Kelly Thomas G, Shattuck Trisha M, Reyes-Mugica Miguel, Stewart Andrew F, Simonds William F, Udelsman Robert, Arnold Andrew, Carpenter Thomas O
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520-8064, USA.
J Bone Miner Res. 2006 Oct;21(10):1666-71. doi: 10.1359/jbmr.060702.
Familial hyperparathyroid syndromes involving mutations of HRPT2 (also CDC73), a tumor suppressor, are important to identify because the relatively high incidence of parathyroid malignancy associated with such mutations warrants a specific surveillance strategy. However, there is a dearth of reports describing experience with surveillance and early detection informed by genetic insight into this disorder.
Familial isolated hyperparathyroidism (FIHP) is a rare cause of parathyroid (PT) tumors without other neoplasms or endocrinopathies. Germline mutations in CASR, MEN1, and rarely, HRPT2 have been identified in kindreds with FIHP. HRPT2 mutations may be enriched in FIHP families with PT carcinoma, underscoring the importance of identifying causative mutations.
A 13-year-old boy, whose father had died of PT carcinoma, developed primary hyperparathyroidism. A left superior PT mass was identified by ultrasonography and removed surgically. Aggressive histological features of the boy's tumor included fibrous trabeculae, mitoses, and microscopic capsular infiltration. Two years later, under close biochemical surveillance, primary hyperparathyroidism recurred 5 months after documentation of normocalcemia and normal parathyroid status. Ultrasound and MRI identified a newly enlarged right superior PT gland but indicated no recurrent disease in the left neck. Histologic features typical of a benign adenoma were evident after surgical extirpation of the gland.
Leukocyte DNA analysis revealed a frameshift mutation in exon 2 of HRPT2. The initial tumor manifested the expected germline HRPT2 mutation, plus a distinct somatic frameshift mutation, consistent with the Knudson "two hit" concept of biallelic inactivation of a classic tumor suppressor gene. Genetic screening of the patient's 7 asymptomatic and previously normocalcemic siblings revealed three with the same germline HRPT2 mutation. One of the siblings newly identified as mutation-positive was noted to be hypercalcemic at the time of the genetic screening. He was found to have a PT adenoma with aggressive features. Two of the five children of another mutation-positive sibling also carry the same HRPT2 mutation.
Despite the reported rarity of HRPT2 mutations in FIHP, a personal or family history of PT carcinoma in FIHP mandates serious consideration of germline HRPT2 mutation status. This information can be used in diagnostic and management considerations, leading to early detection and removal of potentially malignant parathyroid tumors.
涉及肿瘤抑制基因HRPT2（亦称为CDC73）突变的家族性甲状旁腺功能亢进综合征很重要，因为与这些突变相关的甲状旁腺恶性肿瘤发病率相对较高，需要特定的监测策略。然而，缺乏相关报告描述基于对此疾病的基因洞察进行监测和早期检测的经验。
家族性孤立性甲状旁腺功能亢进（FIHP）是甲状旁腺（PT）肿瘤的罕见病因，不伴有其他肿瘤或内分泌疾病。在FIHP家族中已鉴定出钙敏感受体（CASR）、多发性内分泌腺瘤1型基因（MEN1）以及罕见的HRPT2的种系突变。HRPT2突变可能在伴有PT癌的FIHP家族中更为常见，这突出了识别致病突变的重要性。
一名13岁男孩，其父亲死于PT癌，该男孩患原发性甲状旁腺功能亢进。超声检查发现左上甲状旁腺有肿块，并进行了手术切除。该男孩肿瘤的侵袭性组织学特征包括纤维小梁、有丝分裂和显微镜下的包膜浸润。两年后，在密切的生化监测下，原发性甲状旁腺功能亢进在血钙正常和甲状旁腺状态正常记录5个月后复发。超声和磁共振成像（MRI）显示右上甲状旁腺新增大，但左颈部未发现复发疾病。手术切除该腺体后，可见典型的良性腺瘤组织学特征。
白细胞DNA分析显示HRPT2外显子2存在移码突变。最初的肿瘤表现出预期的种系HRPT2突变，加上一个独特的体细胞移码突变，符合经典肿瘤抑制基因双等位基因失活的Knudson“两次打击”概念。对患者7名无症状且之前血钙正常的兄弟姐妹进行基因筛查，发现3人有相同的种系HRPT2突变。在基因筛查时，新确定为突变阳性的一名兄弟姐妹被发现血钙升高。他被发现患有具有侵袭性特征的PT腺瘤。另一名突变阳性兄弟姐妹的5个孩子中有2个也携带相同的HRPT2突变。
尽管报告显示FIHP中HRPT2突变罕见，但FIHP患者个人或家族中有PT癌病史时，必须认真考虑种系HRPT2突变状态。这些信息可用于诊断和管理考量，从而早期发现并切除潜在的恶性甲状旁腺肿瘤。
