia. He has not yet required red cell transfusions. This is the first instance of a Senegalese-type deletion occurring in the homozygous state. The genotype provides insights into regulation of globin gene expression. While the ∼7 Kb deletion in the δβ-intergenic region may be responsible for the increased expression of the γ-globin gene similar to Hb Lepore deletions, the continued low level expression of the β-globin gene is most probably the result of the juxtaposition of the inefficient δ-globin promoter brought in the vicinity of the β-globin gene. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1536 Poster Board I-559 Background Pulmonary hypertension (PHT) is a widely recognized complication of sickle cell disease (SCD). It affects 32% of adults with SCD and is associated with an increased risk for early mortality. Screening of children with SCD by Doppler echocardiography has been recommended, using tricuspid regurgitant jet velocity (TRJV) to estimate pulmonary artery systolic pressure. However, the prevalence and risk factors of elevated TRJV in children with SCD at steady state have not been extensively defined. Methods SCD patients of the CHIC-cohort were prospectively assessed : alpha and beta genotype, G6PD, platelet-CD36 expression were determined; baseline blood parameters between 1 and 3 years of age were recorded and re-assessed every year at steady state with clinical data, TCD screening, abdominal sonography and every two years by Doppler echocardiography, evaluation of lung function and cerebral MRI/MRA. Pulmonary hypertension was defined as a TRJV ≥2.5 m/s. Univariate and multivariate logistic regression analyses were performed to evaluate risk factors for elevated TRJV. Results A total of 662 echocardiograms with available measure of TRJV were performed away from vaso-occlusive crises (VOC) and acute chest syndromes (ACS) in 320 SCD-patients (268 SS, 1 SDPunjab, 7 Sb0; 14 Sb+, 30 SC) between 12/98 and 07/09 and were included in the analyzes: 127/662 were performed in patients on hydroxurea (HU) therapy, 121 on transfusion program (TP) and 63 after stem cell transplantation (SCT). In SS/Sb0 patients, TRJV did not correlate with fractional shortening, ejection fraction, TCD velocities, systemic and diastolic blood pressure, cumulative number of VOC and ACS, LDH and SpO2, but correlated with age (r=0.258,p<0.001), height (SD) (r=-0.119, p=0.008), Hct (r=-0.091, p=0.028), MCV (r=0.109, p=0.009) and bilirubin (r=0.235, p<0.001). Elevated TRJV ≥2.5 m/s was found in 5/44 SC/Sb+ (11%) at the mean age of 12.6 ± 2.1 yr and in 57/276 SS/Sb0 (21%) (p=NS) at the mean age of 12.6 ± 4.5 yr (range 3.5-20). Univariate logistic regression analysis of the data from SS/Sb0 patients showed no significant association between elevated TRJV ≥2.5 m/s and the following variables: gender, alpha-thalassemia, G6PD deficiency, height and weight (SD), baseline blood parameters (recorded between 1 and 3 years of age), systolic/diastolic -blood pressure, cardiac rate, WBC and platelet count, HbF%, LDH, AST/ALT, history of abnormal TCD, overt and silent strokes and ongoing HU therapy and TP or a history of SCT. In contrast, CD36 deficiency (OR=4.55;CI95%:1.73-11.97,p=0.002), age (OR=1.087;CI95%:1.03-1.15,p=0.005), low SpO2 (OR=1.17;CI95%:1.05-1.32,p=0.005), Hb (OR=1.27;CI95%:1.07-1.51,p=0.007), high MCV (OR=1.03; CI95%: 1.01-1.05, p=0.008) and total bilirubin (OR=1.008; CI95%:1.002-1.014,p=0.006) were significantly associated with TRJV ≥2.5 m/s. After adjustment for age, SpO2, Hb, MCV, total bilirubin and CD36 deficiency remained significant risk factors. Conclusion In this pediatric cohort, early assessed by TCD and transfused in case of abnormal occurrence, no association was found between cerebral vasculopathy and elevated TRJV, which could be the result of early initiation of transfusion programs as soon as TCD became abnormal. The data also confirm the link between pulmonary hypertension, low oxygen saturation and hemolysis, previously reported by others. In addition, we show for the first time that CD36 deficiency is a risk factor for elevated TRJV in SCD patients. CD36 deficiency has been shown to be a common occurrence in subjects of African descent. The CD36 scavenger receptor is a multifunctional receptor, which is expressed on the surface of various cell types, and is involved in immunity, metabolism and angiogenesis. Previous studies suggested that CD36 deficiency did not modify the clinical course of SCD patients but echocardiograms had not been analyzed. Recent studies showed that hypoxia increases CD36 expression via its HIF-1 responsive promoter element and activation of the PI3K pathway, suggesting that CD36 deficient SCD patients could have an abnormal response to hypoxia. Additional studies will be needed to understand the relationship between PHT and CD36 deficiency and the role of hypoxia in these patients. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 4033 Poster Board III-969 G6PD deficiency is the more common human enzyme defect, leading typically to an acute intravascular hemolysis occurring when red cells are exposed to an oxidative stress. However, in rare patients, very low enzymatic level induces the class I G6PD deficiency according to the WHO classification, i.e. a chronic non-spherocytic hemolytic anemia. These cases are all sporadic, occur worldwide, and almost all arise from de novo independent mutations. These mutations are found at the genomic level in both hematopoietic and non hematopoietic cells and occur recurrently in “hot spots”: most of them are located in the exon 10 of the G6PD gene, implicated in the dimer formation and the stability of the active enzyme. No null or frameshift mutations have been reported yet, probably because such mutations would be lethal; indeed, a minimal residual G6PD activity is essential during embryogenesis. We report here the case of 65 years-old Caucasian man referred in 1993 for hemolytic anemia. No personal or familial history of anemia was noted. Nine and five years before, the hemoglobin (Hb) level and the mean corpuscular volume (MCV) were normal. At diagnosis, the anemia was moderate (Hb: 11.9 g/dL), macrocytic (MCV: 104 fL) and regenerative (reticulocyte count: 550G/L) with hemolytic features. Platelets and leucocytes counts were normal. No clinical or ultrasound spleen enlargement was noted. The screening tests ruled out all the classical causes of acquired hemolytic anemia. Red cells half life after Cr51 labelling was shortened with autologous (5 days) but not with allogenous red cells confirming the corpuscular mechanism of the hemolysis. Dosage of erythocyte G6PD activity revealed a very low level (from 0.6 to 1.5 UI/g of Hb, normal range 5.3-7.9). Pyruvate kinase, pyrimidine 5'-nucleotidase and hexokinase enzymatic activities were increased in agreement with the reticulocytosis. With a follow-up of 16 years, evolution was marked by a progressive worsening of the anemia, requiring 8 to 16 packed red cell transfusions per year in parallel with an iron chelation and folic acid therapy. Concomittantly, the macrocytosis increased up to 144 fL. At the molecular level, sequencing of the genomic DNA of the G6PD gene revealed presence of a single nucleotide mutation that altered the IVS 10 nucleotide 1 G>A from donor consensus sequence, leading to an impaired splicing between exon 10 and exon 11. The missplicing creates a premature termination codon giving theorically a truncated protein (464 versus 514 amino-acid). This severe genotype was discordant with the normal hemoglobin level five years before the diagnosis. Moreover, such a mutation at the germinal level would be expected to be lethal; therefore, we hypothesized that it arised at the somatic level in an hematopoietic stem cell; we measured the G6PD activity in hematopoietic and non hematopoietic cells and observed that it was decreased in red cells, polymorphonuclear cells and lymphocytes from blood, but was normal in skin fibroblasts; molecular analysis confirmed that the mutation was present in blood mononuclear cells but was absent in the fibroblasts. Bone marrow CD34+ cells were then sorted and plated at one cell per dish in the presence of a cocktail of cytokines including EPO and the different clones were harvested at day 10 for genomic analysis of the G6PD gene. Out of the 44 tested clones, we found that most of them carried the mutation (61%), but we were still able to detect a few unmutated clones (7%), reflecting the persistence of a minor polyclonal unmutated hematopoiesis. Surprisingly, we detect in the rest of the clones both the normal and mutated genotypes; at this time, we have no clear explanation to this finding. Acquired modifications of structure or expression of genes implicated in red cell physiology have been long recognized, occurring principally in myeloid malignancies such as myelodysplastic syndromes (MDS). This includes genes implicated in the red cell membrane skeleton or in haemoglobin synthesis or structure. However, our patient presented no MDS features on repeated bone marrow examination and on cytogenetic analysis. Regardless to all our data, we concluded that our patient present the first case ever reported of chronic non spherocytic anemia related to an acquired somatic mutation of the G6PD gene at the level of a hematopoietic pluripotent cell. Disclosures: No relevant conflicts of interest to declare.

Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17+ T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.

Abstract Abstract 1495 Severe congenital neutropenia (SCN) is a heterogenous group of disorders characterized by an increased susceptibility to bacterial infections. Recently, our discovery of G6PC3 deficiency in 12 patients with SCN and various developmental features highlighted the role of glucose metabolism in the viability of neutrophil granulocytes. To further delineate the molecular and clinical phenotype of this complex syndrome, we analyzed a second cohort of 23 SCN patients referred to us for molecular analysis of G6PC3 mutations. All patients had at least one syndromic feature in addition to congenital neutropenia such as such as congenital heart defects, urogenital malformations or increased venous marking. Among these 23 patients, we identified 14 patients with biallelic mutations in G6PC3. 10 patients had novel mutations in G6PC3. A comprehensive review of the clinical characteristics of these patients underlined the phenotypic variability of G6PC3 deficiency. In addition to known manifestations including cardiac (14/14) and urogenital malformations such as cryptorchidism (3/14), novel features such as facial dysmorphy (11/14) or malformation of the outer genitalia (4/14) were found. No obvious genotype-phenotype correlations could be established. All patients except one had a good response to treatment with G-CSF characterized by increased peripheral neutrophil counts and decreased frequency and severity of infections. To assess the risk of leukemogenesis, we performed a meta-analysis comparing the 14 G6PC3-deficient SCN patients combined with the 12 patients in the original publication with a cohort of 374 patients SCN patients bearing mutations in ELANE or HAX1, in which 61 developed MDS or AML. The rate of MDS/AML was found to be significantly lower in G6PC3-deficient patients (p=0.02). Our analysis suggests that the risk of transition to MDS/AML may be lower in G6PC3-deficient SCN compared with other genetically defined SCN subgroups. Disclosures: No relevant conflicts of interest to declare.

Abstract TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell– specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n = 39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n = 41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P <.001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P < .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD−CD27+ B cells (P = .019), benign lymphoproliferation (P < .001), and autoimmune complications (P = .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.

Background: The spleen is among the first organs negatively affected by sickle cell disease (SCD). Unswitched memory B cells (UMBCs) from the spleen, including the marginal zone B cells, circulate in peripheral blood and have been used as a measure of splenic function in non-hematologic disorders associated with functional asplenia. UMBC deficiency has been associated with adverse infectious and inflammatory outcomes in models of stroke and cardiovascular disease. The role of UMBCs has not been assessed in pediatric SCD. In this study, we sought to test he hypothesis that low UMBC is associated with significant infectious and inflammatory complications of SCD. Design/Method: Children seen at the Texas Children's Cancer and Hematology Centers from March - December 2018 were recruited for participation. Participants were 18 months -18 years of age. Samples were collected for complete blood count, serum analysis, and B cell subset by flow cytometry. For B cell subset quantification, whole blood samples were stained with fluorescent-labelled CD45, CD19, IgD, and CD27. The samples were analyzed by flow cytometry using the BD LSR Fortessa or LSR II (BD Biosciences, USA). In each sample, at least 2500 CD19+ events were captured. Data were analyzed using FlowJo X.V. Clinical data was abstracted from the electronic medical record into an online study database. Statistical analyses were performed using STATA. This study was approved by the Baylor College of Medicine IRB. Results: We enrolled 234 subjects. Among these, 169 had an evaluable UMBC. Those with UMBC data included 114 (67.4%) Hb SS and Hb S/b0-thalassemia, 14 (8.3%) Hb SC, Hb b+-thalassemia, and HbS/other, and 41 (24.2%) controls without SCD. There was no difference in the mean age at sampling between children with SCD and controls without SCD (8.74 vs 8.39 years, P=0.70). The geometric mean UMBC was 5.75% of all CD19+ (B) cells for controls, 4.24 % for HbSS-like group, and 5.29% for SCD patients with any other genotype. UMBC declined by 2.97% per year among all SCD subjects (P<0.01). UMBC declined 0.82% per year among all controls, although the rate of decline was not significant, P= 0.62). The change per year did not significantly differ between cohorts (P=0.26). To determine whether UMBC is associated with clinical complications of SCD, we reviewed the EMR of 127 subjects to identify any lifetime episodes of acute chest syndrome, bacteremia, blood transfusion, dactylitis, or stroke. Patients with any history of acute chest syndrome had significantly lower UMBC than those who have not had acute chest syndrome (median 4.3 vs. 6.2; P< 0.01). Patients with any history of stroke had significantly lower UMBC than those who have not had stroke (median 2.9 vs. 4.7; P=0.04). No significant difference was detected between groups with and without a history of bacteremia, blood transfusion, or dactylitis. Conclusion: We have demonstrated that children with SCD are deficient in UMBCs and that UMBC deficiency worsens with age. UMBC deficiency is associated with history of acute chest syndrome and stroke. Additional studies are needed to establish the mechanisms of UMBC deficiency and the role of UMBCs in the clinical outcomes for children with SCD. Table Disclosures Tubman: Novartis Pharmceuticals: Honoraria.

Introdução: A síndrome de Wiskott-Aldrich (SWA) é uma imunodeficiência primária rara ligada ao X caracterizada pela presença de eczema, trombocitopenia com ou sem microplaquetas e infecções recorrentes. Mais de 300 tipos de mutações associadas com o gene WAS foram descritas, incluindo oito hotspots. A diversidade destas mutações pode levar ao aparecimento de grande variabilidade nas apresentações clínicas, o que dificulta a previsão da evolução da doença baseada apenas nas manifestações iniciais. Além disso, há escassez de informações sobre a população brasileira. Objetivos: Descrever as características clínicas e genéticas de pacientes brasileiros com diagnóstico clínico de SWA. Resultados: Dezoito pacientes foram avaliados. Dezessete pacientes apresentaram os primeiros sintomas no primeiro ano de idade. Idade média para o início dos sintomas foi de 4,5 meses e média de tempo para o diagnóstico foi de 31,2 meses. Três pacientes (16,3%) foram diagnosticados após 10 anos de início dos sintomas. Dezessete pacientes (94,5%) apresentaram eczema. Os níveis plaquetários variaram entre 1.000 e 65.000/mm3 e nove pacientes (50%) apresentaram microtrombocitopenia. Dois pacientes (11,1%) apresentaram macroplaquetas. Dezesseis pacientes (88,9%) tiveram eventos hemorrágicos ao longo de suas vidas, especialmente sangramentos intestinais, urinários e petéquias. Em relação às manifestações infecciosas, otite média aguda foi a infecção mais frequente, relatada por 13 pacientes (72,2%), seguido por infecções cutâneas (66,7%). Três pacientes(16,6%) apresentaram manifestações autoimunes, incluindo nefropatia por IgA, trombose isquêmica e vasculite. A maioria dos pacientes (55,5%) não apresentou alterações nos níveis IgG. Níveis elevados de IgA só foram observados em 4 pacientes (23,5%). Redução dos níveis IgM foi observada em 7 pacientes (38,9%). Os pacientes foram classificados de acordo com um escore clínico previamente descrito. A maioria apresentou pontuações de 3 (33,3%) e 4 (27,8%). Quatro pacientes (22,2%) foram classificados com pontuação 5 devido às manifestações autoimunes ou neoplasias. Em relação à análise genética, foram encontradas mutações em 10 pacientes (55,5%). Apenas três das mutações encontradas neste estudo foram descritas previamente. Conclusão: As características clínicas dos pacientes brasileiros foram semelhantes às características observadas em outras populações, porém a análise genética revelou mutações ainda não descritas.
Introduction: Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by eczema, thrombocytopenia with or no small sized platelets and recurrent infections. More than 300 types of mutations associated with the WAS gene have been described, including eight hotspots. The diversity of these mutations can lead to the appearance of great variation in the clinical presentations, which makes it difficult to predict the evolution of the disease based only on the initial manifestations. Furthermore, there is paucity of information on WAS from the Brazilian population. Objectives: To describe the clinical and genetic characteristics of Brazilian patients with clinical diagnose of WAS. Results: Eighteen patients were evaluated. Seventeen patients presented first symptoms within first year of age. Mean age for initiating symptoms was 4,5 months and mean time for diagnosis was 31,2 months. Three patients (16.6%) were diagnosed after 10 years of initiating symptoms. Seventeen patients (94.5%) had eczema. The platelet levels ranged from 1,000 to 65,000/mm3 and nine patients (50%) presented microthrombocytopenia. Two patients (11.1%) had macroplatelets. Sixteen patients (88.9%) had hemorrhagic events throughout their lives, especially intestinal, urinary and petechial bleedings. In relation to infectious manifestations, acute media otitis was the most frequent infection, reported by 13 patients (72.2%), followed by skin infections (66.7%). Three patients (16.6%) had autoimmune manifestations including IgA nephropathy,ischemic stroke and vasculitis. Most patients (55.5%) did not present alterations in IgG levels. Twelve patients (70.6%) did not present alterations in IgA levels and elevated levels of IgA were only observed in 4 patients (23.5%). Reduction of IgM levels was observed in 7 patients (38.9%). Patients were classified according to a previously described clinical score. Most patients presented scores of 3 (33.3%) and 4 (27.8%). Four patients (22.2%) were classified with score 5 due to autoimmune or neoplastic manifestations. Regarding genetic analysis, mutations were found in 10 patients (55.5%). Only three of mutations found in this study were previously described. Conclusion: Clinical characteristics of Brazilian patients were similar to medical features observed in other populations, however genetic analysis showed undescribed mutations yet