A Rare Case of De novo C634G Germline Mutation of the RET Proto-Oncogene in a Patient With MEN 2A Syndrome With Aggressive Pheochromocytoma

Abstract

Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal inherited disorder induced by mutations in the RET proto-oncogene. It is characterized by medullary thyroid carcinoma (MTC), accompanied in half of cases by pheochromocytoma and less frequently, by primary hyperparathyroidism. The aim of the study was to investigate a clinical case of a MEN 2A syndrome consisting of bilateral aggressive pheochromocytomas and MTC with loco-regional lymph node invasion caused by a rare de novo germline mutation in the RET proto-oncogene (Cys634Gly). We reported herein a 42-year-old man presented with hypertension refractory to various antihypertensive drug regimens administered over the preceding 3 years. Abdominal computed tomography scan showed a large right adrenal mass, and a smaller left adrenal nodule. Comprehensive biochemical analyses (24-hour urinary catecholamines and metabolites) confirmed the diagnosis of pheochromocytoma. ¹²³I-metaiodobenzylguanidine scintigraphy revealed uptake in the left inferior thyroid nodule. Left thyroid ultrasound-guided fine needle aspiration established the diagnosis of MTC. The patient first underwent open right adrenalectomy, and 2 months later, total thyroidectomy with central neck compartment lymph node dissection. Screening for hyperparathyroidism was negative. On follow-up, the patient demonstrated no biochemical abnormalities, or clinical complaints. Genetic testing identified a point mutation in the RET proto-oncogene, confirming the diagnosis of MEN 2A. This missense mutation, located in exon 11, resulted in the replacement of a cysteine 634 residue with glycine.

To the best of our knowledge, this is the first MEN 2A case reported with de novo Cys634Gly RET germline mutation in North America, and also worldwide with regard to the aggressiveness of this genotypic variant.

J Endocrinol Metab. 2012;2(4-5):198-204
doi: https://doi.org/10.4021/jem120w