Bakgrund: Hypotyreos är en av de vanligaste endokrina sjukdomarna. Varje år insjuknar människor i sjukdomen och vanligast är att kvinnor drabbas. Att drabbas av hypotyreos innebär att man har brist på tyreoideahormoner i sköldkörteln och att energiproduktionen går på sparläge. Kompetenskrav sätts på sjuksköterskan i vårdandeprocessen hos patienter med hypotyreos då konsekvenserna av sjukdomen kan förefalla diffusa och svåra att mäta. Syfte: Syftet med denna studie var att beskriva hur personer med hypotyreos upplever sin livskvalité.  Metod: Denna studie är en beskrivande litteraturstudie. Elva artiklar med både kvalitativ och kvantitativ ansats har analyserats och delats upp i teman och subteman. Huvudresultat: Personer med hypotyreos upplevde varken en bättre livskvalitet eller förbättringar gällande sköldkörtelrelaterade symtom trots att de medicinerats. Känslan hos dessa personer var att de kände sig svaga, orkeslösa, dränerade på ork och att deras dagliga aktiviteter begränsades. En känsla av missförståelse upplevdes inom vården då läkarna fokuserade främst på personernas provresultat. Trots det att läkaren talade om att blodvärdena låg inom referens upplevde personerna med hypotyreos att flertalet symtom kvarstått.  Slutsats: Personer med hypotyreos uttryckte missnöje över sin upplevelse av livskvalitet, sin medicinering och även vårdrelationen. Att leva med hypotyreos innebar att man kunde ha kvarvarande symtom trots medicinering och livskvalitén för dessa personer påverkades negativt. Genom en ökad förståelse för denna komplexa sjukdom skulle sjuksköterskan kunna bidra med en större trygghet och hjälpa dessa personer genom att skapa en bättre vårdrelation. / Background: Hypothyroidism is one of the most common endocrine diseases. Every year, people get sick with the disease and most commonly, women are affected. Being affected by hypothyroidism means that there is a lack of thyroid hormones in the thyroid gland and makes the energy production goes to a low saver. Competence requirements are imposed on the nurse in the caring process of patients with hypothyroidism as the consequences of the disease may appear diffuse and difficult to measure. Purpose: The purpose of this study was to describe how people with hypothyroidism experience their quality of life. Method: This study is a descriptive literature study. Eleven articles with both qualitative and quantitative design have been analyzed and divided into themes and sub-themes. Main Results: People with hypothyroidism experienced neither a better quality of life nor improvements in thyroidrelated symptoms despite being medicated. The feeling of these people was that they felt weak, powerless, drained of energy and that their daily activities were limited. A feeling of misunderstanding was experienced in health care when the doctors focused mainly on the person's test results. Although the doctor mentioned that the blood values were within reference, people with hypothyroidism felt that a number of symptoms remained. Conclusion: People with hypothyroidism expressed dissatisfaction with their experience of quality of life, their medication and even the care relationship. Living with hypothyroidism meant that you could have remaining symptoms despite medication and the quality of life for these people was adversely affected. Through an increased understanding of this complex illness, the nurse could contribute with greater security and help these people by creating a better care relationship.

This study was undertaken to investigate whether the developing brain adapts at biochemical level against neonatal hypothyroidism, as it does so against a variety of physiological disturbances. A moderate hypothyroid state in mice neonates was induced by supplementing 0.05% methimazole in drinking water to the mothers up to suckling period, and its effect on concerted development of the enzymes regulating metabolic channeling of glucose vis a vis glucose phosphorylating activity were studied. In the brain of control mice, the activity of glucose-6-phosphate dehydrogenase (G6PDH), that channels glucose in biosynthetic route (Pentose phosphate pathway, PPP), increased slightly (∼ 1.3 times) from day1 to 10w age. However, glucose phosphorylating activity and the enzymes that commit glucose for energy production, viz phosphofructokinase1 (PFK1), pyruvate kinase (PK) and lactate dehydrogenase (LDH) showed a progressive postnatal increase to attain their respective adult levels (∼ 5-10 times higher than 1day value) by 3-10w ages of mice. In comparison to the control, in the brain of age matched neonatal hypothyroid mice, glucose phosphorylating activity, G6PDH and PFK1 increased significantly (p<0.001) at day1. Thereafter, though, glucose phosphorylating activity continued to increase up to 1w age and remained static thereafter, G6PDH declined significantly (p<0.001) from 1w onward ages. On the other hand, as PFK1 activity increased significantly up to 10w age (p<0.001), the ratio of G6PDH/PFK1 showed a marked decline from 1w onward ages. PK and LDH also showed increasing trend up to 3w age in the brain of hypothyroid mice pups. The results suggest that a moderate hypothyroid state, during the period of rapid brain growth (day 1-1w age), stimulates all the enzymes that regulate channeling of glucose in both, the energy yielding and biosynthetic paths. However, the later postnatal ages, it modulates these enzymes in a metabolic path dependent manner.

Bakgrund: Hypotyreos är en av världens vanligaste sjukdomar som drabbar cirka tio procent av befolkningen. Sjukdomen har i Sverige fördubblats från 2006 till 2017 framförallt bland kvinnor mellan 20−40 år. Hypotyreos är en endokrin, kronisk sjukdom som innebär minskad produktion av tyreoideahormoner vilket påverkar kroppens normala funktioner och utan behandling kan det leda till andra kroniska sjukdomstillstånd. Personer med hypotyreos kan dock oberoende av behandling känna ihållande symtom som påverkar deras hälsa. Syfte: Studiens syfte var att beskriva vad som påverkar livskvaliteten hos personer med hypotyreos. Metod: En allmän litteraturstudie utfördes genom att granska och analysera tio artiklar som relaterade till syftet. Resultatet från artiklarna sammanställdes till fyra kategorier vilka belyste faktorer som påverkade livskvaliteten hos personer med hypotyreos. Resultat: Att leva med hypotyreos innebär en påverkan på livskvaliteten för många personer då de har kvarstående symtom trots behandling. Resultatet visade att trötthet, övervikt och viktuppgång, psykisk ohälsa och behandlingen var faktorer som bidrog till en försämrad livskvalitet. Konklusion/Implikation: Forskning kring livskvalitet hos personer med hypotyreos bör vidareutvecklas för att öka sjuksköterskans kunskap om sjukdomen och bidra till en utveckling av omvårdnaden. / Background: Hypothyroidism is one of the most common diseases in the world, affecting about ten percent of the population. The disease has doubled in Sweden from 2006 to 2017, especially among women between the ages of 20−40 years. Hypothyroidism is an endocrine, chronic disease which means reduced production of thyroid hormones which affects the body's normal functions and without treatment it can lead to other chronic disease states. However, people with hypothyroidism, regardless of treatment, can feel persistent symptoms that affect their health. Aim: The aim of the study was to describe what affects the quality of life of people with hypothyroidism. Method: A general literature study was conducted by reviewing and analyzing ten articles related to the purpose. The results from the articles were compiled into four categories which highlighted factors that affected the quality of life of people with hypothyroidism. Results: Living with hypothyroidism has an impact on the quality of life for many people as they have persistent symptoms despite treatment. The results showed that fatigue, overweight and weight gain, mental illness and treatment were factors that contributed to a reduced quality of life. Conclusion/Implication: Research on quality of life in people with hypothyroidism should be further developed to increase the nurse's knowledge of the disease and contribute to the development of nursing.

Myxedema coma and pituitary apoplexy are well-known life-threatening endocrine emergencies. The coincidence of these entities is exceedingly rare. Myxedema coma occurring as a result of pituitary lesion is a much less seen entity. A high index of suspicion is often required for early diagnosis as it is of particular importance in improving survival outcomes. We present a rare case of a patient with myxedema coma presenting as bradycardia and hypotension secondary to pituitary apoplexy, which was confirmed on magnetic resonance imaging (MRI). The patient was managed conservatively with levothyroxine and stress doses of steroid, with the resolution of hemodynamic changes and a decrease in the size of the suprasellar mass.

The aim of this cross-sectional study was to evaluate the frequency of dental allergens and potential co-factors, especially hypothyroidism, for patients with an intraoral contact allergy. From 2015 to 2016, patients with confirmed symptoms of an intraoral contact allergy (study group SG n = 50) were recruited in the dental clinic of the University of Leipzig. The participants of the control group (CG n = 103) were patients without oral diseases or intraoral symptoms of a contact allergy. For the data collection, a new “Allergy questionnaire” was developed. Information on allergies and general diseases were collected. The statistical analysis was carried out with SPSS 23.0. Sensitizations/allergies to metals and composites were higher in SG compared to CG. Of all study participants (n = 148), 14.2% (n = 21) had a nickel allergy. In 18% (n = 8) of the SG a cobalt allergy based on all metal allergens could be seen. In addition, an association between a nickel and cobalt allergy was found. Hypothyroidism occurred significantly more frequently (p = 0.049) in SG than in CG. Sensitizations and allergies can occur to metals in dental alloys. Hypothyroidism increased the risk of having an allergy threefold.

Gestational hypothyroidism is considerably prevalent. Low maternal thyroid hormones (THs) levels during pregnancy may affect several physiological systems in the offspring. Similarly, an inadequate maternal nutrition during pregnancy is implicated as the origin of many metabolic and cardiovascular diseases in the offspring. Therefore, gestational hypothyroidism, in addition to an inadequate maternal nutrition could trigger an even worse profile in the neuroendocrine, metabolic and feeding behavior throughout postnatal life of the offspring. The aim of this study was to assess metabolic aspects and ingestive behavior of the offspring of rats treated with high fat diet (HD) during gestation associated with experimental gestational hypothyroidism (EGH). On gestational day (GD) 3, we started to feed pregnant rats with the HD, and on GD 9, we started to induce EGH with 0.02% methimazole in drinking water, ad libitum. HD and EGH were only interrupted on the day of birth. The pregnant rats were weighted and monitored for the amount of food and water ingested from GD 3 up to GD 20. In the offspring, body development indexes were measured from postnatal day (PND) 1 up to PND 120. At PND 60, we performed the insulin tolerance test (ITT), glucose tolerance test (GTT), biochemical measurements, in both genders. Furthermore, food, water and 0.3 M NaCl ingestive behaviors were measured in male offspring at PND 30, 60, 90 and 120. Data were analyzed by two- or three-way ANOVAs with Bonferroni posttest. Male offspring from hypothyroid rats submitted to HD (OHT + HD) showed higher hematocrit, triglycerides, cholesterol and urea sera levels when compared to male offspring from hypothyroid rats submitted to control diet (OHT + CD). Moreover, female OHT + HD had higher glucose sensitivity at 30 minutes on the GTT when compared to OHT + CD (p<0.05) and also to offspring from euthyroid rats (OET) + HD (p<0.01). However, we observed no differences in fasting glycemia and ITT in female offspring from different groups. In conclusion, the association of EGH and HD during gestation caused a significant deficit in body development and dyslipidemia in male offspring, whereas female offspring exhibit higher glucose sensitivity. Thus, this data show, for the first time, how the association between low maternal THs with HD predict an abnormal metabolic profile in offspring, and give us an insert about the origin of several unknown metabolic diseases. / O hipotireoidismo gestacional apresenta considerável prevalência e já está devidamente documentado que a carência de hormônios tireoideanos durante a gestação gera repercussão na maturação dos sistemas fisiológicos de controle durante a vida pós-natal. Da mesma forma, inúmeras evidências apontam que o aporte nutricional inadequado durante a vida intrauterina, dependente do hábito alimentar materno, afeta o funcionamento orgânico na vida pós-natal. Assim, acredita-se que quantidade insuficiente dos hormônios tireoideanos durante a vida intrauterina associado ao estado nutricional inadequado das mães durante a gestação pode predispor, de modo particular, ao surgimento de diversas desordens neuroendócrinas, metabólicas e comportamentais ao longo da vida pós-natal. O objetivo do presente estudo foi avaliar os aspectos metabólicos e o comportamento ingestivo da prole de ratas induzidas ao hipotireoidismo associado à dieta hiperlipídica durante a gestação. A partir do 3º dia de gestação (DG) as ratas prenhas receberam dieta hiperlipídica e, a partir do 9º DG, iniciou-se, também, a indução do hipotireoidismo gestacional experimental (HGE) adicionando metimazol 0,02% na água de beber. Tanto a dieta quanto a indução ao hipotireoidismo foram interrompidos no dia do parto. Nas ratas prenhas foi realizado o acompanhamento da massa corporal e da ingestão alimentar do 3º DG ao 20º DG. Na prole foram avaliados a massa corporal e o comprimento da cauda, semanalmente, do 1º dia pós-natal (DPN) aos 120º DPN e, aos 60 PDN, realizaram-se o teste de tolerância à insulina (TTI), o teste de tolerância à glicose (TTG), dosagens bioquímicas e o peso relativo dos órgãos, em ambos os sexos. Além disso, foram investigados o comportamento ingestivo de ração, água e NaCl 0,3 M somente nos machos da prole aos 30, 60, 90 e 120 DPN. Os dados foram submetidos à ANOVA de duas ou três vias, e em seguida ao pós-teste de Bonferroni. Os machos da prole de ratas submetidas à associação do hipotireoidismo com a dieta hiperlipídica (PRH + DH) maior hematócrito e maiores concentrações de triglicérides, colesterol e ureia quando comparados aos machos da prole de ratas hipotireoideanas com dieta controle (PRH + DC). As fêmeas da PRH + DH apresentaram maior sensibilidade à glicose, aos 30 minutos, no teste de tolerância à glicose, quando comparadas as fêmeas da PRH + DC (p<0,05) e as fêmeas da prole de ratas eutireoideanas com dieta hiperlipídica (PRE + DH) (p<0,01), entretanto não foram encontradas diferenças, nas fêmeas dos grupos estudados, na glicemia de jejum e no teste de tolerância à insulina. O HGE associado à dieta hiperlipídica, exclusivamente durante a gestação, está associado a déficit no desenvolvimento corporal e dislipidemia na vida pós-natal dos machos dessa prole, enquanto as fêmeas apresentam maior sensibilidade à glicose. Assim, esses dados mostram, pela primeira vez, que a associação do HGE com a dieta hiperlipídica promove alteração no perfil metabólico da prole e demonstra que alterações no ambiente intrauterino pode ser a causa de diversas doenças metabólicas que, atualmente, não apresentam uma causa definida.

Congenital Hypothyroidism (CH) is the most common endocrine disorder, affecting one out of 2000-4000 newborns. Most CH are due to a defect in thyroid embryonic development and they can lead to severe phenotypes if not treated correctly. Multiple observations argue in favor of a genetic cause in a minority of thyroid dysgenesis, but to date, only few cases could be explained by a mutation in one of the genes coding for the factors known to be important in thyroid development and/or function (NKX2-1, PAX8, FOXE1, TSHR). This is the reason why it was important to develop new models allowing the discovery of new genes/mechanisms potentially implicated in the gland organogenesis. To that purpose, we set up in the laboratory a structure enabling the use of zebrafish as an animal model. The latter is indeed more and more used by developmental biologists, including by scientists interested in thyroid development.<p><p>The first step of our project consisted in a deeper characterization of the model, notably by the study of the expression patterns of the thyroid functional differentiation markers. Furthermore, the exact role of the Tsh/Tshr signaling – main regulator of thyroid growth and function in mammals – was dissected. In a second part of the project, we generated a stable transgenic line (tg(tg:mCherry)) allowing the visualization of thyroid development in living embryos and in a dynamic manner, thanks to real-time imaging techniques. On the one hand, this tool enabled us to better understand the morphological aspect of the different stages of thyroid development, such as the budding, evagination, relocalization or folliculogenesis. On the other hand, the use of double transgenic fishes obtained by crossing tg(tg:mCherry) with other lines expressing GFP in surrounding structures of interest, allowed us to highlight the contacts between the cardiovascular system and thyroid, and this along the whole gland development. The introduction of this model within the laboratory paves the way for the discovery and the study of thyroid intrinsic and extrinsic genes/mechanisms which might play a role on its development.<p><p>L’hypothyroïdie congénitale (HC) est une maladie relativement fréquente, touchant un nouveau-né sur 2000-4000. La majorité des HC sont dues à un défaut dans le développement embryonnaire de la glande, et peuvent mener à des phénotypes sévères si elles ne sont pas correctement traitées. Il existe plusieurs arguments en faveur d’une cause génétique dans une minorité de ces dysgénésies thyroïdiennes mais, à ce jour, seuls quelques cas ont pu être reliés à une mutation dans un des gènes codant pour des facteurs connus pour être importants dans le développement/la fonction de la glande (NKX2-1, PAX8, FOXE1, TSHR). C’est pour cette raison qu’il est important de développer de nouveaux modèles pouvant permettre la découverte de nouveaux gènes/mécanismes potentiellement impliqués dans l’organogénèse de la glande. A cette fin, nous avons mis en place au sein du laboratoire une structure permettant l’utilisation du poisson-zèbre comme modèle animal. Ce dernier est en effet de plus en plus utilisé par les biologistes du développement, y compris par les scientifiques qui s’intéressent au développement thyroïdien.<p><p>La première étape de notre travail a consisté en une caractérisation approfondie du modèle, notamment par l’étude du réseau d’expression des marqueurs de différenciation fonctionnelle de la glande. En outre, le rôle exact de la signalisation par la TSH – principal régulateur de la croissance et de la fonction de la thyroïde des mammifères – a été étudié. Dans la deuxième partie du projet, nous avons généré une ligne transgénique stable (tg(tg:mCherry)) permettant la visualisation du développement thyroïdien dans des embryons vivants et ce, de manière dynamique, grâce au principe d’imagerie en temps réel. D’une part, cet outil nous a permis de mieux comprendre l’aspect morphologique des différentes étapes du développement thyroïdien, telles que la formation du bourgeon, l’invagination, la relocalisation ou la folliculogénèse. D’autre part, l’utilisation de poissons doublement transgéniques obtenus par le croisement de tg(tg:mCherry) avec d’autres lignées où les structures environnantes d’intérêt expriment la GFP nous a permis de mettre en avant les contacts entre le système cardiovasculaire et la thyroïde, et ce, tout au long de son développement. La mise en place de ce modèle au sein de notre laboratoire ouvre la voie à la découverte et à l’étude de mécanismes/gènes extrinsèques à la thyroïde mais pouvant jouer un rôle sur son développement. / Doctorat en Sciences agronomiques et ingénierie biologique / info:eu-repo/semantics/nonPublished

Thyroid hormone is a master regulator of growth and development in all vertebrates. Thus, disruption of its synthesis and activity can lead to profound consequences. Past decade studies on thyroid function tests have established an efficient guideline for monitoring thyroid diseases, yet a significant proportion of healthcare providers do not defer to it in their practice. The aim of this study is to assess provider practices in the diagnosis and treatment of primary hypothyroidism due to autoimmunity at Boston Children's Hospital (CHB) for a primarily pediatric patient population. Commonly known as Hashimoto's thyroiditis (HT), this is the most common thyroid disease in the world as well as the most common manifestation of human autoimmune endocrine disease. Through CHB's bioinformatics institute, a rich data set was collected to assess the manner in which healthcare providers utilized relevant thyroid function tests (TFTs). This work assessed and confirmed the superior sensitivity of thyroid peroxidase autoantibodies (TPO) relative to thyroglobulin antibodies (TgAb) for diagnosing HT in children. We also verified proper utilization of thyroid stimulating hormone tests to monitor HT but concluded that there is a low utilization efficiency with regards to measurements of thyroid hormones (thyroxine and triiodothyronine). Based upon the observation of unnecessary monetary loss caused by improper TFTs utilization, it can be concluded that reflex testing at CHB may improve provider practices' efficiency for HT monitoring.

This thesis presents genetic studies aiming at enlarging our knowledge regarding the genetic factors underlying two immune-mediated diseases, hypothyroidism and autoimmune Addison’s disease (AAD), in dogs and humans, respectively. Genetic and environmental factors are indicated to contribute to canine hypothyroidism, which can be considered a model for human Hashimoto’s thyroiditis (HT). In Paper I we performed the first genome-wide association (GWA) study of this disease in three high-risk dog breeds (Gordon Setter, Hovawart and Rhodesian Ridgeback). Using an integrated GWA and meta-analysis strategy, we identified a novel hypothyroidism risk haplotype located on chromosome 12 being shared by the three breeds. The identified haplotype, harboring three genes previously not associated with hypothyroidism, is independent of the dog leukocyte antigen region and significantly enriched across the affected dogs. In Paper II we performed a GWA study in another high-risk breed (Giant Schnauzer) and detected an associated locus located on chromosome 11 and conferring protection to hypothyroidism. After whole genome resequencing of a subset of samples with key haplotypes, we fine mapped the region of association that was subsequently screened for the presence of structural variants. We detected a putative copy number variant overlapping with the upstream region of the IFNA7 gene, which is located in a region of high genomic complexity. Remarkably, perturbed activities of type I Interferons have been extensively associated with HT and general autoimmunity. In Paper III we performed the first large-scale genetic study of human AAD, a rare autoimmune disorder characterized by dysfunction and ultimately destruction of the adrenal cortex. We resequenced 1853 immune-related genes comprising of their coding sequences, untranslated regions, as well as conserved intronic and intergenic regions in extensively characterized AAD patients and control samples, all collected in Sweden. We identified BACH2 gene as a novel risk locus associated with AAD, and we showed its independent association with isolated AAD. In addition, we confirmed the previously established AAD association with the human leukocyte antigen complex. The results of these studies will hopefully help increasing the understanding of such diseases in dogs and humans, eventually promoting their well-being.

A principal função da glândula tireoide é a produção dos hormônios T3 e T4, que promovem a regulação do consumo energético no organismo. O hipotireoidismo congênito (HC) é um distúrbio metabólico sistêmico, onde a produção de T3 e T4 no período neonatal é insuficiente. O HC por disormonogênese é uma doença causada por erros inatos na síntese de T3 e T4, com herança autossômica recessiva. Já foram descritas mutações nos genes NIS, SLC26A4, DUOX2, DUOXA2, TPO, TG e DEHAL-1. O defeito na organificação do iodeto (DOI) é o mais comum na disormonogênese, sendo a falha mais frequente na TPO, seguida pelas proteínas DUOX2 e DUOXA2. A TPO é responsável pela oxidação do iodeto, pela iodação da tireoglobulina e pelo acoplamento das tirosinas iodinizadas. Já foram descritas 70 mutações ao longo de todo o gene TPO. Por ser uma heme peroxidase, a TPO requer H2O2 para sua função. O principal núcleo catalítico gerador de H2O2 na tireoide é o complexo DUOX2/DUOXA2. Foram descritas 25 mutações no gene DUOX2 e uma única mutação no gene DUOXA2. Em estudo anterior, avaliamos pacientes com HC após os 3 anos de idade para estabelecimento do diagnóstico etiológico, através de dosagem de TG sérica, ultrassonografia, captação e mapeamento da tireoide com 131I. Sete pacientes apresentaram DOI. Nestes pacientes avaliamos o gene TPO e identificamos diversos SNPs já descritos na literatura. Um paciente apresentou a mutação p.Q660E em heterozigose, outro paciente o SNP p.R584Q em homozigose, e um terceiro paciente as alterações p.Q660E e p.584Q em heterozigose composta. Os objetivos deste estudo foram pesquisar mutações dos genes DUOX2 e DUOXA2 nos pacientes com DOI e realizar o estudo funcional da alteração p.R584Q na TPO. Para o estudo molecular, extraímos o DNA de leucócitos periféricos dos pacientes e seus familiares, seguido de amplificação por PCR, e sequenciamento automático, e os resultados comparados com as sequencias normais de cada gene (GenBank). Na análise funcional da alteração p.R584Q na TPO, células HeLa foram transfectadas com plasmídios pcDNA contendo o gene da TPO normal e alterado, e a atividade das proteínas produzidas pelas células foi avaliada pelo sistema AmplexRed. Análises in silico foram realizadas com os programas de bioanálise PolyPhen, MutationTaster, SIFT e PSIPRED. Ao final do estudo molecular, no gene DUOX2, identificamos 20 SNPs previamente descritos, incluindo o SNP funcional p.H678R (rs57659670), presente em heterozigose em 3 pacientes. Também identificamos a nova substituição p.A1087V em heterozigose em um paciente. De acordo com dados dos programas de bioanálise, a alteração p.A1087V é prejudicial e o SNP p.H678R é tolerável. No gene DUOXA2 identificamos 5 polimorfismos previamente descritos e nenhuma mutação. No estudo funcional, verificamos uma diminuição significativa da atividade da TPO portadora da alteração p.R584Q em comparação à proteína normal (5% de atividade residual; p=0,0193). De acordo com os dados dos programas de bioanálise, a alteração p.R584Q é prejudicial. Três pacientes não apresentaram alterações nas regiões estudadas dos genes TPO, DUOX2 e DUOXA2. As revisões dos dados clínicos e laboratoriais sugerem a presença de outras proteínas alteradas, como TG, Pendrina ou receptor do TSH. Um paciente apresentou a nova alteração p.A1087V na DUOX2 em heterozigose e nenhuma outra alteração nas regiões estudadas dos genes avaliados. Cogitamos a presença de alterações em regiões não avaliadas ou ainda a expressão monoalélica de DUOX2. O SNP funcional p.H678R na DUOX2 foi identificado em três pacientes com alterações na TPO: um com a alteração p.R584Q em homozigose, outro com a p.R584Q e a mutação p.Q660E em heterozigose composta. Estes dois pacientes apresentam os dois alelos da TPO alterados, justificando o DOI. O terceiro caso apresentou apenas a mutação p.Q660E em heterozigose, podendo apresentar alterações em regiões não avaliadas ou ainda a expressão monoalélica da TPO. Concluímos que definimos o diagnóstico molecular de 4 dos nossos pacientes, que apresentaram importantes alterações nos genes avaliados, e ressaltamos que a alteração p.R584Q na TPO provoca perda da atividade, causando DOI / The main role of the thyroid gland is to produce T3 and T4, which promote the regulation of body energy intake. Congenital hypothyroidism (CH) is a systemic metabolic disorder where T3 and T4 production during neonatal period is insufficient. CH due to dyshormonogenesis is a disease caused by inborn errors in T3 and T4 synthesis, with autosomal recessive inheritance. Mutations in NIS, SLC26A4, DUOX2, DUOXA2, TPO, TG and DEHAL-1 genes have been described. The iodide organification defect (IOD) is the most common cause of dyshormonogenesis, being the TPO defect the most frequent, followed by defects in DUOX2 and DUOXA2 proteins. TPO is responsible for iodide oxidation, tyrosine iodination and its coupling. Seventy mutations have been described throughout the gene. As a heme peroxidase, TPO requires H2O2 to its regular function. The main catalytic core for H2O2 generation in thyroid is the DUOX2/DUOXA2 complex. Twenty five mutations have been described in DUOX2 gene and only one mutation in DUOXA2 gene. In our previous study, we evaluated patients with CH after 3 years of age to establish their etiologic diagnosis, by combining serum TG, thyroid ultrasound, and radioiodide uptake with 131I. Seven patients were diagnosed with IOD. In these patients, we evaluated TPO gene and identified several already described SNPs. One patient had the p.Q660E mutation in heterozygous state, another patient had the SNP p.R584Q in homozygous state and a third one had p.Q660E and p.584Q in compound heterozygous state. The aims of this study were to search for mutations in DUOX2 and DUOXA2 genes in patients with IOD and perform a functional study of TPO p.R584Q change. For the molecular study, DNA was extracted from peripheral blood leukocytes of each patient and parents, followed by PCR, and automatic sequence, and the results were compared with normal sequences of each gene (GenBank). For functional analysis of TPO p.R584Q, HeLa cells were transfected with pcDNA plasmids containing normal and altered TPO gene and the protein activity was assessed by AmplexRed system. In silico analyzes were performed with the bioanalysis programs: PolyPhen, MutationTaster, SIFT and PSIPRED. At the end of the molecular study, in DUOX2 gene we identified 20 previously described SNPs, including the functional p.H678R SNP (rs57659670), present in heterozygous state in 3 patients. We also identified the new p.A1087V change in heterozygous state in one patient. According to bioassay programs datas, p.A1087V change is damage and p.H678R SNP is tolerable. In DUOXA2 gene we identified five previously described polymorphisms and no mutation. In TPO functional study, we observed a significant activity decrease of TPO p.R584Q compared to normal TPO (5% of activity; p=0.0193). According to bioassay programs datas, p.R584Q is damaging. Three patients showed no changes in TPO, DUOX2 and DUOXA2 genes studied regions. A review of clinical and laboratory data suggested the presence of other altered proteins, such as TG, Pendrin or TSH receptor. One patient had the new DUOX2 p.A1087V alteration in heterozygous state and no other changes in the studied regions of evaluated genes, suggesting that there could be changes in other nonevaluated regions or the monoallelic expression of DUOX2. The functional DUOX2 p.H678R SNP was identified in three patients with changes in TPO: one with p.R584Q change in homozygous state and another one with p.R584Q and p.Q660E in compound heterozygous state. These cases have the two alleles of TPO changed, justifying their IOD. A third case showed only the TPO p.Q660E mutation in heterozygous state. We speculate that the patient may present changes in regions nonevaluated or the monoallelic expression of TPO. We conclude that we defined the molecular diagnosis of four patients, that showed significant changes in evaluated genes, and that TPO p.R584Q change is functionally harmful, causing IOD