RESUMEN
Sinusoidal obstruction syndrome (SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT), whose diagnostic criteria changed over time to achieve a timelier diagnosis. Recently, pediatric-specific criteria presented by the European Society for Blood and Marrow Transplantation (pEBMT) incorporated transfusion-refractory thrombocytopenia (RT) as an early indicator of SOS in children. However, a comparison of all individual diagnostic parameters belonging to pEBMT and former SOS diagnostic criteria has never been performed. This retrospective study conducted at a pediatric tertiary care hospital analyzed all pediatric HSCT cases diagnosed with SOS among 170 children transplanted from 2009 to 2023. Eleven patients developed SOS during this period (incidence: 11/170, 6.5%). pEBMT, Seattle, and Baltimore criteria were retrospectively applied to the 11 cases and compared, showing that RT was the earliest fulfilled parameter (median onset: 6 d post-HSCT). pEBMT and Seattle criteria identified 11/11 SOS cases, with pEBMT leading to an earlier diagnosis. RT typically manifested before diagnosis, with significantly higher platelet transfusion requirements before diagnosis than after. RT is the earliest satisfied criterion in pediatric SOS and typically occurs in the initial stages of the disease before diagnosis. Further research is needed to identify additional early indicators of pediatric SOS.
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Mutación con Ganancia de Función , Trasplante de Células Madre Hematopoyéticas , Factor de Transcripción STAT3 , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Factor de Transcripción STAT3/genética , Masculino , Trastornos del Crecimiento/etiología , Trastornos del Crecimiento/genética , Femenino , NiñoRESUMEN
Kabuki Syndrome (KS) is a multisystemic genetic disorder. A portion of patients has immunological manifestations characterized by increased susceptibility to infections and autoimmunity. Aiming to describe the clinical and laboratory immunological aspects of KS, we conducted a retrospective multicenter observational study on patients with KS treated in centers affiliated to the Italian Primary Immunodeficiency Network.Thirty-nine patients were enrolled, with a median age at evaluation of 10 years (range: 3 m-21y). All individuals had organ malformations of variable severity. Congenital heart defect (CHD) was present in 19/39 patients (49%) and required surgical correction in 9/39 (23%), with associated thymectomy in 7/39 (18%). Autoimmune cytopenia occurred in 6/39 patients (15%) and was significantly correlated with thymectomy (p < 0.002), but not CHD. Individuals with cytopenia treated with mycophenolate as long-term immunomodulatory treatment (n = 4) showed complete response. Increased susceptibility to infections was observed in 22/32 patients (69%). IgG, IgA, and IgM were low in 13/29 (45%), 13/30 (43%) and 4/29 (14%) patients, respectively. Immunoglobulin substitution was required in three patients. Lymphocyte subsets were normal in all patients except for reduced naïve T-cells in 3/15 patients (20%) and reduced memory switched B-cells in 3/17 patients (18%). Elevated CD3 + TCRαß + CD4-CD8-T-cells were present in 5/17 individuals (23%) and were correlated with hematological and overall autoimmunity (p < 0.05).In conclusion, immunological manifestations of KS in our cohort include susceptibility to infections, antibody deficiency, and autoimmunity. Autoimmune cytopenia is correlated with thymectomy and elevated CD3 + TCRαß + CD4-CD8-T-cells, and benefits from treatment with mycophenolate.
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Anomalías Múltiples , Cara/anomalías , Enfermedades Hematológicas , Enfermedades Vestibulares , Humanos , Femenino , Estudios Retrospectivos , Masculino , Niño , Enfermedades Hematológicas/inmunología , Enfermedades Hematológicas/terapia , Adolescente , Italia , Enfermedades Vestibulares/inmunología , Preescolar , Adulto Joven , Anomalías Múltiples/inmunología , Lactante , Autoinmunidad , AdultoRESUMEN
ABSTRACT: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.
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Genotipo , Síndrome de Wiskott-Aldrich , Humanos , Adolescente , Niño , Masculino , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/diagnóstico , Síndrome de Wiskott-Aldrich/terapia , Femenino , Preescolar , Adulto , Estudios Retrospectivos , Lactante , Adulto Joven , Biomarcadores , Trasplante de Células Madre Hematopoyéticas , Índice de Severidad de la Enfermedad , Proteína del Síndrome de Wiskott-Aldrich/genética , Estudios de Seguimiento , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
GATA2 deficiency is a rare disorder encompassing a broadly variable phenotype and its clinical picture is continuously evolving. Since it was first described in 2011, up to 500 patients have been reported. Here, we describe a cohort of 31 Italian patients (26 families) with molecular diagnosis of GATA2 deficiency. Patients were recruited contacting all the Italian Association of Pediatric Hematology and Oncology (AIEOP) centers, the Hematology Department in their institution and Italian societies involved in the field of vascular anomalies, otorhinolaryngology, dermatology, infectious and respiratory diseases. Median age at the time of first manifestation, molecular diagnosis and last follow-up visit was 12.5 (age-range, 2-52 years), 18 (age-range, 7-64 years) and 22 years (age-range, 3-64), respectively. Infections (39%), hematological malignancies (23%) and undefined cytopenia (16%) were the most frequent symptoms at the onset of the disease. The majority of patients (55%) underwent hematopoietic stem cell transplantation. During the follow-up rarer manifestations emerged. The clinical penetrance was highly variable, with the coexistence of severely affected pediatric patients and asymptomatic adults in the same pedigree. Two individuals remained asymptomatic at the last follow-up visit. Our study highlights new (pilonidal cyst/sacrococcygeal fistula, cholangiocarcinoma and gastric adenocarcinoma) phenotypes and show that lymphedema may be associated with null/regulatory mutations. Countrywide studies providing long prospective follow-up are essential to unveil the exact burden of rarer manifestations and the natural history in GATA2 deficiency.
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Deficiencia GATA2 , Trasplante de Células Madre Hematopoyéticas , Adolescente , Adulto , Niño , Preescolar , Humanos , Persona de Mediana Edad , Adulto Joven , Deficiencia GATA2/diagnóstico , Deficiencia GATA2/genética , Deficiencia GATA2/terapia , Estudios de Asociación Genética , Italia/epidemiología , Estudios ProspectivosRESUMEN
Background: GATA2 deficiency is an inborn error of immunity (IEI) characterized by infectious susceptibility and increased risk of myelodysplasia leading to acute myeloid leukaemia (AML). Oral anomalies already described in this disorder include recurrent viral and fungal infections and oral ulcers. Material and Methods: We report a 9-year-old girl presenting with AML with myelodysplasia-related changes, monosomy 7 karyotype on marrow aspirate, numerous flat warts on her hands and multiple dental caries at oral cavity inspection. Dental evaluation and genetic testing (Sanger sequencing) for GATA2 were carried out considering the peculiar clinical presentation. Results: Dental evaluation showed extensive caries and periodontal disease, while genetic studies revealed a known c.1009 C>T (p.Arg337X) mutation in GATA2. After multidisciplinary discussion, affected teeth were extracted before chemotherapy, in general anaesthesia, together with scaling and root planning of the alveolar sockets. Subsequently, the patient underwent hematopoietic stem cell transplantation (HSCT) from her HLA-matched GATA2 wild-type sibling, who did not bear any dental anomalies. No dento-alveolar infections were encountered during post-chemotherapy aplasia. Conclusions: This case first describes the association between GATA2 deficiency and extensive dental caries with periodontal disease, highlighting the importance of an early dental evaluation and intervention in children with leukaemia. Key words:GATA2 deficiency, Inborn errors of immunity, teeth, dental decay, multidisciplinary approach.
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Current practices vary widely regarding the immunological work-up and management of patients affected with defects in thymic development (DTD), which include chromosome 22q11.2 microdeletion syndrome (22q11.2del) and other causes of DiGeorge syndrome (DGS) and coloboma, heart defect, atresia choanae, retardation of growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE) syndrome. Practice variations affect the initial and subsequent assessment of immune function, the terminology used to describe the condition and immune status, the accepted criteria for recommending live vaccines, and how often follow-up is needed based on the degree of immune compromise. The lack of consensus and widely varying practices highlight the need to establish updated immunological clinical practice guidelines. These guideline recommendations provide a comprehensive review for immunologists and other clinicians who manage immune aspects of this group of disorders.
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Síndrome CHARGE , Síndrome de DiGeorge , Cardiopatías Congénitas , Humanos , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/terapia , Deleción Cromosómica , Cromosomas , Cardiopatías Congénitas/genéticaRESUMEN
BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.
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Enfermedades del Sistema Inmune , Síndromes de Inmunodeficiencia , Niño , Humanos , Autoinmunidad/genética , Estudios de Cohortes , Mutación con Ganancia de Función , Síndromes de Inmunodeficiencia/genética , Mutación , Factor de Transcripción STAT3/genética , Proliferación Celular , LinfocitosRESUMEN
Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder characterized by benign or malignant lymphoproliferation and autoimmunity. Classically, ALPS is due to mutations in FAS and other related genes; however, recent research revealed that other genes could be responsible for similar clinical features. Therefore, ALPS classification and diagnostic criteria have changed over time, and several ALPS-like disorders have been recently identified. Moreover, mutations in FAS often show an incomplete penetrance, and certain genotypes have been associated to a dominant or recessive inheritance pattern. FAS mutations may also be acquired or could become pathogenic when associated to variants in other genes, delineating a possible digenic type of inheritance. Intriguingly, variants in FAS and increased TCR αß double-negative T cells (DNTs, a hallmark of ALPS) have been identified in multifactorial autoimmune diseases, while FAS itself could play a potential role in carcinogenesis. These findings suggest that alterations of FAS-mediated apoptosis could trespass the universe of inborn errors of immunity and that somatic mutations leading to ALPS could only be the tip of the iceberg of acquired immunodeficiencies.
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Síndrome Linfoproliferativo Autoinmune/genética , Mutación , Receptor fas/genética , Animales , Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/inmunología , Autoinmunidad , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/inmunología , Receptor fas/inmunologíaRESUMEN
BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT). OBJECTIVES: This study sought to characterize HCT outcomes in APDS. METHODS: Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT. RESULTS: Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT. CONCLUSIONS: Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.
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Trasplante de Células Madre Hematopoyéticas , Enfermedades de Inmunodeficiencia Primaria/terapia , Adolescente , Adulto , Anciano , Niño , Preescolar , Fosfatidilinositol 3-Quinasa Clase I , Femenino , Rechazo de Injerto , Humanos , Estimación de Kaplan-Meier , Inhibidores mTOR/uso terapéutico , Masculino , Persona de Mediana Edad , Fosfatidilinositol 3-Quinasas/genética , Enfermedades de Inmunodeficiencia Primaria/mortalidad , Estudios Retrospectivos , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
CD25, Signal transducer and activator of transcription 5B (STAT5B) and Forkhead box P3 (FOXP3) are critical mediators of Interleukin-2 (IL-2) signaling pathway in regulatory T cells (Tregs). CD25 (i.e., IL-2 Receptor α) binds with high affinity to IL-2, activating STAT5B-mediated signaling that eventually results in transcription of FOXP3, a master regulator of Treg function. Consequently, loss-of-function mutations in these proteins give rise to Treg disorders (i.e., Tregopathies) that clinically result in multiorgan autoimmunity. Immunodysregulation, Polyendocrinopathy Enteropathy X-linked (IPEX), due to mutations in FOXP3, has historically been the prototype of Tregopathies. This review describes current knowledge about defects in CD25, STAT5B, and FOXP3, highlighting that these disorders both share a common biological background and display comparable clinical features. However, specific phenotypes are associated with each of these syndromes, while certain laboratory findings could be helpful tools for clinicians, in order to achieve a prompt genetic diagnosis. Current treatment strategies will be outlined, keeping an eye on gene editing, an interesting therapeutic perspective that could definitely change the natural history of these disorders.
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Autoimmune Lymphoproliferative Syndrome (ALPS), commonly caused by mutations in the FAS gene, is a disease with variable penetrance. Subjects may be asymptomatic, or they may present with lymphadenopathy, splenomegaly, cytopenias, or malignancy. Prompt recognition of ALPS is needed for optimal management. We describe a multi-generational cohort presenting with clinical manifestations of ALPS, and a previously unreported heterozygous missense variant of uncertain significance in FAS (c.758G >T, p.G253V), located in exon 9. Knowledge of the underlying genetic defect permitted prompt targeted therapy to treat acute episodes of cytopenia. This cohort underscores the importance of genetic testing in subjects with clinical features of ALPS and should facilitate the reclassification of this variant as pathogenic.
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COVID-19 , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , SARS-CoV-2/metabolismo , Acondicionamiento Pretrasplante , COVID-19/sangre , COVID-19/terapia , Humanos , Lactante , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/terapia , Masculino , Trasplante HomólogoRESUMEN
Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is a rare disorder that has become a model of monogenic autoimmunity. IPEX is caused by mutations in FOXP3 gene, a master regulator of regulatory T cells (Treg). Cases reported in the last 20 years demonstrate that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes (T1D) and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features (e.g., atrophic gastritis, interstitial lung disease, nephropathy etc.). Several atypical presentations have recently been reported, suggesting that IPEX incidence might be underestimated. Immunosuppression (IS) treatment strategies can control the disease, however at the moment allogeneic hematopoietic stem cell transplantation (HSCT) is the only available definitive cure, therefore it is important to achieve a prompt diagnosis. This review aims to describe unusual clinical phenotypes, beyond classical IPEX. Overall, our analysis contributes to increase awareness and finally improve diagnosis and treatment intervention in IPEX in order to ensure a good quality of life.
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Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.
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Anomalías Múltiples , Síndrome Linfoproliferativo Autoinmune , Cara/anomalías , Enfermedades Hematológicas , Enfermedades de Inmunodeficiencia Primaria , Enfermedades Vestibulares , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Anomalías Múltiples/inmunología , Adolescente , Adulto , Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/genética , Síndrome Linfoproliferativo Autoinmune/inmunología , Niño , Preescolar , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/inmunología , Femenino , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/inmunología , Humanos , Lactante , Masculino , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Estudios Prospectivos , Enfermedades Vestibulares/diagnóstico , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/inmunologíaRESUMEN
IKAROS is a transcription factor forming homo- and heterodimers and regulating lymphocyte development and function. Germline mutations affecting the IKAROS N-terminal DNA binding domain, acting in a haploinsufficient or dominant-negative manner, cause immunodeficiency. Herein, we describe 4 germline heterozygous IKAROS variants affecting its C-terminal dimerization domain, via haploinsufficiency, in 4 unrelated families. Index patients presented with hematologic disease consisting of cytopenias (thrombocytopenia, anemia, neutropenia)/Evans syndrome and malignancies (T-cell acute lymphoblastic leukemia, Burkitt lymphoma). These dimerization defective mutants disrupt homo- and heterodimerization in a complete or partial manner, but they do not affect the wild-type allele function. Moreover, they alter key mechanisms of IKAROS gene regulation, including sumoylation, protein stability, and the recruitment of the nucleosome remodeling and deacetylase complex; none affected in N-terminal DNA binding defects. These C-terminal dimerization mutations are largely associated with hematologic disorders, display dimerization haploinsufficiency and incomplete clinical penetrance, and differ from previously reported allelic variants in their mechanism of action. Dimerization mutants contribute to the growing spectrum of IKAROS-associated diseases displaying a genotype-phenotype correlation.
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Células Germinativas/metabolismo , Haploinsuficiencia/genética , Neoplasias Hematológicas/patología , Factor de Transcripción Ikaros/metabolismo , Multimerización de Proteína , Adolescente , Adulto , Anciano , Secuencia de Aminoácidos , Secuencia de Bases , Centrómero/metabolismo , Segregación Cromosómica/genética , ADN/metabolismo , Femenino , Regulación de la Expresión Génica , Heterocromatina/metabolismo , Histona Desacetilasa 1/metabolismo , Humanos , Factor de Transcripción Ikaros/química , Factor de Transcripción Ikaros/genética , Masculino , Persona de Mediana Edad , Proteínas Mutantes/metabolismo , Mutación/genética , Linaje , Unión Proteica , Procesamiento Proteico-Postraduccional , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sumoilación , Transcripción GenéticaRESUMEN
Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.
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Enfermedades de Inmunodeficiencia Primaria/epidemiología , Adolescente , Adulto , Niño , Preescolar , Bases de Datos Factuales , Femenino , Geografía Médica , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Lactante , Recién Nacido , Italia/epidemiología , Masculino , Vigilancia de la Población , Prevalencia , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/historia , Enfermedades de Inmunodeficiencia Primaria/terapia , Pronóstico , Sistema de Registros , Adulto JovenRESUMEN
STAT3 gain-of-function (GOF) mutations can be responsible for an incomplete phenotype mainly characterized by hematological autoimmunity, even in the absence of other organ autoimmunity, growth impairment, or severe infections. We hereby report a case with an incomplete form of STAT3 GOF intensified by a concomitant hereditary hematological disease, which misleads the diagnosis. The patient presented with lymphadenopathy, splenomegaly, hypogammaglobulinemia, and severe autoimmune hemolytic anemia (AIHA) with critical complications, including stroke. A Primary Immune Regulatory Disorders (PIRD) was suspected, and molecular analysis revealed a de novo STAT3 gain-of-function mutation. The response to multiple immune suppressive treatments was ineffective, and further investigations revealed a spectrin deficiency. Ultimately, hematopoietic stem cell transplantation from a matched unrelated donor was able to cure the patient. Our case shows an atypical presentation of STAT3 GOF associated with hereditary spherocytosis, and how achievement of a good long-term outcome depends on a strict clinical and laboratory monitoring, as well as on prompt therapeutic intervention.