Genotype-phenotype correlations in Hungarian patients with hereditary medullary thyroid cancer

Abstract

The genotype and phenotype characteristics of Hungarian patients with RET proto-oncogene mutations operated on for hereditary medullary thyroid cancer (MTC) were studied. The genetic screening was performed in two centers and 40 patients with hereditary MTC or C-cell hyperplasia (CCH) from 18 unrelated families were analyzed. One patient having a mutation in exon 16 (Met918Thr) presented with the MEN2B phenotype, six patients from two families had hereditary MTC without pheochromocytoma (pheo) and primary hyperparathyroidism (PHPT), whereas 33 patients from 15 families showed the MEN2A phenotype. Two different mutations were identified in exon 10 (Cys609Tyr and Cys609Ser), five different mutations were present in exon 11 (Cys634Phe, Cys634Arg, Cys634Tyr, Cys634Trp and Cys634Ser), and two different mutations were localized in exon 14 (Val804Met and Val804Leu). Mutations in exon 10 were associated with hereditary MTC (Cys609Tyr) or with MEN2A syndrome (Cys609Ser). Mutations in exon 11 were always associated with the MEN2A phenotype. PHPT was present in one patient with mutation in exon 14 (Val804Met), whereas all other patients affected with mutations in exon 14 had hereditary MTC without PHPT and/or pheos.

Molecular and clinical analysis of patients with classic and Duarte galactosemia in western Hungary

“…Genotype-phenotype correlations in monogenic disorders are not simple, because the clinical manifestations do not always correlate closely with the genotypes [32][33][34][35]. The phenotypes of classic galactosemia are also complex traits.…”

Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation

“…It is clear that the MEN 2B-defining mutations, M918T and A883F, portend an aggressive course, with management appropriately aggressive and preemptive (Zbuk & Eng 2007). It is also obvious and relatively consistent that the C634R, the most common mutation seen in MEN 2A, predicts for the development of MTC, pheochromocytoma, and HPT, at relatively young ages, and so management is tailored accordingly (Brandi et al 2001, Sanso et al 2002, Machens et al 2003, Patocs et al 2006, Machens & Dralle 2007. However, apart from vague generalizations such as non-634 mutations are not as aggressive, perhaps have later ages of onset and decreased penetrance, the breadth of clinical presentations and course, and the less than firm data preclude clinicians from altering medical management based on genotype.…”

Orolabial signs are important clues for diagnosis of the rare endocrine syndrome MEN 2B. Presentation of two unrelated cases

“…Studies concerning the genotype-phenotype correlation revealed more severe consequences of the mutations affecting the intracellular domain of the ret protein [10,21]. All mutations found in MEN 2 and FMTC syndromes result in either constitutive activation without any ligand binding or enhanced function of the ret protein.…”