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Introduction: Maternal thyroid disease is considered as a risk factor for abnormal thyroid function at birth, as well as for long-term morbidity in offspring. The potential harmful effects on the neonate had led to the clinical practice of thyroid function assessment in infants born to mothers with thyroid disease during pregnancy. In this study, we evaluated the usefulness of routine thyroid function tests for every newborn of a mother with thyroid dysfunction. Methods: Data were collected retrospectively from the medical files of mothers diagnosed with thyroid disease and their infants (496 mother-neonate pairs). All mothers with diagnosed thyroid disease who gave birth in the years 2016-2019 at our medical center were included. Results: Hypothyroidism was the most common maternal diagnosis (91.4%), among which 48.7% had Hashimoto's thyroiditis. Hyperthyroidism was diagnosed in 8.6% of the cohort - 71.6% of them with Graves' disease. None of the newborns was diagnosed with congenital hypothyroidism in the screening program. Thyroid-stimulating hormone was >10 mIU/L in 14.6% and >20 mUI/L in 2.2%; all had free thyroxine within normal range. Serum thyroid function test identified four infants with thyroid disease; two had congenital hypothyroidism not related to maternal thyroid disease, one had transient familial congenital hypothyroidism and one had neonatal Graves' disease. Conclusions: Thyroid function testing for all newborns of mothers with thyroid dysfunction seems redundant. However, in cases of congenital hypothyroidism in siblings, thyroid function test, in addition to newborn thyroid screening, is recommended, and more careful follow-up is indicated. In maternal Graves' disease, thyroid function test on days 2-3 of life is recommended.
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Avoidance of fasting and regular ingestion of uncooked-cornstarch have long been the mainstay dietary treatment of Glycogen Storage Disease type Ia (GSD-Ia). However, GSD-Ia patients who despite optimal dietary treatment show poor glycemic control and are intolerant to cornstarch, present a complex clinical challenge. We pursued Whole Exome Sequencing (WES) in three such unrelated patients, to both confirm a molecular diagnosis of GSD-Ia, and seek additional variants in other genes (e.g. genes associated with amylase production) which may explain their persistent symptoms. WES confirmed the GSD-Ia diagnosis, with all three probands harboring the homozygous p.R83C variant in G6PC. While no other significant variants were identified for patients A and B, a homozygous p.G276V variant in the SI gene was detected in patient C, establishing the dual-diagnosis of GSD-Ia and Sucrase-Isomaltase Deficiency. To conclude, we suggest that WES should be considered in GSD-Ia patients who show persistent symptoms despite optimal dietary management.
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Glucosa-6-Fosfatasa , Enfermedad del Almacenamiento de Glucógeno Tipo I , Glucosa-6-Fosfatasa/genética , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , AlmidónRESUMEN
AIM: Children with inflammatory bowel disease (IBD) are prone to low bone mineral density (BMD). Our aim was to assess longitudinal changes in BMD in this population. METHODS: A retrospective longitudinal study of children with IBD, treated at two tertiary centres in Israel, who underwent two BMD measurements by dual-energy X-ray absorptiometry (DXA). Changes in lumbar spine BMD (∆L1-4 z-scores) were examined for correlations with clinical characteristics. RESULTS: The cohort included 41 patients (age at diagnosis 12.1 ± 3.5 years, 23 females).The mean interval between the scans was 3.4 ± 2.0 years. There was a trend towards improvement in L1-4 z-scores (-1.64 ± 1.02 vs -1.45 ± 0.83, P = .12). ∆L1-4 z-scores correlated positively with ∆weight-standard deviation scores (SDS), ∆height-SDS and ∆BMI-SDS, and with age at the second scan (R = .55, P < .01; R = .42, P < .01; R = .42, P = .01; R = .35, P = .02, respectively); and negatively with L1-4 z-scores at the first scan (R = -.63, P < .01). Stepwise linear regression analysis identified the first scan L1-4 z-scores and ∆weight-SDS as independent predictors of ∆L1-4 z-scores. An L1-4 z-score ≤-2 at the first DXA scan was associated with significant improvement at the second scan. CONCLUSION: Improvement in BMD was more pronounced in children who gained weight or whose BMD was low at the first scan.
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Densidad Ósea , Enfermedades Inflamatorias del Intestino , Absorciometría de Fotón , Adolescente , Niño , Femenino , Humanos , Israel , Estudios Longitudinales , Estudios RetrospectivosRESUMEN
Defects of the glycosylphosphatidylinositol (GPI) biosynthesis pathway constitute an emerging subgroup of congenital disorders of glycosylation with heterogeneous phenotypes. A mutation in the promoter of PIGM, resulting in a syndrome with portal vein thrombosis and persistent absence seizures, was previously described in three patients. We now report four additional patients in two unrelated families, with further clinical, biochemical and molecular delineation of this unique entity. We also describe the first prenatal diagnosis of PIGM deficiency, allowing characterization of the natural history of the disease from birth. The patients described herein expand the phenotypic spectrum of PIGM deficiency to include macrocephaly and infantile-onset cerebrovascular thrombotic events. Finally, we offer insights regarding targeted treatment of this rare disorder with sodium phenylbutyrate.
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Glicosilfosfatidilinositoles/deficiencia , Manosiltransferasas/genética , Megalencefalia/etiología , Vena Porta/patología , Convulsiones/etiología , Trombosis/etiología , Adolescente , Niño , Preescolar , Femenino , Glicosilfosfatidilinositoles/genética , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Megalencefalia/diagnóstico por imagen , Mutación , Regiones Promotoras Genéticas , Convulsiones/complicaciones , Convulsiones/genéticaRESUMEN
OBJECTIVES: Crohn's disease (CD) is a chronic relapsing-remitting gut inflammatory disorder with a heterogeneous unpredictable course. Dysbiosis occurs in CD; however, whether microbial dynamics in quiescent CD are instrumental in increasing the risk of a subsequent flare remains undefined. METHODS: We analyzed the long-term dynamics of microbial composition in a prospective observational cohort of patients with quiescent CD (45 cases, 217 samples) over 2 years or until clinical flare occurred, aiming to identify whether changes in the microbiome precede and predict clinical relapse. Machine learning was used to prioritize microbial and clinical factors that discriminate between relapsers and nonrelapsers in the quiescent phase. RESULTS: Patients with CD in clinical, biomarker, and mucosal remission showed significantly reduced microbial richness and increased dysbiosis index compared with healthy controls. Of the 45 patients with quiescent CD, 12 (27%) flared during follow-up. Samples in quiescent patients preceding flare showed significantly reduced abundance of Christensenellaceae and S24.7, and increased abundance of Gemellaceae compared with those in remission throughout. A composite flare index was associated with a subsequent flare. Notably, higher individualized microbial instability in the quiescent phase was associated with a higher risk of a subsequent flare (hazard ratio 11.32, 95% confidence interval 3-42, P = 0.0035) using two preflare samples. Importantly, machine learning prioritized the flare index and the intrapersonal instability over clinical factors to best discriminate between relapsers and nonrelapsers. DISCUSSION: Individualized microbial variations in quiescent CD significantly increase the risk of future exacerbation and may provide a model to guide personalized preemptive therapy intensification.
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Enfermedad de Crohn/microbiología , Enfermedad de Crohn/patología , Progresión de la Enfermedad , Disbiosis/complicaciones , Microbioma Gastrointestinal/fisiología , Monitoreo Fisiológico/métodos , Adulto , Estudios de Casos y Controles , Enfermedad de Crohn/terapia , Femenino , Estudios de Seguimiento , Humanos , Mucosa Intestinal/microbiología , Modelos Lineales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Recurrencia , Valores de Referencia , Medición de Riesgo , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
OBJECTIVES: Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy characterized by chronic lung disease and cyclic vomiting due to hyper-adrenergic crises. Most FD patients are in a depleted nutritional state; however, the phenotype of the disease is quite different between patients, as for the severity of lung disease and the intensity and frequency of these pathognomonic crises. In this study we wanted to investigate whether resting energy expenditure (REE) levels are increased in this population, and if correlations exist between REE levels and phenotype severity. METHODS: Data was collected from 12 FD patients (6/6 m/f). REE measurements were conducted by indirect calorimeter. Measured REE % predicted were correlated with pulmonary function, severity of the scoliosis, serum C-reactive protein, yearly frequency of hyperadrenergic crisis, hospital admissions and the use of nocturnal noninvasive positive pressure ventilation. RESULTS: Mean REE was 112 ±13% predicted with 50% being in a hypermetabolic state (REE/HBâ>â110%). Body mass index (BMI) was below normal range in 75% of patients, and reduced energy intake was also decreased in 75%. No significant correlations to disease severity factors were found. When dividing the subjects to REE levels above or below 125% predicted, Patients with REE above 125% predicted presented with significantly lower inspiratory capacity (42.7% predicted vs 62.8% predicted; P = 0.04). CONCLUSIONS: Hypermetabolic state was described in 50% of FD patients. The Low BMI is explained by combination of relative anorexia and increased REE. The REE levels are related to the underling respiratory disease.
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Disautonomía Familiar/metabolismo , Metabolismo Energético , Adulto , Índice de Masa Corporal , Calorimetría Indirecta , Disautonomía Familiar/fisiopatología , Femenino , Humanos , Pulmón/fisiopatología , Masculino , Estado Nutricional , Estudios Retrospectivos , Grosor de los Pliegues Cutáneos , Delgadez/metabolismoRESUMEN
BACKGROUND: The clinical, histological, and serological spectrum of celiac disease (CD) vary widely. We aimed to examine relationships between symptoms, serum anti-tissue transglutaminase antibodies (tTG) levels, mucosal damage, and mucosal anti-tTG deposits in pediatric CD. METHODS: A retrospective single-center, cohort study of children referred for endoscopy with suspected CD during 2011-2014. We retrieved the clinical data, blindly reviewed duodenal biopsies, and performed immunohistochemical staining for anti-tTG deposits. Patients were classified as monosymptomatic or polysymptomatic. Mucosal anti-tTG deposits were classified according to the location of deposits, dominant intensity, maximal intensity, and percentage of stained area. RESULTS: Of 252 patients with confirmed CD, complete data were available for 100: 37 males in the age range 1.3-16.7 with median 4.0 years. Monosymptomatic patients (n = 54) presented at an older age than polysymptomatic patients (1.3-15.5, median 8.1 vs. 1.3-16.7, median 6.3 years, p = 0.026). Marsh 2-3c was more prevalent in polysymptomatic patients (93 vs. 78%, p = 0.028). The intensity of mucosal anti-tTG deposits correlated with serum anti-tTG levels but not with the clinical presentation. CONCLUSIONS: Multiple symptoms and high serum anti-tTG antibody levels correlated with mucosal damage in children with CD. The role of immunohistochemical staining for intestinal anti-tTG mucosal deposits in the diagnosis of borderline CD is not yet established.
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Anticuerpos/sangre , Enfermedad Celíaca/sangre , Enfermedad Celíaca/patología , Proteínas de Unión al GTP/inmunología , Transglutaminasas/inmunología , Adolescente , Biopsia , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/inmunología , Niño , Preescolar , Duodeno/patología , Femenino , Humanos , Lactante , Mucosa Intestinal/patología , Masculino , Prevalencia , Proteína Glutamina Gamma Glutamiltransferasa 2 , Estudios RetrospectivosRESUMEN
OBJECTIVES: While infliximab pharmacokinetics are associated with therapy outcome in adult inflammatory bowel disease (IBD) population, limited data are available in pediatric patients. We aimed to define the relationship between infliximab trough and antibodies' levels (IFX-TL, ATI) and clinical, biomarker remission. METHODS: IFX-TL and ATI were routinely obtained between 2011 and 2017. Associations with clinical and inflammatory (C-reactive protein, CRP) end-points were studied throughout the first year of infliximab therapy. RESULTS: A total of 63 patients (50 Crohn disease, 13 ulcerative colitis, median follow-up 16 months, median 8âsamples/patient) were included, and 773 sera-samples were analyzed. Sera of patients in clinical remission had higher median IFX-TLs than sera of those with active disease (4 vs 2.25âµg/mL, Pâ<â0.0001). In addition, patients with normal CRP had a higher median IFX-TL than those with elevated CRP (Pâ=â0.02). Moreover, IFX-TL > 9.2âµg/mL at week 2 predicted clinical remission by week 14 (sensitivity 71.4%, specificity 81.2%, area under curve (AUC)â=â0.73, Pâ=â0.02) and IFX-TL > 2.2âµg/mL at week 6 predicted infliximab retention beyond 1 year of treatment (sensitivity 88.9%, specificity 100.0%, AUCâ=â0.974, Pâ<â0.0001). CONCLUSIONS: A significant association between IFX-TL and ATI and clinical and biomarker remission status in pediatric IBD patients was demonstrated, including a temporal association between week 2, 6 levels and outcome of induction and between week 6 and 14 levels and remission at 1 year of therapy. These findings suggest that therapeutic drug monitoring may be considered for management guidance among pediatric IBD patients.
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Anticuerpos Monoclonales/sangre , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Infliximab/uso terapéutico , Adolescente , Anticuerpos Monoclonales/inmunología , Área Bajo la Curva , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Niño , Colitis Ulcerosa/sangre , Enfermedad de Crohn/sangre , Monitoreo de Drogas , Femenino , Fármacos Gastrointestinales/inmunología , Humanos , Quimioterapia de Inducción , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/inmunología , Masculino , Resultado del TratamientoRESUMEN
BACKGROUND: Ataxia telangiectasia (AT) is a rare, multi-systemic, genetic disorder. Mutations in the ATM gene cause dysfunction in cell-cycle, apoptosis and V (D) J recombination leading to neurodegeneration, cellular, humoral immunodeficiencies and predisposition to malignancies. Previous studies have suggested that a sub-group of AT patients with elevated IgM levels have a distinct and more severe phenotype. In the current study we aimed to better characterize this group of patients. METHODS: We performed a retrospective review of 46 patient records, followed from January 1986 to January 2015 at the Israeli National AT Center. Demographic, clinical, radiological, laboratory data was reviewed and compared between AT patients with elevated IgM levels (EIgM) and patients with normal IgM levels (NIgM). RESULTS: 15/46(32.6%) patients had significantly elevated IgM levels. This group had a unique phenotype characterized mainly by increased risk of infection and early mortality. Colonization of lower respiratory tract with Mycobacterium gordonae and Pseudomonas aeruginosa as well as viral skin infections were more frequent in EIgM patients. Patients with NIgM had a significantly longer survival as compared to patients with EIgM but had an increased incidence of fatty liver or cirrhosis. T-cell recombination excision circles and kappa-deleting element recombination circle levels were significantly lower in the EIgM group, suggesting an abnormal class switching in this group. CONCLUSIONS: EIgM in AT patients are indicative of a more severe phenotype that probably results from a specific immune dysfunction. EIgM in AT should be considered a unique AT phenotype that may require different management.
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Ataxia Telangiectasia/complicaciones , Ataxia Telangiectasia/inmunología , Inmunoglobulina M/sangre , Adolescente , Ataxia Telangiectasia/mortalidad , Biomarcadores/sangre , Niño , Preescolar , Femenino , Humanos , Lactante , Infecciones/etiología , Hepatopatías/etiología , Enfermedades Pulmonares/etiología , Masculino , Neoplasias/etiología , Fenotipo , Pronóstico , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
BACKGROUND: Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease. AIM: To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis. METHODS: Whole-exome sequencing (WES) was performed in a 4-month-old female with history of congenital diarrhea and severe failure to thrive but without hair anomalies or dysmorphism. Since the parents were first-degree cousins, the analysis focused on an autosomal recessive model. Sanger sequencing was used to validate suspected variants. Mutated protein structure was modeled to assess the effect of the mutation on protein function. RESULTS: We identified an autosomal recessive C.1891G > A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome. The mutation was determined to be deleterious in multiple prediction models. Protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, either through conformational changes, interference with the protein's packing, or changes at the protein's interface. CONCLUSIONS: THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features.
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ADN Helicasas/genética , Diarrea Infantil/genética , Retardo del Crecimiento Fetal/genética , Enfermedades del Cabello/genética , Mutación Missense , Diarrea Infantil/diagnóstico , Facies , Femenino , Retardo del Crecimiento Fetal/diagnóstico , Marcadores Genéticos , Enfermedades del Cabello/diagnóstico , Humanos , Lactante , Secuenciación del ExomaRESUMEN
OBJECTIVE: Ataxia telangiectasia (A-T) is a rare genetic disease involving multiple organs, but, to our knowledge, data on long-term gastrointestinal and nutritional involvement are scarce. The aim of this study was to longitudinally review the nutritional and gastrointestinal aspects of A-T. METHODS: This was a retrospective chart review of patients followed from 1986 to 2015 at one center. Demographic, laboratory, and nutritional data were retrieved. Body mass index (BMI) values were converted to BMI Z-score (BMI-Z). Caloric intake was estimated by food diaries and compared with estimated energy requirements for sex and age with a physical activity level factor for light physical activity. RESULTS: The study included 53 patients (28 males [53%], ages 14.6 ± 5.2 y). BMI-Z was inversely correlated with age (r = 0.48; P < 0.004). A decline below minimal BMI percentiles was observed after the age of 4 y in boys and 7 y in girls. The relative percentage of caloric intake decreased with age (r = -0.5; P < 0.002), and was positively correlated with BMI-Z (r = 0.35; P < 0.05). Presence of cough during meals was associated with recurrent lower respiratory tract infections (Fisher exact test, P < 0.01). Gastrostomy tubes were inserted in 12 patients, leading to improvement in BMI-Z from -5.1 ± 2.4 to -4 ± 2.9 (P < 0.05). CONCLUSIONS: There is a progressive growth failure and low nutritional intake with age in patients with A-T, starting in early childhood in males, and more prominent in patients with cough and choking during meals. A proactive approach and insertion of a percutaneous gastrostomy tube as soon as the BMI-Z starts to decrease should be considered.
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Ataxia Telangiectasia/fisiopatología , Tracto Gastrointestinal/fisiopatología , Estado Nutricional/fisiología , Adolescente , Ataxia Telangiectasia/complicaciones , Ataxia Telangiectasia/terapia , Estatura , Índice de Masa Corporal , Peso Corporal , Niño , Preescolar , Tos , Trastornos de Deglución/epidemiología , Trastornos de Deglución/fisiopatología , Ingestión de Alimentos , Ingestión de Energía , Nutrición Enteral , Ejercicio Físico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/epidemiología , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVES: Interleukin-10 (IL-10) is an immunoregulatory cytokine that has a central role in suppressing proinflammatory responses. Patients with deleterious mutations in interleukin (IL)-10 or IL-10 receptor (IL-10R) genes develop severe colitis and perianal disease in the first months of life. Whether IL-10R expression and signaling in pediatric- or adult-onset Crohn disease (CD) are altered is unknown. The objective of this study was to characterize IL-10R expression and IL-10R-mediated suppression in patients with CD. METHODS: Monocytes were sorted from peripheral blood mononuclear cells of patients with CD and control subjects. IL-10R expression was determined by flow cytometry. Monocytes were stimulated with lipopolysaccharide (LPS) for 3âhours in the presence of different concentrations of IL-10 to determine IL-10-mediated suppression of tumor necrosis factor α production. Signaling through the IL-10R was evaluated by quantifying STAT3 phosphorylation in response to IL-10 stimulation. RESULTS: Forty-two subjects were enrolled in this study: 19 with CD and 23 controls. Stimulation of monocytes with LPS markedly increased IL-10R expression in both groups but to a much lower extent in patients with CD. In addition, IL-10-mediated suppression of TNFα production upon LPS stimulation and IL-10-induced STAT3 phosphorylation were attenuated in patients with CD versus controls. Finally, LPS-stimulated monocytes from patients with CD secreted significantly lower quantities of IL-10, compared with control monocytes. CONCLUSIONS: IL-10R expression and signaling are decreased in monocytes from patients with CD. Additional studies are required to assess whether similar patterns occur in other innate immune cells, especially in the gut, and whether disease activity, medical therapy, and genetic factors modulate these findings.
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Enfermedad de Crohn/metabolismo , Monocitos/metabolismo , Receptores de Interleucina-10/metabolismo , Adolescente , Adulto , Enfermedad de Crohn/inmunología , Femenino , Citometría de Flujo , Humanos , Interleucina-10/metabolismo , Lipopolisacáridos/farmacología , Masculino , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
Pediatric data on rapid infliximab infusion are scarce. We report our experience with a 1-hour rapid infusion protocol, prescribed in 3 pediatric inflammatory bowel disease units during 18 to 26 months. Children treated with infliximab for inflammatory bowel disease using a standard 2- to 3-hour infusion protocol were switched to a 1-hour protocol if they had received at least 4 standard duration infusions with no infusion reactions, there was no recent dose increase and no more than 10 weeks had elapsed since the previous infusion. A total of 102 children received infliximab infusions during the study period (85 Crohn disease; mean age 14.6â±â2.6 years) of whom 63 were switched to the rapid infusions. Seven patients on the rapid protocol (11%) and 6 patients on the standard protocol (15%) had infusion reactions (Pâ=â0.55). Consistent with adult data, our study indicates that a 1-hour infliximab protocol in selected patients offers a safe alternative to the traditional 2- to 3-hour infusions.
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Fármacos Gastrointestinales/administración & dosificación , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/administración & dosificación , Adolescente , Niño , Estudios de Cohortes , Esquema de Medicación , Fármacos Gastrointestinales/efectos adversos , Humanos , Infliximab/efectos adversos , Infusiones Intravenosas , Estudios RetrospectivosRESUMEN
The analysis of individuals with telomere defects may shed light on the delicate interplay of factors controlling genome stability, premature aging, and cancer. We herein describe two Coats plus patients with telomere and genomic defects; both harbor distinct, novel mutations in STN1, a member of the human CTC1-STN1-TEN1 (CST) complex, thus linking this gene for the first time to a human telomeropathy. We characterized the patients' phenotype, recapitulated it in a zebrafish model and rescued cellular and clinical aspects by the ectopic expression of wild-type STN1 or by thalidomide treatment. Interestingly, a significant lengthy control of the gastrointestinal bleeding in one of our patients was achieved by thalidomide treatment, exemplifying a successful bed-to-bench-and-back approach.
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Ataxia , Neoplasias Encefálicas , Calcinosis , Quistes del Sistema Nervioso Central , Regulación de la Expresión Génica/efectos de los fármacos , Leucoencefalopatías , Espasticidad Muscular , Mutación , Enfermedades de la Retina , Convulsiones , Proteínas de Unión a Telómeros , Telómero , Talidomida/administración & dosificación , Animales , Ataxia/tratamiento farmacológico , Ataxia/genética , Ataxia/metabolismo , Ataxia/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Calcinosis/tratamiento farmacológico , Calcinosis/genética , Calcinosis/metabolismo , Calcinosis/patología , Quistes del Sistema Nervioso Central/tratamiento farmacológico , Quistes del Sistema Nervioso Central/genética , Quistes del Sistema Nervioso Central/metabolismo , Quistes del Sistema Nervioso Central/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Leucoencefalopatías/tratamiento farmacológico , Leucoencefalopatías/genética , Leucoencefalopatías/metabolismo , Leucoencefalopatías/patología , Masculino , Espasticidad Muscular/tratamiento farmacológico , Espasticidad Muscular/genética , Espasticidad Muscular/metabolismo , Espasticidad Muscular/patología , Enfermedades de la Retina/tratamiento farmacológico , Enfermedades de la Retina/genética , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/patología , Convulsiones/tratamiento farmacológico , Convulsiones/genética , Convulsiones/metabolismo , Convulsiones/patología , Telómero/genética , Telómero/metabolismo , Telómero/patología , Proteínas de Unión a Telómeros/biosíntesis , Proteínas de Unión a Telómeros/genética , Talidomida/efectos adversos , Pez CebraRESUMEN
Protein-losing enteropathy (PLE) is a clinical disorder of protein loss from the gastrointestinal system that results in hypoproteinemia and malnutrition. This condition is associated with a wide range of gastrointestinal disorders. Recently, a unique syndrome of congenital PLE associated with biallelic mutations in the DGAT1 gene has been reported in a single family. We hypothesize that mutations in this gene are responsible for undiagnosed cases of PLE in infancy. Here we investigated three children in two families presenting with severe diarrhea, hypoalbuminemia and PLE, using clinical studies, homozygosity mapping, and exome sequencing. In one family, homozygosity mapping using SNP arrays revealed the DGAT1 gene as the best candidate gene for the proband. Sequencing of all the exons including flanking regions and promoter regions of the gene identified a novel homozygous missense variant, p.(Leu295Pro), in the highly conserved membrane-bound O-acyl transferase (MBOAT) domain of the DGAT1 protein. Expression studies verified reduced amounts of DGAT1 in patient fibroblasts. In a second family, exome sequencing identified a previously reported splice site mutation in intron 8. These cases of DGAT1 deficiency extend the molecular and phenotypic spectrum of PLE, suggesting a re-evaluation of the use of DGAT1 inhibitors for metabolic disorders including obesity and diabetes.
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Diacilglicerol O-Acetiltransferasa/genética , Errores Innatos del Metabolismo Lipídico/genética , Mutación Missense , Enteropatías Perdedoras de Proteínas/genética , Empalme del ARN , Adulto , Células Cultivadas , Niño , Diacilglicerol O-Acetiltransferasa/química , Diacilglicerol O-Acetiltransferasa/metabolismo , Femenino , Humanos , Lactante , Errores Innatos del Metabolismo Lipídico/diagnóstico , Masculino , Linaje , Fenotipo , Dominios Proteicos , Enteropatías Perdedoras de Proteínas/diagnósticoRESUMEN
BACKGROUND: Ataxia telangiectasia (AT) is a genetic multisystem disorder, presenting with progressive ataxia, immune deficiency, and propensity toward malignancy. Endocrine abnormalities (growth retardation, reproductive dysfunction, and diabetes) have been described, however detailed information regarding this aspect is lacking. We aimed to characterize endocrine anomalies and growth patterns in a large cohort of AT patients. METHODS: Retrospective study comprising all 52 patients (aged 2-26.2 y) followed at a national AT Clinic. Anthropometric and laboratory measurements were extracted from the charts. RESULTS: Median height-SDS was already subnormal during infancy, remaining negative throughout follow up to adulthood. Height-SDS was more impaired than weight-SDS up to age 4 y, thereafter weight-SDS steadily decreased, resulting in progressively lower BMI-SDS. IGF-I-SDS was low (-1.53 ± 1.54), but did not correlate with height-SDS. Gonadal failure was present in all 13 females older than 10 y but only in one male. Two patients had diabetes and 10 had dyslipidemia. Vitamin D deficiency was observed in 52.2% of the evaluated patients. CONCLUSION: Our results suggest a primary growth abnormality in AT, rather than secondary to nutritional impairment or disease severity. Sex hormone replacement should be considered for female patients. Vitamin D levels should be followed and supplementation given if needed.
Asunto(s)
Ataxia Telangiectasia/fisiopatología , Estatura , Peso Corporal , Sistema Endocrino/fisiopatología , Adolescente , Adulto , Antropometría , Ataxia Telangiectasia/complicaciones , Glucemia/metabolismo , Niño , Preescolar , Estudios Transversales , Dislipidemias/complicaciones , Femenino , Trastornos del Crecimiento , Humanos , Sistema Inmunológico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Estudios Retrospectivos , Deficiencia de Vitamina D/complicaciones , Adulto JovenRESUMEN
OBJECTIVE: Ataxia telangiectasia (A-T) is a rare genetic multiorgan disease. Although gastrointestinal involvement is known, hepatic involvement in A-T has not been investigated. We aimed to study the hepatic involvement in a large cohort of patients with A-T. METHODS: A retrospective review of patients, studied from January 1986 to January 2015 at a National A-T Center. Clinical data including demographic, genetic, laboratory, nutritional, radiographic, and histological data were retrieved. RESULTS: Fifty-three patients, 27 (49%) boys, age 14.6â±â5.2 years (range 5.9-26.1 years), were included. Twenty-three patients (43.4%), age 9.9â±â5.1 years, had consistently abnormal liver enzymes. The mean enzyme levels were alanine aminotransferase 76.8â±â73.8âIU/L, aspartate aminotransferase 70â±â50âIU/L, alkaline phosphatase 331â±â134âIU/L, and gamma glutamyl transferase 114.7â±â8âIU/L. Evaluation of other etiology of liver disease was negative. Ultrasonography revealed fatty liver in 9 of them (39%). Liver biopsy was performed in 2 patients, revealing mild-to-moderate steatosis in both, and fibrosis in 1 patient. Progression to advanced liver disease occurred in 2 of 23 (9%) patients within 2 to 5 years. Dyslipidemia was significantly associated with abnormal liver enzymes: 3 of 30 (10%) patients without abnormal liver enzymes versus 10 of 23 (45.5%) patients with abnormal liver enzymes, respectively (Pâ<â0.05, Fisher exact test). No correlation was found between hepatic involvement and HbA1C, sex, presence of malignancy, or type of mutation. CONCLUSIONS: Abnormal liver enzymes and fatty liver are common in patients with A-T and may progress to advanced liver disease at a young age. These findings are novel and implicate that patients with A-T with abnormal liver enzymes should be evaluated for the presence of liver disease.
Asunto(s)
Ataxia Telangiectasia/fisiopatología , Hepatopatías/etiología , Hígado/fisiopatología , Adolescente , Adulto , Ataxia Telangiectasia/sangre , Ataxia Telangiectasia/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Biopsia , Niño , Preescolar , Estudios de Cohortes , Progresión de la Enfermedad , Dislipidemias/etiología , Femenino , Estudios de Seguimiento , Humanos , Israel/epidemiología , Hígado/diagnóstico por imagen , Hígado/patología , Hepatopatías/diagnóstico por imagen , Hepatopatías/epidemiología , Hepatopatías/fisiopatología , Masculino , Mutación , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/etiología , Prevalencia , Estudios Retrospectivos , Ultrasonografía , Adulto JovenRESUMEN
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis, are chronic relapsing and remitting diseases of the bowel, with an unknown etiology and appear to involve interaction between genetic susceptibility, environmental factors and the immune system. Although our knowledge and understanding of the pathogenesis and causes of IBD have improved significantly, the incidence in the pediatric population is still rising. In the last decade more drugs and treatment option have become available including 5-aminosalicylate, antibiotics, corticosteroids, immunomodulators and biological agents. Before the use of anti-tumor necrosis factor (TNF)-α became available to patients with IBD, the risk for surgery within five years of diagnosis was very high, however, with anti-TNF-α treatment the risk of surgery has decreased significantly. In the pediatric population a remission in disease can be achieved by exclusive enteral nutrition. Exclusive enteral nutrition also has an important role in the improvement of nutritional status and maintained growth. In this review we summarize the current therapeutic treatments in CD. The progress in the treatment options and the development of new drugs has led to optimized tactics for achieving the primary clinical goals of therapy - induction and maintenance of remission while improving the patient's growth and overall well-being.