A somatic mutation in the thyrotropin receptor gene in a patient with an autonomous nodule within a multinodular goiter

ABSTRACT Thyrotropin (TSH) is the prime regulator of thyroid cell growth and function and acts through the thyrotropin receptor (TSHR) located on the surface membrane of thyrocytes. Somatic heterozygous mutations that cause TSHR activation in the absence of TSH have been found in toxic adenomas and in hot nodules of multinodular goiters. Clinically and histologically heterogeneous nodules can share common gain-of-function mutations. Mutation prevalence varies greatly and is inversely related to iodine intake of the population. We report a Greek patient presenting with subclinical hyperthyroidism due to a fast-growing autonomous hyperplastic nodule in a long-standing multinodular goiter. Direct DNA sequencing showed that the hot nodule harbored a somatic heterozygous activating TSHR mutation: substitution of glutamine for leucine in the third transmembrane helix. This mutation (L512Q) was recently described in two solitary toxic adenomas. This report expands the spectrum of mutations shared by dissimilar hot nodules, supporting a common mechanism for nonautoimmune thyroid autonomy. The identification of the L512Q substitution demonstrates that gainof-function TSHR mutations are encountered in Greece, although iodine deficiency has been significantly corrected over the last three decades

The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity

<p>Abstract</p> <p>Background</p> <p>The clinical syndrome of thalassemia intermedia (TI) results from the β-globin genotypes in combination with factors to produce fetal haemoglobin (HbF) and/or co-inheritance of α-thalassemia. However, very little is currently known of the molecular basis of Chinese TI patients.</p> <p>Methods</p> <p>We systematically analyzed and characterized β-globin genotypes, α-thalassemia determinants, and known primary genetic modifiers linked to the production of HbF and the aggravation of α/β imbalance in 117 Chinese TI patients. Genotype-phenotype correlations were analyzed based on retrospective clinical observations.</p> <p>Results</p> <p>A total of 117 TI patients were divided into two major groups, namely heterozygous β-thalassemia (n = 20) in which 14 were characterized as having a mild TI with the Hb levels of 68-95 g/L except for five co-inherited ααα^anti-3.7triplication and one carried a dominant mutation; and β-thalassemia homozygotes or compound heterozygotes for β-thalassemia and other β-globin defects in which the β⁺-thalassemia mutation was the most common (49/97), hemoglobin E (HbE) variants was second (27/97), and deletional hereditary persistence of fetal hemoglobin (HPFH) or δβ-thalassemia was third (11/97). Two novel mutations, Term CD+32(A→C) and Cap+39(C→T), have been detected.</p> <p>Conclusions</p> <p>Chinese TI patients showed considerable heterogeneity, both phenotypically and genotypically. The clinical outcomes of our TI patients were mostly explained by the genotypes linked to the β- and α-globin gene cluster. However, for a group of 14 patients (13 β⁰/β^Nand 1 β⁺/β^N) with known heterozygous mutations of β-thalassemia and three with homozygous β-thalassemia (β⁰/β⁰), the existence of other causative genetic determinants is remaining to be molecularly defined.</p

The Hellenic type of nondeletional hereditary persistence of fetal hemoglobin results from a novel mutation (g.-109G>T) in the HBG2 gene promoter

Nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH), a rare hereditary condition resulting in elevated levels of fetal hemoglobin (Hb F) in adults, is associated with promoter mutations in the human fetal globin (HBG1 and HBG2) genes. In this paper, we report a novel type of nd-HPFH due to a HBG2 gene promoter mutation (HBG2:g.-109G>T). This mutation, located at the 3′ end of the HBG2 distal CCAAT box, was initially identified in an adult female subject of Central Greek origin and results in elevated Hb F levels (4.1%) and significantly increased Gγ-globin chain production (79.2%). Family studies and DNA analysis revealed that the HBG2:g.-109G>T mutation is also found in the family members in compound heterozygosity with the HBG2:g.-158C>T single nucleotide polymorphism or the silent HBB:g.-101C>T β-thalassemia mutation, resulting in the latter case in significantly elevated Hb F levels (14.3%). Electrophoretic mobility shift analysis revealed that the HBG2:g.-109G>T mutation abolishes a transcription factor binding site, consistent with previous observations using DNA footprinting analysis, suggesting that guanine at position HBG2/1:g.-109 is critical for NF-E3 binding. These data suggest that the HBG2:g-109G>T mutation has a functional role in increasing HBG2 transcription and is responsible for the HPFH phenotype observed in our index cases

Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases

Devices and tasks involved in the objective assessment of standing dynamic balancing – A systematic literature review

Background: Static balancing assessment is often complemented with dynamic balancing tasks. Numerous dynamic balancing assessment methods have been developed in recent decades with their corresponding balancing devices and tasks. Objective: The aim of this systematic literature review is to identify and categorize existing objective methods of standing dynamic balancing ability assessment with an emphasis on the balancing devices and tasks being used. Data Sources Three major scientific literature databases (Science Direct, Web of Science, PLoS ONE) and additional sources were used. Study selection: Studies had to use a dynamic balancing device and a task described in detail. Evaluation had to be based on objectively measureable parameters. Functional tests without instrumentation evaluated exclusively by a clinician were excluded. A total of 63 articles were included. Data extraction: The data extracted during full-text assessment were: author and date; the balancing device with the balancing task and the measured parameters; the health conditions, size, age and sex of participant groups; and follow-up measurements. Data synthesis: A variety of dynamic balancing assessment devices were identified and categorized as 1) Solid ground, 2) Balance board, 3) Rotating platform, 4) Horizontal translational platform, 5) Treadmill, 6) Computerized Dynamic Posturography, and 7) Other devices. The group discrimination ability of the methods was explored and the conclusions of the studies were briefly summarized. Limitations: Due to the wide scope of this search, it provides an overview of balancing devices and do not represent the state-of-the-art of any single method. Conclusions: The identified dynamic balancing assessment methods are offered as a catalogue of candidate methods to complement static assessments used in studies involving postural control. © 2017 Petró et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The frequency of non-syndromic distomolar teeth in a Greek population sample?

Background: To investigate the frequency of non-syndromic distomolars in a Greek population sample. Material and Methods: The study population of this retrospective study consisted of 859 Orthopantomograms (OPGs) of 425 male and 434 female patients, attended the Department of Oral Diagnosis and Radiology, Dental School of Athens seeking for treatment. The OPGs were taken as a part of the patients treatment planning. Patients&apos; mean age was 33.57 years. Exclusion criteria from this study was cleft lip ± palate and diseases associated with systemic conditions and syndromes (such as cleidocranial dysplasia and Gardner syndrome). OPGs were only included in the study if at least one 3rd molar was present. The data collected were the number of 3rd molars, the number of distomolars, the age and the gender of each patient, information concerning previous extraction of 3rd molars. Statistical evaluation of the data included descriptive and bivariate analyses (Chi-square test and Spearman&apos;s rho correlation coefficient). In an attempt to further estimate the correlation between the presence of upper and lower 3rd conditions we assumed that the absence of 3rd molars, the presence of 3rd molars, and the presence of distomolars was ordinal in nature and we calculated the Spearman Correlation Coefficient. Results: The number of distomolars was greater in the maxilla than in the mandible. In the maxilla the distomolars were located almost equally in both left and right side. It was more possible lower left distomolars to be present in males than in females. Furthermore, males present higher prevalence of supernumerary teeth than females. Conclusions: Early radiographic diagnosis of distomolars is fundamental so as to prevent complications such malocclusion, delayed eruption or displacement root or/and resorption of adjacent teeth, pulp necrosis, follicular cyst, pain. © Medicina Oral S. L

Abnormal fasting, post-load or combined glucose values on oral glucose tolerance test and pregnancy outcomes in women with gestational diabetes mellitus

Aims: This study aimed to investigate whether pregnancies complicated by gestational diabetes mellitus (GDM) present differences in the outcomes according to the findings on oral glucose tolerance test (OGTT), including fasting, post-load or combined abnormal blood glucose. Materials: This was a prospective cohort study including 831 singleton pregnancies with GDM per the IADPSG criteria. According to their fasting blood glucose value on OGTT the women were categorized in three groups: (i) GDM women with fasting plasma glucose levels &gt; 92 mg/dl and normal post-load values (T0 abnormal group), (ii) patients with abnormal values at 60′ and/or 120′ and normal fasting values (T-post group) and (iii) patients with combined fasting and post-load abnormal blood glucose values (T-comb). Regression analysis was used to test the independent contribution of the different groups, along with maternal and fetal characteristics, in prediction of (i) large for gestational age (LGA), (ii) need for insulin treatment and (iii) birthweight centile. Results: GDM with abnormal fasting blood glucose was an independent risk factor for LGA (OR 2.91, 95% CI 1.33–6.36) and was associated with higher birthweight centile (10.25, 95% CI 0.27–20.25). GDM with combined fasting and post-load abnormal blood glucose was an independent risk factor for insulin treatment (OR 2.94, 95% CI 1.93–4.47). Conclusions: Women with GDM and abnormal fasting blood glucose are at increased risk for large for gestational age neonates, while women with GDM and combined fasting and post-load abnormal blood glucose are at increased risk for insulin therapy. © 2020 Elsevier B.V