Atypowe cechy fenotypowe u nosicieli nowej mutacji nonsens Q248X w genie HNF1B

Introduction: Hepatocyte transforming factor 1B-maturity onset diabetes mellitus of the young (HNF1B-MODY) is an autosomal dominant type of monogenic diabetes caused by a mutation in the gene encoding hepatocyte nuclear factor 1beta (HNF-1beta). The aim of this study was to determine if a HNF1B gene mutation was responsible for a dominantly inherited form of diabetes mellitus among the members of a three-generation Polish family. Material and methods: The index subject was a 13-year-old boy with metabolic syndrome, spina bifida occulta, posterior urethral valves, congenital ureteropelvic junction obstruction, and a family history of diabetes of autosomal dominant trait of inheritance. We performed clinical and laboratory examinations of his family and sequenced the HNF1B gene. Results: A novel Q248X mutation (nucleotide C to T transition at position 742 of the exon 3 of HNF1B gene, resulting in stop codon formation) was identified. Phenotypes of family members sharing this mutation are highly variable, and include previously known abnormalities of the urinary system and pancreas, diabetes mellitus of variable onset and severity, hyperinsulinaemia, insulin resistance, metabolic syndrome, elevated aminotransferases, hyperbilirubinemia, hyperamylasemia, short stature and cataracts. To the best of our knowledge, spina bifida occulta, pectus carinatum, and splenomegaly have not been previously reported. Conclusions: Our results broaden the spectrum of HNF1B gene mutations and HNF1B-MODY-related phenotypes. Wstęp: Cukrzyca HNF1B-MODY dziedziczona w sposób autosomalnie dominujący jest rodzajem cukrzycy monogenowej, którą powoduje mutacja w genie HNF1B (hepatocyte transforming factor 1B). Celem pracy było zbadanie czy mutacja w HNF1B jest przyczyną występowania cukrzycy w trzech pokoleniach polskiej rodziny. Materiał i metody: Przeprowadzono ocenę kliniczną i laboratoryjną oraz sekwencjonowanie genu HNF1B trzynastoletniego chłopca z zespołem metabolicznym, rozszczepem kręgosłupa, zastawkami cewki tylnej i wrodzonym zwężeniem moczowodu oraz obciążonym wywiadem rodzinnym w kierunku cukrzycy. Ze względu na wywiad rodzinny o autosomalnie dominującym sposobie dziedziczenia cukrzycy zbadano również członków jego rodziny. Wyniki: Stwierdzono obecność nowej mutacji Q248X będącej skutkiem przeniesienia nukleotydu C na miejsce T w pozycji 742 eksonu 3 genu HNF1B i powstaniem kodonu stop. Cechy fenotypowe członków rodziny będących nosicielami tej mutacji okazały być się bardzo zróżnicowane, a niektóre z nich takie jak spina bifida occulta, pectus carinatum i splenomegalia nie były dotychczas opisywane. Wnioski: Wyniki poszerzają spectrum mutacji genu HNF1B oraz związanych z nimi cech fenotypowych cukrzycy HNF1B-MODY

Autoimmune reaction against pancreatic beta cells in children and adolescents with simple obesity

IntroductionOne of the most important complications of obesity is insulin resistance, which leads to carbohydrate metabolism disorders such as type 2 diabetes. However, obesity is also associated with development of an autoimmune response against various organs, including pancreatic beta cells. The prevalence of such autoimmune processes in children and their possible contribution to the increased incidence of type 1 diabetes is currently unclear. Therefore, the present study assessed the prevalence of autoantibodies against pancreatic islet beta cell’s antigens in children and adolescents with simple obesity.Material and methodsThis prospective observational study included pediatric patients (up to 18 years of age) with simple obesity hospitalized between 2011 and 2016 at the Department of Pediatrics, Diabetology, Endocrinology and Nephrology of the Medical University of Lodz. Children with acute or chronic conditions that might additionally affect insulin resistance or glucose metabolism were excluded. Collected clinical data included sex, age, sexual maturity ratings (Tanner`s scale), body height and weight, waist and hip circumference, amount of body fat and lean body mass. Each participant underwent a 2-hour oral glucose tolerance test with simultaneous measurements of glycaemia and insulinemia at 0`, 60` and 120`. In addition, glycated hemoglobin HbA1c, fasting and stimulated c-peptide, total cholesterol, as well as high- and low-density cholesterol and triglycerides were measured. Insulin resistance was assessed by calculating HOMA-IR index. The following autoantibodies against pancreatic islet beta cells were determined in each child: ICA - antibodies against cytoplasmic antigens of pancreatic islets, GAD - antibodies against glutamic acid decarboxylase, ZnT8 - antibodies against zinc transporter, IA2 - antibodies against tyrosine phosphatase, IAA – antibodies against insulin.ResultsThe study group included 161 children (57.4% boys, mean age 13.1 ± 2.9 years) with simple obesity (mean BMI z-score +2.2 ± 1.6). Among them, 28 (17.4%) were diagnosed with impaired glucose metabolism during OGTT [23 (82.2%) – isolated impaired glucose tolerance (IGT), 3 (10.7%) – isolated impaired fasting glucose (IFG), 2 (7.1%) – IFG and IGT]. Of the children tested, 28 (17.4%) were tested positive for at least one islet-specific autoantibody [with similar percentages in boys (15, 17.4%) and girls (13, 17.3%), p=0.9855], with ICA being the most common (positive in 18, 11.2%), followed by IAA (7, 4.3%), ZnT8 (5, 3.1%), GADA (3, 1.9%) and IA2 (1, 0.6%). There was no association between the presence of the tested antibodies and age, sex, stage of puberty, parameters assessing the degree of obesity, HbA1c, lipid levels and basal metabolic rate. However, autoantibody-positive subjects were more likely to present IFG or IGT in OGTT compared to those who tested completely negative (9, 32.1% vs 19, 14.3%, p=0.0280). Their HOMA-IR was also significantly higher (HOMA-IR: 4.3 ± 1.9 vs 3.4 ± 1.9, p=0.0203) and this difference remained statistically significant after adjusting for sex and age (p=0.0340).ConclusionsChildren and adolescents with simple obesity presented a higher prevalence of markers of autoimmune response against pancreatic beta cells than the general population. Most often, they had only one type of antibody - ICA. The presence of autoimmune response indicators against pancreatic islet antigens is more common in obese patients with impaired carbohydrate metabolism and is associated with lower insulin sensitivity

Clinical Study Interleukin 18 as a Marker of Chronic Nephropathy in Children after Anticancer Treatment

Novel markers of nephrotoxicity, including kidney injury molecule 1 (KIM-1), interleukin 18 (IL-18), and beta-2 microglobulin, were used in the detection of acute renal injury. The aim of the study was to establish the frequency of postchemotherapy chronic kidney dysfunction in children and to assess the efficacy of IL-18, KIM-1, and beta-2 microglobulin in the detection of chronic nephropathy. We examined eighty-five patients after chemotherapy (median age of twelve years). The median age at the point of diagnosis was 4.2 years, and the median follow-up time was 4.6 years. We performed classic laboratory tests assessing kidney function and compared the results with novel markers (KIM-1, beta-2 microglobulin, and IL-18). Features of subclinical renal injury were identified in forty-eight children (56.3% of the examined group). Nephropathy, especially tubulopathy, appeared more frequently in patients treated with ifosfamide, cisplatin, and/or carboplatin, following nephrectomy or abdominal radiotherapy ( = 0.14, = 0.11, and = 0.08, resp.). Concentrations of IL-18 and beta-2 microglobulin were comparable with classic signs of tubulopathy ( = 0.0001 and = 0.05). Concentrations of IL-18 were also significantly higher in children treated with highly nephrotoxic drugs ( = 0.0004) following nephrectomy ( = 0.0007) and abdominal radiotherapy ( = 0.01). Concentrations of beta-2 microglobulin were higher after highly toxic chemotherapy ( = 0.004) and after radiotherapy ( = 0.02). ROC curves created utilizing IL-18 data allowed us to distinguish between children with nephropathy (value 28.8 pg/mL) and tubulopathy (37.1 pg/mL). Beta-2 microglobulin and IL-18 seem to be promising markers of chronic renal injury in children after chemotherapy

Zwiększenie ryzyka cukrzycy typu 1 u dzieci w populacji polskiej — zależność od regionu 5’VNTR INS-IGF2 oraz brak zależności od haplotypu HLA

Background: Human leukocyte antigens (HLA) complex and INS-IGF2 5&#8217;VNTR loci are principal determinants of the risk of type 1 diabetes mellitus (T1DM). Carriage of class III allele is protective, while class I/I homozygosity increases the risk of T1DM. Material and methods: HLA and 5&#8217;VNTR allele frequencies were summarised and multivariate logistic regression models with interaction evaluation were employed to determine the presence and types of allele effect interdependency. The study group was planned to number 590 children who would undergo genotyping of 5&#8217;VNTR and HLA. Results: 590 patients (302 with T1DM and 288 controls) were recruited. Frequencies of HLA risk alleles were: 117 carriers of DR3-DQ2; 130 carriers of DR4-DQ8 including 43 DR3-DQ2/DR4-DQ8 heterozygotes. In all cases, risk alleles were vastly overrepresented in the T1DM group compared to the controls (p < 0.0001 in all cases). The most frequent protective haplotype was DQB1 × 0602 observed in 24 controls and two T1DM cases (p < 0.001). Class I 5&#8217;VNTR homozygotes constituted 58% of the control group (n = 174) and 78% (n = 224) of T1DM patients [OR = 2.63 (95% CI: 1.79&#8211;3.57)]. Interactions between 5&#8217;VNTR and DR3-DQ2 or DR4-DQ8 variants did not reach statistical significance for risk of developing T1DM (p = 0.54 and 0.24) or age at its diagnosis (p = 0.14 and 0.67 respectively). Conclusions: Interactions between HLA and 5&#8217;VNTR genotype are not of multiplicative character. Class I homozygosity at 5&#8217;VNTR is a significant risk factor of T1DM and acts independently from HLA haplotype in determining the actual risk of diabetes in children. (Pol J Endocrinol 2011; 62 (5): 436&#8211;442)Wstęp: Układ HLA oraz locus 5&#8217;VNTR INS-IGF2 uznaje się za główne determinanty genetyczne cukrzycy typu 1 (T1DM). Nosicielstwo allela klasy III 5&#8217;VNTR uznaje się za czynnik ochronny, a homozygotyczność klasy I/I jest silnym czynnikiem predysponującym do wystąpienia T1DM. W niniejszej pracy przeanalizowano interakcje genetyczne pomiędzy HLA a 5&#8217;VNTR INS w szacowaniu ryzyka T1DM lub wieku zachorowania. Materiał i metody: Efekt częstości alleli HLA i 5&#8217;VNTR przeanalizowano za pomocą modeli wieloczynnikowej regresji logistycznej uwzględniającej interakcje czynników. Liczebność grupy badanej zaplanowano na 590 dzieci. Wszystkich pacjentów planowano poddać genotypowaniu 5&#8217;VNTR INS i HLA. Wyniki: Wśród 590 pacjentów włączonych do badania 302 chorowało na T1DM, a 288 stanowiło grupę kontrolną. Częstości haplotypów HLA ryzyka wynosiły: 117 DR-DQ2; 130 DR4-DQ8 (w tym 43 heterozygoty DR3-DQ2/DR4-DQ8). Stwierdzono silny związek genetyczny między tymi haplotypami a predyspozycją do cukrzycy (p < 0,0001). Najczęściej występującym allelem ochronnym był DQB1*0602, wykryty u 24 osób z grupy kontrolnej i u 2 z grupy T1DM (p < 0,0001). Homozygoty klasy I stanowiły 58% grupy kontrolnej (n = 174) oraz 78% grupy badanej (n = 224; OR: 2,63; 95% CI: 1,79&#8211;3,57). Interakcje pomiędzy 5&#8217;VNTR a wariantami DR3-DQ2 lub DR4-DQ8 nie były istotne statystycznie pod względem ryzyka T1DM (p = 0,54 i 0,24), ani też pod względem wieku zachorowania na T1DM (p = 0,14 i p = 0,64). Wnioski: Interakcje pomiędzy HLA a genotypem 5&#8217;VNTR nie mają charakteru warunkowego. Oznacza to, że homozygotyczność klasy I 5&#8217;VNTR jest niezależną od HLA determinantą genetyczną T1DM u dzieci. (Endokrynol Pol 2011; 62 (5): 436&#8211;442

One Hundred Consecutive Neutropenic Febrile Episodes Demonstrate That CXCR3 Ligands Have Predictive Value in Discriminating the Severity of Infection in Children with Cancer

This study assesses the value of the CXCR3 ligands CXCL9/MIG, CXCL10/IP-10 and CXCL11/I-TAC when used to supplement the standard infection markers C-reactive protein (CRP) and procalcitonin (PCT) in the diagnostic algorithm of neutropenic fever in children with cancer. The concentration of CRP, PCT and chemokines was determined during the first hour of fever and 12–24 h afterwards in pediatric oncology patients with neutropenia. Among 100 consecutive febrile episodes in neutropenic patients, 34 cases demonstrated fever of unknown origin (FUO) (group A), 47 demonstrated mild clinically or microbiologically proven infection (Group B) and 19 severe infection (Group C). Significantly higher PCT-1 levels were found in group C (0.24 ng/mL) vs. group A (0.16 ng/mL), and PCT-2 in group C (1.2 ng/mL) vs. A (0.17 ng/mL), and in C vs. B (0.2 ng/mL). Chemokine concentrations (I-TAC-1, IP-10-1, IP-10-2) were significantly lower in Group A vs. B+C; I-TAC 1: 48.64 vs. 70.99 pg/mL, p = 0.03; IP-10 1: 59.95 vs. 96.84 pg/mL, p = 0.04; and IP-10 2: 102.40 vs. 149.39 pg/mL, p = 0.05. The selected pro-inflammatory chemokines I-TAC and IP10 might help to distinguish cancer patients with febrile neutropenia with the highest risk of infection. Although procalcitonin could serve as a marker of a high risk of infection, its delayed response diminishes its usefulness

New Insights into Red Blood Cell Microcytosis upon mTOR Inhibitor Administration

The aim of this study was to evaluate the effect of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on red blood cell parameters in the context of iron homeostasis in patients with tuberous sclerosis complex (TSC) and evaluate its effect on cell size in vitro. Everolimus has a significant impact on red blood cell parameters in patients with TSC. The most common alteration was microcytosis. The mean MCV value decreased by 9.2%, 12%, and 11.8% after 3, 6, and 12 months of everolimus treatment. The iron level declined during the first 3 months, and human soluble transferrin receptor concentration increased during 6 months of therapy. The size of K562 cells decreased when cultured in the presence of 5 μM everolimus by approximately 8%. The addition of hemin to the cell culture with 5 μM everolimus did not prevent any decrease in cell size. The stage of erythroid maturation did not affect the response to everolimus. Our results showed that the mTOR inhibitor everolimus caused red blood cell microcytosis in vivo and in vitro. This effect is not clearly related to a deficit of iron and erythroid maturation. This observation confirms that mTOR signaling plays a complex role in the control of cell size