PDF(Pubmed)
Abstract：
Approximately 10% of primary hyperparathyroidism cases are hereditary, due to germline mutations in certain genes. Although clinically relevant, a systematized genetic diagnosis is missing due to a lack of firm evidence regarding individuals to test and which genes to evaluate.
A customized gene panel (AIP, AP2S1, CASR, CDC73, CDKN1A, CDKN1B, CDKN2B, CDKN2C, GCM2, GNA11, MEN1, PTH, RET, and TRPV6) was performed in 40 patients from the Mediterranean area with suspected familial hyperparathyroidism (≤45 years of age, family history, high-risk histology, associated tumour, multiglandular disease, or recurrent hyperparathyroidism). We aimed to determine the prevalence of germline variants in these patients, to clinically characterize the probands and their relatives, and to compare disease severity in carriers versus those with a negative genetic test.
Germline variants were observed in 9/40 patients (22.5%): 2 previously unknown pathogenic/likely pathogenic variants of CDKN1B (related to MEN4), 1 novel variant of uncertain significance of CDKN2C, 4 variants of CASR (3 pathogenic/likely pathogenic variants and 1 variant of uncertain significance), and 2 novel variants of uncertain significance of TRPV6. Familial segregation studies allowed diagnosis and early treatment of PHPT in first-degree relatives of probands.
The observed prevalence of germline variants in the Mediterranean cohort under study was remarkable and slightly higher than that seen in other populations. Genetic screening for suspected familial hyperparathyroidism allows the early diagnosis and treatment of PHPT and other related comorbidities. We recommend genetic testing for patients with primary hyperparathyroidism who present with high-risk features.
A customized gene panel (AIP, AP2S1, CASR, CDC73, CDKN1A, CDKN1B, CDKN2B, CDKN2C, GCM2, GNA11, MEN1, PTH, RET, and TRPV6) was performed in 40 patients from the Mediterranean area with suspected familial hyperparathyroidism (≤45 years of age, family history, high-risk histology, associated tumour, multiglandular disease, or recurrent hyperparathyroidism). We aimed to determine the prevalence of germline variants in these patients, to clinically characterize the probands and their relatives, and to compare disease severity in carriers versus those with a negative genetic test.
Germline variants were observed in 9/40 patients (22.5%): 2 previously unknown pathogenic/likely pathogenic variants of CDKN1B (related to MEN4), 1 novel variant of uncertain significance of CDKN2C, 4 variants of CASR (3 pathogenic/likely pathogenic variants and 1 variant of uncertain significance), and 2 novel variants of uncertain significance of TRPV6. Familial segregation studies allowed diagnosis and early treatment of PHPT in first-degree relatives of probands.
The observed prevalence of germline variants in the Mediterranean cohort under study was remarkable and slightly higher than that seen in other populations. Genetic screening for suspected familial hyperparathyroidism allows the early diagnosis and treatment of PHPT and other related comorbidities. We recommend genetic testing for patients with primary hyperparathyroidism who present with high-risk features.
摘要：
■大约10％的原发性甲状旁腺功能亢进病例是遗传性的，由于某些基因的种系突变。尽管临床相关，由于缺乏有关个人测试和评估哪些基因的确凿证据，因此缺乏系统化的基因诊断。
■定制的基因面板(AIP，AP2S1,CASR,CDC73,CDKN1A,CDKN1B,CDKN2B,CDKN2C,GCM2,GNA11,MEN1,PTH,RET,和TRPV6）在来自地中海地区的40例疑似家族性甲状旁腺功能亢进（≤45岁，家族史,高危组织学,相关肿瘤，多腺体疾病，或复发性甲状旁腺功能亢进)。我们旨在确定这些患者中种系变异的患病率，临床描述先证者及其亲属的特征，并比较携带者和基因检测阴性者的疾病严重程度。
■在9/40患者（22.5％）中观察到种系变异：CDKN1B的2种先前未知的致病性/可能的致病性变异（与MEN4有关），1个具有不确定意义的CDKN2C的新变体，CASR的4种变体（3种致病性/可能致病性变体和1种具有不确定意义的变体），和2个不确定意义的TRPV6的新变体。家族隔离研究允许先证者一级亲属的PHPT诊断和早期治疗。
■在所研究的地中海队列中观察到的种系变异的患病率显着，并且略高于其他人群。对疑似家族性甲状旁腺功能亢进的基因筛查可以早期诊断和治疗PHPT和其他相关合并症。我们建议对具有高危特征的原发性甲状旁腺功能亢进患者进行基因检测。
■定制的基因面板(AIP，AP2S1,CASR,CDC73,CDKN1A,CDKN1B,CDKN2B,CDKN2C,GCM2,GNA11,MEN1,PTH,RET,和TRPV6）在来自地中海地区的40例疑似家族性甲状旁腺功能亢进（≤45岁，家族史,高危组织学,相关肿瘤，多腺体疾病，或复发性甲状旁腺功能亢进)。我们旨在确定这些患者中种系变异的患病率，临床描述先证者及其亲属的特征，并比较携带者和基因检测阴性者的疾病严重程度。
■在9/40患者（22.5％）中观察到种系变异：CDKN1B的2种先前未知的致病性/可能的致病性变异（与MEN4有关），1个具有不确定意义的CDKN2C的新变体，CASR的4种变体（3种致病性/可能致病性变体和1种具有不确定意义的变体），和2个不确定意义的TRPV6的新变体。家族隔离研究允许先证者一级亲属的PHPT诊断和早期治疗。
■在所研究的地中海队列中观察到的种系变异的患病率显着，并且略高于其他人群。对疑似家族性甲状旁腺功能亢进的基因筛查可以早期诊断和治疗PHPT和其他相关合并症。我们建议对具有高危特征的原发性甲状旁腺功能亢进患者进行基因检测。
