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The epidemiology of inborn errors of immunity (IEI) in the Republic of Ireland was first published in 2005 but has not been updated since. IEI prevalence data from Northern Ireland was last published in 2018. Using data from the United Kingdom Primary Immune Deficiency (UKPID) and European Society for Immunodeficiencies (ESID) registries, we reviewed all registered cases of IEI affecting adult patients ≥ 18 years of age from the two largest immunology specialist centres in Northern Ireland and the Republic of Ireland, respectively and calculated the combined minimum adult prevalence of IEI on the island of Ireland for the first time. We also recorded data pertaining to presenting symptoms of IEI, diagnostic delay, immunoglobulin data, and genetic testing, as well as briefly reporting data pertaining to secondary immunodeficiency in both countries. As of 1 May 2020, we identified a minimum adult IEI prevalence in Ireland of 8.85/100,000 population.
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Diagnóstico Tardío , Síndromes de Inmunodeficiencia , Adulto , Humanos , Inmunoglobulinas , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/epidemiología , Sistema de Registros , Reino Unido/epidemiologíaRESUMEN
Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.
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Síndromes de Inmunodeficiencia/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Sistema de Registros , Sirolimus/uso terapéutico , Adolescente , Adulto , Niño , Preescolar , Fosfatidilinositol 3-Quinasa Clase I , Europa (Continente) , Humanos , Persona de Mediana Edad , Enfermedades de Inmunodeficiencia Primaria , Sociedades Médicas , Adulto JovenRESUMEN
BACKGROUND: Gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined immunodeficiency. Disease manifestations can be mild or severe and life-threatening. Hematopoietic stem cell transplantation (HSCT) has been used in some patients with more severe symptoms to treat and cure the disorder. However, the outcome of HSCT for this disorder is not well established. OBJECTIVE: We sought to aggregate the worldwide experience of HSCT in patients with GOF-STAT1 mutations and to assess outcomes, including donor engraftment, overall survival, graft-versus-host disease, and transplant-related complications. METHODS: Data were collected from an international cohort of 15 patients with GOF-STAT1 mutations who had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was in fact a GOF mutation. RESULTS: Primary donor engraftment in this cohort of 15 patients with GOF-STAT1 mutations was 74%, and overall survival was only 40%. Secondary graft failure was common (50%), and posttransplantation event-free survival was poor (10% by 100 days). A subset of patients had hemophagocytic lymphohistiocytosis before transplant, contributing to their poor outcomes. CONCLUSION: Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.
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Mutación con Ganancia de Función , Predisposición Genética a la Enfermedad , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/mortalidad , Trasplante de Células Madre Hematopoyéticas , Factor de Transcripción STAT1/genética , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/inmunología , Humanos , Masculino , Estudios Retrospectivos , Factores de Riesgo , Factor de Transcripción STAT1/inmunología , Tasa de SupervivenciaRESUMEN
PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients. METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients. RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients. CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.
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Candidiasis Mucocutánea Crónica/diagnóstico , Síndromes de Inmunodeficiencia/diagnóstico , Leucocitos Mononucleares/inmunología , Mutación/genética , Factor de Transcripción STAT1/metabolismo , Adulto , Candidiasis Mucocutánea Crónica/genética , Células Cultivadas , Citocinas/metabolismo , Análisis Mutacional de ADN , Femenino , Humanos , Síndromes de Inmunodeficiencia/genética , Masculino , Linaje , Fenotipo , Estructura Terciaria de Proteína/genética , Factor de Transcripción STAT1/genéticaRESUMEN
Hyperimmunoglobulin D and periodic fever syndrome (HIDS) is a rare, autoinflammatory condition caused by mutations in the mevalonate kinase gene. There is no standard treatment for HIDS, and randomized controlled trials are lacking. Corticosteroids, colchicine, nonsteroidal anti-inflammatory drugs, statins, and cyclosporine are of limited efficacy in controlling this condition. Recent case reports suggest that most patients respond to etanercept or anakinra. Interleukin 6 blockade in HIDS has not been described. We report the case of a 13-year-old girl with HIDS, who failed to respond to colchicine, corticosteroids, etanercept, and anakinra but was successfully treated with the anti-IL-6 monoclonal antibody, tocilizumab.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Interleucina-6/antagonistas & inhibidores , Deficiencia de Mevalonato Quinasa/tratamiento farmacológico , Adolescente , Anticuerpos Monoclonales Humanizados/inmunología , Colchicina/uso terapéutico , Etanercept , Femenino , Humanos , Inmunoglobulina G/uso terapéutico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Interleucina-6/inmunología , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
INTRODUCTION: Schnitzler Syndrome is an uncommon, inflammatory condition that presents with a constellation of chronic unremitting urticaria, fever, bone pain, arthralgia or arthritis, and a monoclonal IgM gammopathy. There is usually neutrophilia and raised inflammatory markers. Delayed diagnosis is common and treatment often unsuccessful. CASE PRESENTATION: We report the case of a 43-year-old caucasian man who presented with urticaria unresponsive to conventional therapy. There was considerable delay in recognition of this as Schnitzler Syndrome, and symptoms were unresponsive to conventional immunosuppressive therapy.Commencement of anakinra was associated with a rapid and sustained clinical response. CONCLUSION: Schnitzler Syndrome is a rare disorder that mimics chronic idiopathic urticaria. This diagnosis should be considered in patients with urticaria unresponsive to antihistamines and conventional immunosuppressive therapy. Anakinra is an effective treatment although further studies are required, to determine long term therapeutic requirements and assess any potential adverse effects.
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OBJECTIVE: To determine and compare the prevalence of MSH6 (a mismatch repair gene) mutations in a cohort of families with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), and in an unselected cohort of endometrial cancer patients (EC). DESIGN: Two patient cohorts participated in the study. A cohort of HNPCC families who were known to the Regional Medical Genetics department, and an unselected cohort of patients with a history of EC. All participants received genetic counselling on the implications of molecular testing, and blood was taken for DNA extraction with consent. All samples underwent sequencing and Multiple Ligation probe analysis (MLPA) for mutations in MSH6. POPULATIONS: DNA from one hundred and forty-three probands from HNPCC families and 125 patients with EC were included in the study. METHODS: Molecular analysis of DNA in all participants from both cohorts for mutations in MSH6. OUTCOME MEASURES: Prevalence of pathogenic mutations in MSH6. RESULTS: A truncating mutation in MSH6 was identified in 3.8% (95% CI 1.0-9.5%) of patients in the endometrial cancer cohort, and 2.6% (95% CI 0.5-7.4%) of patients in the HNPCC cohort. A missense mutation was identified in 2.9% and 4.4% of the same cohorts respectively. No genomic rearrangements in MSH6 were identified. CONCLUSION: MSH6 mutations are more common in EC patients than HNPCC families. Genomic rearrangements do not contribute to a significant proportion of mutations in MSH6, but missense variants are relatively common and their pathogenicity can be uncertain. HNPCC families may be ascertained through an individual presenting with EC, and recognition of these families is important so that appropriate cancer surveillance can be put in place.
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Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Endometriales/genética , Mutación de Línea Germinal , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Proteínas de Unión al ADN/genética , Neoplasias Endometriales/epidemiología , Femenino , Asesoramiento Genético , Humanos , Masculino , Persona de Mediana Edad , Irlanda del Norte/epidemiología , Prevalencia , Factores de RiesgoRESUMEN
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 and TSC2 genes on chromosomes 9 and 16 respectively. Diagnosis is based on clinical features but can be difficult as a result of variable phenotypic expression. With the advantage of mutation analysis in making a diagnosis of TSC, and improved identification of the associated clinical features, there have been few new data on its prevalence and on the proportion of cases due to new mutations. We have performed a retrospective epidemiological study on the prevalence of TSC, the clinical features attributed to it, and the availability of mutational analysis. We identified 73 known patients with TSC (5 deceased): 39 were female and 34 male. Ages ranged from 10 months to 69 years, with a mean age of 27 years 11 months (SD 16y 10mo). The point prevalence of TSC in our study was estimated at 1 out of 24 956 on the prevalence day (30 April 2004). The majority of patients (42.5%) were diagnosed at less than 15 months of age; 25% were not given a diagnosis on first developing symptoms. In all, 93.2% had epilepsy and 71.2% had a learning disability. A mutation was identified in 95.8% of those tested (26% TSC1 and 74% TSC2). TSC2 mutations were correlated with a more severe phenotype. The new mutation rate was calculated at 64%. We conclude that the prevalence of TSC is higher than previously calculated. We recommend that all children with epilepsy be assessed for features of TSC. Larger studies will be required to assess the prevalence of mutations in each gene, and genotype-phenotype correlation.