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CONTEXT: Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency. OBJECTIVE: We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency. METHODS: We treated two monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, Vital signs, anthropometric measurements and neurocognitive functions. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In-vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P321L mutation. The effects of GPB were compared to the effects of DITPA and TRIAC, thyromimetic medications that the patients received in the past. RESULTS: NaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment reduced high T3 and increased low T4 levels. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neuro-cognitive improvement was observed, in hyperreflexia score and in cognitive functions. Serum metabolites did not exceed the toxic range but elevated liver transaminases were observed. CONCLUSIONS: In the first report of GPB treatment in MCT8 deficiency we found an improvement in TH profile and body-mass index, with minor neuro-developmental changes.
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To assess the long-term efficacy of burosumab for pediatric patients with X-linked hypophosphatemia, focusing on linear growth. This multi-center retrospective study included 35 pediatric patients who began treatment with burosumab between January 2018 and January 2021. We collected clinical data, anthropometric measurements, laboratory results, and Rickets Severity Score (RSS), from 2 years prior to treatment initiation and up to 4 years after. Burosumab was initiated at a mean age of 7.5 ± 4.4 years (range 0.6-15.9), with a mean initial dose of 0.8 ± 0.3 mg/kg, which was subsequently increased to 1.1 ± 0.4 mg/kg. The patients were followed for 2.9 ± 1.4 years (range 1-4) after initiating burosumab. Serum phosphorus levels increased from 2.7 ± 0.8 mg/dl at burosumab initiation to 3.4 ± 0.6 mg/dl after 3 months and remained stable (p < 0.001). Total reabsorption of phosphorus increased from 82.0 ± 6.8 to 90.1 ± 5.3% after 12 months of treatment (p = 0.041). The RSS improved from 1.7 ± 1.0 at burosumab initiation to 0.5 ± 0.6 and 0.3 ± 0.6 after 12 and 24 months, respectively (p < 0.001). Both height z-score and weight z-score improved from burosumab initiation to the end of the study: from - 2.07 ± 1.05 to - 1.72 ± 1.04 (p < 0.001) and from - 0.51 ± 1.12 to - 0.11 ± 1.29 (p < 0.001), respectively. Eight children received growth hormone combined with burosumab treatment. Height z-score improved among those who received growth hormone (from - 2.33 ± 1.12 to - 1.94 ± 1.24, p = 0.042) and among those who did not (from - 2.01 ± 1.01 to - 1.66 ± 1.01, p = 0.001). CONCLUSION: Burosumab treatment in a real-life setting improved phosphate homeostasis and rickets severity and enhanced linear growth. WHAT IS KNOWN: ⢠Compared to conventional therapy, burosumab treatment has been shown to increase serum phosphate levels and reduce the severity of rickets. ⢠The effect of burosumab on growth is still being study. WHAT IS NEW: ⢠Height z-score improved between the start of burosumab treatment and the end of the study (-2.07 ± 1.05 vs. -1.72 ± 1.04, p < 0.001). ⢠Eight children received burosumab combined with growth hormone treatment without side effects during the concomitant treatments.
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Raquitismo Hipofosfatémico Familiar , Niño , Humanos , Lactante , Preescolar , Adolescente , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Estudios Retrospectivos , Fósforo/uso terapéutico , Hormona del Crecimiento/uso terapéutico , FosfatosRESUMEN
Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY GONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.
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Disgenesia Gonadal , Células Madre Pluripotentes Inducidas , Discapacidad Intelectual , Masculino , Humanos , Testículo/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Antígenos de NeoplasiasRESUMEN
INTRODUCTION: Activating mutation of the calcium-sensing receptor gene (CASR) reduces parathyroid hormone secretion and renal tubular reabsorption of calcium, defined as autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 may present with hypocalcemia-induced seizures. Calcitriol and calcium supplementation in symptomatic patients may exacerbate hypercalciuria, leading to nephrocalcinosis, nephrolithiasis, and compromised renal function. METHODS: We report on a family with seven members over three generations with ADH1 due to a novel heterozygous mutation in exon 4 of CASR: c.416T>C. RESULTS: This mutation leads to substitution of isoleucine with threonine in the ligand-binding domain of CASR. HEK293T cells transfected with wild type or mutant cDNAs demonstrated that p.Ile139Thr substitution led to increased sensitivity of the CASR to activation by extracellular calcium relative to the wild-type CASR (EC50 of 0.88 ± 0.02 m
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Hipocalcemia , Nefrocalcinosis , Nefrolitiasis , Humanos , Hipocalcemia/genética , Receptores Sensibles al Calcio/genética , Calcio , Hipercalciuria/genética , Creatinina , Células HEK293 , Mutación , ConvulsionesRESUMEN
OBJECTIVE: To evaluate the incidence and severity of ketoacidosis (DKA) at type 1 diabetes diagnosis during the first wave of the coronavirus disease 2019 (COVID-19) pandemic in Israel. RESEARCH DESIGN AND METHODS: A population-based study the product of a national collaboration of Israeli pediatric diabetes centers investigated the presentation of childhood-onset type 1 diabetes. The frequencies of DKA and severe DKA observed during the COVID-19 period from March 15, 2020 (commencement of the first nationwide lockdown) until June 30, 2020 were compared with the same periods in 2019, 2018, and 2017 using multivariable logistic regression, adjusting for age, sex, and socioeconomic position. RESULTS: During the COVID-19 period, DKA incidence was 58.2%, significantly higher than in 2019 (adjusted OR [aOR] 2.18 [95% CI, 1.31-3.60], P = 0.003); 2018 (aOR 2.05 [95% CI, 1.26-3.34], P = 0.004); and 2017 (aOR, 1.79 [95% CI, 1.09-2.93], P = 0.022). The incidence of severe DKA was 19.9%, significantly higher than in 2018 (aOR, 2.49 [95% CI, 1.20-5.19], P = 0.015) and 2017 (aOR, 2.73 [95% CI, 1.28-5.82], P = 0.009). In 2020, admissions and duration of stay in the intensive care unit were higher than in previous years (P = 0.001). During the COVID-19 pandemic, children aged 6-11 years had higher incidences of DKA (61.3% vs. 34.0%, 40.6%, and 45.1%, respectively, P = 0.012), and severe DKA (29.3% vs. 15.1%, 10.9%, and 5.9%, respectively, P = 0.002). CONCLUSIONS: The dramatic increase in DKA at presentation of childhood-onset type 1 diabetes during the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.
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COVID-19/epidemiología , Diabetes Mellitus Tipo 1/diagnóstico , Cetoacidosis Diabética/epidemiología , Pandemias , Vigilancia de la Población , SARS-CoV-2 , Adolescente , Niño , Comorbilidad , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/epidemiología , Cetoacidosis Diabética/etiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Israel/epidemiología , Masculino , Estudios RetrospectivosRESUMEN
CONTEXT: First-voided urinary LH (FVU-LH) has been suggested as an alternative to GnRH stimulation test for detection of precocious puberty. OBJECTIVE: To evaluate the reproducibility of FVU-LH, its correlation with basal and GnRH-stimulated gonadotropins, and its diagnostic value for differentiating progressive from nonprogressive puberty. DESIGN AND PARTICIPANTS: Clinical and endocrine data were obtained from the medical records of 95 girls with suspected progressive puberty who underwent 2 consecutive FVU-LH tests. In 55 of these participants, GnRH stimulation test was performed close to the FVU-LH test. The reported cutoff levels of 5 IU/L and 1.16 IU/L for GnRH-stimulated LH and FVU-LH, respectively, were used as markers of progressive puberty, clinically defined as bone age advancement of ≥1 year and/or growth velocity SD score ≥2, in addition to thelarche. RESULTS: The 2 consecutive measurements of FVU-LH were highly correlated (r = 0.830; P < 0.001). The higher of the 2 results was better correlated with basal gonadotropins and GnRH-stimulated LH. Furthermore, it aligned better with the clinical outcome of girls with early thelarche, which supports the approach of double tests of FVU-LH to distinguish progressive from nonprogressive puberty. By comparison to GnRH-stimulated LH, the higher FVU-LH value had better sensitivity (68%), whereas peak LH had better specificity (91%) for the diagnosis of progressive puberty. Both tests had high positive predictive value and poor negative predictive value. CONCLUSIONS: The higher value of paired FVU-LH tests can be used to screen girls with suspected progressive puberty and can reduce the need for GnRH stimulation test.
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Hormona Luteinizante , Pubertad Precoz , Femenino , Hormona Folículo Estimulante , Hormona Liberadora de Gonadotropina , Gonadotropinas , Humanos , Pubertad , Pubertad Precoz/diagnóstico , Reproducibilidad de los ResultadosRESUMEN
Objectives Recommendations for vitamin D (VitD) intake and target serum levels of 25(OH)D in preterm infants are diverse. We hypothesized that preterm infants with low birth weight (BW) have low dietary intake of VitD and therefore should be supplemented with higher amounts of VitD. Methods Infants with BW < 2 kg were supplemented with 600 units of VitD a day during the first 2-6 weeks of life, whereas infants with BW>2 kg continued with the routine supplementation of 400 units of VitD daily. Serum levels of 25(OH)D, calcium, phosphorous, alkaline phosphatase (AP) and parathyroid hormone (PTH) were assessed 24 h after birth and before discharge. The total daily intake of vitD was calculated in each infant. Results Sixty-two infants were enrolled, 49 with BW < 2 kg. After birth, only 24% had sufficient levels of 25(OH)D, whereas before discharge 45 of 54 infants (83%) available for analysis reached sufficient levels of 25(OH)D. All 54 infants demonstrated significant elevation in serum levels of calcium, phosphorous, AP and significant reduction in PTH levels. The total daily intake of VitD was lower than recommended (800-1000 IU/d) in 16 of 45 infants with BW < 2 kg (36%) and in all nine infants with BW>2 kg. Nevertheless, only 2 of 25 infants with insufficient intake of VitD demonstrated insufficient levels of serum 25(OH)D. No case of vitamin D excess was recorded. Conclusions Increased supplementation of VitD (600 IU/d) for premature newborns with BW < 2 kg is effective in increasing both total daily intake of VitD and serum levels of 25(OH)D.
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Biomarcadores/sangre , Suplementos Dietéticos , Recien Nacido Prematuro/sangre , Deficiencia de Vitamina D/tratamiento farmacológico , Vitamina D/administración & dosificación , Vitaminas/administración & dosificación , Adulto , Femenino , Estudios de Seguimiento , Humanos , Recién Nacido , Israel/epidemiología , Masculino , Pronóstico , Estudios Prospectivos , Vitamina D/sangre , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/epidemiología , Vitaminas/sangre , Adulto JovenRESUMEN
AIM: To assess the association of seasonal and perinatal parameters with early age of type 1 diabetes (T1D) onset. METHODS: A cross-sectional review of all medical records of T1D patients born between the years 1990 and 2005, and diagnosed before/by the age of 10 years, from 13 university-affiliated paediatric medical centres in Israel, was performed. Data included: gender, ethnicity, seasons of birth and disease onset, birth gestational age and weight, and autoimmune diseases of the probands and their first-degree family members. Statistical analysis included the Chi-square test or Mann-Whitney test, as appropriate and multivariate regression analysis. RESULTS: Enrolled were 1571 T1D patients at a median age of T1D onset 6.9 years (IQR 4.4,8.4); 336 of them presented before 4 years of age. The median age of this group was 2.5 years (IQR 1.7,3.2), and of the 1235 patients who presented after 4 years of age, median presentation age was 7.5 years (IQR 6.1,8.8). Multivariate regression analysis demonstrated that a more recent birth year; OR = 1.06, 95% CI 1.02-1.1, P = 0.003, and birth during the moderate weather months (September, October, March, and April) were significantly associated with younger age at T1D onset; OR = 1.68, 95% CI 1.17-2.4, P = 0.005. CONCLUSIONS: Our novel finding demonstrates the association between younger than 4 years old age at presentation and birth during moderate weather months. The results also support previous reports, that there is a slight increase in the annual incidence of T1D in the youngest age groups.
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OBJECTIVE: To assess the clinical and neurological outcomes in newborns with primary congenital hypothyroidism presented with delayed TSH elevation (dTSH), and to define parameters that may predict the evolution of transient vs. permanent hypothyroidism in these newborns. DESIGN AND PATIENTS: An observational study was performed of a cohort of 113 children with a history of dTSH. MEASUREMENTS: Birth parameters, thyroid screening results, thyroid gland imaging, levothyroxine dose and neurological outcome were compared between newborns with spontaneous recovery and children with a final diagnosis of either transient or permanent hypothyroidism. RESULTS: Of the children with a history of dTSH, 93% demonstrated recovery, either spontaneously or following levothyroxine treatment (transient hypothyroidism). Newborns with spontaneous recovery demonstrated milder thyroid dysfunction at the newborn screening compared to those who started levothyroxine treatment. Levothyroxine dose was lower in children with transient vs. permanent hypothyroidism only during the first 6 months of life; otherwise, these groups were similar in birth parameters, thyroid screening results and gland images. Seventeen out of 61 children (28%) that underwent neurological assessment demonstrated a developmental delay. Duration of treatment was highly variable in children with transient hypothyroidism. CONCLUSIONS: Thyroid dysfunction is transient in most cases of dTSH. No reliable parameters can predict a priori transient vs. permanent hypothyroidism.
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Hipotiroidismo Congénito , Niño , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/tratamiento farmacológico , Humanos , Recién Nacido , Cuidado Intensivo Neonatal , Tamizaje Neonatal , Tirotropina , Tiroxina/uso terapéuticoRESUMEN
PURPOSE: The aim of the study was to estimate the current incidence and the distribution of etiologies of primary ovarian insufficiency (POI) in a nationwide study. The prevalence of POI in young adult women has recently increased, but the data cited for adolescents are more than three decades old. METHODS: Data regarding females aged <21 years diagnosed with POI during the years 2000-2016 were collected from all the pediatric endocrinology units in Israel. POI was defined by at least 4 months of amenorrhea in association with menopausal levels of follicle-stimulating hormone. Iatrogenic cases were excluded. RESULTS: For the 130 females aged <21 years included in the study, the distribution of POI etiologies was Turner syndrome/mosaicism in 56 (43%), idiopathic in 35 (27%), and other (developmental, genetic, metabolic, adrenal, and autoimmune) in 39 (30%) females. During the years 2009-2016, compared with 2000-2008, the incidence rate of new POI diagnoses per 100,000 person-years doubled (4.5 vs. 2.0; p value <.0001), and incidence rates of idiopathic and other etiologies increased by 2.6 (p value = .008) and 3.0 (p value = .002), respectively. In contrast, the incidence of Turner syndrome was constant (p value = .2). In the age group of 15-21 years, the current incidence of non-Turner POI in adolescents is one per 100,000 person-years. CONCLUSIONS: In this nationwide study, the incidence rate of POI in youth aged <21 years was one tenth of the rate that is commonly cited. A significant increase in the rate of POI in non-Turner females was observed over the last decade. Contributions of environmental and epigenetic factors should be studied.
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Insuficiencia Ovárica Primaria , Adolescente , Adulto , Amenorrea/epidemiología , Amenorrea/etiología , Niño , Femenino , Hormona Folículo Estimulante , Humanos , Incidencia , Israel/epidemiología , Insuficiencia Ovárica Primaria/epidemiología , Insuficiencia Ovárica Primaria/etiología , Adulto JovenRESUMEN
Permanent neonatal diabetes mellitus (PNDM) is caused by reduced ß-cell number or impaired ß-cell function. Understanding of the genetic basis of this disorder highlights fundamental ß-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for ß-cells and highlight EIF2B1's fundamental role within this pathway.
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Diabetes Mellitus/genética , Factor 2B Eucariótico de Iniciación/genética , Hepatopatías/genética , Adolescente , Preescolar , Simulación por Computador , Factor 2 Eucariótico de Iniciación/metabolismo , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Modelos Moleculares , Mutación , Mutación Missense , Recurrencia , Análisis de Secuencia de ADN , Estrés FisiológicoRESUMEN
CONTEXT: Congenital adrenal hyperplasia (CAH) was among the first genetic disorders included in newborn screening (NBS) programs worldwide, based on 17α-hydroxyprogesterone (17-OHP) levels in dried blood spots. However, the success of NBS for CAH is hampered by high false positive (FP) rates, especially in preterm and low-birthweight infants. OBJECTIVE: To establish a set of cutoff values adjusting for both gestational age (GA) and birthweight (BW), with the aim of reducing FP rates. DESIGN: This cross-sectional, population-based study summarizes 10 years of experience of the Israeli NBS program for diagnosis of CAH. Multitiered 17-OHP cutoff values were stratified according to both BW and GA. PARTICIPANTS: A total of 1,378,132 newborns born between 2008 and 2017 were included in the NBS program. RESULTS: Eighty-eight newborns were ultimately diagnosed with CAH; in 84 of these, CAH was detected upon NBS. The combined parameters-adjusted approach significantly reduced the recall FP rate (0.03%) and increased the positive predictive value (PPV) (16.5%). Sensitivity among those referred for immediate attention increased significantly (94%). There were four false negative cases (sensitivity, 95.4%), all ultimately diagnosed as simple-virilizing. Sensitivity and specificity were 95.4% and 99.9%, respectively, and the percentage of true-positive cases from all newborns referred for evaluation following a positive NBS result was 96%. CONCLUSIONS: The use of cutoff values adjusted for both GA and BW significantly reduced FP rates (0.03%) and increased overall PPV (16.5%). Based on our 10 years of experience, we recommend the implementation of this two parameter-adjusted approach for NBS of classic CAH in NBS programs worldwide.
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Hiperplasia Suprarrenal Congénita/diagnóstico , Peso al Nacer , Edad Gestacional , Tamizaje Neonatal , Estudios Transversales , Reacciones Falso Positivas , Femenino , Humanos , Recién Nacido , Masculino , Proyectos PilotoRESUMEN
The aim of the study was to assess the epidemiology and risk factors of adrenal crises (AC) in children with adrenal insufficiency (AI). Children diagnosed with AI between 1990 and 2017 at four Israeli pediatric endocrinology units were studied. Demographic and clinical data were retrieved retrospectively from their files. The study population consisted of 120 children (73 boys, 47 girls) and comprised 904 patient years. Median age at diagnosis was 0.3 years (0-17.5). Thirty-one AC events in 26 children occurred during the study period, accounting for a frequency of 3.4 crises/100 patient years. Fifty-two percent of AC events occurred at presentation. The significant risk factors for developing AC were the following: younger age at diagnosis (P = 0.003), primary AI vs. secondary AI (P = 0.016), specific diagnosis of autoimmune AI, adrenal hypoplasia congenita and salt wasting congenital adrenal hyperplasia (P < 0.001), mineralocorticoid treatment (P < 0.001), and recurrent hospital admissions (P > 0.001). After applying a stepwise logistic regression model, only the group of diagnoses, including salt wasting CAH, AHC, and Addison's disease, remained significant predictor of AC (OR 17.5, 95% CI 4.7-64.9, P < 0.001). There was no AC-associated mortality during the study period.Conclusions: Since significant percent of AC events occurred at presentation, measures to increase the awareness to signs and symptoms of AI among primary care physicians should be taken. Efforts to prevent AC should be focused on younger patients, especially those with primary AI. What Is Known: ⢠Diagnosis and long-term management of pediatric patients with adrenal insufficiency (AI) remain a challenge. ⢠Adrenal crises (AC) pose life-threatening emergencies in affected youngsters. Studies on the rate and risk factors of AC in children with AI are scarce, and they were done mainly on children with congenital adrenal hyperplasia (CAH). What Is New: ⢠The rate of AC was relatively low and there was no AC-associated mortality during the study period. ⢠Children with primary AI were at higher risk for AC than children with secondary AI. Specifically, children with salt wasting CAH, adrenal hypoplasia congenita, and Addison's disease at the highest risk.
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Insuficiencia Suprarrenal/epidemiología , Adolescente , Insuficiencia Suprarrenal/diagnóstico , Insuficiencia Suprarrenal/etiología , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Israel/epidemiología , Modelos Logísticos , Masculino , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The incidence of type 1 diabetes mellitus (T1DM) has increased in recent decades, as has the incidence of preterm births (<37 weeks). We aimed to evaluate and compare the prevalence of prematurity and early prematurity (<34 weeks) and birth season variability among T1DM and non-T1DM children. METHODS: A nationwide cross-sectional study was conducted, with linkage of data from 13 paediatric diabetes centers and Israeli National Registries, including T1DM patients and general non-T1DM population, born during 2000 to 2013. Gathered data included ethnicity, gender, birth week, weight, and season. The prevalence of prematurity and birth season were compared with the general population birth registry using Pearson Chi-square test. RESULTS: The study population included 1452 T1DM patients, 52.7% males, and 2 138 668 subjects in the general non-T1DM population, 51.2% males. The prevalence of late and early prematurity was similar between groups (6.1% and 2.2% in the T1DM group vs 5.6% and 2.0% in the general non-T1DM group, P = 0.25 and P = 0.38, respectively). OR for prematurity among T1DM patients was 1.15 (0.95-1.39), P = 0.16. No difference in birth season was demonstrated between preterm and term, in T1DM and general non-T1DM populations. Ethiopian descent was more prevalent among T1DM patients compared with the non-T1DM population, in both term and preterm born. CONCLUSIONS: This is the largest population-based study, and the first in the Middle East geographical area, indicating that prematurity, including early prematurity, is not associated with T1DM during childhood. The study was registered at https://clinicaltrials.gov/: NCT02929953.
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Diabetes Mellitus Tipo 1/fisiopatología , Recien Nacido Prematuro , Nacimiento Prematuro/epidemiología , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Recién Nacido , Israel/epidemiología , Masculino , Embarazo , Prevalencia , PronósticoRESUMEN
BACKGROUND: The global rise in incidence of type 1 diabetes (T1D) is too rapid to be attributed to susceptible genetic background, pinpointing a significant role for environmental factors. Unlike the theory that the need for genetic susceptibility has lessened over time, we hypothesized that the rise in T1D incidence is faster in a genetically susceptible population. SUBJECTS AND METHODS: The study population comprised of 5080 patients aged 0 to 17 years who were reported to the National Israel Diabetes Registry between 1997 and 2014. The patients were divided into familial cases (first-degree relative has T1D), and sporadic cases. Demographic and clinical data were retrieved from the registry. The change in annual percent (from the entire cohort) was computed separately for the sporadic and familial cohorts. RESULTS: The familial (n = 546; 10.7%) and sporadic (n = 4534; 89.3%) cases were comparable for gender, ethnicity, and age at diagnosis. Consanguinity was more common in the familial vs sporadic group (10% vs 6.1%; P = .001). The average annual percent change increased by 1.9% in the familial cases and decreased by 0.2% in the sporadic cases (P = .04). CONCLUSIONS: The rapid rise in the proportion of familial cases of T1D suggests that environmental factors impose higher diabetogenic pressure in patients with a susceptible genetic background.
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Diabetes Mellitus Tipo 1/epidemiología , Familia , Adolescente , Niño , Preescolar , Consanguinidad , Diabetes Mellitus Tipo 1/genética , Salud de la Familia/estadística & datos numéricos , Femenino , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Lactante , Recién Nacido , Israel/epidemiología , Masculino , Sistema de RegistrosRESUMEN
Context: Delayed thyrotropin (TSH) elevation (dTSH) is defined as elevated TSH at the second neonatal screening (after normal TSH levels at the initial screening) in premature, low-birth-weight, and ill newborns, mostly in the neonatal intensive care unit (NICU) setting. The pathogenesis of dTSH is elusive. Objective: To identify the risk factors for dTSH development among newborns in the NICU. Design, Setting, and Patients: A retrospective medical record review of neonates with dTSH was conducted in eight university-affiliated NICUs. Two controls were selected for each patient, matched for sex and birth weight. The risk factors for dTSH were identified by univariate analysis, followed by multivariate analysis. Main Outcome Measures: Maternal variables, types of NICU treatments and procedures, syndromes, and various medical conditions were compared between dTSH patients and their matched controls. Results: We enrolled 100 dTSH patients and 200 matched controls and 46 variables were compared between the two groups. Twelve risk factors for dTSH were identified on univariate analysis: cesarean section, mechanical ventilation, patent ductus arteriosus (PDA), pneumothorax, and administration of cefotaxime, vancomycin, fluconazole, dopamine, ibuprofen, furosemide, insulin, and packed red blood cells. On multivariate analysis, four risk factors were identified: PDA and vancomycin, insulin, and furosemide administration. In 26 twin pairs, in which one twin had dTSH, all variables presented similarly in both twins. Conclusions: Although some variables had direct effects on pituitary-thyroid axis dysfunction, these variables, altogether, reflect the severity of the clinical conditions in the NICU, which is the common basis for dTSH.
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Hipotiroidismo/diagnóstico , Tirotropina/sangre , Antibacterianos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Antifúngicos/uso terapéutico , Cefotaxima/uso terapéutico , Cesárea , Diuréticos/uso terapéutico , Dopamina/uso terapéutico , Conducto Arterioso Permeable/epidemiología , Transfusión de Eritrocitos , Femenino , Fluconazol/uso terapéutico , Furosemida/uso terapéutico , Humanos , Hipoglucemiantes/uso terapéutico , Hipotiroidismo/sangre , Ibuprofeno/uso terapéutico , Recién Nacido de Bajo Peso , Recién Nacido , Recien Nacido Prematuro , Insulina/uso terapéutico , Unidades de Cuidado Intensivo Neonatal , Masculino , Análisis Multivariante , Tamizaje Neonatal , Neumotórax/epidemiología , Respiración Artificial , Estudios Retrospectivos , Factores de Riesgo , Simpatomiméticos/uso terapéutico , Factores de Tiempo , Vancomicina/uso terapéuticoRESUMEN
OBJECTIVES: To elucidate the incidence, clinical characteristics, and short-term outcome of delayed thyroid stimulating hormone (TSH) elevation (dTSH) in a large cohort of newborns admitted to the neonatal intensive care unit. STUDY DESIGN: Data were gathered from a cohort of 13 201 newborns admitted to the neonatal intensive care unit born between January 1, 2008, and October 31, 2014, who underwent TSH measurements because of low T4 levels on the second screen. The data from the newborn screening program included gestational age, birth weight (BW), T4 levels, and short-term outcome. RESULTS: Of 13 201 newborns, 333 (1:40) presented with dTSH (TSH >15 IU/L). dTSH had a peak proportion at gestational age of 37-39 weeks, and 66% of the patients had BW >1500 g. T4 levels in the 333 patients were negatively correlated with TSH levels (R = -0.505; P < .001), and significantly lower than levels in the other newborns: 5.9 ± 2.8 vs 7.6 ± 1.7 µg/dL; P < .001. TSH levels in dTSH newborns were already higher on the initial screen compared with the other newborns: 8.3 ± 5.2 vs 4.2 ± 3.7 IU/L; P < .001. Fifty-eight percent of 193 patients with dTSH were started on levothyroxine treatment. CONCLUSIONS: dTSH has a higher incidence than previously reported, especially among newborns with BW >1500 g. Relatively high TSH and low T4 levels on the initial and second screen respectively are predictors for dTSH. Levothyroxine treatment is required in most cases.
Asunto(s)
Hipotiroidismo/diagnóstico , Tamizaje Neonatal/métodos , Tirotropina/sangre , Peso al Nacer , Femenino , Edad Gestacional , Humanos , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , MasculinoRESUMEN
Two recent reports describe a new syndrome of intellectual disability, short stature, microcephaly, and young onset diabetes or disturbed glucose metabolism in association with inactivating mutations in the TRMT10A gene. We investigated the clinical spectrum presented by a 17-year-old female with a homozygous contiguous gene deletion involving the TRMT10A gene. From infancy, she presented with failure to thrive and microcephaly. Puberty was characterized by a slow and an inconsistent course of progression. Concomitantly, gonadotropin levels fluctuated between low and high levels which were compatible with gonadal failure. Unlike the previous reports, the patient had ketoacidosis at onset of diabetes and islet cell autoantibodies. Nevertheless, glycemic control was excellent (HbA1C 5.0%-6.2%). RT-PCR and Western blot analysis demonstrated a complete abolishment of TRMT10A mRNA and its translated protein. In order to elucidate the nature of diabetes in this patient, endogenous insulin secretion and glycemic control were evaluated by a glucagon stimulation test and continuous glucose monitoring both during insulin treatment and off therapy. Endogenous insulin secretion still persisted 22 months after onset of diabetes and relatively normal glucose levels were kept over 3 days without insulin treatment. The fluctuating course of puberty and diabetes may reflect intermittent apoptotic damages due to sensitization of the relevant cells to various stress agents in the absence of functional TRMT10A.
Asunto(s)
Diabetes Mellitus/genética , Insuficiencia de Crecimiento/genética , Eliminación de Gen , Discapacidad Intelectual/genética , Metiltransferasas/genética , Pubertad Tardía/genética , Maduración Sexual/genética , Adolescente , Glucemia/análisis , Diabetes Mellitus/patología , Insuficiencia de Crecimiento/patología , Femenino , Homocigoto , Humanos , Discapacidad Intelectual/patología , Pronóstico , Pubertad Tardía/patología , SíndromeRESUMEN
AIM: The objective of this study was to validate basal, post-gonadotropin-releasing hormone analogue (post-GnRHa) and first-voided urinary LH (ULH) as alternatives to an LHRH stimulation test in monitoring treatment efficacy in central precocious puberty (CPP). METHODS: Seventeen girls with CPP were followed over 22.5±9.1 months during GnRHa (triptorelin) treatment. ULH and post-GnRHa LH levels were obtained every 4 months before and 24 h after GnRHa administration, respectively, along with clinical and bone age (BA) evaluation. LHRH stimulation tests were performed annually. RESULTS: A total of 36 LHRH stimulation tests demonstrated adequate suppression with a peak LH of 0.57±0.33 IU/L. The corresponding basal LH was 0.27±0.16 IU/L. Ninety post-GnRHa LH measurements were similar to LHRH-stimulated LH levels (0.56±0.31 IU/L), whereas 8% of ULH levels were above prepubertal threshold. Fourteen episodes of growth acceleration and ten episodes of BA advancement resolved without treatment modification. CONCLUSION: Suppressed basal and post-GnRHa LH levels indicate adequate suppression of puberty. Clinical breakthroughs during treatment are transient and resolved spontaneously.