One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: is this a new syndrome--MEN 2C?
BACKGROUND
The rearranged during transfection (RET) V804M proto-oncogene mutation is rare and associated with medullary thyroid carcinoma (MTC). We present 40 members from a total cohort of 107 family members with this mutation.


METHODS
Family members were tested for RET mutations, calcitonin levels, and screened for pheochromocytoma and primary hyperparathyroidism (PHPT). Thyroidectomies were performed on 15 members. Surgery and pathology reports were obtained and reviewed. A pedigree was constructed.


RESULTS
A high penetrance was found for MTC and simultaneous papillary thyroid carcinoma (PTC; 40%). The incidence of PHPT was low (13%). There were no findings of pheochromocytoma. The course in the first family generation was indolent, with late onset of MTC. The second generation experienced earlier disease development; onset occurred earliest in the third generation. The second generation experienced a higher incidence of PTC than the first.


CONCLUSIONS
This is the largest family with this mutation reported to date. However, it does not fit the classic familial MTC or MEN 2A cancer syndrome. Considering that PTC is not an incidental finding, but the result of an inherited RET V804 M mutation, we propose to identify this phenotypic expression as a unique syndrome consistent with manifestations of MTC, PHPT, and PTC.
Shifrin
Alexander L
AL
Department of Surgery, Jersey Shore University Medical Center, Neptune, NJ 07754, USA. ashifrin@meridianhealth.com
Xenachis
Cristina
C
Fay
Angela
A
Matulewicz
Theodore J
TJ
Kuo
Yen-Hong
YH
Vernick
Jerome J
JJ
D000310:Adrenal Gland Neoplasms / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D020132:Anticipation, Genetic; D018276:Carcinoma, Medullary / Q000235:genetics*; D002291:Carcinoma, Papillary / Q000235:genetics*; D005260:Female; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000235:genetics*; D007558:Italy; D008297:Male; D008875:Middle Aged; D009377:Multiple Endocrine Neoplasia / Q000145:classification / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D010673:Pheochromocytoma / Q000235:genetics; D017354:Point Mutation; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D011519:Proto-Oncogenes; D012189:Retrospective Studies; D013577:Syndrome; D013964:Thyroid Neoplasms / Q000235:genetics*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human