Circular RNAs and thyroid cancer: Closed molecules, open possibilities.

Thyroid neoplasms requiring differential diagnosis between thyroid cancer and benign tumors can be detected in more than half of the healthy population. A generally accepted method that allows assessing the risk of malignant potential and determining the indications for surgical treatment of thyroid tumor is a fine-needle aspiration biopsy followed by a cytological examination. Nevertheless, in patients with indeterminate categories of cytological conclusions according to Bethesda system, the positive predictive value of the cytology result is significantly lower than desired and often leads to unjustified surgical treatment. In this regard, the search for alternative diagnostic solutions continues. Circular RNAs are a group of non-coding RNAs distinguished by a closed structure formed by covalent bonding of the nucleotide chain ends. Recent studies allow us to conclude that many different circular RNAs are involved in processes mediating oncogenesis in the thyroid gland, and their altered expression in tissue, blood, and exosomes of plasma may be a characteristic sign of thyroid cancer and certain clinicopathological features of its course. The purpose of this review is to analyze the accumulated data on the association of various circular RNAs with thyroid cancer and to discuss possible ways to improve the diagnosis and treatment of the disease based on the assessment of the expression of these molecules.

Successful Use of Denosumab for Life-Threatening Hypercalcemia in a Pediatric Patient with Primary Hyperparathyroidism.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is rare and usually symptomatic in children. There is no approved medication to lower serum calcium levels in this patient group. Denosumab is used in adult patients with osteoporosis and hyperparathyroidism. To our knowledge, only 1 case of denosumab treatment in a child with severe PHPT has been reported to date. CASE PRESENTATION: A 16-year-old female was referred to our clinic with symptoms including pathologic fractures, nausea, emesis, and progressive weight loss. At admission, her serum total calcium was 4.17 mmol/L (reference range 2.15-2.55), parathyroid hormone 2,151 pg/mL (15-65), and phosphate 1.07 mmol/L (1.45-1.78). Due to potentially life-threatening hypercalcemia, denosumab 60 mg subcutaneously was administered after obtaining informed consent. Serum calcium levels were reduced within 12 h of injection and the patient's condition rapidly improved, which allowed genetic testing to be done prior to surgery. A heterozygous mutation in the CDC73 gene was revealed, and a parathyroidectomy was performed on day 22 after denosumab administration. Morphological examination revealed solitary parathyroid adenoma. After surgery, hypocalcemia developed requiring high doses of alfacalcidol and calcium supplements. CONCLUSION: Our case supports the previous observations in adults that denosumab can be safely and effectively used as a preoperative treatment in patients with PHPT and severe hypercalcemia and shows that it may be used in pediatric patients.

High frequency of mutations in 'dyshormonogenesis genes' in severe congenital hypothyroidism.

OBJECTIVE: 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. DESIGN: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A Novel Mutation in the Critical P-Box Residue of Steroidogenic Factor-1 Presenting with XY Sex Reversal and Transient Adrenal Failure.

BACKGROUND: Although the importance of steroidogenic factor-1 (SF1, NR5A1) for adrenal development is supported by numerous in vitro and in vivo studies, cases of SF1 deficiency associated with adrenal failure are exceptionally rare. The first human NR5A1 mutation was a heterozygous de novo p.G35E variant identified in a patient with disorder of sex development (DSD) 46,XY and primary adrenal insufficiency. Here we describe another association of the "classic" SF1 phenotype with a novel NR5A1 mutation affecting G35 residue. METHODS: We describe the clinical characteristics of a phenotypically female patient presenting at 2 months with signs of adrenal insufficiency. DSD 46,XY was diagnosed at 4 years. The NR5A1 gene was analyzed by Sanger sequencing. Minigene splicing and dual luciferase reporter assays were used to characterize effects of the novel mutation on splicing and transcription, respectively. RESULTS: Sequencing of the NR5A1 gene revealed a de novo heterozygous c.104G>A:p.G35D substitution. The minigene experiments demonstrated that c.104G>A substitution did not affect splicing. However, transactivation activity of the p.G35D mutant was clearly impaired, which was comparable with the effect of the p.G35E mutation. CONCLUSIONS: The findings stress the importance of G35 residue for adrenal development. The current observation also suggests that some patients with SF1 deficiency may present with transient adrenal failure.

Torque Teno Virus (TTV) distribution in healthy Russian population.

BACKGROUND: Torque teno virus (TTV) is a circular, single-stranded DNA virus that chronically infects healthy individuals of all ages worldwide. There is a lot of data on the prevalence and genetic heterogeneity of TTV in healthy populations and in patients with various diseases now available. However, little is known about TTV load among healthy human population. In this study we analyzed TTV load in the group of 512 Russian elite athletes, who are supposed to be, by some standards, the healthiest part of the human population. RESULTS: The prevalence rate of TTV among the Russian Olympic Reserve members was 94% (for test sensitivity about 1000 genome equivalents per 1 ml of blood). Quantities varied from 103 (which corresponded to detection limit) to 1010 copies per 1 ml of blood, with median at 2.7 x 106 copies. CONCLUSION: About 94% of healthy individuals in Russian population have more than 1000 TTV genome copies per 1 ml of blood. This result exceeds the previously published data, and can be explained by either more sensitive PCR test system or by higher TTV distribution in Russian population or both. TTV viral load neither depends on gender, nor age.