Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
Department of Clinical Cancer Genetics, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
J Clin Endocrinol Metab. 2018 Apr 1;103(4):1269-1272. doi: 10.1210/jc.2017-02402.
Germline RET K666N mutation has been described as a pathogenic mutation with low disease penetrance for medullary thyroid cancer (MTC) without other features of multiple endocrine neoplasia type 2A. We describe a patient with homozygous RET K666N mutation with MTC and bilateral pheochromocytoma (PHEO).
A 59-year-old woman received a diagnosis of MTC after biopsy of two thyroid nodules. Coincident biochemical and radiologic testing was suspicious for bilateral PHEO, confirmed after bilateral adrenalectomy. There was no evidence of primary hyperparathyroidism (PHPT). She had a total thyroidectomy with neck dissection revealing bilateral MTC with lymph node metastases. Germline RET testing identified homozygous K666N mutations. Genetic testing of family members showed that both adult children harbor a heterozygous K666N mutation. Her 32-year-old son had an elevated calcitonin level and underwent thyroidectomy, which identified MTC. Her 30-year-old daughter had a normal calcitonin level. Prophylactic thyroidectomy showed C-cell hyperplasia only. Three of seven other family members were tested and found to carry the mutation. All had normal calcitonin levels, and none had biochemical evidence of PHEO or PHPT. Given the absence of PHEO in reported RET K666N families, our proband underwent genetic testing for causes of hereditary paragangliomas or PHEO. No additional mutations were identified.
Here we report a case of a homozygous RET K666N mutation leading to coincident MTC and PHEO. Heterozygous presentations of RET K666N mutations have low penetrance for isolated MTC. We believe that the gene dosage associated with the homozygosity of this variant contributed to the occurrence of bilateral PHEO.
胚系 RET K666N 突变被描述为一种致病性突变，其导致的甲状腺髓样癌（MTC）疾病外显率较低，且无 2A 型多发性内分泌肿瘤的其他特征。我们描述了一例 MTC 合并双侧嗜铬细胞瘤（PHEO）的纯合 RET K666N 突变患者。
一名 59 岁女性因甲状腺结节活检诊断为 MTC。同时进行的生化和影像学检查怀疑为双侧 PHEO，双侧肾上腺切除术证实了这一诊断。没有原发性甲状旁腺功能亢进症（PHPT）的证据。她接受了甲状腺全切除术和颈部清扫术，发现双侧 MTC 伴淋巴结转移。胚系 RET 检测发现纯合 K666N 突变。对家庭成员的基因检测显示，两个成年子女均携带杂合 K666N 突变。她 32 岁的儿子降钙素水平升高，行甲状腺切除术，发现 MTC。她 30 岁的女儿降钙素水平正常。预防性甲状腺切除术仅显示 C 细胞增生。对其他 7 名家庭成员中的 3 名进行了检测，发现他们携带该突变。所有患者的降钙素水平均正常，且无生化证据显示 PHEO 或 PHPT。鉴于报道的 RET K666N 家族中无 PHEO，我们的先证者进行了遗传性副神经节瘤或 PHEO 病因的基因检测。未发现其他突变。
我们在此报告一例纯合 RET K666N 突变导致 MTC 和 PHEO 同时发生的病例。RET K666N 突变的杂合表现对孤立性 MTC 的外显率较低。我们认为该变体的纯合性与基因剂量相关，导致双侧 PHEO 的发生。
