[Thyroid cancer in children and adolescents and its molecular genetic background]. / Nádory stítné zlázy u detí a dospívajících a jejich molekulárne genetická podstata.

Thyroid cancer is the main endocrine malignancy. Its incidence is steadily growing and what is alarming is its increase in children and adolescent population. Pediatric thyroid carcinomas differ from the adult ones in phenotype as well as in genetics. These carcinomas tend to be clinically more aggressive, with more frequent local and distant metastases. However, their long-term prognosis is better in comparison with the adult thyroid cancers. Due to the rarity of the disease, there is lack of data on genetic changes in this age group. Knowledge on the genetic background of thyroid cancer in children will help to precise diagnosis and prognosis of the disease and to personalized treatment.Key words: adolescents - carcinoma - gene - genetics - children - mutation - next generation sequencing - thyroid.

Cystic ovarian teratoma as a novel tumor and growth hormone deficiency as a new condition presenting in Multiple Endocrine Neoplasia type 2B: Case reports and review of the literature.

BACKGROUND: We describe early and typical nonendocrine symptoms of Multiple Endocrine Neoplasia type 2B (MEN2B) presented in our patients with de novo M918T mutation in the RET proto-oncogene in early childhood, however, the diagnosis of MEN2B and medullary thyroid carcinoma (MTC) was confirmed late, in the second decade of life. In this paper, we emphasize the possibility of growth retardation, growth hormone (GH) deficiency and ovarian teratoma as a new symptom of MEN2B. CASE REPORTS: Advanced MTC with palpable mass on the neck and nonendocrine symptoms such as marfanoid habitus, thickened lips, mucosal neuromas led to the diagnosis in case 1 at the age of 13 years and GH deficiency and nonendocrine symptoms in case 2 at the age of 11 years. The earliest feature of MEN2B was alacrima and constipation. Patient 1 was operated on for a slipped femoral capital epiphysis and for a cystic ovarian teratoma. CONCLUSIONS: Improved awareness of nonendocrine signs of MEN2B could lead to earlier diagnosis, when surgical cure of MTC is possible. Alacrima is the first sign of MEN2B. We confirmed the possibility of growth retardation and GH deficiency in MEN2B, which had been previously rarely described. We suggest that patients with MEN2B may develop cystic ovarian teratoma, to the best of our knowledge, which has never been described so far in the literature. The results of this study could be used to guide further diagnosing of MENB2 at the early stage for better clinical outcome. We emphasize that MEN2B carries a risk for development of cystic ovarian teratoma as a novel tumor in this disease.

[The occurrence of microcarcinomas in the patients after thyroidectomy--retrospective analysis]. / Výskyt mikrokarcinomu stítné zlázy u operovaných pacientu--retrospektivní analýza.

BACKGROUND: Microcarcinomas, minimum carcinomas, are tumours, which are in clinical practice defined as tumours < or = 1 cm in size. WHO defines thyroid microcarcinomas as tumours < or = 2 cm in size, which have different biological behaviour. The aim of the study was to analyze the occurrence of MC in post-operative patients. METHODS: Using retrospective analysis we evaluated the occurrence of thyroid microcarcinoma in post-operative patients. Except for basic demographic data, carcinoma size and histological variance, the occurrence of bilateral impairment, presence of multi-focuses and occurrence of regional throat metastases were considerd. RESULTS: From 2004 to 2008 thyroid surgeries were performed in 400 patients. Microcarcinoma was diagnosed in 34 patients (8.5%), 5 men and 29 women. The average age of patients with microcarcinoma was 52 years, similarly to other patients undergoing surgery. Histologically, 32 cases (94%) were papillary carcinoma, from which 4 cases were papillary follicular and 2 were follicular carcinomas. There were multifocal findings of microcarcinomas in 5 patients (15%), and 4 patients (12%) had bilateral involvement. The average size of the tumours was 5 mm, sd 2.6. Two patients (6%) had metastases in the lymph nodes of the neck. Total thyroidectomies were carried out in 32 patients (94%) and hemithyroidectomies in 2 patients (6%). Five patients (15%), i. e. both patients with metastases in the lymph nodes of the neck and three patients with bilateral multifocal carcinomas underwent postoperative adjuvant radioiodine 131I ablation therapy. CONCLUSIONS: Due to the possibility of the future growth, metastasizing andreoccurrence, microcarcinomas cannot be considered harmless or almost insignificant findings. The increased risk of the MC occurrence was found in chronic lymphoplasmocellular thyroiditis (17%).

Somatic genetic alterations in a large cohort of pediatric thyroid nodules.

There is a rise in the incidence of thyroid nodules in pediatric patients. Most of them are benign tissues, but part of them can cause papillary thyroid cancer (PTC). The aim of this study was to detect the mutations in commonly investigated genes as well as in novel PTC-causing genes in thyroid nodules and to correlate the found mutations with clinical and pathological data. The cohort of 113 pediatric samples consisted of 30 benign lesions and 83 PTCs. DNA from samples was used for next-generation sequencing to identify mutations in the following genes: HRAS, KRAS, NRAS, BRAF, IDH1, CHEK2, PPM1D, EIF1AX, EZH1 and for capillary sequencing in case of the TERT promoter. RNA was used for real-time PCR to detect RET/PTC1 and RET/PTC3 rearrangements. Total detection rate of mutations was 5/30 in benign tissues and 35/83 in PTCs. Mutations in RAS genes (HRAS G13R, KRAS G12D, KRAS Q61R, NRAS Q61R) were detected in benign lesions and HRAS Q61R and NRAS Q61K mutations in PTCs. The RET/PTC rearrangement was identified in 18/83 of PTCs and was significantly associated with higher frequency of local and distant metastases. The BRAF V600E mutation was identified in 15/83 of PTCs and significantly correlated with higher age of patients and classical variant of PTC. Germline variants in the genes IDH1, CHEK2 and PPM1D were found. In conclusion, RET/PTC rearrangements and BRAF mutations were associated with different clinical and histopathological features of pediatric PTC. RAS mutations were detected with high frequency in patients with benign nodules; thus, our results suggest that these patients should be followed up intensively.

Polymorphisms in selected DNA repair genes and cell cycle regulating genes involved in the risk of papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. In addition to causal somatic mutations in the BRAF gene and RET/PTC rearrangements, the contribution of single nucleotide polymorphisms (SNPs) in low-penetrance genes in the development of PTC has been proposed. METHODS: Four SNPs in the XRCC1 (Arg399Gln, Arg280His, Arg194Trp and T-77C) and one SNP from each of three other genes participating in DNA repair pathways and/or cell cycle regulation (ATM Asp1853Asn, TP53 Arg72Pro, CDKN1B Val109Gly) were selected. The allelic and genotypic distributions of these variants as well as haplotypes of the XRCC1 were examined in 583 individuals comprising well-characterized cohorts of 209 PTC patients and 374 healthy volunteers. Correlations of polymorphism with clinical-pathological data and mutation status were performed. RESULTS: XRCC1 T-77C polymorphism affects the genetic susceptibility for PTC development in men, the specific combination of XRCC1 haplotypes correlates with RET/PTC incidence, CDKN1B Val109Gly significantly influences the risk of developing PTC regardless of gender and in PTC cases, selected genotypes of TP53 Arg72Pro and ATM Asp1853Asn were significantly associated with monitored tumour characteristics. CONCLUSION: It seems that SNPs in studied regulating genes contribute to the development of PTC and modify the tumour behaviour or characteristics.

A novel RET/PTC variant detected in a pediatric patient with papillary thyroid cancer without ionization history.

Papillary thyroid carcinoma (PTC) is the most frequent type of thyroid cancer. Its development is often caused by the formation of RET/PTC fused genes. RET/PTC1 is the most prevalent form, where exon 1 of CCDC6 gene is fused with the intracellular portion of RET protooncogene starting with exon 12. We have discovered a novel RET/PTC1 variant which we have named RET/PTC1ex9 in metastatic PTC of 8-year-old boy. RET/PTC1ex9 detection was performed by real-time polymerase chain reaction with melting curve analysis and subsequent Sanger and next-generation sequencing. A fusion of exon 1 of CCDC6 with exon 9 of extracellular domain of RET followed by exon 12 of RET was revealed. This is the first RET/PTC variant among PTC cases that contain the extracellular part of RET. This observation could be probably explained by incorrect splicing of RET due to the somatic 32-bp deletion in exon-intron 11 boundary of RET.

Thyroid carcinoma surgery in children and adolescents - 15 years experience surgery of pediatric thyroid carcinoma.

OBJECTIVES: The purpose of this study is to evaluate the characteristics of thyroid gland surgery focusing on malignancies at the pediatric age with the main concern on treatment results and complications in extensive primary treatment. METHODS: The records of all patients 18 years and younger with surgically treated thyroid diseases in the Prague Hospital, Motol, between 1991 and 2006 were retrospectively reviewed. RESULTS: Thyroid surgery was performed on 148 pediatric patients (including 56 carcinomas). The youngest patient involved in the study was seven years old, the oldest patient 18 years old (mean 13.7 years). Most frequent histological cancer type was PTC (42 cases, 75%). Follicular cancer was diagnosed in five cases (8.9%) and medullar cancer in nine cases (16.1%). A prophylactic thyroidectomy was performed in three cases (5.4%) without clinical signs of thyroid tumor with diagnosed RET gene mutation. CONCLUSIONS: We consider total thyroidectomy with subsequent radioiodine ablation and TSH suppression as the basic approach in the treatment protocol of pediatric WDTC. The observed 100% recurrence-free and overall survival together with a low incidence of postoperative complications strongly supports the idea of a total thyroidectomy with selective neck dissection in the treatment of metastases of WDTC and MTC.

Homonymous hemianopia and related visual defects: Restoration of vision after a stroke.

The term homonymous hemianopia refers to visual impairment due to a post-chiasmatic brain lesion. Mammalian neurons of the central nervous system do not have the ability to regenerate. However, the cerebral cortex shows plasticity in certain cases. Motor or speech disorders due to frontal lobe brain damage can be improved with well-directed rehabilitation techniques. If such plasticity is possible, it raises the question whether specialized training could improve a cortical visual disorder. There is need for simple visual training which could be used in rehabilitation. A few different approaches have been developed to treat patients with hemianopia: (1) substitution including special devices, such as optical prisms; (2) compensation using intact residual abilities - especially training of eye movements; (3) restitution which is based on stimulating the blind hemifield. The third method of rehabilitation is the most controversial; however, it has the largest potential. To support concepts of the targeted rehabilitation outlined here, first: further development of the theory of plasticity in visual pathways is required and second: the efficacy of the rehabilitation procedures has to be demonstrated by clinical evidence. We review methods and approaches of hemianopia rehabilitation and treatment. We also review results of contemporary clinical studies and meta-studies.