Results of the screening of disease causative mutations in congenital hypothyroidism (CH) vary significantly, depending on the sequence strategy, patients’ inclusion criteria and bioinformatics. The objective was to study the molecular basis of severe congenital hypothyroidism, using the next generation sequencing (NGS) and the recent guidelines for assessment of sequence variants. 243 patients with CH (TSH levels at neonatal screening or retesting greater than 90 mU/l) and 56 control subjects were included in the study. A custom NGS panel targeting 12 CH causative genes was used for sequencing. The sequence variants were rated according to American College of Medical Genetics and Genomics (ACMG) guidelines. In total, 48 pathogenic, 7 likely pathogenic and 57 variants of uncertain significance were identified in 92/243 patients (37.9%), while 4 variants of uncertain significance were found in 4/56 control subjects (7.1%). 13.1% (12/92) of the cases showed variants in ‘thyroid dysgenesis’ (TD) genes: TSHR, n = 6; NKX2-1, n = 2; NKX2-5, n = 1; PAX8, n = 3. The variants in ‘dyshormonogenesis’ (DH) genes were found in 84.8% (78/92) of cases: TPO, n = 30; DUOX2, n = 24; TG, n = 8; SLC5A5, n = 3; SLC26A4, n = 6; IYD, n = 1. 8 patients showed oligonenic variants. The majority of variants identified in DH genes were monoallelic. In contrast to earlier studies demonstrating the predominance of TD in severe CH, the majority of variants identified in our study were in DH genes. A large proportion of monoallelic variants detected among DH genes suggests that non-mendelian mechanisms may play a role in the development of CH.

Congenital hypothyroidism is an important issue of pediatric endocrinology at which timely diagnosis and treatment can prevent the development of severe cases of the disease. The developed clinical guidelines are a working tool for a practicing physician. The target audience is pediatric endocrinologists and pediatricians. They briefly and logically set out the main definition of the disease, epidemiology, classification, methods of diagnosis and treatment, based on the principles of ­evidence-based medicine.

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.

Gonadotropin-dependent precocious puberty (central) is a condition resulting from the early (up to 8 years in girls and 9 years in boys) reactivation of the hypothalamic-pituitary-gonadal axis. An increase in the secretion of sex steroids by the gonads in this form is a consequence of the stimulation of the sex glands by gonadotropic hormones of the pituitary gland. In the absence of central nervous system abnormalities, CPP is classified as idiopathic and as familial in some cases, emphasizing the genetic origin of this disorder. Loss-of-function mutations in Makorin Ring Finger Protein 3 (MKRN3) are the most common identified genetic cause of central precocious puberty compared to sporadic cases. In the present study we performed the first descrition of 3 family cases of central precocious puberty duo to novel MKRN3 gene mutation detected by NGS in the Russian Federation.