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.).

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.

[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.