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BACKGROUND: The hereditary form of medullary thyroid carcinoma may occur isolated as a familial medullary thyroid carcinoma (FMTC) or as part of Multiple Endocrine Neoplasia 2A (MEN2A) and 2B (MEN2B). MEN2B is a rare syndrome, its phenotype mayusually, but not always, be noted by the physician. In the infant none of the MEN2B characteristics are present, except by early gastrointestinal dysfunction caused by intestinal neuromas. When available, genetic analysis confirms the diagnosis and guides pre-operative evaluation and extent of surgery. Here we report four cases of MEN2B in which the late diagnosis had a significant impact in clinical evolution and, potentially, in overall survival. CASE REPORT: We report four cases, 2 men and 2 women, with differences in their phenotypes and with a late diagnosis. The first case has a history of severe gastrointestinal obstruction requiring a surgery intervention two days after his birth. The second told had nodules in the oral mucosa and constipation since childhood. The third case referred a history of constipation from birth until 5 months of life. The fourth has had a history of chronic constipation since childhood. DISCUSSION: New concepts have emerged since the RET oncogene was identified in 1993 as the responsible gene for hereditary medullary thyroid carcinoma. The majority of MEN2B individuals have M918T mutation in the exon 16 of RET, with a few cases having a mutation A883F or the association of V804M with E805K, Y806C or S904C mutations. The consensus classifies the RET mutation in codon 918 as of highest risk and recommends total thyroidectomy and central lymph node dissection until 6 months after birth. A fast and precise diagnosis is essential to reach these goals. The identification of early manifestations such as intestinal ganglioneuromatosis and oral mucosal neuromas should prompt the physician to initiate an investigation for multiple endocrine neoplasia type 2B. CONCLUSION: The diagnosis of MEN2B is very important to allow appropriate investigation of associated diseases and to allow counseling and appropriate screening of relatives for a RET mutation. Even patients with MEN2B, which often have typicalphysical features, may not be properly recognized and be followed as a sporadic case. Based on this, ALL suspicious cases of multiple endocrine neoplasia shouldundergo a molecular genetic test.

Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal-dominant hereditary disease characterized by the occurrence of tumors of the parathyroids, duodenum and/or pancreas, and anterior pituitary. The syndrome is caused by germline mutations of the MEN1 tumor suppressor gene. The identification of the causativemutations is of paramount importance for the long-term management of affected individuals and their relatives. Multiple endocrine neoplasia type 2 (MEN2) is less frequent than MEN1 and represents a cancer syndrome caused by autosomal-dominant inherited mutations of the RET proto-oncogene, and displays agenotype-phenotype correlation of remarkable clinical relevance. Major components of MEN-2 comprise medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism. Since 25-30% of patients with MTC display a hereditary background, genetic testing is indicated once MTC is diagnosed. Occurrence of MTC can be avoided by prophylactic thyroidectomy in early childhood in gene carriers. Early diagnosis and therapy of simultaneous pheochromocytoma avoids the development of complications caused by acute or chronic hypertension.

BACKGROUND: The clinical association of multiple endocrine neoplasia type 2A (MEN 2A) and Hirschsprung's disease (HD), although rare, has been previously observed. Recently, germline mutations in the RET proto-oncogene, a transmembrane receptorwith tyrosine kinase activity, have been detected in patients with familial HD. RET is also the predisposition gene for the inherited cancer syndrome MEN 2A. METHODS: We describe a DNA sequence variation within the coding region of RET intwo large unrelated kindreds with MEN 2A (with 83 and 42 persons affected) in which HD cosegregated with MEN 2A in seven patients. mutational analysis was performed with a highly sensitive polymerase chain reaction-based denaturing gradient gel electrophoresis technique followed by direct sequencing of mutants.RESULTS: Genetic analysis by denaturing gradient gel electrophoresis detected mutant bands in RET exon 10 in patients with MEN 2A from both kindreds. Direct DNA sequencing of mutants revealed a thymine-to-adenine base change in codon 618, resulting in a cysteine-to-serine substitution. The identical mutation was present in ALL seven children with HD. Of these children five underwent thyroidectomy for C-cell abnormalities; one 3-year-old child is awaiting thyroidsurgery, and the remaining patient died at age of 12 weeks. CONCLUSIONS: The RETcodon 618 Ser mutation could predispose patients with MEN 2A to HD. RET may assume a critical role in embryologic enteric nerve migration and tumorigenesis of cells from neural crest lineage.