Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis.

Purpose Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the preventable causes of both cognitive and motor deficits. We present a genetic and bioinformatics investigation of rational clinical design in 16 Argentine patients suspected of CH due to thyroid dyshormonogenesis (TDH). Methods Next-Generation Sequencing approach was used to identify variants in Thyroid Peroxidase (TPO) and Dual Oxidase 2 (DUOX2) genes. A custom panel targeting 7 genes associated with TDH [(TPO, Iodothyrosine Deiodinase I (IYD), Solute Carrier Family 26 Member 4 (SLC26A4), Thyroglobulin (TG), (DUOX2), Dual Oxidase Maturation Factor 2 (DUOXA2), Solute Carrier Family 5 Member 5 (SLC5A5)] and 4 associated with thyroid dysembryogenesis [PAX8, FOXE1, NKX2-1, Thyroid Stimulating Hormone Receptor (TSHR)] has been designed. Additionally, bioinformatic analysis and structural modeling were carried out to predict the disease-causing potential variants. Results Five novel variants have been identified, two in TPO: c.2749-2A>C and c.2752_2753delAG, [p.Ser918Cysfs*62] and three variants in DUOX2 gene: c.425C>G [p.Pro142Arg]; c.790delC [p.Leu264Cysfs*57] and c.2695delC [p.Gln899Serfs*21]. Seventeen identified TPO, DUOX2 and IYD variants were previously described. We identified potentially pahogenic bi-allelic variants in TPO and DUOX2 in 8 and 2 patients, respectively. We also detected a potentially pathogenic mono-allelic variant in TPO and DUOX2 in 4 and 1 patients respectively. Only two patients were heterozygous for digenic variants in TPO/IYD and in TPO/DUOX2 genes. Conclusions 22 variants have been identified associated with TDH. All described novel mutations occur in domains important for protein structure and function, predicting the TDH phenotype.

The Positivity of Anti-TPO and Anti-tTGA in Children with Type 1 Diabetes Mellitus in Albania

Background: Type 1 diabetes mellitus (T1 DM) is the most common type of diabetes in children. T1DM patients are also at higher risk of other comorbid autoimmune diseases, including autoimmune thyroid disease (AITD), celiac disease (CD). The thyroid-specific immune damage of AITD is strongly associated with elevated serum thyroid peroxidase (TPO). Tissue transglutaminase antibody (tTGA) is a specific antibody and a serological marker of CD. This study aimed to evaluate the positivity of anti - TPO and anti - tTGA in children with T1DM after they were diagnosed. Materials and Methods: This study was conducted from January 2019 to October 2020, included 105 children with T1DM. 44 children matching in aged (1 - 14 years) and gender were taken as control with other diagnoses (16 with viral infection, 24 with short stature, 4 with genetic disorders). The antibodies were checked up for the first time after they were diagnosed. Anti - TPO and anti - tTGA were carried out by ELISA. Results: 55.2% of T1DM children were girls. The anti-TPO was positive in 30.5% of T1DM children compared to 4.5% of children in control group. The anti-tTGA was positive in 7.6% of T1DM children compared to 2.3% of children in control group. Risk of Hashimoto's hypothyroidism was more in children older than 10 years old. 21.9% of children 11 - 14 years old were anti - TPO positive, but it was 16.2%, more common in girls. While, anti - tTGA was positive in 3.85% of children 1 - 5 years old with no difference between boys and girls. Conclusion The most frequent autoimmune disease resulted Hashimoto's hypothyroidism. Girls with T1DM have a higher predisposition to Hashimoto's Hypothyroidism in the 11-14 age group compared to boys. Children with T1DM were found to have a lower predisposition to CD. Children with T1DM have a higher predisposition to develop CD at the age of 1 - 5 years. In conclusion we can say that antibodies to other autoimmune diseases must be performed together with diagnostic examinations for T1DM. Key words: Type 1 diabetes mellitus, Autoimmune Thyroid Disease, Celiac Disease, Thyroid Peroxidase, Tissue Transglutaminase Antibody.

Does foetal gender influence maternal thyroid parameters in pregnancy?

Objective It is unknown if foetal gender influences maternal thyroid function during pregnancy. We therefore investigated the prevalence of thyroid disorders and determined first-trimester TSH reference ranges according to gender. Methods A cross-sectional study involving 1663 women with an ongoing pregnancy was conducted. Twin and assisted pregnancies and l-thyroxine or antithyroid treatment before pregnancy were exclusion criteria. Serum TSH, free T4 (FT4) and thyroid peroxidase antibodies (TPOAb) were measured at median (interquartile range; IQR) 13 (11–17) weeks of gestation. Subclinical hypothyroidism (SCH) was present when serum TSH levels were >3.74 mIU/L with normal FT4 levels (10.29–18.02 pmol/L), and thyroid autoimmunity (TAI) was present when TPOAb were ≥60 kIU/L. Results Eight hundred and forty-seven women were pregnant with a female foetus (FF) and 816 with a male foetus (MF). In women without TAI and during the gestational age period between 9 and 13 weeks (with presumed high-serum hCG levels), median (IQR range) serum TSH in the FF group was lower than that in the MF group: 1.13 (0.72–1.74) vs 1.24 (0.71–1.98) mIU/L; P = 0.021. First-trimester gender-specific TSH reference range was 0.03–3.53 mIU/L in the FF group and 0.03–3.89 mIU/L in the MF group. The prevalence of SCH and TAI was comparable between the FF and MF group: 4.4% vs 5.4%; P = 0.345 and 4.9% vs 7.5%; P = 0.079, respectively. Conclusions Women pregnant with an MF have slightly but significantly higher TSH levels and a higher upper limit of the first-trimester TSH reference range, compared with pregnancies with a FF. We hypothesise that this difference may be related to higher hCG levels in women pregnant with a FF, although we were unable to measure hCG in this study. Further studies are required to investigate if this difference has any clinical relevance.

Thyroid autoimmunity among type 2 diabetes mellitus: assessing anti-thyroid peroxidase (anti-TPO) antibodies

Introduction and Aim: Thyroid disorder, the most abundant endocrine disorder in the globe ranks second after diabetes mellitus. Because of immune resistance to thyroid gland, it leads to the development of hyperthyroidism and hypothyroidism. Autoantibodies against thyroid peroxidase (TPO) - a critical enzyme in the thyroid hormone biogenesis is responsible for thyroid autoimmunity and is increasingly found among type 2 diabetes mellitus (T2DM). So, the present study was designed to assess the serum anti-TPO antibodies among type 2 diabetes mellitus in hospital setting. Materials and Methods: 100 clinically diagnosed type 2 diabetes mellitus was included with 50 age and sex matched apparently healthy controls in the age range 35-70 years. Mean age (in Years) of male and female T2DM cases had 57.40±5.93 and 55.96±7.39 respectively. Also, the male and female controls had mean age as 56.24±8.74 and 54.20±8.90 respectively. Results: The mean glycated hemoglobin (HbA1c) value among T2DM male and female cases was found to be 8.53±2.02% and 8.66±1.90% respectively. The mean value of serum TSH was found to be highly significant statistically among T2DM as compared to healthy controls, whereas mean value of serum anti-TPO antibodies was significant statistically among T2DM as compared to healthy controls. The occurrence of anti-TPO antibodies among T2DM was found to be 13 out of 100 (13%) in the present study. Conclusion: The association between serum TSH and anti-TPO antibodies among T2DM patients was found to be highly significant statistically. Thus, the existence of higher anti-TPO antibodies among T2DM points out the future development of functional thyroid problem in such patients.

Autoimmune thyroid disease in diabetic children and adolescents: a single center study from south Punjab

Objective: To evaluate the prevalence of autoimmune thyroid disease (AITD) in diabetic children in south Punjab. Methods: This was an observational cross sectional study from Jan 2019 to Dec 2019 in the outpatient diabetic clinic of the department of pediatric endocrinology at Children Hospital and The Institute of Child Health Multan. A total of 161 consecutive patients of both genders with TIDM were enrolled in this study after taking informed consent. Blood samples for Thyroid functions testes including thyroid stimulating hormone (TSH), free thyroxin (fT4), Thyroid peroxidase antibody (TPO-Ab), thyroglobulin antibody (TG-Ab) and glycosylated hemoglobin (HbA1C) level were sent. Results: Among diabetic children males were 83 (51.6%). Age range was 2-15 years. Mean age and standard deviation was 9.7± 4.3. TPO-Ab was positive in 34 patients (21.1%) and TG-Ab in 27 patients (16.7%), whereas both antibodies were positive in 17 patients (10.5%). Six patients (3.7%) had evidence of subclinical hypothyroidism, 8 patients (4.9%) had overt hypothyroidism and 1 patient (0.62%) had hyperthyroidism Conclusion: The prevalence of AITD among children and adolescents with type 1 diabetes mellitus was 21.1% in our study. Hypothyroidism was more prevalent in these children compared to hyperthyroidism. All diabetic children should be screened for AITD. Thyroid functions should be checked where TPO antibody is positive. Keywords: Autoimmune thyroid disease, anti thyroid peroxidase antibody, anti thyroglobulin Continuous...

Автоімунні захворювання щитоподібної залози та основні маркери їх патогенезу і діагностики

Огляд присвячено оцінці основних гуморальних факторів у патогенезі автоімунних захворювань щитоподібної залози (АЗЩЗ) та можливості їх використання при діагностиці та складанні прогнозу. Показано, що клінічно різні тиреоїдит Хашимото (ТХ), хвороба Грейвса (ХГ) та офтальмопатія Грейвса (ОГ) тісно пов’язані патофізіологічно і мають подібні імуноопосередковані механізми — продукцію автоантитіл до тиреоїдних антигенів і лімфоїдну інфільтрацію тиреоїдної паренхіми. Втрата імунної толерантності до автоантигенів тиреоїдної пероксидази (thyroid peroxidase, TPO), тиреоглобуліну (thyroglobulin, Tg) та рецептору тиреотропного гормону (thyroid-stimulating hormone receptor, TSHR) є основою розвитку АЗЩЗ. Наголошується на ролі прозапальних та протизапальних цитокінів, які продукуються клітинами імунної системи та тиреоцитами. Цитокіни беруть участь в індукторній та ефекторній фазі імунної відповіді та запалення, відіграючи ключову роль у патогенезі АЗЩЗ. Значний вплив на розвиток і прогресування АЗЩЗ має дисбаланс між Th17- лімфоцитами, які підтримують автоімунну відповідь, та регуляторними Т-клітинами (regulatory T cells, Treg), які пригнічують автоімунний процес. Недостатність регуляторних В-клітин (regulatory B cells, Breg) та Тreg, які виробляють протизапальні цитокіни, порушує імунологічну толерантність і викликає аномальну продукцію прозапальних цитокінів, відіграє певну роль у патогенезі АЗЩЗ. Виявлення імунних клітин та антитиреоїдних антитіл у тканині щитоподібної залози (ЩЗ) та визначення рівнів прозапальних та протизапальних цитокінів у сироватці крові можуть дати інформацію про їх участь у патогенезі АЗЩЗ та можуть служити маркерами активності захворювання. Розглянуто діагностичне значення рівня цитокінів, тиреоїдних автоантитіл при ТХ, ХГ і ОГ та їх здатність відображати наявність та активність захворювання.

Pandora’s Box: Autoimmune Hypothyroidism Treatment During Pregnancy

There are international protocols for the management of hypothyroidism induced by autoimmune thyroid disease during pregnancy. In this descriptive study, we analyzed the implementation of international protocols regarding these pathologies, in local clinical practice. Analyzing the cases admitted to the Obstetrics and Gynecology department of Bucharest University Emergency Hospital on a period of 55 months, we identified the pregnancies with autoimmune hypothyroidism treated with Levothyroxine (LT4). We determined the prevalence of specific immunological markers for autoimmune hypothyroidism in pregnant women, we analyzed whether they are associated with distinct clinical phenotypes and ultrasound characteristics, and also, we evaluated the treatment of choice. Measurement of thyroglobulin antibodies, thyroid peroxidase antibodies, Thyroid-Stimulating Hormone, free fractions of Triiodothyronine and Thyroxine with substitute treatment instituted early (in the first 2 weeks postnatal) determine the normalization of cognitive development, especially in areas known for iodine deficiency, including Romania.

Screening and Functional Analysis of TPO Gene Mutations in a Cohort of Chinese Patients With Congenital Hypothyroidism

BackgroundsAs a crucial enzyme in thyroid hormone synthesis, the genetic defective thyroid peroxidase (TPO) was one of the main genetic factors leading to congenital hypothyroidism (CH).MethodsMutations in the TPO gene were screened and identified in 219 patients with CH from northwest China by using high-throughput sequencing and bioinformatics analysis. The biological function of detected variants was studied by in vitro experiments and homology modeling.ResultsNineteen rare variants, including seven novel ones, were detected in 17 of 219 patients (7.8%). Most cases were detected with one single heterozygous variant, and only two patients were detected with multiple variants, i.e., compounds for (1) IVS7-1G>A, p.Ala443Val, and p.Arg769Trp and (2) p.Asn592Ser and p.Asn798Lys. The biological function of the four missense mutations (i.e., p.Ala443Val, p.Arg769Trp, p.Asn592Ser, and p.Asn798Lys) they carried were further studied. Experimental data showed that these four mutations did not affect the protein expression level of the TPO gene but remarkably reduced the peroxidase activity toward guaiacol oxidation, retaining 8–32% of activity of the wild-type protein. The comparison of the predicted 3-D structures of wild-type and mutant TPO proteins showed that these four amino acid substitutions changed the non-covalent interactions of studied residues that might alter the structure and function of the TPO protein.ConclusionThis study was the first to analyze the TPO mutation spectrum of patients with CH in northwest China. Our data indicated that the TPO mutation was not a common reason to cause CH in China. The functional data may help to clarify the structure-function relationship of the TPO protein and provide further evidence for the elucidation of the genetic etiology of CH.