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一个多发性内分泌腺瘤2A家系的临床特征与基因突变分析

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  • 1.上海交通大学附属第六人民医院骨质疏松和骨病科 上海市骨疾病临床研究中心,上海 200233
    2.苏州大学附属第二医院内分泌科,苏州 江苏 215004

收稿日期: 2020-05-25

  网络出版日期: 2022-07-14

基金资助

国家自然科学基金(81770874);国家自然科学基金(81974126);上海申康医院发展中心临床科技创新项目(SHDC 12018120);上海市自然科学基金(16ZR1425700)

Clinical manifestation and gene mutation of multiple endocrine neoplasia 2A: analysis of a pedigree data

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  • 1. Shanghai Clinical Research Center of Bone Diseases, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
    2. Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Soochow University, Jiangsu Suzhou 215004, China

Received date: 2020-05-25

  Online published: 2022-07-14

摘要

目的: 分析1例多发性内分泌腺瘤2A(multiple endocrine neoplasia 2A, MEN2A)患者及其家系的临床特征,同时复习相关文献进行综合探讨。方法: 先证者为女性,33岁,收集其家系的临床资料,并采集先证者及家庭成员的外周血,抽提基因组DNA,对RET基因编码区进行Sanger测序,并以300名不相关的健康志愿者作为对照,对突变的基因进行致病性及保守性分析。结果: 先证者的血生化检测结果显示,血钙、甲状旁腺激素(parathyroid hormone,PTH)和降钙素水平升高,分别为3.25 mmol/L、1 252 ng/L和37.24 ng/L;术后病理检查结果证实其存在单侧甲状旁腺腺瘤和甲状腺髓样癌(medullary thyroid carcinoma, MTC)。Sanger测序显示,先证者RET基因11号外显子存在杂合错义突变c.1901G>A,导致p.Cys634Tyr,该致病基因来自先证者母亲,而其健康姐姐及对照者均未发现相同突变。结论: 本研究中先证者为RET基因11号外显子错义突变c.1901G>A导致的MEN2A。MEN2A的确诊依靠对RET基因突变的检测。早期手术干预是该病最佳的治疗手段,术后对MTC复发情况进行随访是评估MEN2A患者预后的关键。已有RET基因突变的先证者应对其胎儿进行致病基因筛查,从而进行早期干预以降低MEN2A的发病率和死亡率。

本文引用格式

林小云, 戚露月, 章振林, 岳华 . 一个多发性内分泌腺瘤2A家系的临床特征与基因突变分析[J]. 诊断学理论与实践, 2020 , 19(05) : 481 -486 . DOI: 10.16150/j.1671-2870.2020.05.007

Abstract

Objective: To analyze the clinical characteristics, gene mutation of a pedigree diagnosed with multiple endocrine neoplasia 2A (MEN2A) and comprehensively review the related literature. Methods: The proband was a 33-year-old female,and the clinical data of the pedigree was collected. The genomic DNA was extracted from peripheral blood withdrawn from the proband and family members, and coding region of RET gene was analyzed by Sanger sequencing.Three hundred unrelated healthy volunteers were enrolled as controls. Pathogenicity and conservativeness analysis were carried on the detected mutant gene. Results: The blood biochemical examination of the proband showed the increased calcium (3.25 mmol/L), parathyroid hormone(1 252 ng/L) and calcitonin (37.24 ng/L) in serum. The presence of unilateral parathyroid adenoma and medullary thyroid carcinoma(MTC) were confirmed by postoperative pathology. Sanger sequen-cing identified that a heterozygous missense mutation in exon 11 of RET gene c.1901G>A in proband led to p.Cys634Tyr. The pathogenic gene came from the mother, while the healthy sister or the controls did not show the same mutation. Conclusions: The proband with MEN2A is caused by a missense mutation in exon 11 of RET gene (c. 1901G> A). The diagnosis of MEN2A depends on the detection of RET gene mutation. Early surgical intervention is the best treatment choice for MEN2A patients. Postoperative follow-up of the recurrence of MTC is the key to assessing the prognosis in MEN2A patients. Screening RET gene mutation in the fetus of proband with RET mutation is necessary, and intervention as early as possible may decrease the incidence and mortality of MEN2A.

参考文献

[1] Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland[J]. Am J Med, 1961, 31:163-166.
[2] Mathiesen JS, Kroustrup JP, Vestergaard P, et al. Incidence and prevalence of multiple endocrine neoplasia 2A in Denmark 1901-2014: a nationwide study[J]. Clin Epidemiol, 2018, 10:1479-1487.
[3] Raue F, Frank-Raue K. Update multiple endocrine neoplasia type 2[J]. Fam Cancer, 2010, 9(3):449-457.
[4] Larsen LV, Mirebeau-Prunier D, Imai T, et al. Primary hyperparathyroidism as first manifestation in multiple endocrine neoplasia type 2A: an international multicenter study[J]. Endocr Connect, 2020, 9(6):489-497.
[5] 王秀杰, 邵新宇, 施毕旻, 等. 3例散发的2A型多发性内分泌腺瘤病患者及其子代RET基因突变观察[J]. 山东医药, 2017, 57(27):87-89.
[6] 顾丽群, 赵咏桔, 张连珍, 等. 多发性内分泌腺瘤病2A家系的RET原癌基因突变研究[J]. 上海第二医科大学学报, 2004, 24(2):88-90.
[7] Lu F, Chen X, Bai Y, et al. A large Chinese pedigree of multiple endocrine neoplasia type 2A with a novel C634Y/D707E germline mutation in RET exon 11[J]. Oncol Lett, 2017, 14(3):3552-3558.
[8] Du ZF, Li PF, Zhao JQ, et al. Genetic diagnosis of a Chinese multiple endocrine neoplasia type 2A family through whole genome sequencing[J]. J Biosci, 2017, 42(2):209-218.
[9] Raue F, Frank-Raue K. Genotype-phenotype correlation in multiple endocrine neoplasia type 2[J]. Clinics (Sao Paulo), 2012, 67(Suppl 1):69-75.
[10] 龚莉琳, 田波, 李蓉, 等. 一个多发性内分泌腺瘤病2型家系的RET基因检测[J]. 中华内分泌外科杂志, 2014, 8(6):482-485.
[11] Brown SJ, Riconda DL, Zheng F, et al. Features of multiple endocrine neoplasia type 1 and 2A in a patient with both RET and MEN1 germline mutations[J]. J Endocr Soc, 2020, 4(4):bvaa020.
[12] Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma[J]. Thyroid, 2015, 25(6):567-610.
[13] Pappachan JM, Tun NN, Arunagirinathan G, et al. Pheochromocytomas and hypertension[J]. Curr Hypertens Rep, 2018, 20(1):3.
[14] Davison AS, Jones DM, Ruthven S, et al. Clinical evalua-tion and treatment of phaeochromocytoma[J]. Ann Clin Biochem, 2018, 55(1):34-48.
[15] Taïeb D, Timmers HJ, Hindié E, et al. EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma[J]. Eur J Nucl Med Mol Imaging, 2012, 39(12):1977-1995.
[16] Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC[J]. Hum Mol Genet, 1993, 2(7):851-856.
[17] Castellone MD, Melillo RM. RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2(MEN2)[J]. Endocr Relat Cancer, 2018, 25(2):T105-T119.
[18] Febrero B, Rodríguez JM, Ríos A, et al. Prophylactic thyroidectomy in multiple endocrine neoplasia 2 (MEN2) patients with the C634Y mutation: a long-term follow-up in a large single-center cohort[J]. Eur J Surg Oncol, 2019, 45(4):625-630.
[19] Ponder BA, Ponder MA, Coffey R, et al. Risk estimation and screening in families of patients with medullary thyroid carcinoma[J]. Lancet, 1988, 1(8582):397-401.
[20] Machens A. Early malignant progression of hereditary medullary thyroid cancer[J]. N Engl J Med, 2004, 350(9):943.
[21] 蔡洁. 多发性内分泌腺瘤病2型的临床及遗传学研究[D]. 上海: 上海交通大学, 2013.
[22] 翁育, 黎锋, 张少玲, 等. 两个多发性内分泌腺瘤病2A型家系RET原癌基因突变方式的研究[J]. 中华医学遗传学杂志, 2018, 35(5):648-652.
[23] O'Riordain DS, O'Brien T, Weaver AL, et al. Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B[J]. Surgery, 1994, 116(6):1017-1023.
[24] Spanheimer PM, Ganly I, Chou J, et al. Long-term oncologic outcomes after curative resection of familial medullary thyroid carcinoma[J]. Ann Surg Oncol, 2019, 26(13):4423-4429.
[25] Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1)[J]. J Clin Endocrinol Metab, 2012, 97(9):2990-3011.
[26] Redaelli S, Plaza-Menacho I, Mologni L. Novel targeted therapeutics for MEN2[J]. Endocr Relat Cancer, 2018, 25(2):T53-T68.
[27] Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer[J]. J Clin Oncol, 2013, 31(29):3639-3646.
[28] Chuk MK, Widemann BC, Minard CG, et al. A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: trial ADVL1211, a report from the Children's Oncology Group[J]. Pediatr Blood Cancer, 2018, 65(8):e27077.
[29] Chen S, Li S, Zhang J, et al. Preimplantation genetic dia-gnosis of multiple Eendocrine neoplasia type 2A using informative markers identified by targeted sequencing[J]. Thyroid, 2018, 28(3):281-287.
[30] Hu WW, Zhang Z, He JW, et al. Establishing reference intervals for bone turnover markers in the healthy Shanghai population and the relationship with bone mineral density in postmenopausal women[J]. Int J Endocrinol, 2013, 2013:513925.
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