在比利时，RET基因（密码子666）中的c.1998delinsTTCT变异与髓样甲状腺癌相关。我们旨在研究预测性变异携带者的临床表型和年龄相关的穿透率。通过2001年至2020年的家族级联检测，我们进行了索引患者和预测性变异携带者的回顾性研究。总队列包括119名患者：15名索引患者，102名杂合子型和2名纯合子型预测性变异携带者。在杂合子型携带者中，25名患者在初始评估时存在高度疑似临床疾病，而3名患者在随访期间存在高度疑似临床疾病。在56名患者的监测期间未观察到高度疑似临床疾病，并且18名患者未进行临床疾病筛查。与索引患者相比，接受手术治疗的杂合子型预测性变异携带者具有更低的术前基础降钙素、更低的疾病分期、较少的辅助治疗需求和更高的缓解机会。在杂合子型携带者中，高度疑似疾病发生的中位年龄为52岁（范围为7-75岁），在70岁时预计穿透率为62%（标准误差为9%）。有两名患者被识别出患有嗜铬细胞瘤，一名患者患有原发性增生性甲状旁腺功能亢进症。两名纯合子型预测性变异携带者在首次临床评估时表现出较严重的疾病程度。RET基因中的c.1998delinsTTCT-变异是致病性的，并且与中等风险的髓样甲状腺癌以及罕见的MEN2A表现相关。对于首次临床评估结果为阴性的杂合子型基因携带者，积极监测是一种可行的选择。© 作者们 2023. 由牛津大学出版社代表欧洲内分泌学会发表。

The c.1998delinsTTCT variant in the RET gene (codon 666) is linked to medullary thyroid carcinoma in Belgium. We aimed to study the clinical phenotype and the age-dependent penetrance in predictive variant carriers.retrospective study of index patients and predictive variant carriers, identified through familial cascade testing between 2001 and 2020.The total cohort comprised 119 patients: 15 index patients, 102 heterozygous and 2 homozygous predictive variant carriers. Among heterozygous carriers, high suspicion of clinical disease was present in 25 patients at initial evaluation and in 3 patients during follow-up. No high suspicion of clinical disease was observed during surveillance in 56 patients, and 18 patients did not proceed to screening for clinical disease. Compared to index patients, surgically treated heterozygous predictive variant carriers had a lower presurgical basal calcitonin, a lower disease stage, less need for adjuvant therapy, and higher chances of remission. In heterozygous carriers, median age at developing high suspicion of disease is 52 years (range 7-75), with a predicted penetrance of 62% (9% SE) at the age of 70 years. Two patients were identified with pheochromocytoma and 1 patient with primary hyperparathyroidism. The 2 homozygous predictive variant carriers presented with higher disease severity at first clinical evaluation.The c.1998delinsTTCT- variant in the RET gene is pathogenic and associated with a moderate risk for medullary thyroid carcinoma and rarely with other MEN2A manifestations. Active surveillance is a possible option in heterozygous gene carriers with a negative first clinical evaluation.© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.