Abstract
Context
Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene and characterized by chronic ...mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. Comprehensive characterizations of large patient cohorts are rare.
Objective
To perform an extensive clinical, immunological, and genetic characterization of a large nationwide Russian APS-1 cohort.
Subjects and Methods
Clinical components were mapped by systematic investigations, sera were screened for autoantibodies associated with APS-1, and AIRE mutations were characterized by Sanger sequencing.
Results
We identified 112 patients with APS-1, which is, to the best of our knowledge, the largest cohort described to date. Careful phenotyping revealed several additional and uncommon phenotypes such as cerebellar ataxia with pseudotumor, ptosis, and retinitis pigmentosa. Neutralizing autoantibodies to interferon-ω were found in all patients except for one. The major Finnish mutation c.769C>T (p.R257*) was the most frequent and was present in 72% of the alleles. Altogether, 19 different mutations were found, of which 9 were unknown: c.38T>C (p.L13P), c.173C>T (p.A58V), c.280C>T (p.Q94*), c.554C>G (p.S185*), c.661A>T (p.K221*), c.821del (p.Gly274Afs*104), c.1195G>C (p.A399P), c.1302C>A (p.C434*), and c.1497del (p.A500Pfs*21).
Conclusions
The spectrum of phenotypes and AIRE mutation in APS-1 has been expanded. The Finnish major mutation is the most common mutation in Russia and is almost as common as in Finland. Assay of interferon antibodies is a robust screening tool for APS-1.
Studying several typings of a Russian APS-1 cohort, we found wide clinical variation and what to our knowledge were novel components and nine novel mutations in AIRE, p.R257* being the most common.
The rapid increase in overweight and obesity in children is a global public health problem. Interventions to reduce the prevalence of obesity before puberty are considered to be the most effective, ...but the results of trials are not consistent enough. We performed a meta-analysis of the efficacy of interventions to prevent or correct overweight and obesity in pre-pubertal children. Thirty-one Cochrane systematic reviews were analyzed, the results of 10 RCTs and two prospective comparative studies were extracted. All trials had an moderate or high risk of bias. According to the results of meta-analyzes, the prevention of overweight and obesity through recommendations of lifestyle modification is effective, the difference in a BMI decrease is -0.19, 95% CI -0.35; -0.03, compared with the absence of intervention, in children 78 years old if applied within 24 years, but not within one year or less. The effect of non-drug interventions in children with overweight or obesity was not revealed.
Rationale: Healthcare access plays a significant role in the improvement and maintaining of glycemic control and quality of life in type 1 diabetes mellitus (T1DM) patients on continuous subcutaneous ...insulin infusion (CSII).
Aims: The aim of the study was to evaluate the feasibility of remote support in children and adolescents with type 1 diabetes mellitus (T1DM) and its effect on glycemic control and quality of life.
Materials and methods: In 40 children and adolescents (132,7 years, 18/22 m/f) on CSII with inadequately controlled T1DM (HbA1c7,5%) we evaluated the effectiveness of telemedical support (TS), as compared with conventional support (CS). Parameters of glycemic control (HbA1c, average glycemia, SD, etc.) and quality of a life were obtained on follow-up visits. Patients and their parents in ТМ group twice a month sent their insulin pump data using to CSII center and diabetologists sent back their advice via e-mail, phone or Skype. The primary end point was the change from the baseline HbA1c level and the proportion of patients achieving HbA1c of less than 7.5%.
Results: At 24 weeks, the baseline mean HbA1c (8.7% in the two study groups) had decreased to 7.7% in the TS group, as compared with 8.4% in the CS group (P0,05). The proportion of patients who reached the HbA1c target (7,5%) was greater in the TS group (50%) than in the CS group (20%, p0,05). A number of quality of life indicators for both parents and children with T1DM at the end of the study compared to baseline significantly increased in the TS group compared with the TC group (p0.05). During the study period rate of severe hypoglycemia and DKA in TS group (0 and 10 cases per 100 person-years) did not differ significantly from that in CS group (0 and 20 cases per 100 person-years, P0,05).
Conclusion: In children with inadequately controlled T1DM, telemedical support proved to be feasible and resulted in significant improvement in glucose control (HbA1c, glucose variability) and quality of life without the increase in the incidence of DKA and severe glycemia.
Meta-analysis has shown a modest improvement in first-year growth response to recombinant human GH (r-hGH) for carriers of the exon 3-deleted GH receptor (GHRd3) polymorphism but with significant ...interstudy variability. The associations between GHRd3 and growth response to r-hGH over 3 years in relation to severity of GH deficiency (GHD) were investigated in patients from 14 countries. Treatment-naïve pre-pubertal children with GHD were enrolled from the PREDICT studies (NCT00256126 and NCT00699855), categorized by peak GH level (peak GH) during provocation test: ≤4 μg/l (severe GHD; n=45) and >4 to <10 μg/l mild GHD; n=49) and genotyped for the GHRd3 polymorphism (full length (fl/fl, fl/d3, d3/d3). Gene expression (GE) profiles were characterized at baseline. Changes in growth (height (cm) and SDS) over 3 years were measured. There was a dichotomous influence of GHRd3 polymorphism on response to r-hGH, dependent on peak GH level. GH peak level (higher vs lower) and GHRd3 (fl/fl vs d3 carriers) combined status was associated with height change over 3 years (P<0.05). GHRd3 carriers with lower peak GH had lower growth than subjects with fl/fl (median difference after 3 years −3.3 cm; −0.3 SDS). Conversely, GHRd3 carriers with higher peak GH had better growth (+2.7 cm; +0.2 SDS). Similar patterns were observed for GH-dependent biomarkers. GE profiles were significantly different between the groups, indicating that the interaction between GH status and GHRd3 carriage can be identified at a transcriptomic level. This study demonstrates that responses to r-hGH depend on the interaction between GHD severity and GHRd3 carriage.
Background:
Hypothalamic obesity often develops after surgical treatment of craniopharyngioma and is characterized by rapid weight gain, high frequency of metabolic disorders, body composition ...specificity and resistance to standard lifestyle modification approaches and medication therapy of obesity. Recent studies show that one of the mechanisms, explaining weight gain in these children is decrease in resting energy expenditure (REE).
Aims:
To compare REE, body composition parameters, and the frequency of metabolic disorders in children with hypothalamic and simple obesity.
Materials and methods
: The study included 60 obese children aged 7 to 17 years, divided into two groups. The study group included 20 children with hypothalamic obesity, developed after craniopharyngioma treatment. The control group consisted of 40 children with simple obesity. Body composition, REE, and metabolic disorders were associated in all children.
Results:
Children with hypothalamic obesity showed a significant decrease of resting energy expenditure. The average decrease in REE was 13.1%, but in single patients it reached 33.4%. The percentage of fat mass in hypothalamic and simple obesity does not differ significantly (39.7% 36.2; 42.6 vs 38.8 % 35.9; 43.2; p=0.69). Screening for metabolic disorders revealed a high prevalence of metabolic disorders in hypothalamic obesity: impaired glucose tolerance - in 10%; dyslipidemia - 55%, insulin resistance-50%, non-alcoholic fatty liver disease - 60 %.
Conclusions:
Children with hypothalamic obesity showed a significant decrease of resting energy expenditure. When planning a diet in this group of patients it is preferable to use indirect calorimetry. Hypothalamic obesity even at an early age is associated with a high frequency of metabolic disturbance. Hypothalamic obesity in children is not associated with more pronounced hyperinsulinemia and insulin resistance compared to the simple obesity.
Autoimmune polyglandular syndrome type 1 (APS-1) (OMIM 240300) is a rare autosomal recessive disorder associated with three major manifestations: chronic mucocutaneous candidiasis, ...hypoparathyroidism, and adrenal insufficiency. There are, however, multiple minor components of APS-1 that induce significant phenotype variability. Subsequently, the diagnosis of APS-1 during early stages is often challenging.
We aimed to provide clinical and mutational data for a large number of APS-1 patients in the Russian population.
We analyzed clinical variations and component prevalence in APS-1 patients. DNA screening for autoimmune regulator (AIRE) gene mutations was performed in established APS-1 patients and in patients with the single components of chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency, or alopecia.
We identified 46 patients from 42 families with APS-1. Eighteen different components were present in the patients, including very rare conditions - bone dysplasia and retinitis pigmentosa. We identified 10 different mutations, 3 of which were novel (M1T, E298K, c1053_1060del). The common Finnish mutation, R257X, was the most frequent in our population, present in 64/92 (70%) of the alleles.
We found that the R257X AIRE mutation is common in Russian APS-1 patients. The majority of children with hypoparathyroidism and chronic mucocutaneous candidiasis were carriers of the AIRE mutations.
A 26-year-old female with the classic major and minor components of autoimmune polyglandular syndrome type 1 was diagnosed as having pure red cell aplasia. Treatment with 1.5 g/d mycofenolate mofetil ...for 3 months failed to restore erythroid production. Treatment with cyclosporine A produced a good partial response but led to renal toxicity and was therefore substituted with cyclophosphamide, which had a good partial effect and lasted for 18 months. The relapse of anemia was not observed during the 6-month follow-up period after the cessation of treatment.
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