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.

• Klíčová slova
• growth hormone deficiency, medullary thyroid carcinoma, multiple endocrine neoplasia type 2B, ovarian teratoma,
• MeSH
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mnohočetná endokrinní neoplazie typ 2B * diagnóza   genetika   patologie   MeSH
• nádory štítné žlázy * komplikace   chirurgie   MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• růstový hormon MeSH
• teratom * komplikace   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• přehledy MeSH
• Názvy látek
• protoonkogenní proteiny c-ret MeSH
• růstový hormon MeSH

Activating germline RET mutations are presented in patients with familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia (MEN) types 2A and 2B, whereas inactivating germline mutations in patients with Hirschsprung's disease (HSCR). The aim of this study was to evaluate genotype-phenotype correlations of the frequently discussed Tyr791Phe mutation in exon 13 of the RET proto-oncogene. Screening of three groups of patients was performed (276 families with medullary thyroid carcinoma (MTC), 122 families with HSCR, and 29 patients with pheochromocytoma). We found this mutation in 3 families with apparently sporadic MTC, 3 families with FMTC/MEN2, 1 patient with pheochromocytoma, and 3 families with HSCR. All gene mutation carriers have a silent polymorphism Leu769Leu in exon 13. In three families second germline mutations were detected: Cys620Phe (exon 10) in MEN2A family, Met918Thr (exon 16) in MEN2B family, and Ser649Leu (exon 11) in HSCR patient. Detection of the Tyr791Phe mutation in MEN2/MTC and also in HSCR families leads to the question whether this mutation has a dual character (gain-of-function as well as loss-of-function). A rare case of malignant pheochromocytoma in a patient with the Tyr791Phe mutation is presented. This study shows various clinical characteristics of the frequently discussed Tyr791Phe mutation.

• MeSH
• crista neuralis patologie   MeSH
• dítě MeSH
• dospělí MeSH
• fenylalanin genetika   MeSH
• genetické asociační studie MeSH
• Hirschsprungova nemoc genetika   MeSH
• jednonukleotidový polymorfismus fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• medulární karcinom genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mnohočetná endokrinní neoplazie typ 2A genetika   MeSH
• nádory štítné žlázy genetika   MeSH
• nemoc genetika   MeSH
• protoonkogen Mas MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• rodina MeSH
• senioři MeSH
• substituce aminokyselin genetika   MeSH
• tyrosin genetika   MeSH
• zárodečné mutace MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fenylalanin MeSH
• MAS1 protein, human MeSH Prohlížeč
• protoonkogen Mas MeSH
• protoonkogenní proteiny c-ret MeSH
• RET protein, human MeSH Prohlížeč
• tyrosin MeSH

Hirschsprung's disease (HD) can be associated with the development of neuroendocrine tumours such as medullary thyroid carcinoma (MTC). The RET proto-oncogene is the major gene responsible for both HD and MTC. Mutations in exon 10 (codons 609, 611, 618, 620) were found in patients with co-occurrence of HD and MTC. The aim of the study was to screen the MTC risk in patients with HD. The prospective and retrospective genetic analyses comprised 56 HD patients (41 males, 15 females, aged 0-47). The prospective subgroup of patients consisted of 34 patients (25 boys, 9 girls) operated on between June 2003 and December 2005. The retrospective subgroup comprised 22 patients (16 boys, 6 girls) of 194 patients who were operated on between December 1979 and May 2003, non-systematically chosen preferably for total colonic aganglionosis (TCA). DNAs were isolated from blood and resected segments of aganglionic bowel. The HD patients and nine available family members (2 HD) were tested for RET mutations in exons 10, 11, 13, 14, 15 and 16. Direct double-stranded fluorescent sequencing revealed typical germline heterozygous MTC risk RET mutations in 3/56 (5.4%) female HD patients: Cys609Tyr, Cys620Arg (both exon 10) and Tyr791Phe (exon 13). Two of these patients had TCA and one patient had classical type of HD. One TCA patient developed clinical stage of MTC and underwent total thyroidectomy (TTE). The other two RET positive HD patients (aged 7 and 25 years) are screened for calcitonin level and they are without TTE till now. Two family members (mothers of TCA patients) with detected RET mutation underwent prophylactic TTE with MTC finding. Results showed the benefit of systematic RET mutation screening in HD patients in order to identify the risk of MTC in preclinical stage of the disease in patients with HD and their family members. We recommend to investigate not only exon 10 but also exon 13.

• MeSH
• dítě MeSH
• dospělí MeSH
• Hirschsprungova nemoc epidemiologie   genetika   MeSH
• kojenec MeSH
• komorbidita MeSH
• lidé středního věku MeSH
• lidé MeSH
• medulární karcinom epidemiologie   genetika   MeSH
• mladiství MeSH
• nádory štítné žlázy epidemiologie   genetika   MeSH
• předškolní dítě MeSH
• protoonkogen Mas MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• riziko MeSH
• zárodečné mutace MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• MAS1 protein, human MeSH Prohlížeč
• protoonkogen Mas MeSH
• protoonkogenní proteiny c-ret MeSH
• RET protein, human MeSH Prohlížeč

Familial medullary thyroid carcinoma (FMTC) is an autosomal dominant inherited disease, characterized by germ-line mutations in the RET proto-oncogene, mainly in exons 10 and 11, but also in exons 13, 14 and 15. Recently, mutations in exons 8 and 16 associated with FMTC were also described. In the herein presented study, single strand conformation polymorphism (SSCP) method for rapid screening of mutations in the RET proto-oncogene and fluorescent sequencing method were used. In one Czech family with FMTC, we have identified a novel missense point mutation of the RET proto-oncogene in exon 5, that results in substitution of arginine by glycine at codon 321 in the cadherin-like domain of ret protein. It seems that this mutation causes FMTC as no other mutation was found in the classical risk exons (10, 11, 13, 14, 15 and 16) of the RET proto-oncogene. The mutation cosegregates with medullary thyroid carcinoma (MTC) or C cell hyperplasia (CCH) in two patients; two other family members are mutation carriers without clinical signs of MTC so far. To improve the diagnosis of FMTC, analysis of exon 5 of the RET proto-oncogene should be considered in families with no identified classical RET mutations.

• MeSH
• arginin analýza   MeSH
• bodová mutace MeSH
• DNA nádorová analýza   genetika   MeSH
• dospělí MeSH
• exony * MeSH
• genetické testování MeSH
• glycin analýza   MeSH
• kodon genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• medulární karcinom diagnóza   genetika   chirurgie   MeSH
• missense mutace MeSH
• nádory štítné žlázy diagnóza   genetika   chirurgie   MeSH
• protoonkogen Mas MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• protoonkogeny * MeSH
• rodokmen MeSH
• senioři MeSH
• tyreoidektomie MeSH
• zárodečné mutace * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• arginin MeSH
• DNA nádorová MeSH
• glycin MeSH
• kodon MeSH
• MAS1 protein, human MeSH Prohlížeč
• protoonkogen Mas MeSH
• protoonkogenní proteiny c-ret MeSH
• RET protein, human MeSH Prohlížeč