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.).

Intensive Calcium Monitoring Following Parathyroidectomy: Prevention of Hungry Bone Syndrome in Children.

Cite this article as: García Díaz FJ, Martin LB, Gómez Gila AL, Navarro Moreno C. Intensive calcium monitoring following parathyroidectomy: Prevention of hungry bone syndrome in children. Turk Arch Pediatr. 2024;59(1):109-111.

Identification of a novel mutation in FGFR1 gene in mother and daughter with Kallmann syndrome.

OBJECTIVES: Congenital hypogonadotropic hypogonadism combined with anosmia or hyposmia is considered Kallmann syndrome (KS). It is often accompanied by bone defects. CASE PRESENTATION: Here, we report a girl and her mother with KS caused by a novel mutation in the fibroblast growth factor receptor 1 gene (FGFR1). Interestingly, the daughter presented syndactyly and oligodactyly of the feet. CONCLUSIONS: The presence of bone malformations in a KS patient should direct the geneticist towards a search for specific mutations in FGFR1. Our finding contributes to enrich the spectrum of FGFR1 mutations in patients with KS.

Intralymphatic GAD-Alum (Diamyd®) Improves Glycemic Control in Type 1 Diabetes With HLA DR3-DQ2.

AIMS: Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM). METHODS: DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 µg GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values. RESULTS: We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR. CONCLUSIONS: Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.

Hypoparathyroidism after thyroidectomy: A 20-year experience at a children's hospital.

INTRODUCTION: Hypoparathyroidism (HP) is the most common complication of total thyroidectomy and can be an emergency. OBJECTIVES: To describe the prevalence of HP after total thyroidectomy in children under 14 years of age, the variables related to its appearance and its clinical expression. PATIENTS AND METHODS: Retrospective study at a children's hospital in the last 20 years. HP was defined by the need to supplement calcium after the intervention and was considered permanent if it could not be suspended within 12 months. Fisher's statistical method of comparison of proportions. RESULTS: Thirty-nine children and adolescents (26 females) with an age range of 3.67-14.00 years. In 25 patients, the intervention was prophylactic and in 14 it was therapeutic; 14 suffered accidental excision of some parathyroid gland, but none more than two of them; 12 presented HP, of which 3 were permanent; 5 presented clinical symptoms; 1 of them was an emergency. The frequency of HP was 4/4 when 2 parathyroids were dissected, 2/10 when one was dissected, and 6/25 when none were dissected (p = 0.02). In the prophylactic interventions, it was 6/25 compared to 6/14 in the therapeutic ones (p = 0.29). The three cases of permanent HP were in children under 6 years of age, and it did not occur in any older children (p = 0.09). CONCLUSIONS: HP is a common and sometimes serious complication in children after total thyroidectomy. It can occur, and even be permanent, even if the intervention is prophylactic and parathyroid glands remain in situ. Younger age could be a risk factor.

Hypoparathyroidism after thyroidectomy: A 20-year experience at a children's hospital. / Hipoparatiroidismo postiroidectomía: experiencia de 20 años en un hospital infantil.

INTRODUCTION: Hypoparathyroidism (HP) is the most common complication of total thyroidectomy and can be an emergency. OBJECTIVES: To describe the prevalence of HP after total thyroidectomy in children under 14 years of age, the variables related to its appearance and its clinical expression. PATIENTS AND METHODS: Retrospective study at a children's hospital in the last 20 years. HP was defined by the need to supplement calcium after the intervention and was considered permanent if it could not be suspended within 12 months. Fisher's statistical method of comparison of proportions. RESULTS: Thirty-nine children and adolescents (26 females) with an age range of 3.67 to 14.00 years. In 25 patients, the intervention was prophylactic and in 14 it was therapeutic. Fourteen suffered accidental excision of some parathyroid gland, but none more than t2 of them. Twelve presented HP, of which 3 were permanent; 5 presented clinical symptoms; one of them was an emergency. The frequency of HP was 4/4 when 2 parathyroids were dissected, 2/10 when one was dissected, and 6/25 when none were dissected (P=.02). In the prophylactic interventions, it was 6/25 compared to 6/14 in the therapeutic ones (P=.29). The 3 cases of permanent HP were in children under 6 years of age, and it did not occur in any older children (P=.09). CONCLUSIONS: HP is a common and sometimes serious complication in children after total thyroidectomy. It can occur, and even be permanent, even if the intervention is prophylactic and parathyroid glands remain in situ. Younger age could be a risk factor.

Intralymphatic Glutamic Acid Decarboxylase With Vitamin D Supplementation in Recent-Onset Type 1 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial.

OBJECTIVE: To evaluate the efficacy of aluminum-formulated intralymphatic glutamic acid decarboxylase (GAD-alum) therapy combined with vitamin D supplementation in preserving endogenous insulin secretion in all patients with type 1 diabetes (T1D) or in a genetically prespecified subgroup. RESEARCH DESIGN AND METHODS: In a multicenter, randomized, placebo-controlled, double-blind trial, 109 patients aged 12-24 years (mean ± SD 16.4 ± 4.1) with a diabetes duration of 7-193 days (88.8 ± 51.4), elevated serum GAD65 autoantibodies, and a fasting serum C-peptide >0.12 nmol/L were recruited. Participants were randomized to receive either three intralymphatic injections (1 month apart) with 4 µg GAD-alum and oral vitamin D (2,000 IE daily for 120 days) or placebo. The primary outcome was the change in stimulated serum C-peptide (mean area under the curve [AUC] after a mixed-meal tolerance test) between baseline and 15 months. RESULTS: Primary end point was not met in the full analysis set (treatment effect ratio 1.091 [CI 0.845-1.408]; P = 0.5009). However, GAD-alum-treated patients carrying HLA DR3-DQ2 (n = 29; defined as DRB1*03, DQB1*02:01) showed greater preservation of C-peptide AUC (treatment effect ratio 1.557 [CI 1.126-2.153]; P = 0.0078) after 15 months compared with individuals receiving placebo with the same genotype (n = 17). Several secondary end points showed supporting trends, and a positive effect was seen in partial remission (insulin dose-adjusted HbA1c ≤9; P = 0.0310). Minor transient injection site reactions were reported. CONCLUSION: Intralymphatic administration of GAD-alum is a simple, well-tolerated treatment that together with vitamin D supplementation seems to preserve C-peptide in patients with recent-onset T1D carrying HLA DR3-DQ2. This constitutes a disease-modifying treatment for T1D with a precision medicine approach.

Rare Germline DICER1 Variants in Pediatric Patients With Cushing's Disease: What Is Their Role?

Context: The DICER1 syndrome is a multiple neoplasia disorder caused by germline mutations in the DICER1 gene. In DICER1 patients, aggressive congenital pituitary tumors lead to neonatal Cushing's disease (CD). The role of DICER1 in other corticotropinomas, however, remains unknown. Objective: To perform a comprehensive screening for DICER1 variants in a large cohort of CD patients, and to analyze their possible contribution to the phenotype. Design, setting, patients, and interventions: We included 192 CD cases: ten young-onset (age <30 years at diagnosis) patients were studied using a next generation sequencing panel, and 182 patients (170 pediatric and 12 adults) were screened via whole-exome sequencing. In seven cases, tumor samples were analyzed by Sanger sequencing. Results: Rare germline DICER1 variants were found in seven pediatric patients with no other known disease-associated germline defects or somatic DICER1 second hits. By immunohistochemistry, DICER1 showed nuclear localization in 5/6 patients. Variant transmission from one of the parents was confirmed in 5/7 cases. One patient had a multinodular goiter; another had a family history of melanoma; no other patients had a history of neoplasms. Conclusions: Our findings suggest that DICER1 gene variants may contribute to the pathogenesis of non-syndromic corticotropinomas. Clarifying whether DICER1 loss-of-function is disease-causative or a mere disease-modifier in this setting, requires further studies. Clinical trial registration: ClinicalTrials.gov: NCT00001595.

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.

GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus.

BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).