OBJECTIVE 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. DESIGN Retrospective study of index patients and predictive variant carriers, identified through familial cascade testing between 2001 and 2020. RESULTS 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. CONCLUSION The c.1998delinsTTCT variant in the RET gene is pathogenic and associated with a moderate risk for medullary thyroid carcinoma and rarely with other multiple endocrine neoplasia type 2A (MEN2A) manifestations. Active surveillance is a possible option in heterozygous gene carriers with a negative first clinical evaluation.

中文翻译：

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RET 癌基因中的种系创始人变体 c.1998delinsTTCT：一项针对 15 个比利时家庭的队列研究。

目的 RET 基因（密码子 666）中的 c.1998delinsTTCT 变异与比利时的甲状腺髓样癌有关。我们的目的是研究预测变异携带者的临床表型和年龄依赖性外显率。设计对指标患者和预测变异携带者的回顾性研究，通过 2001 年至 2020 年间的家族级联测试确定。 结果 总队列由 119 名患者组成：15 名指标患者、102 名杂合子和 2 名纯合预测变异携带者。在杂合子携带者中，25 名患者在初次评估时和 3 名患者在随访期间高度怀疑临床疾病。56 名患者在监测过程中未观察到高度怀疑临床疾病，18 名患者未进行临床疾病筛查。与指标患者相比，经过手术治疗的杂合预测变异携带者的术前基础降钙素水平较低，疾病阶段较低，辅助治疗需求较少，缓解机会较高。在杂合子携带者中，高度怀疑患病的中位年龄为 52 岁（范围 7-75 岁），70 岁时的预测外显率为 62% (9% SE)。两名患者被确诊为嗜铬细胞瘤，一名患者被确诊为原发性甲状旁腺功能亢进症。2 名纯合预测变异携带者在首次临床评估时表现出较高的疾病严重程度。结论 RET 基因中的 c.1998delinsTTCT 变异具有致病性，与甲状腺髓样癌的中度风险相关，但很少与其他 2A 型多发性内分泌肿瘤 (MEN2A) 表现相关。对于首次临床评估为阴性的杂合基因携带者，主动监测是一种可能的选择。