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 locoregional 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 followup, 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.

Genetic testing identifies the potential risk of multiple endocrine neoplasia in a Vietnamese family

“…Such mutations with disrupted cysteine may allow the partner cysteine to become available for aberrant disulfide bonding with other mutant RET molecules. The activation of constitutive receptor dimerization induced by aberrant disulfide bonding leads to overregulation of the extracellular signals for processes as diverse as differentiation, cell growth, survival, and programmed cell death (Santoro et al, 1995 Jr et al, 2015) and the recommendations for the family members who genetically tested positive are prophylactic thyroidectomy before the age 5, annual albumincorrected calcium or ionized serum calcium measurements (with or without serum intact parathyroid hormone) beginning at the age of 8, and annual plasma free metanephrines and normetanephrines or 24-hour urine collection for metanephrine and normetanephrine beginning by the age 20 (Pop et al, 2012). In this particular case, the replacement of a cysteine 634 residue with arginine was detected not only in the patient, but also in his daughter and son.…”

“…However, different family members carrying the same RET variation can display different levels of MTC. This might result from diverging levels of genetic penetrance or the presence of genetic modifiers (Pop et al, 2012).…”