Multiple endocrine neoplasia type 2B with a RET proto-oncogene A883F mutation displays a more indolent form of medullary thyroid carcinoma compared with a RET M918T mutation

Abstract

Background: Most cases of multiple endocrine neoplasia type 2B (MEN-2B) are attributable to a germline methionine to threonine mutation at codon 918 (M918T) of the RET proto-oncogene; very few cases of a germline alanine to phenylalanine mutation at codon 883 (A883F) are reported without a clear description of the clinical course. Nevertheless, RET-A883F is currently considered to be among the highest risk mutations, and prophylactic thyroidectomy is recommended as early as 6 months of life. Further characterization of the clinical behavior of RET-A883F mutation is warranted. We present the clinical data for a family with MEN-2B associated with RET-A883F mutation.

Summary: The proband, a 39-year-old woman, had multifocal medullary thyroid carcinoma (MTC) with cervical lymphadenopathy, but no evidence of distant metastases. She was disease free after surgical resection. She also had bilateral pheochromocytomas and mucosal neuromas leading to the clinical diagnosis of MEN-2B. Genetic testing showed that the woman and her three children (3-5 years old) had the RET-A883F mutation. The children had near-normal calcitonin levels, and none had sonographic evidence of suspicious thyroid nodules or cervical lymphadenopathy.

Conclusion: A family with MEN-2B due to RET-A883F mutation displayed a less aggressive form of MTC than what is usually seen in patients with RET-M918T mutation. RET-A883F mutation could be a lower-risk mutation than previously thought and the current recommendation of prophylactic thyroidectomy in the first year of life may not be warranted. Further reports will help clarify the natural history of MTC caused by this mutation.

FIG. 1.

Multiple mucosal neuromas (black arrows) on the proband's tongue (A) and lips (B). Color images available online at www.liebertonline.com/thy.

FIG. 2.

Coronal view of [¹²³I] metaiodobenzylguanidine scans with single-photon emission computed tomography/computed tomography, showing [¹²³I] metaiodobenzylguanidine-avid lesions in both adrenal glands (white arrows). Color images available online at www.liebertonline.com/thy.

FIG. 3.

Transverse view of neck ultrasonography of the patient's 5-year-old son showing very small hypoechoic nodules (white arrows) without increased vascular flow and no cervical lymphadenopathy (T, Trachea; R, Right thyroid lobe; L, Left thyroid lobe).