Hyperparathyroidism -- Etiology, Diagnosis and Treatment

甲状旁腺功能亢进症——病因、诊断和治疗

基本信息

批准号：
10919416
负责人：
Smita Jha
金额：
$ 91万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10919416
关键词：
Biological Assay Blood CCND1 gene CDK6-associated protein p18 Calcium Catheters Clinical Collaborations Cyclin D1 Cyclin-Dependent Kinase Inhibitor Gene Diagnosis Disease Disease remission Endocrine Gland Neoplasms Endocrine Glands Etiology Excision Familial hypocalciuric hypercalcemia Family Fracture Frequencies GCM2 gene Genes Genetic Counseling Genotype Germ-Line Mutation Gland Growth Hyperparathyroidism Hypoparathyroidism Image Impairment Infarction Inherited Jaw Kidney Calculi Low Prevalence Measurement Mediastinal Medical Records Modeling Multiple Endocrine Neoplasia Type 1 Mutate Mutation Neck Operative Surgical Procedures Osteopenia Other Genetics Parathyroid Adenoma Parathyroid Neoplasms Parathyroid gland Parathyroidectomy Pathologic Patients Pharmaceutical Preparations Phenotype Polyamines Process Recurrence Recurrent Laryngeal Nerve Refractory Repeat Surgery Risk Serum Severities Signs and Symptoms Somatic Mutation Structure Syndrome Testing Tissues United States National Institutes of Health Variant Work adenoma adverse outcome bone demineralization exome sequencing gain of function mutation indexing interest ionization kinase inhibitor malignant parathyroid gland tumor men neuromuscular operation proband skills success tumor tumorigenesis venous thromboembolism

项目摘要

85% of sporadic hyperparathyroidism cases have a solitary adenoma. The remaining 15% of cases have multiple tumors. About 95% of all cases achieve a long remission at initial operation. Adverse outcomes are increased in multigland disease and in cases with prior failed operation; the adverse outcomes include damage to important structures such as the recurrent laryngeal nerve(s), hypoparathyroidism, persistent hyperparathyroidism, and late recurrent hyperparathyroidism. Approximately half of new referrals to NIH have had prior failed neck exploration for hyperparathyroidism and are referred because of our expertise in such cases. The surgical success rate at NIH in these difficult cases has been 95%. This group is enriched for multi gland hyperparathyroidism and thus for hereditary causes. We have contributed to an intramural NIH collaboration that has cloned the MEN1 gene. We are continuing to explore its clinical and its basic implications. We find germline mutations in 70-80% of probands with familial MEN1 or at lower prevalence in cases with sporadic MEN1. In contrast, probands with familial isolated hyperparathyroidism have rare (about 5%) MEN1 mutations. Among the MEN1-like families without MEN1 mutation, a rare family shows mutation of the p27 cylclin dependent kinase inhibitor (CDKI) gene. p27 germline mutation in MEN1 is about 1% the frequency of MEN1 mutation. We have also found rare germline mutation of p15, p18, or p21 CDKIs. We have also found somatic MEN1 mutation in 15 to 35% of sporadic tumors of many endocrine organs. Thus MEN1 is the gene most frequently implicated in common endocrine tumors. We found p18 CDKI in a sporadic parathyroid adenoma. We will also determine the spectrum of pathologic states that the MEN1 or the CDKI genes contribute to through mutation and other mechanisms. The cause of solitary (non-familial) parathyroid adenoma is believed to be somatic mutation of some gene, with overgrowth of a tumor clone. Mutation of the cyclin D1 (PRAD1) gene accounts for about 3-4%. Sporadic (nonhereditary) mutation of the MEN1 gene is the most common known mutation, causing 25-30% of solitary and common variety adenomas. The ZFX gene is mutated in 6%. Of the 15% of cases with multigland disease, 5% (1/3 of 15%) have a familial form. 4% of the 5% have familial MEN1 or familial hypocalciuric hypercalcemia. About 1% have familial isolated hyperparathyroidism (FIHP). The underlying gene for FIHP is GCM2 (gain-of-function mutation) in approximately 20% of cases. The underlying gene(s)for the remaining 80% of FIHP are not known. Among all MEN1-like cases without identified mutation, 3.5% have mutation in a cyclin dependent kinase inhibitor gene, specifically p15, p18, p21, or p27. Recent studies show that MEN1 patients are at increased risk of venous thromboembolism. Furthermore, as part of a multi-institute collaboration, we identified blood-based polyamines as a potential predictor for MEN1 patients likely to develop aggressive disease. Our work has also identified variants in FLCN gene as a cause of parathyroid cancer. We are working to identify and genotype -phenotype correlation in MEN1 and other genetic forms of primary hyperparathyroidism.

85% 的散发性甲状旁腺功能亢进病例有孤立性腺瘤。其余15%的病例有多个肿瘤。约 95% 的病例在初次手术时获得长期缓解。多腺体疾病和既往手术失败的病例中不良后果会增加；不良后果包括重要结构的损伤，如喉返神经、甲状旁腺功能减退症、持续性甲状旁腺功能亢进症和晚期复发性甲状旁腺功能亢进症。大约一半的新转诊到 NIH 的患者之前曾因甲状旁腺功能亢进症进行过颈部探查失败，并且由于我们在此类病例方面的专业知识而被转诊。 NIH 对这些疑难病例的手术成功率高达 95%。该群体富含多腺体甲状旁腺功能亢进症，因此也富含遗传性原因。我们为 NIH 的校内合作做出了贡献，克隆了 MEN1 基因。我们正在继续探索其临床及其基本意义。我们发现 70-80% 具有家族性 MEN1 的先证者存在种系突变，而在散发性 MEN1 的先证者中，种系突变的发生率较低。相比之下，患有家族性孤立性甲状旁腺功能亢进症的先证者具有罕见（约 5%）的 MEN1 突变。在没有 MEN1 突变的 MEN1 样家族中，一个罕见的家族显示 p27 细胞周期蛋白依赖性激酶抑制剂 (CDKI) 基因突变。 MEN1 中的 p27 种系突变约为 MEN1 突变频率的 1%。我们还发现了 p15、p18 或 p21 CDKI 的罕见种系突变。我们还在许多内分泌器官的散发性肿瘤中发现了 15% 至 35% 的体细胞 MEN1 突变。因此，MEN1 是常见内分泌肿瘤中最常涉及的基因。我们在散发性甲状旁腺腺瘤中发现了 p18 CDKI。我们还将确定 MEN1 或 CDKI 基因通过突变和其他机制导致的病理状态谱。孤立性（非家族性）甲状旁腺腺瘤的病因被认为是某些基因的体细胞突变，以及肿瘤克隆的过度生长。细胞周期蛋白D1（PRAD1）基因突变约占3-4%。 MEN1 基因的散发（非遗传性）突变是最常见的已知突变，导致 25-30% 的孤立性和常见品种腺瘤。 ZFX基因有6%发生突变。在 15% 的多腺体疾病病例中，5%（15% 的 1/3）具有家族性。 5% 中的 4% 患有家族性 MEN1 或家族性低钙尿性高钙血症。大约 1% 患有家族性孤立性甲状旁腺功能亢进症 (FIHP)。在大约 20% 的病例中，FIHP 的潜在基因是 GCM2（功能获得突变）。其余 80% 的 FIHP 的潜在基因尚不清楚。在所有未发现突变的 MEN1 样病例中，3.5% 的细胞周期蛋白依赖性激酶抑制剂基因发生突变，特别是 p15、p18、p21 或 p27。最近的研究表明，MEN1 患者发生静脉血栓栓塞的风险增加。此外，作为多机构合作的一部分，我们发现血液中的多胺是可能发展为侵袭性疾病的 MEN1 患者的潜在预测因子。我们的工作还发现 FLCN 基因变异是甲状旁腺癌的一个原因。我们正在努力鉴定 MEN1 和原发性甲状旁腺功能亢进症的其他遗传形式的基因型-表型相关性。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cockayne syndrome, MEN1, and genomic variants: Exome sequencing is changing our view of the genetic landscape.

DOI：
10.1111/pde.14655
发表时间：
2021-07
期刊：
PEDIATRIC DERMATOLOGY
影响因子：
1.5
作者：
Oska, Sandra R.;Tamura, Deborah;Blau, Jenny E.;Khan, Sikandar G.;Kraemer, Kenneth H.;DiGiovanna, John J.
通讯作者：
DiGiovanna, John J.

Endocrine neoplasms in familial syndromes of hyperparathyroidism.

甲状旁腺功能亢进症家族综合征中的内分泌肿瘤。