RESUMEN
BACKGROUND: Allogenic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are potentially curative treatments for severe combined immunodeficiency (SCID). Late-onset posttreatment manifestations (such as persistent hepatitis) are not uncommon. OBJECTIVE: We sought to characterize the prevalence and pathophysiology of persistent hepatitis in transplanted SCID patients (SCIDH+) and to evaluate risk factors and treatments. METHODS: We used various techniques (including pathology assessments, metagenomics, single-cell transcriptomics, and cytometry by time of flight) to perform an in-depth study of different tissues from patients in the SCIDH+ group and corresponding asymptomatic similarly transplanted SCID patients without hepatitis (SCIDH-). RESULTS: Eleven patients developed persistent hepatitis (median of 6 years after HSCT or GT). This condition was associated with the chronic detection of enteric viruses (human Aichi virus, norovirus, and sapovirus) in liver and/or stools, which were not found in stools from the SCIDH- group (n = 12). Multiomics analysis identified an expansion of effector memory CD8+ T cells with high type I and II interferon signatures. Hepatitis was associated with absence of myeloablation during conditioning, split chimerism, and defective B-cell function, representing 25% of the 44 patients with SCID having these characteristics. Partially myeloablative retransplantation or GT of patients with this condition (which we have named as "enteric virus infection associated with hepatitis") led to the reconstitution of T- and B-cell immunity and remission of hepatitis in 5 patients, concomitantly with viral clearance. CONCLUSIONS: Enteric virus infection associated with hepatitis is related to chronic enteric viral infection and immune dysregulation and is an important risk for transplanted SCID patients with defective B-cell function.
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Infecciones por Enterovirus , Trasplante de Células Madre Hematopoyéticas , Hepatitis , Inmunodeficiencia Combinada Grave , Virosis , Humanos , Inmunodeficiencia Combinada Grave/terapia , Inmunodeficiencia Combinada Grave/etiología , Linfocitos T CD8-positivos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Virosis/etiología , Hepatitis/etiologíaRESUMEN
BACKGROUND & AIMS: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood. METHODS: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120× depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000× depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls. RESULTS: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor. CONCLUSIONS: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk.
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Neoplasias Encefálicas , Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales , Síndromes Neoplásicos Hereditarios , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Inestabilidad de Microsatélites , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Encefálicas/diagnóstico , Genotipo , Reparación de la Incompatibilidad de ADN/genética , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genéticaRESUMEN
Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5-13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10-11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie â¼10% of hospitalizations for COVID-19 pneumonia in children.
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COVID-19 , Interferón Tipo I , Neumonía , Adulto , COVID-19/genética , Niño , Humanos , Patrón de Herencia , SARS-CoV-2RESUMEN
BACKGROUND: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant. OBJECTIVE: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant. METHOD: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. RESULTS: Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. CONCLUSION: The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.
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Proteínas Adaptadoras Transductoras de Señales/deficiencia , Trasplante de Células Madre Hematopoyéticas , Síndromes de Inmunodeficiencia/terapia , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Síndromes de Inmunodeficiencia/mortalidad , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues. MATERIALS AND METHODS: Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers. RESULTS: The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564). CONCLUSIONS: The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.
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Neoplasias Encefálicas/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/genética , Inestabilidad de Microsatélites , Proteína 2 Homóloga a MutS/genética , Síndromes Neoplásicos Hereditarios/genética , Adolescente , Adulto , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/patología , Niño , Preescolar , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/sangre , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Reparación de la Incompatibilidad de ADN/genética , Femenino , Mutación de Línea Germinal/genética , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Síndromes Neoplásicos Hereditarios/sangre , Síndromes Neoplásicos Hereditarios/patología , Adulto JovenRESUMEN
DOCK2 is a guanine-nucleotide-exchange factor for Rac proteins. Activated Rac serves various cellular functions including the reorganization of the actin cytoskeleton in lymphocytes and neutrophils and production of reactive oxygen species in neutrophils. Since 2015, six unrelated patients with combined immunodeficiency and early-onset severe viral infections caused by bi-allelic loss-of-function mutations in DOCK2 have been described. Until now, the function of phagocytes, specifically neutrophils, has not been assessed in human DOCK2 deficiency. Here, we describe a new kindred with four affected siblings harboring a homozygous splice-site mutation (c.2704-2 A > C) in DOCK2. The mutation results in alternative splicing and a complete loss of DOCK2 protein expression. The patients presented with leaky severe combined immunodeficiency or Omenn syndrome. The novel mutation affects EBV-B cell migration and results in NK cell dysfunction similar to previous observations. Moreover, both cytoskeletal rearrangement and reactive oxygen species production are partially impaired in DOCK2-deficient neutrophils.
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Linfocitos B/inmunología , Proteínas Activadoras de GTPasa/genética , Factores de Intercambio de Guanina Nucleótido/genética , Células Asesinas Naturales/inmunología , Neutrófilos/inmunología , Eliminación de Secuencia/genética , Inmunodeficiencia Combinada Grave/genética , Empalme Alternativo/genética , Humanos , Estrés Oxidativo , LinajeRESUMEN
Constitutional mismatch repair deficiency (CMMRD) is caused by germline pathogenic variants in both alleles of a mismatch repair gene. Patients have an exceptionally high risk of numerous pediatric malignancies and benefit from surveillance and adjusted treatment. The diversity of its manifestation, and ambiguous genotyping results, particularly from PMS2, can complicate diagnosis and preclude timely patient management. Assessment of low-level microsatellite instability in nonneoplastic tissues can detect CMMRD, but current techniques are laborious or of limited sensitivity. Here, we present a simple, scalable CMMRD diagnostic assay. It uses sequencing and molecular barcodes to detect low-frequency microsatellite variants in peripheral blood leukocytes and classifies samples using variant frequencies. We tested 30 samples from 26 genetically-confirmed CMMRD patients, and samples from 94 controls and 40 Lynch syndrome patients. All samples were correctly classified, except one from a CMMRD patient recovering from aplasia. However, additional samples from this same patient tested positive for CMMRD. The assay also confirmed CMMRD in six suspected patients. The assay is suitable for both rapid CMMRD diagnosis within clinical decision windows and scalable screening of at-risk populations. Its deployment will improve patient care, and better define the prevalence and phenotype of this likely underreported cancer syndrome.
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Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Leucocitos/metabolismo , Inestabilidad de Microsatélites , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Alelos , Estudios de Asociación Genética/métodos , Mutación de Línea Germinal , Humanos , Repeticiones de MicrosatéliteAsunto(s)
Proteínas Adaptadoras Transductoras de Señales/deficiencia , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/terapia , Trasplante de Células Madre Hematopoyéticas , Aloinjertos , Niño , Preescolar , Inmunodeficiencia Variable Común/patología , Femenino , Humanos , Lactante , MasculinoRESUMEN
BACKGROUND: Data on anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis are scarce in children. The current study is aimed at describing the clinical features and outcomes of childhood-onset ANCA-associated vasculitis (AAV). METHODS: We conducted a retrospective French multicentre study involving patients in whom AAV was diagnosed before the age of 18 years. Inclusion criteria were (i) granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) according to classification criteria of the European League Against Rheumatism/Paediatric Rheumatology European Society, and (ii) ANCA positivity. Patient and renal survival were analysed. RESULTS: Among 66 children included, 80% were female, 42% had GPA and 58% MPA including renal-limited vasculitis, 67% were pANCA+ and 33% cANCA+. The mean incidence of reported cases increased to 0.45 per million children/year in the period 2006-10. Median age at diagnosis was 11.5 years, and median time to diagnosis was 1 month. Initial symptoms included fever and fatigue (79%), skin lesions (41%), arthritis (42%), pulmonary (45%) and renal involvement (88%). Clinical features were similar between GPA and MPA with the exception of upper airway impairment (28%) specific of GPA. Ninety percent of the patients achieved remission after induction treatment. After a median follow-up of 5.2 years, 4 patients (6%) died, corresponding to a mortality rate of 1.2 per 100 person-years, and 22 patients (34%) developed end-stage renal disease (ESRD). Renal survival was 74, 70 and 59% at 1, 5 and 10 years, respectively. In a multivariable Cox regression model, baseline glomerular filtration rate, ethnic origin, histopathological classification and era of treatment were associated with the occurrence of ESRD. Relapse-free survival was 57% at 5 years and 34% at 10 years of follow-up. Patient and renal outcome did not significantly differ between GPA and MPA. CONCLUSION: Childhood-onset AAV is a rare disease characterized by female predominance, delayed diagnosis, frequent renal impairment and a high remission rate. Baseline GFR and new histopathological classification system are strong predictors of ESRD. Renal survival in childhood AAV has improved over time.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Enfermedades Renales/etiología , Poliangitis Microscópica/complicaciones , Adolescente , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/mortalidad , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/terapia , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Niño , Etnicidad , Femenino , Francia/epidemiología , Tasa de Filtración Glomerular , Humanos , Incidencia , Enfermedades Renales/epidemiología , Enfermedades Renales/mortalidad , Masculino , Poliangitis Microscópica/mortalidad , Poliangitis Microscópica/terapia , Pronóstico , Recurrencia , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
A 5-month-old boy developed splenomegaly, anemia, thrombocytopenia with elevated white cells, monocytosis and immature granulocytes in the peripheral blood. Bone marrow showed dysplasia without blastosis. Increased colony-forming unit-granulocyte-macrophage was found in the peripheral blood, mimicking granulocyte-macrophage colony-stimulating factor hypersensitivity. These findings fulfilled the diagnosis criteria for juvenile myelomonocytic leukemia (JMML), but no mutations in the CBL, NRAS, KRAS, or PTPN11 genes were detected. In addition to these findings severe hypogammaglobulinemia and elevated alkaline phosphatase were present. Bone X-ray showed dense and radiopaque bones with a bone-in-bone appearance characteristic of infantile malignant osteopetrosis (IMO). Genetic mutation in T-cell, immune regulator 1 (TCIRG1) was identified, confirming the diagnosis of IMO. Careful differential diagnosis including osteopetrosis, is therefore recommended in patients with clinical features and hematologic findings consistent with JMML.
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Leucemia Mielomonocítica Juvenil/diagnóstico , Osteopetrosis/diagnóstico , Diagnóstico Diferencial , Humanos , Lactante , MasculinoRESUMEN
Autoimmune lymphoproliferative syndrome (ALPS) caused by impaired FAS-mediated apoptosis of lymphocytes is characterized by lymphoproliferation, autoimmunity, but also an increased risk of invasive bacterial infection, notably following splenectomy. We surveyed a cohort of 100 ALPS patients (including 33 splenectomized) and found that 12 (10 splenectomized) had experienced 23 invasive bacterial infections mainly caused by Streptococcus pneumoniae. This vulnerability was associated with evidence of defective B-cell function characterized by low serum immunoglobulin (Ig) M, low IgM antibody production in response to S pneumoniae following nonconjugated immunization, and low blood memory B-cells counts (including marginal zone [MZ] B-cell counts). This immunodeficiency strongly correlated with intensity of lymphoproliferation. Spleen sections from 9 ALPS patients revealed double-negative T-cell (DN-T) infiltration of the MZ, which was depleted of B cells. MZ in ALPS patients contained an abnormally thick layer of MAdCAM-1((+)) stromal cells and an excess of DN-Ts. DN-Ts were shown to express MAdCAM-1 ligand, the α4ß7 integrin. These observations suggest that accumulating DN-Ts are trapped within stromal cell meshwork and interfere with correct localization of MZ B cells. Similar observations were made in spleens of fas-deficient mice. Our data revealed an unexpected mechanism by which ALPS results in anti-polysaccharide IgM antibody production-specific defect. Splenectomy should be avoided.
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Formación de Anticuerpos , Síndrome Linfoproliferativo Autoinmune/inmunología , Síndrome Linfoproliferativo Autoinmune/patología , Lipopolisacáridos/inmunología , Bazo/inmunología , Bazo/patología , Adolescente , Adulto , Animales , Síndrome Linfoproliferativo Autoinmune/epidemiología , Síndrome Linfoproliferativo Autoinmune/cirugía , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Ratones , Ratones Transgénicos , Bazo/cirugía , Esplenectomía/efectos adversos , Esplenectomía/estadística & datos numéricos , Infecciones Estreptocócicas/epidemiología , Infecciones Estreptocócicas/inmunología , Streptococcus pneumoniae/crecimiento & desarrollo , Streptococcus pneumoniae/inmunología , Adulto JovenRESUMEN
OBJECTIVES: Clinical data are lacking on optimal levels of specific antipneumococcal antibodies (PnPsAbs) in patients with primary immunodeficiency (PID) receiving intravenous immunoglobulin (IVIG) replacement. Objectives were to conduct a prospective multicenter study providing data on total immunoglobulin G (IgG) and peak/trough levels of PnPsAbs specifically targeting the 16 most prevalent pneumococcal serotypes in IVIG-treated children with PID; to compare trough PnPsAb levels with those measured in healthy adults and the IVIG product; and to evaluate PnPsAb protection correlates with thresholds based on World Health Organization. METHODS: Patients received 7 consecutive IVIG infusions. Total IgG and PnPsAb levels were determined on plasma samples obtained before and after infusion. RESULTS: Twenty-two children with PID were treated with IVIG (mean weekly dose: 0.10 g/kg). The mean trough and peak levels of total IgG were 7.77 and 13.93 g/L, respectively. Trough and peak geometric mean concentrations and distribution curves differed between serotypes and showed wide dispersion (0.17-7.96 µg/mL). In patients (89%-100%), antibodies against most serotypes reached trough levels ≥ 0.2 µg/mL, a threshold considered protective against invasive pneumococcal infection. For several serotypes, trough levels reached ≥ 1.0 to 1.3 µg/mL, the level found in adults. Trough geometric mean concentrations correlated well with the PnPsAb contents of the IVIG product. CONCLUSIONS: In IVIG-treated children with PID, protective PnPsAb levels for most pathogenic serotypes were obtained. A correlation was observed between PnPsAb levels in patients and in the IVIG product. This offers the potential to improve infection prevention by adapting the IVIG product and dose according to epidemiology.
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Anticuerpos Antibacterianos/sangre , Inmunoglobulina G/sangre , Inmunoglobulinas Intravenosas/uso terapéutico , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Streptococcus pneumoniae/inmunología , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Preescolar , Esquema de Medicación , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Síndromes de Inmunodeficiencia/sangre , Síndromes de Inmunodeficiencia/inmunología , Lactante , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Nefelometría y Turbidimetría , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Anakinra pharmacokinetics and pharmacodynamics were investigated in children and adolescents treated for systemic-onset juvenile idiopathic arthritis (SJIA) and autoinflammatory syndromes. METHODS: Anakinra was given subcutaneously at doses between 2 and 10 mg/kg (maximum 100 mg) per day. Anakinra concentrations were recorded in patients, as well as C-reactive protein (CRP) levels, on different occasions. The data were fitted to a pharmacokinetic-pharmacodynamic model via a population approach using Monolix. RESULTS: A total of 87 children and adolescents, 8 months to 21 years old, were available for pharmacokinetic evaluation. A one compartment model with linear absorption and elimination described the pharmacokinetics. Taking into account bodyweight to explain variations in apparent clearance (CL/F) and distribution volume (V/F) significantly reduced the associated between-subject and between-occasion variabilities. The final estimates were 6.24 L/h/70 kg and 65.2 L/70 kg for CL/F and V/F respectively. A mixture pharmacodynamic model described the CRP level change during anakinra treatment for the SJIA patients with 2 subpopulations, patients with high baseline and large CRP decrease and patients with low baseline and small CRP decrease followed by a re-increase in CRP levels. There was no significant effect of the combined anti-inflammatory treatment. The proportion of patients for which the development of a resistance to treatment was significant was 62% and the corresponding time was approximately 60 days. CONCLUSIONS: Based on effects in SJIA, a prospective dosage adjustment was proposed based on a 0.4 mg/L Css target in order to obtain a CRP decrease to 10 mg/L or below.
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Artritis Juvenil/tratamiento farmacológico , Enfermedades Autoinflamatorias Hereditarias/tratamiento farmacológico , Proteína Antagonista del Receptor de Interleucina 1/farmacocinética , Modelos Biológicos , Adolescente , Algoritmos , Artritis Juvenil/metabolismo , Proteína C-Reactiva/metabolismo , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Enfermedades Autoinflamatorias Hereditarias/metabolismo , Humanos , Lactante , Inyecciones Subcutáneas , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Masculino , Tasa de Depuración Metabólica , Estudios Prospectivos , Síndrome , Distribución Tisular , Resultado del Tratamiento , Adulto JovenRESUMEN
Cernunnos is a DNA repair factor of the nonhomologous end-joining machinery. Its deficiency in humans causes radiosensitive severe combined immune deficiency (SCID) with microcephaly, characterized in part by a profound lymphopenia. In contrast to the human condition, the immune system of Cernunnos knockout (KO) mice is not overwhelmingly affected. In particular, Cernunnos is dispensable during V(D)J recombination in lymphoid cells. Nevertheless, the viability of thymocytes is reduced in Cernunnos KO mice, owing to the chronic activation of a P53-dependent DNA damage response. This translates into a qualitative alteration of the T cell repertoire to one in which the most distal Vα and Jα segments are missing. This results in the contraction of discrete T cell populations, such as invariant natural killer T (iNKT) and mucosa-associated invariant T (MAIT) cells, in both humans and mice.
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Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Técnicas de Inactivación de Genes , Linfocitos T/citología , Timocitos/citología , Animales , Secuencia de Bases , Proliferación Celular , Supervivencia Celular , Reparación del ADN , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Humanos , Recuento de Linfocitos , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Linfocitos T/metabolismo , Timocitos/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Recombinación V(D)JRESUMEN
Pycnodysostosis is a rare sclerosing bone dystrophy. The main clinical features are short stature and oral and maxillofacial abnormalities such as a large head, a small and underdeveloped face with prominent nose and eyes, irregular dentition, small hands and feet with dystrophic nails, and trunk deformities such as scoliosis. The differential diagnosis is established with other skeletal dysplasias such as osteopetrosis, cleidocranial dysplasia, and idiopathic acro-osteolysis. Since its first description in 1962 by Maroteaux and Lamy, about 100 cases have been published, some of these with uncommon features. We describe the case of a 22-year-old European man with pycnodysostosis who developed a chondroblastic osteosarcoma of the right femur. No case of bone cancer in this sclerosing bone disease had been described so far.
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Neoplasias Femorales/etiología , Osteosarcoma/etiología , Picnodisostosis/complicaciones , Adulto , Humanos , MasculinoRESUMEN
Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder characterized by early-onset, chronic, nonmalignant lymphoproliferation, autoimmune manifestations, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline (ALPS-FAS) or somatic mutations (ALPS-sFAS) of the TNFRSF6 gene coding for FAS. Although the clinical features of ALPS have been described previously, long-term follow-up data on morbidity and mortality are scarce. We performed a retrospective analysis of clinical and genetic features of 90 ALPS-FAS and ALPS-sFAS patients monitored over a median period of 20.5 years. Heterozygous germline mutations of TNFRSF6 were identified in 83% of probands. Somatic TNFRSF6 mutations were found in 17% of index cases (all located within the intracellular domain of FAS). Sixty percent of the ALPS-FAS patients with mutations in the extracellular domain had a somatic mutation affecting the second allele of TNFRSF6; age at onset was later in these patients. No other genotype-phenotype correlations could be found. Long-term analysis confirmed a trend toward spontaneous remission of lymphoproliferation in adulthood but mixed outcomes for autoimmune manifestations. We observed significant and potentially life-threatening disease and treatment-related morbidity, including a high risk of sepsis after splenectomy that calls for careful long-term monitoring of ALPS patients. We also noted a significantly greater occurrence of disease-related symptoms in male than in female patients.
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Síndrome Linfoproliferativo Autoinmune/genética , Mutación , Receptor fas/genética , Adolescente , Adulto , Anciano , Síndrome Linfoproliferativo Autoinmune/sangre , Síndrome Linfoproliferativo Autoinmune/complicaciones , Síndrome Linfoproliferativo Autoinmune/epidemiología , Niño , Preescolar , Estudios de Cohortes , Recolección de Datos , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación/fisiología , Adulto JovenRESUMEN
OBJECTIVE: The goal of this study was to describe the spectrum of clinical signs of mevalonate kinase deficiency (MKD). METHODS: This was a retrospective French and Belgian study of patients identified on the basis of MKD gene mutations. RESULTS: Fifty patients from 38 different families were identified, including 1 asymptomatic patient. Symptoms began during the first 6 months of life in 30 patients (60%) and before the age of 5 years in 46 patients (92%). Symptoms consisted of febrile diarrhea and/or rash in 23 of 35 patients (66%). Febrile attacks were mostly associated with lymphadenopathy (71%), diarrhea (69%), joint pain (67%), skin lesions (67%), abdominal pain (63%), and splenomegaly (63%). In addition to febrile attacks, 27 patients presented with inflammatory bowel disease, erosive polyarthritis, Sjögren syndrome, and other chronic neurologic, renal, pulmonary, endocrine, cutaneous, hematologic, or ocular symptoms. Recurrent and/or severe infections were observed in 13 patients, hypogammaglobulinemia in 3 patients, and renal angiomyolipoma in 3 patients. Twenty-nine genomic mutations were identified; the p.Val377Ile mutation was the most frequently found (29 of 38 families). Three patients died of causes related to MKD. The disease remained highly active in 17 of the 31 surviving symptomatic patients followed up for >5 years, whereas disease activity decreased over time in the other 14 patients. Interleukin 1 antagonists were the most effective biological agents tested, leading to complete or partial remission in 9 of 11 patients. CONCLUSION: MKD is not only an autoinflammatory syndrome but also a multisystemic inflammatory disorder, a possible immunodeficiency disorder, and a condition that predisposes patients to the development of renal angiomyolipoma.
Asunto(s)
Errores Innatos del Metabolismo/diagnóstico , Fosfotransferasas (Aceptor de Grupo Alcohol)/deficiencia , Femenino , Humanos , Lactante , Recién Nacido , Inflamación/diagnóstico , Masculino , Estudios RetrospectivosRESUMEN
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by splenomegaly, lymphadenopathy, hypergammaglobulinemia, accumulation of double-negative TCRalphabeta(+) CD4(-)CD8(-) T cells (DNT cells), and autoimmunity. Previously, DNT cell detection and a functional defect of T cells in a FAS-induced apoptosis test in vitro had been used for ALPS diagnosis. However, a functional defect can also be detected in mutation-positive relatives (MPRs) who remain free of any ALPS-related disease. In contrast, lymphocytes from patients carrying a somatic mutation of FAS exhibit normal sensitivity to FAS-induced apoptosis in vitro. We assessed the soluble FAS-L concentration in the plasma of ALPS patients carrying FAS mutations. Overall, we showed that determination of the FAS-L represents, together with the IL-10 concentration and the DNT cell percentage, a reliable tool for the diagnosis of ALPS.
Asunto(s)
Enfermedades Autoinmunes/diagnóstico , Proteína Ligando Fas/metabolismo , Interleucina-10/metabolismo , Trastornos Linfoproliferativos/diagnóstico , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Linfocitos T/metabolismo , Receptor fas/genética , Adolescente , Adulto , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/metabolismo , Biomarcadores/sangre , Biomarcadores/metabolismo , Antígenos CD4/sangre , Antígenos CD4/metabolismo , Antígenos CD8/sangre , Antígenos CD8/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Proteína Ligando Fas/sangre , Humanos , Lactante , Recién Nacido , Interleucina-10/sangre , Trastornos Linfoproliferativos/sangre , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/metabolismo , Persona de Mediana Edad , Mutación/fisiología , Síndrome , Linfocitos T/patología , Adulto Joven , Receptor fas/fisiologíaRESUMEN
Activation-induced cell death (AICD) is involved in peripheral tolerance by controlling the expansion of repeatedly stimulated T cells via an apoptotic Fas (CD95; APO-1)-dependent pathway. The TNFRSF-6 gene encoding Fas is mutated in children suffering from autoimmune lymphoproliferative syndrome (ALPS), which is characterized by lymphoproliferation and autoimmunity. We examined AICD in Fas-deficient T cells from ALPS patients. We showed that primary activated Fas-deficient T cells die by apoptosis after repeated T cell antigen receptor (TCR) stimulation despite resistance to Fas-mediated cell death. This Fas-independent AICD was found to be mediated through a cytotoxic granules-dependent pathway. Cytotoxic granules-mediated AICD was also detected in normal T lymphocytes though to a lesser extent. As expected, the cytotoxic granules-dependent AICD was abolished in T cells from Rab27a- or perforin-deficient patients who exhibited defective granules-dependent cytotoxicity. Supporting an in vivo relevance of the cytotoxic granules-dependent AICD in ALPS patients, we detected an increased number of circulating T lymphocytes expressing granzymes A and B. Altogether, these data indicated that the cytotoxic granules-dependent cell death in ALPS may compensate for Fas deficiency in T lymphocytes. Furthermore, they identified a novel AICD pathway as a unique alternative to Fas apoptosis in human peripheral T lymphocytes.