Background. Gestational diabetes (GDM) due to GCK gene mutations is the most frequent form of monogenic diabetes mellitus (DM) presenting during pregnancy. It has been suggested that the use of insulin in pregnancies with fetuses carrying GCK mutations may lead to intrauterine growth retardation. In the present study we evaluated the effect of insulin therapy during pregnancy on birth weight and length in the offsprings of mothers with GDM due to GCK mutations. Aims. The aim was to study birth weight and length in offsprings of mothers with gestational diabetes mellitus due to mutations in GCK, depending on the therapy during pregnancy. Materials and methods. The study included 38 patients with GDM caused by GCK gene mutations (18.7%) and the 45 offsprings. To define molecular basis of GDM in pregnant women we used a targeted NGS. Diabetes panel genes were sequenced using a custom Ion Ampliseq gene panel and PGM semiconductor sequencer (Ion Torrent). To found the same mutations in their offsprings was used Sanger sequencing. All children were divided into 3 groups depending of their genotype and therapy received by the mothers during pregnancy. Results. We found statistically significant differences in birth length (p=0.04) and weight (p=0,031) depending on the genotype of the child and therapy in the mother. The risk of macrosomia was shown in non-mutation-carrying offsprings only. The birth weight in children with GCK gene mutations whose mothers received insulin during pregnancy was significantly lower. However, the birth weight remained in the normal range. Conclusions. Since prenatal diagnostics in the mothers with GCK gene mutations is not always justified, we recommend insulin therapy in order to prevent fetal macrosomia, which, however, should be less aggressive than in GDM due to other causes.
Врожденный гипотиреоз -гетерогенная группа заболеваний, объединенных общим признаком -снижением функции щитовидной железы (ЩЖ) к моменту рождения. 80-85% случаев заболевания обусловлены различными вариантами нарушения органогенеза ЩЖ. На сегодняшний день в литературе описано 5 генов: TSHR, PAX8, FOXE1, NKX2-1, NKX2-5, задействованных в патогенезе дисгенезии щитовидной железы. Цель. Оценить частоту мутаций в генах TSHR, PAX8, FOXE1, NKX2-1, NKX2-5 среди пациентов с тяжелым врожденным гипотиреозом. Методы. В исследование включен 161 пациент с врожденным гипотиреозом (64 мальчика, 97 девочек) с уровнем тирео-тропного гормона по данным скрининга или ретестирования более 90 мМЕ/л. При ультразвуковом исследовании ЩЖ у 138 обследуемых диагностированы различные варианты дисгенезии, у 23 пациентов объем железы соответствовал нор-мальным значениям относительно площади поверхности тела. Для молекулярно-генетического анализа применялся метод высокопроизводительного параллельного секвенирования. Секвенирование осуществлялось на полупроводнико-вом секвенаторе PGM (Ion Torrent, Life Technologies, США) с использованием панели праймеров "Гипотиреоз" (Custom DNA Panel). Оценка патогенности мутаций осуществлялась согласно последним международным рекомендациям (ACMG, 2015). Результаты. Мутации в генах, приводящие к дисгенезии щитовидной железы, были выявлены у 13 пациентов (8,1%, 13/161): TSHR, n = 6; NKX2-1, n = 3; NKX2-5, n = 1; PAX8, n = 3; FOXE1, n = 0. Заключение. Мутации в генах, обусловливающие развитие дисгенезии щитовидной железы, являются редкой патологией. Среди наших пациентов наибольшее количество мутаций выявлено в гене TSHR. Клю че вые сло ва: дисгенезия, высокопроизводительное параллельное секвенирование, врожденный гипотиреоз.Congenital hypothyroidism is a heterogeneous group of diseases, which is manifested by loss of function of the thyroid gland that affects infants from birth. 80-85% of cases are due to different types of thyroid dysgenesis. 5 genes have been described that are involved in the pathogenesis of thyroid dysgenesis: TSHR, PAX8, FOXE1, NKX2-1, NKX2-5. Aims. To evaluate the prevalence of mutations in the genes TSHR, PAX8, FOXE1, NKX2-1, NKX2-5 among patients with severe congenital hypothyroidism. Materials and methods. 161 patients (64 boys, 97 girls) with congenital hypothyroidism (TSH levels at neonatal screening or retesting greater than 90 mU/l) were included in the study. 138 subjects had different variants of thyroid dysgenesis, and 23 patients had normal volume of the gland. A next generation sequencing was used for moleculargenetic analysis. Sequencing was performed using PGM semiconductor sequencer (Ion Torrent, Life Technologies, USA) and a panel "Hypothyroidism" (Custom DNA Panel). Assessment of the pathogenicity of sequence variants were carried out according to the latest international guidelines (ACMG, 2015). Results. 13 patients had variants in thyroid dysgenesis genes (8,1%, 13/161): TSHR, n = 6; NKX2-1, n = 3; NKX2-5, n = 1; PAX8, n = 3; FOXE1, n = 0. Conclusions. Mutations in thyroi...
MODY1 and MODY3 represent rare causes of diabetes in pregnancy. Establishing a molecular diagnosis of MODY1 or MODY3 during pregnancy may be important for minimizing risk of perinatal complications and for improving glycemic control after pregnancy. The objective of the study was to evaluate the contribution of mutations in HNF4A and HNF1A genes in development of diabetes in pregnancy and to describe clinical characteristics of diabetes in pregnancy associated with these mutations. 230 pregnant women (20-43 years) with different type of glucose intolerance complicated during their current pregnancy were included in the study. A custom NGS panel targeting 28 diabetes causative genes was used for sequencing. Heterozygous mutations in HNF4A and HNF1A genes were detected in 3% of cases. Mutations p.I271T in HNF4A gene and p.L148F, p.Y265C, p.G288W in HNF1A gene were novel. This study includes a description of patients with pregnancy diabetes due to mutations in hepatocyte nuclear factors.
NKX2-1 is a transcription factor. Gene NKX2-1 is expressed in tissues of the thyroid gland, brain and lungs. Mutations of NKX2-1 can lead to neurological disorders, hypothyroidism, and respiratory distress syndrome. The combinations of these symptoms are known as brain-lung-thyroid syndrome. Benign hereditary chorea is the characteristic feature of this disease and the most common manifestation of it. Chorea progresses into the second decade after which it remains stable or may even spontaneously remit. Pulmonary dysfunction is the second most common manifestation of NKX2-1-related disorders. They include respiratory distress syndrome of the newborns, interstitial lung disease between ages four months and seven years and pulmonary fibrosis in older individuals. Thyroid dysfunction can present as congenital hypothyroidism or subclinical hypothyroidism in adolescents. The combination of triad of the syndrome is present in only 50% of patients. This study includes a description of patient with brain-lung-thyroid syndrome. We described the novel mutation c.628_772del in the gene NKX2-1.
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