SURGERY 509 MEDULLARY THYROID CARCINOMA (MTC) arises from the parafollicular cells located in the connective tissue of the thyroid and accounts for between 5% and 10% of all thyroid malignancies. Although most patients with MTC represent sporadic cases, in approximately 20% to 25% of patients the dis- ease is familial, caused by allelic germline muta- tions of the RET proto-oncogene and inherited in an autosomal dominant pattern. 1 The RET proto- oncogene encodes a membrane-bound tyrosine kinase receptor characterized by a cadherin-like domain and a cysteine-rich domain, both of which occur in the extracellular region. 2 Specific muta- tions in the RET proto-oncogene have been found to be associated with multiple endocrine neoplasia type 2A (MEN2A), type 2B (MEN2B), and familial MTC. 3 The prognosis of the familial forms of MTC varies substantially and is generally most severe with MEN2B and most favorable in familial MTC. Because of the variable phenotype of the known mutations, 4-6 the question of whether all gene car- riers should undergo thyroidectomy is still a sub- ject of debate. 7 Missense mutations among the 5 cysteine codons (609, 611, 618, 620, and 634) that encode part of the extracellular cysteine-rich domain have V804M RET mutation and familial medullary thyroid carcinoma: Report of a large family with expression of the disease only in the homozygous gene carriers Albert Lecube, MD, Cristina Hernandez, MD, PhD, Josep Oriola, PhD, Rosa Galard, PhD, Enrique Gémar, MD, PhD, Jorge Mesa, MD, PhD, and Rafael Simó, MD, PhD, Barcelona, Spain Background. Only 9 families with familial medullary thyroid carcinoma due to V804M mutation have been reported until now. We describe a large kindred with not only heterozygous but also homozygous members with the V804M mutation. This is, to our knowledge, the first report of a homozygous RET mutation. Methods. Fifty-three members from 4 successive generations of a family with a high level of consanguini- ty underwent genetic analysis. The pentagastrin provocative test and biochemical screening to rule out either hyperparathyroidism or pheochromocytoma were performed only on gene carriers of the mutation. Results. Twenty-six gene carriers for V804M mutation were identified (4 homozygous and 22 heterozy- gous). Three of 4 homozygous patients underwent total thyroidectomy. In 1 patient neither medullary thyroid carcinoma nor C-cell hyperplasia was detected, and in another patient only 3 small foci of C-cell hyperplasia were found on the histologic examination. The pentagastrin stimulation test result was with- in the normal range in all the heterozygous gene carriers and, consequently, thyroidectomy was not indi- cated. The screening for both hyperparathyroidism and pheochromocytoma was negative in all patients. Conclusions. In the family reported, the V804M mutation in heterozygous patients seems not to be enough to express the full disease. This finding strongly supports the concept of the indolent behavior of V804M RET proto-oncogene mutation. In addition, our results suggest that when counseling for preven- tive total thyroidectomy, the specific mutation of RET proto-oncogene and also the natural history of the disease within a particular family should be considered. (Surgery 2002;131:509-14.) From the Departments of Endocrinology, Biochemistry, and Surgery, Hospital Vall d’Hebron, and the Hormonology Department, Hospital Clínic, Barcelona, Spain Accepted for publication January 10, 2002. Supported by a grant from the Fundació per la Recerca i la Docència Hospital Vall d’Hebron (A.L.). Reprint requests: Rafael Simó, MD, PhD, Endocrinology Division, Hospital General Vall d’Hebron, Pg Vall d’Hebron 119 – 129, Barcelona, 08035, Spain. Copyright © 2002 by Mosby, Inc. All rights reserved. 0039-6060/2002/$35.00 + 0 11/56/123006 doi:10.1067/msy.2002.123006