RESUMEN
Recent studies suggest that both high and low levels of vitamin B12 (vitB12) may have negative health impacts. We measured VitB12 in patients with the Neurodevelopmental disorders (ND) (n = 222), comprised of Autism Spectrum Disorders, specific Developmental disorders, and Intellectual Disability (aged 2-53 years), schizophrenia (n = 401), and healthy controls (HC) (n = 483). Age-and gender-adjusted vitB12 z-scores were calculated by comparisons with a reference population (n = 76 148). We found higher vitB12 in ND (median 420 pmol/L, mean z-score: 0.30) than in HC (316 pmol/L, z-score: 0.06, P < .01) and schizophrenia (306 pmol/L, z-score: -0.02, P < .001), which was significant after adjusting for age, gender, vitB12 supplement, folate, hemoglobin, leukocytes, liver, and kidney function (P < .02). In ND, 20% (n = 44) had vitB12 above 650 pmol/L, and 1% (n = 3) had below 150 pmol/L (common reference limits). In 6.3% (n = 14) of ND, vitB12 was above 2SD of mean in the age-and gender-adjusted reference population, which was more frequent than in HC (n = 8, 1.6%), OR: 4.0, P = .001. Low vitB12 was equally frequent as in HC, and vitB12 z-scores were equal across the age groups. To conclude, vitB12 was higher in ND than in HC and schizophrenia, suggesting a specific feature of ND, which warrants further studies to investigate the underlying mechanisms.
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Trastornos del Neurodesarrollo/metabolismo , Esquizofrenia/metabolismo , Vitamina B 12/metabolismo , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Suplementos Dietéticos , Femenino , Ácido Fólico/metabolismo , Hemoglobinas/metabolismo , Humanos , Leucocitos/metabolismo , Masculino , Persona de Mediana Edad , Deficiencia de Vitamina B 12/metabolismo , Adulto JovenRESUMEN
AIM: To evaluate health-related quality of life, mental health and treatment-related stress responses in children with primary antibody deficiency and both their parents. METHODS: Children and their parents completed the standardised questionnaires Pediatric Quality of life Inventory, Strength and Difficulties Questionnaire and Impact of Event Scale. Parents also completed standardised questionnaires regarding their own mental health and quality of life. The results were compared to those of healthy children, kidney transplanted children and children in remission from acute lymphoblastic leukaemia. RESULTS: Children with primary antibody deficiency reported a poorer health-related quality of life compared to healthy children and children in remission from acute lymphoblastic leukaemia. They reported poorer mental health compared with healthy children. Mothers of children with primary antibody deficiency reported poorer mental health compared to mothers of healthy children but comparable to mothers of chronically ill children. Parents reported a similar quality of life as the general Norwegian population. Treatment with subcutaneous immunoglobulin infusions at home is generally well tolerated, but some report severe treatment-related stress. CONCLUSION: Primary antibody deficiency has a significant impact on quality of life and mental health of affected children. Patients and parents with severe treatment-related stress should be identified and helped.
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Enfermedades de Inmunodeficiencia Primaria , Calidad de Vida , Niño , Humanos , Salud Mental , Noruega , Padres , Encuestas y CuestionariosRESUMEN
The 22q11.2 deletion syndrome (22q11.2 del), also known as DiGeorge syndrome, is a genetic disorder with an estimated incidence of 1:3000 to 1:6000 births. These patients may suffer from affection of many organ systems with cardiac malformations, immunodeficiency, hypoparathyroidism, autoimmunity, palate anomalies, and psychiatric disorders being the most frequent. The importance of the complement system in 22q11.2 del has not been investigated. The objective of this study was to evaluate the complement system in relation to clinical and immunological parameters in patients. A national cohort of patients (n = 69) with a proven heterozygous deletion of chromosome 22q11.2 and a group of age and sex matched controls (n = 56) were studied. Functional capacity of the classical, lectin, and alternative pathways of the complement system as well as complement activation products C3bc and terminal complement complex (TCC) were accessed and correlated to clinical features. All patients in our study had normal complement activation in both classical and alternative pathways. The frequency of mannose-binding lectin deficiency was comparable to the normal population. The patients had significantly raised plasma levels of C3bc and a slight, but not significant, increase in TCC compared with controls. This increase was associated with the presence of psychiatric disorders in patients. The present study shows no complement deficiencies in 22q11.2 deletion syndrome. On the contrary, there are signs of increased complement activation in these patients. Complement activation is particularly associated with the presence of psychiatric disorders.
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Activación de Complemento/fisiología , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Síndrome de DiGeorge/inmunología , Trastornos Mentales/epidemiología , Fragmentos de Péptidos/sangre , Adolescente , Niño , Preescolar , Estudios de Cohortes , Complemento C3b , Vía Alternativa del Complemento , Síndrome de DiGeorge/epidemiología , Femenino , Humanos , Masculino , Noruega/epidemiología , Regulación hacia ArribaRESUMEN
In the fetus, the cardiac neural crest gives rise to both the thymus and the conotruncus of the heart. In newborn screening for severe T-cell lymphopenia neonates with congenital heart defects may be detected. In this study, we investigated the occurrence of T-cell lymphopenia in neonates with or without 22q11.2 deletion syndrome (del) suffering from heart defects. This retrospective cohort study included 125 patients with heart defects. T-cell receptor excision circles (TRECs), a measure for T-cell lymphopenia, were quantified by RT-PCR using stored newborn screening blood spots. Three patient groups were compared: non-conotruncal defects (n = 57), conotruncal defects (n = 42), and 22q11.2 del with conotruncal defects (n = 26). Significantly lower TREC values were detected in patients with 22q11.2 del and conotruncal heart defects compared to those with non-syndromic conotruncal (p < 0.001) and non-conotruncal (p < 0.001) defects. In contrast, no significant difference was found between patients with non-syndromic conotruncal and non-conotruncal heart defects (p = 0.152). Low TREC levels were obtained in neonates treated with heart surgery/intervention within 2 weeks after birth and in those with a fatal outcome (p = 0.02) independent of patient group. A correlation was found between low TREC numbers and oxygen saturation, SpO2 below 95% (p = 0.017). The SpO2 was significantly lower in the non-syndromic conotruncal group compared to non-conotruncal (p < 0.001) and 22q11.2 del group (p = 0.015). No correlation was found between low neonatal TRECs and infections needing hospitalization later in life (p = 0.135). Patients with 22q11.2 del and conotruncal defects have significantly lower TREC levels compared to patients with heart defects without this syndrome.
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Síndrome de DiGeorge/diagnóstico , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/genética , Receptores de Antígenos de Linfocitos T/inmunología , Síndrome de DiGeorge/complicaciones , Síndrome de DiGeorge/genética , Femenino , Cardiopatías Congénitas/complicaciones , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal , Receptores de Antígenos de Linfocitos T/genética , Estudios RetrospectivosRESUMEN
PURPOSE: Immunodeficiency is one of the key features of 22q11.2 deletion syndrome (del), and it is seen in approximately 75% of the patients. The degree of immunodeficiency varies widely, from no circulating T cells to normal T cell counts. It has been hypothesized that the low number of T cells may at least in part be due to increased apoptosis of T cells. Increased spontaneous T cell apoptosis has been reported in one patient with 22q11.2del, but this has not been further investigated. METHODS: A national cohort of patients with a proven heterozygous deletion of chromosome 22q11.2 diagnosed by FISH or MLPA and a group of age and sex matched controls were studied. Spontaneous and activation-induced apoptosis, in addition to FAS expression on lymphocytes, were measured using flow cytometry. Serum levels of FASL were analyzed using ELISA. RESULTS: There was no increased spontaneous apoptosis in patients with 22q11.2del. Upon activation, anti-FAS-induced apoptosis was significantly increased in patients compared to those in controls, while there was no difference in activation induced cell death or activated cell autonomous death. We also found a significant increase in expression of FAS on freshly isolated lymphocytes from patients, while there was no difference in serum levels of FASL. Patients with congenital heart defects (CHD) had significantly higher serum levels of FASL compared to non-CHD patients. CONCLUSION: We have shown increased FAS expression on lymphocytes from patients with 22q11.2del as well as increased levels of FASL in patients with CHD. Those changes may contribute to the pathophysiology of the 22q11.2del.
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Apoptosis/inmunología , Cromosomas Humanos Par 22/genética , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/inmunología , Linfocitos T/inmunología , Receptor fas/genética , Adolescente , Niño , Preescolar , Cromosomas Humanos Par 22/inmunología , Femenino , Humanos , MasculinoRESUMEN
AIM: We evaluated a strict strategy that aimed to avoid fluctuations in glucose infusion rates (GIRs) and assessed the independent effects of maximal daily GIRs on the hyperglycaemia risk among extremely low birth weight (ELBW) infants receiving early enhanced parenteral nutrition. METHODS: This study comprised all ELBW infants admitted to the neonatal intensive care unit of Oslo University Hospital Rikshospitalet, Norway, before (2007-2009) and after (2012-2013) implementing a strict GIR strategy. Severe hyperglycaemia was defined as two consecutive blood glucose values over 12 mmol/L. Maximum daily GIRs (mg/kg/min) were categorised into low (<5.1), intermediate (5.1-7.0) or high (>7.0). Mixed effects logistic regression modelling for repeated measurements was applied to investigate independent determinants of hyperglycaemia. RESULTS: We included 1293 treatment days for 195 infants. The maximum daily GIR decreased (6.3 versus 5.8 mg/kg/min), while mean daily glucose and energy intakes were maintained in the post-strategy period. The prevalence of severe hyperglycaemia (48% versus 23%), insulin use (39% versus 16%) and mortality (26% versus 10%) fell. Intermediate GIR (odds ratio 2.11) and high GIR (odds ratio 2.85) were significant independent predictors of severe hyperglycaemia compared to low GIR. CONCLUSION: A strict GIR strategy reduced the risk of severe hyperglycaemia and adverse outcomes.
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Glucosa/administración & dosificación , Hiperglucemia/prevención & control , Recien Nacido con Peso al Nacer Extremadamente Bajo , Cuidado Intensivo Neonatal/métodos , Glucemia/metabolismo , Femenino , Estudios de Seguimiento , Mortalidad Hospitalaria , Hospitales Universitarios , Humanos , Recién Nacido , Infusiones Intravenosas/normas , Unidades de Cuidado Intensivo Neonatal , Modelos Logísticos , Masculino , Noruega , Estudios Prospectivos , Medición de Riesgo , Conducta de Reducción del Riesgo , Estadísticas no Paramétricas , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. RESULTS: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
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Síndromes de Inmunodeficiencia/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Femenino , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Human phosphoglucomutase 3 (PGM3) catalyzes the conversion of N-acetyl-glucosamine (GlcNAc)-6-phosphate into GlcNAc-1-phosphate during the synthesis of uridine diphosphate (UDP)-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways. We identified three unrelated children with recurrent infections, congenital leukopenia including neutropenia, B and T cell lymphopenia, and progression to bone marrow failure. Whole-exome sequencing demonstrated deleterious mutations in PGM3 in all three subjects, delineating their disease to be due to an unsuspected congenital disorder of glycosylation (CDG). Functional studies of the disease-associated PGM3 variants in E. coli cells demonstrated reduced PGM3 activity for all mutants tested. Two of the three children had skeletal anomalies resembling Desbuquois dysplasia: short stature, brachydactyly, dysmorphic facial features, and intellectual disability. However, these additional features were absent in the third child, showing the clinical variability of the disease. Two children received hematopoietic stem cell transplantation of cord blood and bone marrow from matched related donors; both had successful engraftment and correction of neutropenia and lymphopenia. We define PGM3-CDG as a treatable immunodeficiency, document the power of whole-exome sequencing in gene discoveries for rare disorders, and illustrate the utility of genomic analyses in studying combined and variable phenotypes.
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Enfermedades del Desarrollo Óseo/genética , Trastornos Congénitos de Glicosilación/genética , Síndromes de Inmunodeficiencia/genética , Mutación , Fosfoglucomutasa/genética , Femenino , Humanos , Masculino , LinajeRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) infection is an important cause of hospitalization in previously healthy infants. Immunological mechanisms predisposing infants to severe disease are poorly understood. Early biomarkers for disease severity may assist clinical decisions. We investigated T-cell receptor excision circles (TREC), episomal DNA made during thymic T-cell receptor rearrangement, and a marker for thymus activity, both during disease and in neonatal screening cards as a risk factor for RSV disease severity. METHODS: One hundred thirteen patients hospitalized with RSV infection <12 months of age, grouped by disease severity, were available for this investigation, in which we conducted both a prospective and a case-control study. The prospective study included 47 RSV positive infants (mild n = 13, moderate n = 10, severe n = 24). TREC counts were determined by PCR of DNA extracted from EDTA-blood collected on hospitalization, and corrected for lymphocytes using ANCOVA. The case-control study included 85 newborns who later in infancy became RSV positive (mild n = 32, moderate n = 24, severe n = 29) and 47 newborns who never developed RSV disease as healthy controls included from health centres in the same catchment area. TRECs were measured using DNA extracted from dry blood spots from stored neonatal screening cards, followed by PCR. Student's T-test compared patients with controls, ANOVA compared disease severity groups. RESULTS: During RSV infection patients in the severe disease group had significantly lower (p = 0.017) TREC/200 µL blood compared to the other two disease groups, after correction for lymphocyte count. Newborn TREC levels, were significantly higher in RSV patients compared to controls (p < 0.0001). No significant differences in TREC copies at birth were found between disease severities. CONCLUSION: During acute RSV infection a lower number of TREC is found in the severe disease group. TREC has potential as an immunological marker for severe RSV infection. Higher neonatal TREC counts indicate that infants later presenting with severe RSV do not have reduced thymic activity at birth and probably no congenital T-cell defect.
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ADN/sangre , Receptores de Antígenos de Linfocitos T/genética , Infecciones por Virus Sincitial Respiratorio/genética , Timo/virología , Estudios de Casos y Controles , Pruebas con Sangre Seca , Femenino , Humanos , Lactante , Recién Nacido , Recuento de Linfocitos , Masculino , Estudios Prospectivos , Infecciones por Virus Sincitial Respiratorio/etiología , Infecciones por Virus Sincitial Respiratorio/inmunologíaRESUMEN
PURPOSE: Newborns with severe T-cell lymphopenia, including those with 22q11.2 deletion syndrome (DS), have low numbers of T-cell receptor excision circles (TRECs). The aim of this study was to determine a possible correlation between neonatal TRECs in 22q11.2DS and the development of different phenotypes to elucidate the prognostic value of TREC in this disease. METHODS: In this national survey including 46 patients with 22q11.2DS born after 2005, TREC levels were determined using stored newborn screening blood spots on filter cards. Patients were grouped into quartiles according to their TREC values, except the two infants with thymus aplasia. RESULTS: The two patients with thymic aplasia had no detectable TREC. The rest had no severe clinical immunodeficiency. There was a significant correlation between low TRECs and the proportion of patients with CD3(+)CD4(+)T-cells below the 5th percentile of healthy infants (p = 0.027) as well as the proportion with an abnormal thymus feature either no thymus or remnant thymus as observed during heart surgery (p = 0.022). Significantly lower TRECs (p = 0.019) were found in patients with cardiac defects compared to no such defects. Patients within the lowest quartile of TREC values (<71 TRECs/µL, n = 11) had more frequent severe cardiac defects than the other quartiles (p = 0.010). Eight of these patients in the lowest quartile needed an operation/intervention within two weeks after birth or died because of a cardiac defect. CONCLUSION: The low TREC values not only correlate with decreased T-cell immunity, but also with the occurrence of heart defects in the patients.
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ADN Circular/genética , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Receptores de Antígenos de Linfocitos T/genética , Subgrupos de Linfocitos T/metabolismo , Deleción Cromosómica , ADN Circular/sangre , Síndrome de DiGeorge/sangre , Síndrome de DiGeorge/complicaciones , Femenino , Cardiopatías Congénitas , Humanos , Inmunofenotipificación , Recién Nacido , Infecciones/etiología , Masculino , Tamaño de los Órganos , Receptores de Antígenos de Linfocitos T/sangre , Timo/patologíaRESUMEN
AIM: The World Health Organization recommends the defined daily dose (DDD) as the standard unit of measurement for antibiotic use, but this is not applicable in children. We aimed to assess paediatric antibiotic use in a Norwegian tertiary care hospital using a novel weight-adjusted method. METHODS: We obtained antibiotic purchase data from the hospital pharmacy and administrative data for all admissions from 2002 to 2009 to the paediatric wards at Oslo University Hospital, Rikshospitalet. Recommended daily doses per 100 kg days (RDDs/kg days) were calculated based on national guidelines for paediatric antibiotic use, length of stay and estimated weight for sex and age using national growth references. RESULTS: Total antibiotic use increased significantly from 51.8 to 65.5 RDDs/100 kg days. We found statistically significant annual increases in the consumption of carbapenems (18.0%), third-generation cephalosporins (6.0%) and imidazole derivatives (6.6%) and a considerable difference between total antibiotic use measured in RDDs/100 kg days and DDDs/100 bed days for neonates. CONCLUSION: Weight-adjusted antibiotic use provided a more meaningful description of the quantities of antibiotics consumed than DDDs/100 bed days, particularly for neonates. Total antibiotic use, use of meropenem, third-generation cephalosporins and imidazole derivatives increased significantly despite low prevalence of antibiotic-resistant pathogens.
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Antibacterianos/administración & dosificación , Peso Corporal , Pautas de la Práctica en Medicina , Centros de Atención Terciaria , Adolescente , Factores de Edad , Niño , Preescolar , Utilización de Medicamentos , Hospitalización , Humanos , Lactante , Recién Nacido , NoruegaRESUMEN
BACKGROUND: There are no previous blinded studies for comparison of preoperative versus postoperative perceptual speech assessments when using a pharyngeal flap for treating velopharyngeal insufficiency (VPI) in patients diagnosed with 22q11.2 deletion syndrome. The aim of the study was to evaluate the effect of superiorly based pharyngeal flap surgery on speech in these patients using blinded judgments of experienced speech therapists. METHODS: A retrospective study of 12 consecutive patients who had undergone pharyngeal flap surgery for treatment of VPI between 2002 and 2009 was conducted. Seven girls and 5 boys between 4 and 15 (median, 6) years old at the time of surgery were included in the study. Six patients were born with a submucous cleft palate (including 2 occult), and 1 patient, with an overt cleft palate. The remaining 5 patients had no signs of a palatal pathology. All palatal clefts had been repaired before pharyngeal flap surgery except in 2 patients with occult submucous cleft palate. Preoperative and postoperative audio recordings were blinded for scoring independently by 3 senior speech therapists. RESULTS: There was a significant improvement in hypernasality (P = 0.002), audible nasal emission (P = 0.033), weak pressure consonants (P = 0.008), and speech intelligibility (P = 0.021) after pharyngeal flap surgery. Hyponasality did not develop significantly with surgery. One patient was diagnosed with obstructive sleep apnea. CONCLUSIONS: Superiorly based pharyngeal flap resulted in a significant speech improvement in 12 consecutive patients with 22q11.2 deletion syndrome having VPI.
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Síndrome de DiGeorge/complicaciones , Síndrome de DiGeorge/genética , Faringe/cirugía , Colgajos Quirúrgicos , Insuficiencia Velofaríngea/genética , Insuficiencia Velofaríngea/cirugía , Adolescente , Niño , Preescolar , Fisura del Paladar/complicaciones , Fisura del Paladar/cirugía , Femenino , Humanos , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Complement component C5 is crucial for experimental animal inflammatory tissue damage; however, its involvement in human inflammation is incompletely understood. The responses to gram-negative bacteria were here studied taking advantage of human genetic complement-deficiencies--nature's own knockouts--including a previously undescribed C5 defect. Such deficiencies provide a unique tool for investigating the biological role of proteins. The experimental conditions allowed cross-talk between the different inflammatory pathways using a whole blood model based on the anticoagulant lepirudin, which does not interfere with the complement system. Expression of tissue factor, cell adhesion molecules, and oxidative burst depended highly on C5, mediated through the activation product C5a, whereas granulocyte enzyme release relied mainly on C3 and was C5a-independent. Release of cytokines and chemokines was mediated to varying degrees by complement and CD14; for example, interleukin (IL)-1beta and IL-8 were more dependent on complement than IFN-gamma and IL-6, which were highly dependent on CD14. IL-1 receptor antagonist (IL-1ra) and IFN-gamma inducible protein 10 (IP-10) were fully dependent on CD14 and inversely regulated by complement, that is, complement deficiency and complement inhibition enhanced their release. Granulocyte responses were mainly complement-dependent, whereas monocyte responses were more dependent on CD14. Notably, all responses were abolished by combined neutralization of complement and CD14. The present study provides important insight into the comprehensive role of complement in human inflammatory responses to gram-negative bacteria.
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Proteínas del Sistema Complemento/deficiencia , Proteínas del Sistema Complemento/genética , Inflamación/genética , Inflamación/inmunología , Adolescente , Adulto , Estudios de Casos y Controles , Adhesión Celular/inmunología , Activación de Complemento , Complemento C2/deficiencia , Complemento C2/genética , Complemento C5/deficiencia , Complemento C5/genética , Escherichia coli/inmunología , Femenino , Bacterias Gramnegativas/inmunología , Bacterias Gramnegativas/patogenicidad , Humanos , Inmunidad Innata/genética , Técnicas In Vitro , Inflamación/etiología , Receptores de Lipopolisacáridos/metabolismo , Masculino , Modelos Inmunológicos , Monocitos/inmunología , Monocitos/microbiología , Neisseria meningitidis/inmunología , Fagocitosis , Estallido Respiratorio/inmunología , Tromboplastina/biosíntesisRESUMEN
OBJECTIVE: The aims of the study were to examine tooth and enamel disturbances in individuals with 22q11.2 deletion syndrome and to analyze associations with medical conditions, birth characteristics and blood values of calcium and PTH. MATERIALS AND METHODS: Fifty individuals participated in the study (27 females, median age 10 years, range 1.5-44). Congenital absence of teeth was studied on orthopantomograms; 1148 teeth were examined, both clinically and radiologically, and enamel hypomineralizations and hypoplasias were recorded. Medical history and findings were recorded as part of a larger study on the manifestations of 22q11.2-deletion syndrome in Norway. RESULTS: Tooth agenesis was observed in 15% of study participants. Sixty-six percent of the participants and 26.0% of teeth presented with enamel disturbances. Of these, 12 individuals (24.0%) and 215 teeth (18.7%) had hypomineralizations and four individuals (8.0%) and 86 teeth (7.5%) had hypoplasias. Seventeen participants (34.0%) presented with both types of disturbance, but rarely in the same tooth. Only two teeth (0.17%) had both types of disturbance. Hypomineralizations were twice as frequent in permanent as in primary teeth. No correlations were found to medical conditions, except that participants with congenital cardiac anomalies presented with fewer total enamel disturbances and hypomineralizations in permanent teeth than those without. CONCLUSIONS: Enamel disturbances were frequently seen. There were more hypomineralizations than hypoplasias. Hypoparathyroidism and/or hypocalcemia are not clear etiological factors for enamel disturbances and there were no major correlations between medical conditions and enamel disturbances.
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Esmalte Dental/anomalías , Síndrome de DiGeorge/complicaciones , Anomalías Dentarias/complicaciones , Desmineralización Dental/complicaciones , Adolescente , Adulto , Anodoncia/complicaciones , Anodoncia/diagnóstico , Anodoncia/genética , Calcio/sangre , Niño , Preescolar , Atención Dental para Enfermos Crónicos , Hipoplasia del Esmalte Dental/complicaciones , Hipoplasia del Esmalte Dental/genética , Dentición Permanente , Síndrome de DiGeorge/sangre , Femenino , Humanos , Lactante , Masculino , Hormona Paratiroidea/sangre , Anomalías Dentarias/diagnóstico , Anomalías Dentarias/genética , Desmineralización Dental/genética , Diente Primario , Adulto JovenRESUMEN
Thymectomy is an established treatment in adult MG and also recommended for the treatment of post-pubertal onset juvenile MG. Whether the youngest children should be thymectomized is still debated. Signs of premature aging of the immune system have been shown in studies on early perioperative thymectomy in children with congenital heart defect. In this retrospective cohort study the objective was to investigate the long-term effects of treatment related thymectomy on T cell subsets and T cell receptor rearrangement excision circles (TRECs) in peripheral blood of juvenile myasthenia gravis (MG) patients, as well as clinical occurrence of autoimmune disorders, malignancies and infectious diseases. Forty-seven patients with onset of myasthenia gravis before the age of 19 years were included; 32 (68.1%) had been thymectomized and 15 (31.8%) had not. They were studied at varying times after thymectomy (7-26 years). We found a significant lower number of naïve helper T cells (CD4+CD45RA+) with an increased proportion of memory helper T cells (CD4+CD45RO+), and a significant lower number of naïve cytotoxic T cells (CD8+CD27+CD28+) in the thymectomized patients. In addition they showed a significant reduction in the number of TRECs and proportion of recent thymic emigrants (RTE) compared to non-thymectomized patients. In none of them an increased frequency of malignancies or infections was found. Our findings indicate a premature aging of the immune system after thymectomy in juvenile MG, but associated clinical consequences could not be verified.
RESUMEN
Patients with the 22q11.2 deletion syndrome display a wide phenotypic variation that is important for clinical follow-up. In this national survey of 60 patients (ages 1 to 54 years) diagnosed by Fluorescence in situ hybridization test, data were collected from medical records, a physical examination, and a semistructured interview. Ultrasound investigation of the kidneys was also performed. In addition, multiplex ligation probe amplification assay was performed to detect deletion size. Phenotypic features leading to the genetic diagnosis were noted. The patients showed a variety of organ malformations including 39 with heart anomalies. Only 20 individuals had been diagnosed with 22q11.2 DS in the first year of life. Four patients had renal and five males had genital malformations. The increased infection susceptibility (excluding otitis media) and most feeding difficulties subsided during early childhood. Speech difficulties started early and were a major problem for many patients at least until 10 years of age. Ten patients developed kyphoscoliosis in late childhood. In teenagers and adults, abnormal social behavior, learning disabilities, and psychiatric symptoms dominated. Our study which also includes adult patients emphasizes a marked change in challenges in individuals with the 22q11.2 deletion syndrome with increasing age.
Asunto(s)
Anomalías Múltiples , Cromosomas Humanos Par 22/genética , Eliminación de Gen , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/diagnóstico por imagen , Síndrome de DiGeorge/epidemiología , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/fisiopatología , Fluorescencia , Genitales/anomalías , Humanos , Hibridación in Situ , Lactante , Infecciones/epidemiología , Riñón/anomalías , Riñón/diagnóstico por imagen , Discapacidades para el Aprendizaje/epidemiología , Masculino , Registros Médicos , Persona de Mediana Edad , Noruega/epidemiología , Fenotipo , Ultrasonografía , Adulto JovenRESUMEN
Severe combined immunodeficiency (SCID) and other T cell lymphopenias can be detected during newborn screening (NBS) by measuring T cell receptor excision circles (TRECs) in dried blood spot (DBS) DNA. Second tier next generation sequencing (NGS) with an amplicon based targeted gene panel using the same DBS DNA was introduced as part of our prospective pilot research project in 2015. With written parental consent, 21 000 newborns were TREC-tested in the pilot. Three newborns were identified with SCID, and disease-causing variants in IL2RG, RAG2, and RMRP were confirmed by NGS on the initial DBS DNA. The molecular findings directed follow-up and therapy: the IL2RG-SCID underwent early hematopoietic stem cell transplantation (HSCT) without any complications; the leaky RAG2-SCID received prophylactic antibiotics, antifungals, and immunoglobulin infusions, and underwent HSCT at 1 year of age. The child with RMRP-SCID had complete Hirschsprung disease and died at 1 month of age. Since January 2018, all newborns in Norway have been offered NBS for SCID using 1st tier TRECs and 2nd tier gene panel NGS on DBS DNA. During the first 20 months of nationwide SCID screening an additional 88 000 newborns were TREC tested, and four new SCID cases were identified. Disease-causing variants in DCLRE1C, JAK3, NBN, and IL2RG were molecularly confirmed on day 8, 15, 8 and 6, respectively after birth, using the initial NBS blood spot. Targeted gene panel NGS integrated into the NBS algorithm rapidly delineated the specific molecular diagnoses and provided information useful for management, targeted therapy and follow-up i.e., X rays and CT scans were avoided in the radiosensitive SCID. Second tier targeted NGS on the same DBS DNA as the TREC test provided instant confirmation or exclusion of SCID, and made it possible to use a less stringent TREC cut-off value. This allowed for the detection of leaky SCIDs, and simultaneously reduced the number of control samples, recalls and false positives. Mothers were instructed to stop breastfeeding until maternal cytomegalovirus (CMV) status was determined. Our limited data suggest that shorter time-interval from birth to intervention, may prevent breast milk transmitted CMV infection in classical SCID.
Asunto(s)
Biomarcadores/sangre , Pruebas con Sangre Seca/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Tamizaje Neonatal/métodos , Inmunodeficiencia Combinada Grave/diagnóstico , Ácidos Nucleicos Libres de Células/sangre , ADN Circular/sangre , Diagnóstico Precoz , Femenino , Humanos , Recién Nacido , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND: Atypical mycobacteria can cause systemic infections in patients with certain types of immunodeficiency. METHODS: Clinical samples were decontaminated and cultured to assess the presence of mycobacterial species. Gene sequencing was performed to reveal interferon-gamma receptor 1 (IFN-gamma R1) deficiency. RESULTS: The index patient received a diagnosis of dominant IFN-gamma R1 deficiency during treatment for a serious infection due to atypical mycobacteria. She belongs to a Norwegian multiplex family comprising 3 generations and 5 patients with dominant IFN-gamma R1 deficiency. Four of these patients have been treated with tuberculostatics because of extensive infection due to atypical mycobacteria, such as Mycobacterium avium-intracellulare, Mycobacterium scrofulaceum, Mycobacterium bovis (bacille Calmette-Guérin), Mycobacterium bohemicum, and Mycobacterium gordonae. Two of the patients have also received subcutaneous injections of IFN-gamma. One family member with the deficiency has not received treatment and is still healthy at 13 years of age. CONCLUSIONS: Serious infection due to atypical mycobacteria should initiate a search for primary immunodeficiencies, particularly IFN-gamma R1 deficiency. Treatment with IFN-gamma should be started when serious infection due to atypical mycobacteria is verified and dominant partial IFN-gamma R1 deficiency is suspected.
Asunto(s)
Infecciones por Mycobacterium no Tuberculosas/genética , Micobacterias no Tuberculosas/aislamiento & purificación , Receptores de Interferón/deficiencia , Adolescente , Niño , Femenino , Genes Dominantes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/inmunología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Noruega , Linaje , Reacción en Cadena de la Polimerasa/métodos , ARN Ribosómico 16S/genética , Receptores de Interferón/genética , Receptores de Interferón/inmunología , Receptor de Interferón gammaRESUMEN
A controlled intervention study was performed in a paediatric hospital in Russia to improve antibiotic use and to see whether improvements persisted. During October-December 2002, clinical and microbiological data, antibiotic use, costs and outcome were recorded at two wards for gastrointestinal infections (GIIs) and two wards for respiratory tract infections (RTIs). Guidelines for diagnosis and treatment of infections were developed and implemented at one ward for GIIs and one ward for RTIs in 2003. The other two wards served as controls. The same data were recorded during the same 3-month periods in 2003 and 2004. At the intervention ward, the percentage of patients with GII who received antibiotics decreased from 94% in 2002 to 41% in 2003, but increased to 73% in 2004. In RTI patients these percentages were 90% in 2002, 53% in 2003 and 83% in 2004. The proportions of patients who received antibiotics in 2004 were still lower than in 2002: risk difference (RD)=0.217 (P=0.001) in GIIs and RD=0.073 (P=0.013) in RTIs. From 2002 to 2004 there was a decrease in cephalosporin use (P=0.021) and an increase in penicillin use (P=0.032) in pneumonia. There was no difference in mortality, duration of fever or duration of hospital stay between the intervention and control wards. Antibiotic use could be halved without compromising the quality of patient care, but 1 year after the intervention the use of antibiotics approached pre-intervention levels. Strategies to sustain the effect of interventions are needed.