Double Germline Mutations in the RET Proto-oncogene in MEN 2A and MEN 2B Kindreds

Introduction

The RET proto-oncogene is located on 10q11.2 and encodes a transmembrane tyrosine kinase receptor that plays a role in differentiation and development of neuroendocrine cells ([Ishizaka et al., 1989]). Activating germline mutations affecting different domains of the ret protein are associated with autosomal dominant familial cancer syndromes: multiple endocrine neoplasia types 2A and 2B (MEN 2A and 2B) and familial medullary thyroid carcinoma (FMTC). The majority of germline activating mutations of the RET proto-oncogene are located in exons 8, 10, 11, 13, 14, 15 and 16. FMTC is characterized by the familial occurrence of MTC without other lesions. MEN 2A is characterized by MTC, pheochromocytoma (50 % of cases), and/or hyperparathyroidism (20 % of cases). The most aggressive variant of MTC appears in conjunction with marfanoid habitus, ganglioneuromatosis, bumpy lips, diarrhea, mucosal neuromas and pheochromocytoma (in 50 % of cases) in MEN 2B syndrome ([Hansford and Mulligan, 2000]).

In very few cases, multiple germline mutations in the RET proto-oncogene have been described (Table [1]) ([Tessitore et al., 1999]; [Poturnajova et al., 2005]; [Nunes et al., 2002]; [Koch et al., 2000]; [Miyauchi et al., 1999]; [Bartsch et al., 2000]; [Menko et al., 2002]; [Kitamura et al., 1995]). We report here two families with MEN 2A and MEN 2B syndromes with different double mutations on the same RET allele (in cis) and we compare their clinical features to the other previously reported cases with multiple germline mutations. To the best of our knowledge, no combination of germline mutations in exons 10 and 13 (codons 620 and 791) and in exons 13 and 16 (codons 791 and 918) of the RET proto-oncogene have been reported so far.

Table 1 Clinical and genetic features of the patients of our study and other previously described pedigrees with multiple germline mutations in the RET proto-oncogene Family Exon Mutation Phenotype De novo/mutation carriers Age at diagnosis of index patient Reference 1 10 Cys620Phe MEN 2A 6 58 yrs - MTC current study 13 Tyr791Phe 2 11 Cys634Arg MEN 2A de novoa 26 yrs - MTC, pheo Tessitore et al., 1999 11 Ala640Gly 3 11 Cys634Ser MEN 2A 3 26 yrs - MTC Poturnajova et al., 2005 11 Ala641Ser 46 yrs - pheo 4 11 Cys634Arg MEN 2A de novob 34 yrs - MTC, ACTH-producing pheo (Cushing syndrome) Nunes et al., 2002 11 Val648Ile different alleles 5 11 Asp631Tyr MEN 2A de novoc 40 yrs - MTC, pheo Koch et al., 2000 14 Ser819Ile 14 Glu843Asp 6 13 Tyr791Phe MEN 2B 3 14 yrs - MTC, Marfanoid habitus current study 16 Met918Thr 31 yrs - pheo, 33 yrs - dead 7 14 Val804Met MEN 2B de novod 23 yrs - MTC, precursor state of pheo Miyauchi et al., 1999 14 Tyr806Cys thickening of corneal nerves by slit lamp examination 8 14 Val804Met FMTC 5 56 yrs - MTC Bartsch et al., 2000 14 Arg844Leu 9 14 Val804Met MEN 2B 4 34 yrs - MTC, mucosal neurilemmomas Menko et al., 2002 15 Ser904Cys 10 16 Met918Thr MEN 2B de novoe 32 yrs - MTC, neuromas on lips and tongue, Marfanoid habitus Kitamura et al., 1995 16 Ser922Tyr a parents and relatives unaffected, without double mutation b 2 children with MEN 2A carry Cys634Arg mutation, 2 other still unaffected children carry Val648Ile mutation c described index patient only d father and brother without MEN 2B carry Tyr806Cys mutation, Val804Met second mutation in index patient only e mother without MEN 2B carries Ser922Tyr, Met918Thr second mutation in index patient only

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