RESUMO
Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular genotypes. In 2014, the Primary Immune Deficiency Treatment Consortium published criteria for diagnosing SCID, which are now revised to incorporate contemporary approaches. Patients with typical SCID must have less than 0.05 × 109 autologous T cells/L on repetitive testing, with either pathogenic variant(s) in a SCID-associated gene, very low/undetectable T-cell receptor excision circles or less than 20% of CD4 T cells expressing naive markers, and/or transplacental maternally engrafted T cells. Patients with less profoundly impaired autologous T-cell differentiation are designated as having leaky/atypical SCID, with 2 or more of these: low T-cell numbers, oligoclonal T cells, low T-cell receptor excision circles, and less than 20% of CD4 T cells expressing naive markers. These patients must also have either pathogenic variant(s) in a SCID-associated gene or reduced T-cell proliferation to certain mitogens. Omenn syndrome requires a generalized erythematous rash, absent transplacentally acquired maternal engraftment, and 2 or more of these: eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly. Thymic stromal defects and other causes of secondary T-cell deficiency are excluded from the definition of SCID. Application of these revised Primary Immune Deficiency Treatment Consortium 2022 Definitions permits precise categorization of patients with T-cell defects but does not imply a preferred treatment strategy.
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Síndromes de Imunodeficiência , Imunodeficiência Combinada Severa , Humanos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Síndromes de Imunodeficiência/terapia , Linfócitos T CD4-Positivos , Timo , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous non-Hodgkin lymphoma involving CD8+ T cells, the genetic underpinnings of which remain incompletely understood. Here we report two unrelated patients with B cell Expansion with NF-κB and T cell Anergy (BENTA) disease and a novel presentation of SPTCL. Patient 1 presented early in life with recurrent infections and B cell lymphocytosis, linked to a novel gain-of-function (GOF) CARD11 mutation (p.Lys238del). He developed SPTCL-like lesions and membranoproliferative glomerulonephritis by age 2, treated successfully with cyclosporine. Patient 2 presented at 13 months with splenomegaly, lymphadenopathy, and SPTCL with evidence of hemophagocytic lymphohistiocytosis. Genetic analysis revealed two in cis germline GOF CARD11 variants (p.Glu121Asp/p.Gly126Ser). Autologous bone marrow transplant resulted in SPTCL remission despite persistent B cell lymphocytosis. These cases illuminate an unusual pathological manifestation for BENTA disease, suggesting that CARD11 GOF mutations can manifest in cutaneous CD4+and CD8+ T cell malignancies.
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Síndromes de Imunodeficiência , Linfocitose , Linfoma de Células T , Paniculite , Masculino , Humanos , Pré-Escolar , Linfócitos T CD8-Positivos/patologia , Paniculite/genética , Paniculite/patologia , Paniculite/terapia , Linfoma de Células T/genética , Linfoma de Células T/terapiaRESUMO
PURPOSE: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype. METHODS: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy. RESULTS: All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family. CONCLUSION: Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings.
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Encefalopatia Aguda Febril , Encefalopatias , Leucoencefalite Hemorrágica Aguda , Criança , Humanos , Leucoencefalite Hemorrágica Aguda/diagnóstico , Leucoencefalite Hemorrágica Aguda/genética , Inflamassomos , Encefalopatias/genética , Fatores de Transcrição , Ribonucleases , Proteínas de TransporteRESUMO
Paramphistomosis, caused by the rumen fluke, Calicophoron daubneyi, is a parasitic infection of ruminant livestock, which has seen a rapid rise in prevalence throughout Western Europe in recent years. After ingestion of metacercariae (parasite cysts) by the mammalian host, newly excysted juveniles (NEJs) emerge and invade the duodenal submucosa, which causes significant pathology in heavy infections. The immature flukes then migrate upward, along the gastrointestinal tract, and enter the rumen where they mature and begin to produce eggs. Despite their emergence, and sporadic outbreaks of acute disease, we know little about the molecular mechanisms used by C. daubneyi to establish infection, acquire nutrients, and avoid the host immune response. Here, transcriptome analysis of four intramammalian life-cycle stages, integrated with secretome analysis of the NEJ and adult parasites (responsible for acute and chronic diseases, respectively), revealed how the expression and secretion of selected families of virulence factors and immunomodulators are regulated in accordance with fluke development and migration. Our data show that while a family of cathepsins B with varying S2 subsite residues (indicating distinct substrate specificities) is differentially secreted by NEJs and adult flukes, cathepsins L and F are secreted in low abundance by NEJs only. We found that C. daubneyi has an expanded family of aspartic peptidases, which is upregulated in adult worms, although they are under-represented in the secretome. The most abundant proteins in adult fluke secretions were helminth defense molecules that likely establish an immune environment permissive to fluke survival and/or neutralize pathogen-associated molecular patterns such as bacterial lipopolysaccharide in the microbiome-rich rumen. The distinct collection of molecules secreted by C. daubneyi allowed the development of the first coproantigen-based ELISA for paramphistomosis which, importantly, did not recognize antigens from other helminths commonly found as coinfections with rumen fluke.
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Proteínas de Helminto/genética , Proteínas de Helminto/metabolismo , Paramphistomatidae/genética , Paramphistomatidae/metabolismo , Animais , Antígenos de Helmintos/genética , Antígenos de Helmintos/imunologia , Antígenos de Helmintos/metabolismo , Bovinos , Cisteína Proteases/genética , Cisteína Proteases/metabolismo , Fezes/parasitologia , Proteínas de Helminto/imunologia , Estágios do Ciclo de Vida , Paramphistomatidae/crescimento & desenvolvimento , Rúmen/parasitologia , Secretoma , Transcriptoma , Infecções por Trematódeos/diagnóstico , Infecções por Trematódeos/imunologia , Infecções por Trematódeos/parasitologiaRESUMO
BACKGROUND: Germline pathogenic variants impairing the caspase recruitment domain family member 11 (CARD11)-B cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) (CBM) complex are associated with diverse human diseases including combined immunodeficiency (CID), atopy, and lymphoproliferation. However, the impact of CARD11 deficiency on human B-cell development, signaling, and function is incompletely understood. OBJECTIVES: This study sought to determine the cellular, immunological, and biochemical basis of disease for 2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis. METHODS: Patients underwent next-generation sequencing, immunophenotyping by flow cytometry, signaling assays by immunoblot, and transcriptome profiling by RNA-sequencing. RESULTS: Both patients carried identical novel pathogenic biallelic loss-of-function variants in CARD11 (c.2509C>T; p.Arg837∗) leading to undetectable protein expression. This variant prevented CBM complex formation, severely impairing the activation of nuclear factor-κB, c-Jun N-terminal kinase, and MALT1 paracaspase activity in B and T cells. This functional defect resulted in a developmental block in B cells at the naive and type 1 transitional B-cell stage and impaired circulating T follicular helper cell (cTFH) development, which was associated with impaired antibody responses and absent germinal center structures on lymph node histology. Transcriptomics indicated that CARD11-dependent signaling is essential for immune signaling pathways involved in the development of these cells. Both patients underwent hematopoietic stem cell transplantations, which led to functional normalization. CONCLUSIONS: Complete human CARD11 deficiency causes profound CID by impairing naive/type 1 B-cell and cTFH cell development and abolishing activation of MALT1 paracaspase, NF-κB, and JNK activity. Hematopoietic stem cell transplantation functionally restores impaired signaling pathways.
Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Centro Germinativo/imunologia , Guanilato Ciclase/genética , Transplante de Células-Tronco Hematopoéticas , Mutação/genética , Células Precursoras de Linfócitos B/imunologia , Doenças da Imunodeficiência Primária/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Proteína 10 de Linfoma CCL de Células B/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Criança , Perfilação da Expressão Gênica , Guanilato Ciclase/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Lactente , Masculino , NF-kappa B/metabolismo , Doenças da Imunodeficiência Primária/terapia , Transdução de SinaisRESUMO
PURPOSE: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study's objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention. METHODS: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management. RESULTS: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p = 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p = 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented. CONCLUSION: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS. TRIAL REGISTRATION: NCT01186913.
Assuntos
Controle de Infecções , Infecções/epidemiologia , Infecções/etiologia , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/epidemiologia , Idade de Início , Antibioticoprofilaxia , Tomada de Decisão Clínica , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Infecções/diagnóstico , Masculino , Triagem Neonatal , Prognóstico , Vigilância em Saúde Pública , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia , Inquéritos e Questionários , Tempo para o TratamentoRESUMO
Various reduced-intensity conditioning regimens are in use for allogeneic hematopoietic cell transplant (HSCT) in patients with idiopathic severe aplastic anemia (SAA). We describe the use of fludarabine, Campath, and low-dose cyclophosphamide (FCClow) conditioning in 15 children undergoing related or unrelated donor transplants. Total body irradiation (TBI) of 2 Gy was added for unrelated donor HSCT. At a median follow-up of 2.3 years, the failure-free survival was 100%, with low rates of infection and toxicity. There was no occurrence of grade III to IV acute graft-versus-host disease (GVHD). All patients had full donor myeloid chimerism post-HSCT, even with mixed chimerism in the T cell lineage. The absence of chronic GVHD and long-term stable mixed donor T cell chimerism confirms immune tolerance following FCClow (± TBI) conditioned transplantation in children with SAA.
Assuntos
Anemia Aplástica , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Alemtuzumab , Anemia Aplástica/terapia , Criança , Ciclofosfamida/uso terapêutico , Humanos , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Irradiação Corporal TotalRESUMO
Severe combined immune deficiency (SCID) is caused by an array of genetic disorders resulting in a diminished adaptive immune system due to impaired T lymphocytes. In these patients, active infection at the time of hematopoietic transplantation has been shown to increase morbidity and mortality. To prevent transmission of infections in SCID patients, standardized infection control precautions should be implemented. An online survey regarding SCID-specific protocols was distributed through several immunodeficiency organizations. Seventy-three responses were obtained, with the majority (55%) of responses from the USA, 15% from Canada, and the remainder from 12 other countries. Only 50% of respondents had a SCID-specific infection control protocol at their center, and while a majority of these centers had training for physicians, a small minority had training for other healthcare workers such as nursing and housekeeping staff. Significant variability of infection control practices, such as in-patient precautions, required personal protective equipment (PPE), diet restrictions, visitor precautions and discharge criteria, was found between different treatment centers. There is a paucity of evidence-based data regarding the safest environment to prevent infection in SCID patients. Institutional protocols may have significant impact on infection risk, survival, family well-being, child development and cost of care. From these results, it is evident that further multi-center research is required to determine the safest and healthiest environment for these children, so that evidence-based infection control protocols for patients with SCID can be developed.
Assuntos
Infecção Hospitalar/prevenção & controle , Medicina Baseada em Evidências/estatística & dados numéricos , Controle de Infecções/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Imunodeficiência Combinada Severa/imunologia , Aleitamento Materno , Cuidadores/normas , Protocolos Clínicos , Infecção Hospitalar/imunologia , Medicina Baseada em Evidências/instrumentação , Medicina Baseada em Evidências/organização & administração , Medicina Baseada em Evidências/normas , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Higiene/normas , Lactente , Recém-Nascido , Controle de Infecções/instrumentação , Controle de Infecções/organização & administração , Controle de Infecções/normas , Educação de Pacientes como Assunto , Equipamento de Proteção Individual/normas , Padrões de Prática Médica/organização & administração , Padrões de Prática Médica/normas , Imunodeficiência Combinada Severa/cirurgia , Inquéritos e Questionários/estatística & dados numéricosRESUMO
OBJECTIVE: Chronic blood transfusion remains the most feasible therapeutic option for lifelong transfusion-dependent ß-thalassemia (lifelong TDßT). However, it is associated with serious risks and complications. Hydroxyurea (HU), an oral chemotherapeutic drug, is expected to increase hemoglobin levels, thereby minimizing the burden of blood transfusion and its complications. Growing literature over the last twenty years suggests promising results of the use HU in lifelong TDßT; however, its role and safety remain unanswered questions. The objective of this study was to evaluate the clinical efficacy and safety of HU in patients with lifelong TDßT. METHODS: MEDLINE, EMBASE, Cochrane databases, and major preceding conferences for studies that assessed HU in lifelong TDßT patients were searched. The effect size was estimated as a proportion (responder/sample size). RESULTS: Eleven observational studies, collectively involving 859 patients, fulfilled eligibility criteria. HU was associated with a significant decrease in transfusion need with complete and overall (≥50%) response rates of 26% [95% confidence interval (CI), 13-41%] and 60% (95% CI, 41-78%), respectively. No serious adverse effects were reported. All of the studies had several limitations, such as lack of a comparison group. CONCLUSION: HU appears to be effective, well tolerated; however, large randomized clinical trials should be done to confirm such findings.
Assuntos
Hidroxiureia/uso terapêutico , Talassemia beta/tratamento farmacológico , Feminino , Humanos , Hidroxiureia/efeitos adversos , Masculino , Estudos Observacionais como Assunto , Talassemia beta/sangueRESUMO
BACKGROUND: Pediatric patients with chronic and/or refractory autoimmune multi-lineage cytopenias present challenges in both diagnosis and management. Increasing availability of diagnostic testing has revealed an underlying immune dysfunction in patients previously diagnosed with Evans Syndrome. However, the data are sparse and the majority of patients are adults. PROCEDURE: We performed a retrospective chart review to document the natural history of 23 pediatric patients with autoimmune multi-lineage cytopenias followed at three tertiary care pediatric hematology clinics. RESULTS: Investigations revealed seven patients (30.4%) with an autoimmune lymphoproliferative-like syndrome and six patients (26.1%) with other primary immunodeficiencies. Only one (4.3%) patient was suspected to have systemic lupus erythematosus and six patients (26.1%) had other types of autoimmunity. Treatment consisted of immunosuppressive therapy, intravenous gammaglobulin, and splenectomy. Supportive care included granulocyte-colony stimulating factor, and blood product transfusions. Two patients (8.7%) died. Complete remission was achieved in 3 patients (13.0%); of the remaining, 14 patients (60.9%) had chronic immune thrombocytopenic purpura, 10 patients (43.5%) chronic autoimmune neutropenia, and 4 patients (17.4%) chronic autoimmune hemolytic anemia with a median follow up of 5 years (2 months-12 years). CONCLUSIONS: These data suggest that pediatric patients presenting with autoimmune multi-lineage cytopenias should undergo investigation for underlying immune dysregulation, including autoimmune lymphoproliferative syndrome, other primary immunodeficiencies and autoimmune disorders. The development of an international registry for such patients is imperative to improve the understanding of their complex natural history.
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Doenças Autoimunes/imunologia , Síndromes de Imunodeficiência/imunologia , Doenças Autoimunes/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Imunossupressores/uso terapêutico , Lactente , Masculino , Estudos RetrospectivosAssuntos
Linfo-Histiocitose Hemofagocítica , Piebaldismo , Doenças da Imunodeficiência Primária , Proteínas rab27 de Ligação ao GTP/genética , Adolescente , Autoenxertos , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico por imagem , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Piebaldismo/diagnóstico por imagem , Piebaldismo/genética , Piebaldismo/patologia , Doenças da Imunodeficiência Primária/diagnóstico por imagem , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/patologiaRESUMO
The detection of genomic sequences and their alterations is crucial for basic research and clinical diagnostics. However, current methodologies are costly and time-consuming and require outsourcing sample preparation, processing, and analysis to genomic companies. Here, we establish One-pot DTECT, a platform that expedites the detection of genetic signatures, only requiring a short incubation of a PCR product in an optimized one-pot mixture. One-pot DTECT enables qualitative, quantitative, and visual detection of biologically relevant variants, such as cancer mutations, and nucleotide changes introduced by prime editing and base editing into cancer cells and human primary T cells. Notably, One-pot DTECT achieves quantification accuracy for targeted genetic signatures comparable with Sanger and next-generation sequencing. Furthermore, its effectiveness as a diagnostic platform is demonstrated by successfully detecting sickle cell variants in blood and saliva samples. Altogether, One-pot DTECT offers an efficient, versatile, adaptable, and cost-effective alternative to traditional methods for detecting genomic signatures.
Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Humanos , Edição de Genes/métodos , Mutação/genética , GenômicaRESUMO
In April 2019, the Alberta Newborn Screening Program expanded to include screening for classic galactosemia using a two-tier screening approach. This approach secondarily identifies infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The goals of this study were (i) to evaluate the performance of a two-tier galactosemia screening protocol, (ii) to explore the impact on and acceptability to families of reporting G6PD deficiency as a secondary finding, and (iii) assess the communication and follow-up process for positive G6PD deficiency screening results. The two-tiered galactosemia approach increased the positive predictive value (PPV) for galactosemia from 8% to 79%. An additional 119 positive newborn screen results were reported for G6PD deficiency with a PPV of 92%. The results show that there may be utility in reporting G6PD deficiency results. Most parents who participated in the study reported having some residual worry around the unexpected diagnosis; however, all thought it was helpful to know of their child's diagnosis of G6PD deficiency. Finally, the communication process for reporting G6PD deficiency newborn screen results was determined to result in appropriate follow up of infants.
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Introduction: Purpura fulminans in the neonatal population is a rare but potentially life-threatening condition complicated by thrombosis, resultant vital organ necrosis, and gangrene of the extremities. Considering the rapid evolution of the pathogenetic mechanism, an index of suspicion, early identification, and prompt intervention are imperative for improved outcomes. The majority of purpura fulminans cases have an infectious etiology, but it is essential to consider other congenital and acquired causes. Case description: We present a clinical case of a female neonate to emphasize the correlation between purpura fulminans, congenital chylothorax, involvement of the PAK2 gene, and the occurrence of retinal detachment in both eyes. After draining the congenital chylothorax, the neonate developed purpura fulminans due to a loss of protein C, S, and antithrombin factors, previously not reported in the literature. The purpuric lesions resolved after the administration of fresh frozen plasma. Subsequently, no recurring purpura fulminans lesions were noted following the normalization of the antithrombotic factor levels in the serum. Subsequently, the child also developed retinal detachment in both eyes.
RESUMO
BACKGROUND: ADAGEN, a bovine-based enzyme replacement therapy (ERT), has been used to treat adenosine deaminase severe combined immunodeficiency (ADA-SCID). In 2018, ADAGEN was replaced by REVCOVI (elapegademase), a modified bovine recombinant protein. OBJECTIVE: To determine the real-life long-term benefits of REVCOVI in ADA-SCID. METHODS: Data on ERT, infectious and noninfectious complications, and metabolic and immune evaluations were collected from 17 patients with ADA-SCID treated for 6 months or more with REVCOVI. RESULTS: Eleven patients had previously received ADAGEN for 16 to 324 months, whereas 6 patients were ERT-naive. REVCOVI was administered twice weekly at 0.4 mg/kg/wk in ERT-naive patients, whereas patients transitioning to REVCOVI from ADAGEN typically continued at the same frequency and equivalent dosing as ADAGEN, resulting in a significantly lower (P = .007) total REVCOVI dose in the transitioning group. REVCOVI treatment in the ERT-naive group led to the resolution of many clinical and laboratory complications of ADA deficiency, whereas there were no new adverse effects among the transitioning patients. REVCOVI treatment increased plasma ADA activity and decreased dAXP (which included deoxyadenosine mono-, di-, and tri phosphate) among most patients, effects that persisted throughout the 7- to 37-month treatment periods, except in 2 patients with incomplete adherence. Among some patients, after 0.5 to 6 months, injection frequency was reduced to once a week, while maintaining adequate metabolic profiles. All ERT-naive infants treated with REVCOVI demonstrated an increase in the number of CD4+ T and CD19+ B cells, although these counts remained stable but lower than normal in most transitioning patients. CONCLUSIONS: REVCOVI is effective for the management of ADA-SCID.
Assuntos
Reconstituição Imune , Imunodeficiência Combinada Severa , Lactente , Humanos , Animais , Bovinos , Adenosina Desaminase/uso terapêutico , Imunodeficiência Combinada Severa/terapiaAssuntos
Adenilato Quinase/genética , Transplante de Medula Óssea , Perda Auditiva Neurossensorial/terapia , Leucopenia/terapia , Imunodeficiência Combinada Severa/terapia , Quimerismo , Análise Mutacional de DNA , Feminino , Antígenos HLA/imunologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Histocompatibilidade , Humanos , Recém-Nascido , Leucopenia/diagnóstico , Leucopenia/genética , Mães , Período Pós-Parto , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Doadores de Tecidos , Condicionamento Pré-TransplanteRESUMO
Ataxia-telangiectasia (AT) is a complex neurodegenerative disease with an increased risk for bone marrow failure and malignancy. AT is caused by biallelic loss of function variants in ATM, which encodes a phosphatidylinositol 3-kinase that responds to DNA damage. Herein, we report a child with progressive ataxia, chorea, and genome instability, highly suggestive of AT. The clinical ataxia gene panel identified a maternal heterozygous synonymous variant (NM_000051.3: c.2250G > A), previously described to result in exon 14 skipping. Subsequently, trio genome sequencing led to the identification of a novel deep intronic variant [NG_009830.1(NM_000051.3): c.1803-270T > G] inherited from the father. Transcript analyses revealed that c.1803-270T > G results in aberrant inclusion of 56 base pairs of intron 11. In silico tests predicted a premature stop codon as a consequence, suggesting non-functional ATM; and DNA repair analyses confirmed functional loss of ATM. Our findings highlight the power of genome sequencing, considering deep intronic variants in undiagnosed rare disease patients.
RESUMO
Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results from loss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits of the phagocyte NADPH oxidase. These include gp91(phox) and p22(phox), which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47(phox) and p67(phox). A fifth subunit, p40(phox), plays an important role in phagocytosis-induced superoxide production via a phox homology (PX) domain that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P). We report the first case of autosomal recessive mutations in NCF4, the gene encoding p40(phox), in a boy who presented with granulomatous colitis. His neutrophils showed a substantial defect in intracellular superoxide production during phagocytosis, whereas extracellular release of superoxide elicited by phorbol ester or formyl-methionyl-leucyl-phenylalanine (fMLF) was unaffected. Genetic analysis of NCF4 showed compound heterozygosity for a frameshift mutation with premature stop codon and a missense mutation predicting a R105Q substitution in the PX domain. Parents and a sibling were healthy heterozygous carriers. p40(phox)R105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-induced oxidase activity in p40(phox)-deficient granulocytes, with premature loss of p40(phox)R105Q from phagosomes. Thus, p40(phox) binding to PtdIns(3)P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease.
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Códon de Terminação , Genes Recessivos , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/genética , Doença Granulomatosa Crônica/enzimologia , Doença Granulomatosa Crônica/genética , Mutação de Sentido Incorreto , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Neutrófilos/enzimologia , Adulto , Substituição de Aminoácidos , Carcinógenos , Linhagem Celular Tumoral , Criança , Análise Mutacional de DNA , Feminino , Doença Granulomatosa Crônica/patologia , Heterozigoto , Humanos , Masculino , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/patologia , Fagocitose/genética , Ésteres de Forbol , Fosfatos de Fosfatidilinositol , Superóxidos/metabolismoRESUMO
Childhood cancer and its treatment often impact the haematopoietic and lymphatic systems, with immunological consequences. Immunological assessments are not routinely included in surveillance guidelines for most survivors of childhood cancer, although a robust body of literature describes immunological outcomes, testing recommendations, and revaccination guidelines after allogeneic haematopoietic cell transplantation. Survivorship care providers might not fully consider the impaired recovery of a child's immune system after cancer treatment if the child has not undergone haematopoietic cell transplantation. We did a scoping review to collate the existing literature describing immune function after childhood cancer therapy, including both standard-dose chemotherapy and high-dose chemotherapy with haematopoietic cell rescue. This Review aims to summarise: the principles of immunology and testing of immune function; the body of literature describing immunological outcomes after childhood cancer therapy, with an emphasis on the risk of infection, when is testing indicated, and preventive strategies; and knowledge gaps and opportunities for future research.