RESUMEN
NK cell deficiency (NKD) occurs when an individual's major clinical immunodeficiency derives from abnormal NK cells and is associated with several genetic etiologies. Three categories of ß-actin-related diseases with over 60 ACTB (ß-actin) variants have previously been identified, none with a distinct NK cell phenotype. An individual with mild developmental delay, macrothrombocytopenia, and susceptibility to infections, molluscum contagiosum virus, and EBV-associated lymphoma had functional NKD for over a decade. A de novo ACTB variant encoding G342D ß-actin was identified and was consistent with the individual's developmental and platelet phenotype. This novel variant also was found to have direct impact in NK cells because its expression in the human NK cell line YTS (YTS-NKD) caused increased cell spreading in lytic immune synapses created on activating surfaces. YTS-NKD cells were able to degranulate and perform cytotoxicity, but they demonstrated defective serial killing because of prolonged conjugation to the killed target cell and thus were effectively unable to terminate lytic synapses. G342D ß-actin results in a novel, to our knowledge, mechanism of functional NKD via increased synaptic spreading and defective lytic synapse termination with resulting impaired serial killing, leading to overall reductions in NK cell cytotoxicity.
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Actinas , Síndromes de Inmunodeficiencia , Humanos , Actinas/metabolismo , Células Asesinas Naturales , Línea Celular , Plaquetas/metabolismo , Síndromes de Inmunodeficiencia/metabolismoRESUMEN
BACKGROUND: Although most individuals effectively control herpesvirus infections, some suffer from severe and/or recurrent infections. A subset of these patients possess defects in natural killer (NK) cells, lymphocytes that recognize and lyse herpesvirus-infected cells; however, the genetic etiology is rarely diagnosed. PLCG2 encodes a signaling protein in NK-cell and B-cell signaling. Dominant-negative or gain-of-function variants in PLCG2 cause cold urticaria, antibody deficiency, and autoinflammation. However, loss-of-function variants and haploinsufficiency have not been reported to date. OBJECTIVES: The investigators aimed to identify the genetic cause of NK-cell immunodeficiency in 2 families and herein describe the functional consequences of 2 novel loss-of-function variants in PLCG2. METHODS: The investigators employed whole-exome sequencing in conjunction with mass cytometry, microscopy, functional assays, and a mouse model of PLCG2 haploinsufficiency to investigate 2 families with NK-cell immunodeficiency. RESULTS: The investigators identified novel heterozygous variants in PLCG2 in 2 families with severe and/or recurrent herpesvirus infections. In vitro studies demonstrated that these variants were loss of function due to haploinsufficiency with impaired NK-cell calcium flux and cytotoxicity. In contrast to previous PLCG2 variants, B-cell function remained intact. Plcg2+/- mice also displayed impaired NK-cell function with preserved B-cell function, phenocopying human disease. CONCLUSIONS: PLCG2 haploinsufficiency represents a distinct syndrome from previous variants characterized by NK-cell immunodeficiency with herpesvirus susceptibility, expanding the spectrum of PLCG2-related disease.
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Haploinsuficiencia , Síndromes de Inmunodeficiencia , Fosfolipasa C gamma , Animales , Humanos , Ratones , Infecciones por Herpesviridae , Síndromes de Inmunodeficiencia/genética , Células Asesinas Naturales , Transducción de Señal , Fosfolipasa C gamma/genéticaRESUMEN
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
Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.
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Agammaglobulinemia/genética , Linfocitos B/patología , Cardiomiopatía Hipertrófica/genética , Proteínas Portadoras/genética , Síndromes de Inmunodeficiencia/genética , Linfopenia/genética , Adulto , Animales , Linfocitos B/metabolismo , Niño , Preescolar , Cromosomas Humanos Par 5/genética , Codón sin Sentido , Consanguinidad , Enfermedad de Crohn/genética , Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo/genética , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Cardiopatías Congénitas/genética , Humanos , Infecciones/etiología , Mutación con Pérdida de Función , Masculino , Ratones , Neutropenia/genética , Linaje , Disomía Uniparental , Secuenciación del ExomaRESUMEN
BACKGROUND: Newborn screening can identify neonatal T-cell lymphopenia through detection of a low number of copies of T-cell receptor excision circles in dried blood spots collected at birth. After a positive screening result, further diagnostic testing is required to determine whether the subject has severe combined immunodeficiency or other causes of T-cell lymphopenia. Even after thorough evaluation, approximately 15% of children with a positive result of newborn screening for T-cell receptor excision circles remain genetically undiagnosed. Identifying the underlying genetic etiology is necessary to guide subsequent clinical management and family planning. OBJECTIVE: We sought to elucidate the genetic basis of patients with T-cell lymphopenia without an apparent genetic diagnosis. METHODS: We used clinical genomic testing as well as functional and immunologic assays to identify and elucidate the genetic and mechanistic basis of T-cell lymphopenia. RESULTS: We report 2 unrelated individuals with nonsevere T-cell lymphopenia and abnormal T-cell receptor excision circles who harbor heterozygous loss-of-function variants in forkhead box I3 transcription factor (FOXI3). CONCLUSION: Our findings support the notion that haploinsufficiency of FOXI3 results in T-cell lymphopenia with variable expressivity and that FOXI3 may be a key modulator of thymus development.
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Genómica , Receptores de Antígenos de Linfocitos T , Recién Nacido , Niño , Humanos , Receptores de Antígenos de Linfocitos T/genética , Linfocitos TRESUMEN
BACKGROUND: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. OBJECTIVE: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. METHODS: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing. RESULTS: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. CONCLUSIONS: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.
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Trastornos Linfoproliferativos/genética , Adolescente , Autoinmunidad , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Pruebas Genéticas , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Inmunidad/genética , Lactante , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/mortalidad , Masculino , Secuenciación del Exoma , Adulto JovenRESUMEN
SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.
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Inestabilidad Cromosómica , Daño del ADN , Variación Genética , Anomalías Musculoesqueléticas/patología , FN-kappa B/genética , Osteocondrodisplasias/patología , Adolescente , Adulto , Alelos , Animales , Células Cultivadas , Niño , Preescolar , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Estudios de Asociación Genética , Humanos , Ratones , Ratones Noqueados , Anomalías Musculoesqueléticas/genética , Osteocondrodisplasias/genética , Secuenciación del Exoma , Adulto Joven , Pez CebraRESUMEN
Premature termination codon (PTC)-bearing transcripts are often degraded by nonsense-mediated decay (NMD) resulting in loss-of-function (LoF) alleles. However, not all PTCs result in LoF mutations, i.e., some such transcripts escape NMD and are translated to truncated peptide products that result in disease due to gain-of-function (GoF) effects. Since the location of the PTC is a major factor determining transcript fate, we hypothesized that depletion of protein-truncating variants (PTVs) within the gene region predicted to escape NMD in control databases could provide a rank for genic susceptibility for disease through GoF versus LoF. We developed an NMD escape intolerance score to rank genes based on the depletion of PTVs that would render them able to escape NMD using the Atherosclerosis Risk in Communities Study (ARIC) and the Exome Aggregation Consortium (ExAC) control databases, which was further used to screen the Baylor-Center for Mendelian Genomics disease database. This analysis revealed 1,996 genes significantly depleted for PTVs that are predicted to escape from NMD, i.e., PTVesc; further studies provided evidence that revealed a subset as candidate genes underlying Mendelian phenotypes. Importantly, these genes have characteristically low pLI scores, which can cause them to be overlooked as candidates for dominant diseases. Collectively, we demonstrate that this NMD escape intolerance score is an effective and efficient tool for gene discovery in Mendelian diseases due to production of truncated or altered proteins. More importantly, we provide a complementary analytical tool to aid identification of genes associated with dominant traits through a mechanism distinct from LoF.
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Mutación con Ganancia de Función/genética , Mutación/genética , Alelos , Codón sin Sentido/genética , Bases de Datos Genéticas , Exoma/genética , Humanos , Degradación de ARNm Mediada por Codón sin Sentido/genética , FenotipoRESUMEN
The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.
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Predisposición Genética a la Enfermedad , Chaperonas Moleculares/genética , Mutación/genética , Degradación de ARNm Mediada por Codón sin Sentido/genética , Secuencia de Bases , Línea Celular , Estrés del Retículo Endoplásmico , Exones/genética , Familia , Mutación del Sistema de Lectura/genética , Heterocigoto , Humanos , Síndromes de Inmunodeficiencia/genética , Inmunofenotipificación , Recién Nacido , Inflamación/patología , Interferón Tipo I/metabolismo , Masculino , Proteínas Mutantes/metabolismo , Fenotipo , Complejo de la Endopetidasa Proteasomal/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Síndrome , Respuesta de Proteína DesplegadaRESUMEN
PURPOSE: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. RESULTS: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. CONCLUSION: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.
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Epilepsia , N-Metiltransferasa de Histona-Lisina , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Epilepsia/diagnóstico , Epilepsia/genética , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Masculino , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Fenotipo , Convulsiones/diagnóstico , Convulsiones/genéticaRESUMEN
Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)-associated lymphoma. Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.
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Enfermedades Autoinmunes/genética , Síndromes de Inmunodeficiencia/genética , Linfoma/genética , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Enfermedades Autoinmunes/inmunología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Síndromes de Inmunodeficiencia/inmunología , Linfoma/inmunología , Masculino , Linaje , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/deficienciaRESUMEN
Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have a profound effect on clinical management decisions. Therefore clinical providers must demonstrate proficiency in interpreting genetic data. Because of the need for increased knowledge regarding this practice, the American Academy of Allergy, Asthma & Immunology Primary Immunodeficiency Diseases Committee established a work group that reviewed and summarized information concerning appropriate methods, tools, and resources for evaluating variants identified by genetic testing. Strengths and limitations of tests frequently ordered by clinicians were examined. Summary statements and tables were then developed to guide the interpretation process. Finally, the need for research and collaboration was emphasized. Greater understanding of these important concepts will improve the diagnosis and management of patients with suspected primary immunodeficiency diseases.
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Pruebas Genéticas , Enfermedades de Inmunodeficiencia Primaria , Asma , Humanos , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/terapia , Estados UnidosRESUMEN
The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age (P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy (P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.
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Pruebas Genéticas , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Linfohistiocitosis Hemofagocítica/genética , Adolescente , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Recién Nacido , Linfohistiocitosis Hemofagocítica/patología , Linfohistiocitosis Hemofagocítica/terapia , Masculino , Herencia MultifactorialRESUMEN
BACKGROUND: Natural killer (NK) cells are critical innate effector cells whose development is dependent on the Janus kinase-signal transducer and activator of transcription (STAT) pathway. NK cell deficiency can result in severe or refractory viral infections. Patients with STAT1 gain-of-function (GOF) mutations have increased viral susceptibility. OBJECTIVE: We sought to investigate NK cell function in patients with STAT1 GOF mutations. METHODS: NK cell phenotype and function were determined in 16 patients with STAT1 GOF mutations. NK cell lines expressing patients' mutations were generated with clustered regularly interspaced short palindromic repeats (CRISPR-Cas9)-mediated gene editing. NK cells from patients with STAT1 GOF mutations were treated in vitro with ruxolitinib. RESULTS: Peripheral blood NK cells from patients with STAT1 GOF mutations had impaired terminal maturation. Specifically, patients with STAT1 GOF mutations have immature CD56dim NK cells with decreased expression of CD16, perforin, CD57, and impaired cytolytic function. STAT1 phosphorylation was increased, but STAT5 was aberrantly phosphorylated in response to IL-2 stimulation. Upstream inhibition of STAT1 signaling with the small-molecule Janus kinase 1/2 inhibitor ruxolitinib in vitro and in vivo restored perforin expression in CD56dim NK cells and partially restored NK cell cytotoxic function. CONCLUSIONS: Properly regulated STAT1 signaling is critical for NK cell maturation and function. Modulation of increased STAT1 phosphorylation with ruxolitinib is an important option for therapeutic intervention in patients with STAT1 GOF mutations.
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Síndromes de Inmunodeficiencia/inmunología , Células Asesinas Naturales/efectos de los fármacos , Pirazoles/farmacología , Factor de Transcripción STAT1/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Mutación con Ganancia de Función , Humanos , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Síndromes de Inmunodeficiencia/genética , Quinasas Janus/antagonistas & inhibidores , Células Asesinas Naturales/inmunología , Masculino , Nitrilos , PirimidinasRESUMEN
BACKGROUND: Heterozygous gain-of-function mutations in PI3K110δ lead to lymphadenopathy, lymphoid hyperplasia, EBV and cytomegalovirus viremia, and sinopulmonary infections. OBJECTIVE: The known role of natural killer (NK) cell function in the control of EBV and cytomegalovirus prompted us to investigate the functional and phenotypic effects of PI3K110δ mutations on NK cell subsets and cytotoxic function. METHODS: Mutations in patients were identified by using whole-exome or targeted sequencing. We performed NK cell phenotyping and functional analysis of patients' cells using flow cytometry, standard Cr51 cytotoxicity assays, and quantitative confocal microscopy. RESULTS: PI3K110δ mutations led to an altered NK cell developmental phenotype and cytotoxic dysfunction. Impaired NK cell cytotoxicity was due to decreased conjugate formation with susceptible target cells and abrogated activation of cell machinery required for target cell killing. These defects were restored partially after initiation of treatment with rapamycin in 3 patients. CONCLUSION: We describe novel NK cell functional deficiency caused by PI3K110δ mutation, which is a likely contributor to the severe viremia observed in these patients. Rapamycin treatment partially restores NK cell function, providing a further rationale for its use in patients with this disease.
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Infecciones por Citomegalovirus/genética , Citomegalovirus/fisiología , Infecciones por Virus de Epstein-Barr/genética , Herpesvirus Humano 4/fisiología , Síndromes de Inmunodeficiencia/genética , Células Asesinas Naturales/fisiología , Mutación/genética , Fosfatidilinositol 3-Quinasas/genética , Sirolimus/uso terapéutico , Diferenciación Celular , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase I , Citotoxicidad Inmunológica/efectos de los fármacos , Heterocigoto , Humanos , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Sinapsis Inmunológicas/metabolismo , Inmunofenotipificación , Activación de Linfocitos , Microscopía Confocal , Viremia , Secuenciación del ExomaRESUMEN
PURPOSE OF REVIEW: Genetic testing serves an increasingly important role in the diagnosis and management of primary immunodeficiency. In this review, the strengths and limitations of various genetic testing methods are summarized, providing a foundation for the clinical approach to achieving a molecular diagnosis. RECENT FINDINGS: Rapid advances in sequencing technology have enabled the incorporation of comprehensive genetic testing into first-line clinical diagnostics. Recent articles enable comparisons of the diagnostic utility of new testing strategies while simultaneously reminding clinicians of the strengths of traditional methods. SUMMARY: Genetic testing in primary immunodeficiency cannot be standardized, but instead needs to be personalized based on the presenting phenotype and a basic understanding of the utility of different molecular methods. These tools, when correctly employed, can achieve a molecular diagnosis and inform the natural history, prognosis, recurrence risk, and therapeutic options.
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Pruebas Genéticas/métodos , Genómica , Síndromes de Inmunodeficiencia/diagnóstico , Interpretación Estadística de Datos , Manejo de la Enfermedad , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/terapia , Fenotipo , Pronóstico , Factores de RiesgoRESUMEN
OBJECTIVES: Hemophagocytic lymphohistiocytosis poses significant challenges due to limited tools to guide clinical decisions in a population at high risk of death. We sought to assess whether disseminated intravascular coagulation and hepatobiliary dysfunction, significant comorbidities seen in critical care settings, would identify hemophagocytic lymphohistiocytosis patients with increased risk of mortality. DESIGN: Retrospective chart review. SETTING: Single-center PICU. PATIENTS: All patients admitted to a tertiary care children's hospital diagnosed with hemophagocytic lymphohistiocytosis from 2005 to 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-three patients were diagnosed with hemophagocytic lymphohistiocytosis with median age of 61 months. The 5-year overall survival was 51% (22/43). Univariate analyses revealed ferritin levels greater than 10,000 (ng/mL), international normalized ratio greater than 1.5, or platelet counts less than 100,000/µL at initiation of dexamethasone were individually associated with mortality. Development of disseminated intravascular coagulation, hepatobiliary dysfunction, or both increased the likelihood of death in hemophagocytic lymphohistiocytosis patients (relative risk; 95% CI) (6; 1.4-34; p < 0.05), (4.1; 1.8-10; p < 0.05), and (7.5; 1.8-42; p < 0.05). Of 12 autopsies performed, 75% had at least one active infection, 66% had chronic lymphopenia, 50% had lymphocyte depletion in the spleen, thymus, or bone marrow, 42% had evidence of microvascular thrombosis, and 92% had evidence of hepatocellular injury. CONCLUSIONS: Hemophagocytic lymphohistiocytosis continues to have high mortality with hemophagocytic lymphohistiocytosis-1994/2004 (dexamethasone/etoposide), the current standard of care for all children with hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis patients who developed disseminated intravascular coagulation, hepatobiliary dysfunction, or both had higher risk of death with mortalities of 60%, 77%, and 77%, respectively. Phenotypic classifications are urgently needed to guide individualized treatment strategies to improve outcomes for children with hemophagocytic lymphohistiocytosis.
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Enfermedades de las Vías Biliares/epidemiología , Coagulación Intravascular Diseminada/epidemiología , Hepatopatías/epidemiología , Linfohistiocitosis Hemofagocítica/mortalidad , Adolescente , Estudios de Casos y Controles , Causas de Muerte , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Ferritinas/sangre , Humanos , Lactante , Hepatopatías/patología , Masculino , Insuficiencia Multiorgánica/etiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Human immunoglobulin preparations for intravenous or subcutaneous administration are the cornerstone of treatment in patients with primary immunodeficiency diseases affecting the humoral immune system. Intravenous preparations have a number of important uses in the treatment of other diseases in humans as well, some for which acceptable treatment alternatives do not exist. We provide an update of the evidence-based guideline on immunoglobulin therapy, last published in 2006. Given the potential risks and inherent scarcity of human immunoglobulin, careful consideration of its indications and administration is warranted.