A Familial Case of a Whole Germline CDC73 Deletion Discordant for Primary Hyperparathyroidism
A Familial Case of a Whole Germline CDC73 Deletion Discordant for Primary Hyperparathyroidism
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原发性甲状旁腺功能亢进症全种系 CDC73 缺失不一致的家族病例
DOI：
10.1159/000495800
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发表时间：
2019
影响因子：
3.2
通讯作者：
Yamazawa Kazuki
中科院分区：
文献类型：
--
作者：
Hatabu Naomi;Katori Naho;Sato Takeshi;Maeda Naonori;Suzuki Eri;Komiyama Osamu;Tsutsui Hidemitsu;Nagao Toshitaka;Nakauchi-Takahashi Hana;Matsunaga Tatsuo;Ishii Tomohiro;Hasegawa Tomonobu;Yamazawa Kazuki
简介原发性甲状旁腺功能亢进 (PHPT) 作为家族综合征的一部分发生，包括由 CDC73 基因种系致病变异引起的 CDC73 相关疾病，特别是在成年早期。在此，我们报告一例全种系CDC73缺失与PHPT不一致的家族病例。病例描述一名15岁男孩因持续恶心和呕吐入院。实验室检查显示高钙血症（13.6 mg/dL）、低磷血症（2.4 mg/dL）和完整 PTH 水平升高（149 pg/mL）。影像学研究显示单个甲状旁腺增大。由此，诊断为PHPT。外周血 DNA 的微阵列分析显示 1q31 存在 3.4 Mb 杂合缺失，涵盖 11 个基因，其中包括 CDC73。进行了甲状腺全切除术/甲状旁腺切除术；组织学与甲状旁腺腺瘤相符，没有任何恶性肿瘤的证据。对切除的腺瘤进行 DNA 测序，证实了 CDC73 基因中存在马赛克形式的半合子无义变异，该变异可能作为“第二次打击”参与甲状旁腺肿瘤的发生。重要的是，在他 52 岁的父亲身上也发现了同样的缺失，而他的父亲没有任何异常的病史。结论这些数据从分子角度清楚地证明了克努森两次打击理论。 CDC73 相关疾病的表型变异和不完全外显率，即使是由总体缺失引起的，也应在临床环境中予以注意。
IntroductionPrimary hyperparathyroidism (PHPT) occurs as part of familial syndromes, including CDC73-related disorders caused by germline pathogenic variants of the CDC73 gene, particularly in early adulthood. Herein, we report a familial case of a whole germline CDC73 deletion discordant for PHPT.Case DescriptionA 15-year-old boy was admitted to our hospital because of persistent nausea and vomiting. Laboratory tests showed hypercalcemia (13.6 mg/dL), hypophosphatemia (2.4 mg/dL), and elevated intact PTH level (149 pg/mL). Imaging studies showed an enlarged single parathyroid gland. Thus, the diagnosis of PHPT was made. Microarray analysis of peripheral blood DNA showed a 3.4-Mb heterozygous deletion of 1q31 encompassing 11 genes, including CDC73. Total thyroidectomy/parathyroidectomy was performed; histology was compatible with parathyroid adenoma without any evidence of malignancy. DNA sequencing of the removed adenoma confirmed a hemizygous nonsense variant in the CDC73 gene in a mosaic manner, which was potentially involved in parathyroid tumorigenesis as the “second hit.” Importantly, the same deletion was identified in his 52-year-old father who had an unremarkable medical history.ConclusionsThese data clearly demonstrate the Knudson two-hit theory from a molecular viewpoint. Phenotypic variability and incomplete penetrance of CDC73-related disorders, even if caused by a gross deletion, should be noted in a clinical setting.