Di Benedetto Guenda, Barca Ignazio, De Gregorio Laura, Scollo Claudia, Gianì Fiorenza, Martorana Federica, Russo Marco, Frasca Francesco, Pellegriti Gabriella, Sapuppo Giulia
Endocrinology Unit, Garibaldi-Nesima Hospital, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
Molecular Biology Service, Multi-diagnostic Health Services Centre, Catania, Italy.
Front Oncol. 2025 Jan 7;14:1464890. doi: 10.3389/fonc.2024.1464890. eCollection 2024.
Multiple endocrine neoplasia type 2 syndrome (MEN2) is a hereditary disease resulting from mutations of the rearranged during transfection (RET) protooncogene subclassified into MEN2A [medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism] and MEN2B (MTC, pheochromocytoma, Marfanoid habitus, mucous neuromas, and intestinal ganglioneuromatosis). Prophylactic thyroidectomy is recommended in RET-mutated patients. The age at which it should be performed depends on the type and aggressiveness of the mutation.
This study aimed to evaluate the genotype/phenotype correlation and outcome in pediatric/adolescent carriers of MEN2 RET mutation.
In a retrospective series of 23 carriers of RET MEN2 mutation who were ≤19 years old at diagnosis and had undergone total thyroidectomy ± lymphadenectomy, the following were analyzed: 1) specific RET mutation, 2) clinical and histopathological characteristics, 3) genotype/phenotype correlation, and 4) outcome at last follow-up.
In our series, the female gender was more prevalent (F/M ratio 2.8/1), and the median age was 14.9 years [interquartile range (IQR) 12.6-17.2]. RET mutations were at very high risk in 4.3% of patients (M918T), high risk in 43.5% (C634), and moderate risk in 52.2% (47.8% C618 and 4.3% C620). All patients underwent surgery: at histology, MTC was found in 19/23 (82.6%) patients, C-cell hyperplasia in 2/23 (8.7%), and benign histology in 2/23 (8.7%). Ten patients (52.6%) had a disease event during the follow-up: 2/19 (10.5%) showed biochemical disease, 6/19 (31.6%) lymph node recurrences, and 2/19 (10.5%) distant metastases (50% liver, 50% bone). At the last follow-up, nine MTCs were not cured. One patient died after 9 years of follow-up at 21 years old (M918T RET+).
From these data, it is clear to see the importance of genetic counseling and RET screening in all first-degree relatives of patients with proven MEN2. The goal should be to subject patients to surgery for prophylactic and not curative purposes, i.e., before the onset of MTC, given the high risk of persistent or recurrent disease also in pediatric/adolescent patients.
2型多发性内分泌腺瘤综合征（MEN2）是一种遗传性疾病，由转染重排（RET）原癌基因突变引起，可细分为MEN2A[甲状腺髓样癌（MTC）、嗜铬细胞瘤和原发性甲状旁腺功能亢进]和MEN2B（MTC、嗜铬细胞瘤、类马凡体型、黏膜神经瘤和肠道神经节瘤病）。建议对RET突变患者进行预防性甲状腺切除术。手术时机取决于突变的类型和侵袭性。
本研究旨在评估MEN2 RET突变的儿科/青少年携带者的基因型/表型相关性及预后。
回顾性分析23例诊断时年龄≤19岁且接受了全甲状腺切除术±淋巴结清扫术的RET MEN2突变携带者，分析以下内容：1）特定RET突变；2）临床和组织病理学特征；3）基因型/表型相关性；4）末次随访时的预后。
在我们的研究系列中，女性更为常见（女性/男性比例为2.8/1），中位年龄为14.9岁[四分位间距（IQR）12.6 - 17.2]。4.3%的患者RET突变处于极高风险（M918T），43.5%处于高风险（C634），52.2%处于中度风险（47.8%为C618，4.3%为C620）。所有患者均接受了手术：组织学检查发现，19/23（82.6%）的患者患有MTC，2/23（8.7%）为C细胞增生，2/23（8.7%）为良性组织学。10例患者（52.6%）在随访期间出现疾病事件：19例中有两名（10.5%）出现生化疾病，6/19（31.6%）出现淋巴结复发，2/19（10.5%）出现远处转移（50%为肝脏，50%为骨骼）。在末次随访时，9例MTC未治愈。1例患者在21岁时随访9年后死亡（M918T RET+）。
从这些数据可以清楚地看出，对确诊为MEN2患者的所有一级亲属进行遗传咨询和RET筛查的重要性。目标应该是让患者接受手术以进行预防而非治疗，即在MTC发病前进行手术，因为儿科/青少年患者也存在疾病持续或复发的高风险。
