The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Manifestaciones endocrinas de los tumores germinales del sistema nervioso central en niños / Endocrine manifestations of central nervous system germ cell tumors in children

INTRODUCCIÓN: Los tumores germinales del sistema nervioso central deben ser correctamente diagnosticados, pues su tratamiento suele ser eficaz y no siempre requieren cirugía. Los objetivos del estudio son describir las manifestaciones endocrinas de estas neoplasias y comparar su momento de aparición con el de las alteraciones neurológicas y visuales. PACIENTES Y MÉTODOS: Revisión de historias de pacientes menores de 14 años atendidos en una unidad de endocrinología pediátrica desde 2000 hasta 2018. Pruebas estadísticas: Wilcoxon y Fisher. RESULTADOS: Se estudió a 12 pacientes (10 mujeres) con una edad al diagnóstico de 9,4±1,7 años y un tiempo de seguimiento de 5,5±3,0 años; 10 presentaban tumores de la región selar, uno pineal y uno bifocal. Las alteraciones clínicas que llevaron al diagnóstico eran neurológicas o visuales en 9casos y hormonales en 3. De los que consultaron por síntomas neurológicos o visuales, 7 refirieron previamente alteraciones hormonales, luego, estas estaban presentes en 10 de los niños al diagnóstico; la más frecuente fue la diabetes insípida central (8 casos). El periodo medio de presencia de síntomas endocrinológicos previos al diagnóstico fue de 25,0±26,2 meses, mucho más largo que el de los neurooftalmológicos, de 2,0±2,1 meses (p = 0,012). CONCLUSIONES: Casi todos los tumores germinales intracraneales presentaron al diagnóstico manifestaciones endocrinas, la más frecuente de las cuales fue la diabetes insípida central. Los síntomas hormonales suelen presentarse bastante antes que los neurooftalmológicos. La correcta valoración clínica y endocrinológica puede adelantar el diagnóstico de estos tumores

INTRODUCTION: Central nervous system germ cell tumors need to be adequately diagnosed because their treatment is usually effective and they do not always require surgery. The study objectives are to describe the endocrine manifestations of these tumors and to compare the time of their onset to that of the occurrence of neurological and visual changes. PATIENTS AND METHODS: The medical histories of patients under 14 years of age seen at a pediatric endocrinology unit between 2000 and 2018 were reviewed. Wilcoxon and Fisher statistical tests were performed. RESULTS: We found 12patients (10 females) with an age at diagnosis of 9.4±1.7 years and a follow-up time of 5.5±3.0 years, 10with tumors in the sellar region, and each one with a pineal gland and a bifocal tumor. Clinical changes leading to diagnosis were neurological and/or visual in 9patients and hormonal in three. Seven patients diagnosed on the basis of neurological or visual symptoms had previously reported hormonal changes, giving us a total of 10 children at diagnosis (the most common diagnosis was central diabetes insipidus, found in 8). Endocrine symptoms had been present before diagnosis for 25.0±26.2 months, considerably longer than neuro-ophthalmological complaints (2.0±2.1 months, p = 0.012). CONCLUSIONS: Almost all intracranial germ cell tumors have associated endocrine manifestations at diagnosis, with central diabetes insipidus the most common. Hormonal symptoms usually appear long before neuro-ophthalmological manifestations. Adequate clinical and endocrinological assessment may allow for an earlier diagnosis of these tumors

Endocrine manifestations of central nervous system germ cell tumors in children. / Manifestaciones endocrinas de los tumores germinales del sistema nervioso central en niños.

INTRODUCTION: Central nervous system germ cell tumors need to be adequately diagnosed because their treatment is usually effective and they do not always require surgery. The study objectives are to describe the endocrine manifestations of these tumors and to compare the time of their onset to that of the occurrence of neurological and visual changes. PATIENTS AND METHODS: The medical histories of patients under 14 years of age seen at a pediatric endocrinology unit between 2000 and 2018 were reviewed. Wilcoxon and Fisher statistical tests were performed. RESULTS: We found 12patients (10 females) with an age at diagnosis of 9.4±1.7 years and a follow-up time of 5.5±3.0 years, 10with tumors in the sellar region, and each one with a pineal gland and a bifocal tumor. Clinical changes leading to diagnosis were neurological and/or visual in 9patients and hormonal in three. Seven patients diagnosed on the basis of neurological or visual symptoms had previously reported hormonal changes, giving us a total of 10 children at diagnosis (the most common diagnosis was central diabetes insipidus, found in 8). Endocrine symptoms had been present before diagnosis for 25.0±26.2 months, considerably longer than neuro-ophthalmological complaints (2.0±2.1 months, p=0.012). CONCLUSIONS: Almost all intracranial germ cell tumors have associated endocrine manifestations at diagnosis, with central diabetes insipidus the most common. Hormonal symptoms usually appear long before neuro-ophthalmological manifestations. Adequate clinical and endocrinological assessment may allow for an earlier diagnosis of these tumors.

Situación de la diabetes mellitus tipo 1 en Andalucía. Datos asistenciales, uso de terapias avanzadas y recursos humanos / The situation as regards diabetes mellitus type 1 in Andalusia. Care data, use of advanced therapies and human resources

INTRODUCCIÓN: La representación de nuestro país en los estudios epidemiológicos europeos en diabetes es exigua, tan solo un centro en el estudio Hvidoere y otro en el SWEET. No existen estudios publicados en España que combinen datos epidemiológicos y recursos asistenciales. El objetivo de este estudio es conocer los datos epidemiológicos, los recursos asistenciales y el uso de nuevas tecnologías en los hospitales andaluces que atienden a niños con diabetes mellitus tipo 1 (DM1) menores de 14 años. MATERIAL Y MÉTODOS: Un cuestionario electrónico de 18 preguntas fue enviado a los endocrinólogos pediátricos que atendían a niños con DM1 en todos los hospitales andaluces. RESULTADOS: La media de la ratio de endocrinólogo pediátrico por 100 pacientes fue 3,12 (DE: 2,58). La media de la ratio de enfermero educador en diabetes por 100 pacientes y centro fue de 2,50 (DE: 3,94). Solo uno de los 29 centros disponía de psicólogo, 9/29 disponían de hospital de día y 11/29 disponían de atención telefónica durante 24 h. La media de días de consulta a la semana destinados exclusivamente a pacientes con DM1 fue de 1,56 días (DE: 1,21). Un 5% de los pacientes fueron tratados con infusor continuo de insulina, con un aumento significativo en los centros que tenían más de 150 pacientes. CONCLUSIONES: Este estudio ofrece por primera vez datos actuales de la situación epidemiológica en Andalucía en relación con los datos asistenciales; comparándolos con las recomendaciones de estándares europeos, destaca una baja ratio de endocrinólogos y educadores en diabetes, ausencia de psicólogo y baja penetrancia de tecnología

INTRODUCTION: The representation of Spain in European epidemiological studies on diabetes is limited, with only one centre in the Hvidoere study and another in the SWEET study. No Spanish studies have been published that combine epidemiological data and care resources. The aim of this study was to determine the epidemiological data, care resources, and use of new technologies in all Andalusian hospitals that care for children with Diabetes Mellitus type 1 (DM1) under 14 years. MATERIAL AND METHODS: An electronic questionnaire of 18 questions was sent to all paediatric endocrinologists who treated children with diabetes in Andalusian hospitals. RESULTS: There was a mean of 3.12 (SD: 2.58) paediatric endocrinologist for every 100 patients, with a mean diabetes nurse educator ratio of 2.50 (SD: 3.94) per 100 patients and centre. Only 1 of the 29 centres had a psychologist, 9/29 had a day hospital, and 11/29 had a 24-hour telephone line. The mean of days of consultations exclusively for patients with DM1 was 1.56 days (SD: 1.21) per week. Continuous insulin infusion was used to treat 5% of patients, with a significant increase in centres with more than 150 patients. CONCLUSIONS: This study offers, for the first time, current data on the epidemiological situation related to health care data, comparing them with the recommendations of European standards, highlighting a low ratio of endocrinologists and educators in diabetes, absence of psychologists and low technology penetrance

[The situation as regards diabetes mellitus type 1 in Andalusia. Care data, use of advanced therapies and human resources]. / Situación de la diabetes mellitus tipo 1 en Andalucía. Datos asistenciales, uso de terapias avanzadas y recursos humanos.

INTRODUCTION: The representation of Spain in European epidemiological studies on diabetes is limited, with only one centre in the Hvidoere study and another in the SWEET study. No Spanish studies have been published that combine epidemiological data and care resources. The aim of this study was to determine the epidemiological data, care resources, and use of new technologies in all Andalusian hospitals that care for children with Diabetes Mellitus type 1 (DM1) under 14 years. MATERIAL AND METHODS: An electronic questionnaire of 18 questions was sent to all paediatric endocrinologists who treated children with diabetes in Andalusian hospitals. RESULTS: There was a mean of 3.12 (SD: 2.58) paediatric endocrinologist for every 100 patients, with a mean diabetes nurse educator ratio of 2.50 (SD: 3.94) per 100 patients and centre. Only 1 of the 29 centres had a psychologist, 9/29 had a day hospital, and 11/29 had a 24-hour telephone line. The mean of days of consultations exclusively for patients with DM1 was 1.56 days (SD: 1.21) per week. Continuous insulin infusion was used to treat 5% of patients, with a significant increase in centres with more than 150 patients. CONCLUSIONS: This study offers, for the first time, current data on the epidemiological situation related to health care data, comparing them with the recommendations of European standards, highlighting a low ratio of endocrinologists and educators in diabetes, absence of psychologists and low technology penetrance.

Achievement of metabolic control among children and adolescents with type 1 diabetes in Spain.

AIMS: To assess metabolic control in a paediatric T1D population in Spain and analyse the rate of severe acute decompensations and chronic complications. METHODS: Data from patients treated at eight paediatric diabetes units with experienced diabetes teams between June and December 2014 were analysed in an observational prospective study. Variables included: age, sex, diabetes duration, number of follow-up visits/year, anthropometrical data, insulin treatment modalities, mean annual HbA1c and the prevalence of acute and chronic complications. SPSS statistics 21.0 was used. RESULTS: A total of 853 patients (49.7% female) with a mean age of 12.1 ± 3.7 years were included. Anthropometric data were normal. Mean diabetes duration was 8 ± 3.4 years. Mean outpatient follow-up was 4.7 ± 0.04 visits/year. Twenty-five per cent were on continuous subcutaneous insulin infusion (CSII). Mean HbA1c was 7.3 ± 1% (56 ± 8 mmol/mol) and 66.6% had HbA1c < 7.5% (58 mmol/mol). HbA1c value correlated negatively with age at onset and positively with years of diabetes, number of visits/year and current age (F = 7.06; p = 0.01). Patients on CSII (n = 213) were younger, attended the outpatient clinic more frequently, were diagnosed earlier, had better metabolic control and had presented more severe hypoglycaemic episodes the previous year. The rate of severe decompensation (episodes/100 patients/year) was ketoacidosis 1.5 and severe hypoglycaemia 4.5. The prevalence of chronic complications was very low. CONCLUSIONS: Our data describe the good compliance of paediatric T1D patients treated at eight paediatric units in Spain following international standards of metabolic control.

Transición del paciente con diabetes tipo 1 desde la Unidad de Diabetes pediátrica a la Unidad de Diabetes de adultos / Transition of adolescents with type 1 diabetes from paediatric to adult Health Care

La transición de los pacientes pediátricos con diabetes tipo 1 (DM1) a Unidades de adultos puede conllevar efectos adversos para la salud de los pacientes si no se hace de forma adecuada. El paso tiene lugar durante la adolescencia, periodo especialmente crítico de la vida caracterizado por cambios específicos tanto psicológicos como fisiológicos, durante el que se incrementa el riesgo de aparición y progresión de las complicaciones crónicas así como de los ingresos relacionados con la DM1. Coincidiendo con el cambio de equipo médico se han objetivado pérdidas en el seguimiento de los pacientes y un empeoramiento en su grado de control metabólico que debemos intentar evitar. Se precisan programas planificados, progresivos y estructurados que incluyan la participación del individuo, de la familia y del servicio de salud para que la transición sea lo más favorable posible. El momento óptimo para hacer el cambio de equipo sanitario es cuando el paciente tenga madurez suficiente para ser casi autónomo en el tratamiento de la DM1, situación que en la mayoría de las personas no se alcanza antes de los 16-18 años. La coordinación entre los profesionales de pediatría y de adultos, la educación grupal, el uso de tecnologías y el abordaje psicosocial favorecen la adherencia y el seguimiento en esta fase de transición. Tras la valoración de las recomendaciones de las Sociedades Científicas Internacionales se propone un modelo de transición consensuado entre las Sociedad Española de Diabetes y la Sociedad Española de Endocrinología Pediátrica

The transition of adolescents with type 1 diabetes mellitus (T1DM) from paediatric health care to adult health care has been recognized as an important and difficult process, with a high risk of interruption of care and associated with poor glycaemic control. Transition to adult units takes place during adolescence in an especially critical period of life with changes, both in psychological and physiological aspects that increase the risk of onset and progression of chronic complications related to T1DM.Adverse outcomes that may affect the health of these patients can appear if transition is not done properly. Previous studies have shown that planned and structured transition programs are required, including the participation of the individual, the family, and the health service. The best time to make the transition is when they are mature enough to be almost capable of managing their T1DM. The majority of patients do not reach this stage before the age of 16-18 years. There should be coordination between professionals of paediatric and adult health care in the planning of this transition. Group education programs, the use of new technologies, and the approach to psychosocial aspects are suggested in order to improve adherence and followup during this period. After assessing the recommendations of some International Scientific Societies, the Spanish Society of Diabetes and the Spanish Society for Pediatric Endocrinology propose following a planned transition model