A Novel RET D898Y Germline Mutation in a Patient with Pheochromocytoma

Hindawi Case Reports in Endocrinology Volume 2018, Article ID 8657914, 6 pages https://doi.org/10.1155/2018/8657914 Case Report A Novel RET D898Y Germline Mutation in a Patient with Pheochromocytoma Jin Wook Yi ,1,2 Hye In Kang,1 Su-jin Kim ,1,2 Chan Yong Seong,1 Young Jun Chai,3 June Young Choi ,4 Moon-Woo Seong,5 Kyu Eun Lee ,1,2 and Sung Sup Park5 1 Department of Surgery, Seoul National University Hospital and College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea 2 Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea 3 Department of Surgery, Seoul National University Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul 156-70, Republic of Korea 4 Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea 5 Department of Laboratory Medicine, Seoul National University Hospital and College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea Correspondence should be addressed to Su-jin Kim; and Kyu Eun Lee; Received 20 September 2017; Revised 19 January 2018; Accepted 20 February 2018; Published 15 April 2018 Academic Editor: Eli Hershkovitz Copyright © 2018 Jin Wook Yi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Pheochromocytoma and paraganglioma are tumors of neuroectoderm origin. Up to 40% of patients with these tumors have germline mutations in known susceptibility genes. We report a novel RET germline mutation (exon 15; c.2692G>T (D898Y)) in a pheochromocytoma patient, as well as in her two asymptomatic sons and older sister. A 49-year-old female came to our clinic presenting with a right adrenal gland mass detected during a healthcare examination. Her mother and two sisters had previously undergone thyroidectomy for papillary thyroid carcinomas. The levels of vanillylmandelic acid and other catecholamines were elevated in 24-hour urine, and an imaging study revealed a right adrenal mass. She underwent laparoscopic adrenalectomy and the final pathologic diagnosis was pheochromocytoma. Mutation screening detected a RET p.D898Y mutation, both in the patient and in the patient’s two sons and older sister. This is the first description of a RET D898Y mutation in a pheochromocytoma patient and her family. The mutation should be categorized as a variant of unknown significance because no RET gene related disorders were detected in this family. Long term follow-up will be required to determine the clinical significance of the RET D898Y mutation. 1. Introduction Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin cell origin neuroendocrine tumors. PCCs arise from the adrenal medulla and produce catecholamines, whereas paragangliomas occur in the thoracoabdominal sympathetic or parasympathetic ganglia and may, or may not, be associated with catecholamine secretion [1]. World Health Organization tumor classification (2004) defined PCC as an intra-adrenal paraganglioma, due to evidence for shared genetic predisposition to these tumors [2]. With the advancement of molecular pathogenesis, germline mutations in pheochromocytoma and/or paraganglioma (PPGL) susceptibility genes, such as NF1, RET, VHL, SDHD, SDHC, SDHB, SDHAF2, SDHA, TMEM127, MAX, EPAS1, and FH, have been identified during the past 15 years. The total incidence of germline mutations in both familial and sporadic PPGL is up to 40% [3–6]. Among the many PPGL susceptibility genes, RET is a well-known protooncogene, germline mutations of which cause multiple endocrine neoplasia type 2 (MEN2), which is characterized by medullary thyroid carcinoma (MTC), PCC, and hyperparathyroidism [7, 8]. Almost 100% of MEN2 patients will develop MTC, and there is a 50% risk of PCC 2 penetrance in their lifetime [9–12]. To date (2018), over 100 genetic alterations in RET have been reported and registered in the “RET protooncogene database” [13], and the penetrance of RET mutation-related diseases varies depending on the site of the RET mutation [10]. In patients with some RET gene mutation types, the occurrence of PCC as an initial clinical manifestation is more frequent than the occurrence of MTC [14–18]. For this reason, mutation screening of RET in PPGL patients and their families is important for the establishment of appropriate treatment management plans [10, 11]. In the present study, a novel germline RET gene mutation (c.2692G>T, p.Asp898Tyr) of unknown significance was identified in a patient with PCC and her family members at the Seoul National University Hospital, South Korea. We evaluated the genomic features and familial characteristics of the mutation using a computational biology tool. This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB number: H-1677-006-772). 2. Methods 2.1. Case Presentation. In November 2012, a 49-year-old Korean woman was referred to the Department of Endocrine Surgery due to a right adrenal mass, identified by abdominal sonography during a routine healthcare checkup. She had been suffering from headache, tachycardia, palpitations, and cold sweats for 5 years but had not previously undergone adrenal disease related diagnostic tests. Her mother and two sisters had a history of thyroidectomy as treatment for papillary thyroid cancer. Twenty-four-hour urine collection revealed elevated vanillyl mandelic acid (VMA; 11.7 mg/day, reference: 2–7 mg/day), metanephrine (1625.6 𝜇g/day, reference: 52–341 𝜇g/day), normetanephrine (5459.5 𝜇g/day, reference: 88–444 𝜇g/day), epinephrine (256.4 𝜇g/day, reference: 0.20 𝜇g/day), and norepinephrine (153.2 𝜇g/day, reference: 15–80 𝜇g/day). An abdominal computed tomography (CT) scan revealed a heterogeneous right adrenal mass of approximately 4.7 × 3.5 cm (Figure 1(a)). Metaiodobenzylguanidine scintigraphy and single-photon emission CT showed increased uptake in the right adrenal gland (Figure 1(b)). The patient underwent right adrenalectomy using the posterior retroperitoneoscopic approach. The final pathologic diagnosis was a PCC with a size of 6.0 × 4.0 × 3.0 cm and a high risk of malignancy with a “PCC of the adrenal gland scaled score” of 13. During the 65-month follow-up after adrenalectomy, the levels of urine VMA, catecholamine, serum calcitonin, calcium, carcinoembryonic antigen, and parathyroid hormone remained within normal ranges. There was no evidence of malignant thyroid nodules on neck ultrasound examination. Genetic counseling was performed by a specialist nurse. Due to the family history of thyroid cancer, we suggested germline mutation screening of the RET gene to the patient and her family members. The index patient and her two sons, two younger brothers, one younger sister, and mother agree (...truncated)