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To the Editor: Testing of the RET gene in patients with multiple endocrine neoplasia type 2 (MEN 2) and apparently isolated medullary thyroid carcinoma (MTC) is standard in molecular medicine. The MEN 2 syndromes and familial MTC are autosomal dominant disorders comprising 3 subtypes. MEN 2A includes MTC, pheochromocytoma (PC), and hyperparathyroidism. MEN 2B comprises MTC, PC, and characteristic developmental abnormalities (ie, marfanoid habitus and gastrointestinal tract ganglioneuromas). The operational classification of familial MTC is 4 or more family members with MTC without objective evidence of PC and hyperparathyroidism on screening of all living affected and at-risk individuals.¹

The International RET Mutation Consortium analyzed 477 independent MEN type 2 families and related the specific RET proto-oncogene mutations to disease phenotype.¹ Most families with MEN 2A and familial MTC had germline mutations in 1 of 5 cysteine codons (609, 611, 618, 620, and 634), which is the coding part of the extracellular cysteine-rich domain. Mutations in codon 768 (exon 13) and 804 (exon 14) within the intracellular tyrosine kinase domain of RET have been associated with familial MTC. In the Consortium analysis, 34 MTC families were identified with cysteine codon mutations, evenly distributed among the 5 cysteine codons.¹ Noncysteine mutations (E768D or V804L) appeared in 3 MTC families and in 3 families with fewer than 4 MTC patients. To date, no family with MEN 2A or MEN 2B has been found to carry either of these mutations.^1-3

Report of Case:
A family was found to have a V804L mutation, based on standard polymerase chain reaction conditions, primers, and semiautomated sequencing.^4-5 Four members from 3 different branches of the family had MTC, and 2 of these also had PC (Figure 1). These patients had small thyroid tumors and bilateral C-cell hyperplasia, but no metastases. They had normal serum concentrations of calcium and parathyroid hormone. The proband had an intra-adrenal PC and hyperplasia of the extratumoral medulla. Another patient had an extra-adrenal intra-abdominal PC, which can exist in MEN 2A families.

View larger version (10K): [in this window] [in a new window] Figure. A Family With RET V804L Mutation The family's genetic makeup was traced back to the mid-1800s. The coding system referred to in the key may apply to either men or women.

Comment.
The present observations suggest that the V804L mutation is associated with a MEN 2A syndrome (ie, the mutation is not exclusively associated with familial MTC). To exclude coincidental von Hippel-Lindau (VHL) disease, we performed germline VHL mutation analysis in the patients with PC but found no mutations. After the Consortium's analysis, it was hoped that mutations at codons 768 and 804 would only be associated with familial MTC. The Consortium recommended accrual of families with these mutations and longer follow-up to decide if these were indeed familial MTC-specific mutations. Although this case family might represent familial MTC with coincidental PC, this seems unlikely with 2 distinct cases of PC in patients with MTC as well as adrenal medullary hyperplasia in another patient.

These data suggest that germline V804L mutations can be associated with MEN 2A. Pending other data, we recommend that patients with mutations at codons 768 and 804 be medically managed like MEN 2A patients (ie, attention to the development of PC, hyperparathyroidism, and MTC). We suggest that familial MTC is not a separate entity but represents 1 end of the MEN 2A spectrum reflecting low penetrance of the disease mutation.

AUTHOR INFORMATION
Financial Disclosure: This study was supported by grants from the Swedish Cancer Society (3911), Swedish MRC (5220) and the Ingabritt och Arne Lundberg Foundation. Dr Eng is the Lawrence and Susan Marx Investigator in Herman Cancer Genetics and a Barr Investigator.

Ola Nilsson, MD, PhD; Lars E. Tisell, MD, PhD; Svante Jansson, MD, PhD; Håkan Ahlman, MD, PhD
University of Göteborg
Göteborg, Sweden

Oliver Gimm, MD; Charis Eng, MD, PhD
Ohio State University
Columbus

1. Eng C, Clayton D, Schuffenecker I, et al for the International RET Mutation Consortium Analysis. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. JAMA. 1996;276:1575-1579. ABSTRACT 2. Eng C, Smith DP, Mulligan LM, et al. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene. 1995;10:509-513. ISI | PUBMED 3. Fink M, Weinhusel A, Niederle B, Haas OA for the Study Group Multiple Endocrine Neoplasia Austria (SMENA). Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. Int J Cancer. 1996;69:312-316. FULL TEXT | ISI | PUBMED 4. Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet. 1994;6:70-74. FULL TEXT | ISI | PUBMED 5. Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16:64-67. FULL TEXT | ISI | PUBMED

Edited by Margaret A. Winker, MD, Deputy Editor, and Phil B. Fontanarosa, MD, Interim Coeditor.

JAMA. 1999;281:1587-1588.

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