Cetani F, Pardi E, Ambrogini E, Viacava P, Borsari S, Lemmi M, Cianferotti L, Miccoli P, Pinchera A, Arnold A, Marcocci C
Department of Endocrinology and Metabolism, University of Pise, Pise, Italy.
Endocr Relat Cancer. 2007 Jun;14(2):493-9. doi: 10.1677/ERC-06-0092.
Early onset of primary hyperparathyroidism (PHPT) and multiglandular involvement suggest a familial form in which germline mutation of a PHPT-related gene(s) and a somatic event at the same locus can be often demonstrated. We investigated the involvement of multiple endocrine neoplasia type 1 (MEN1) and HRPT2 genes in a 39-year-old man with recurrent PHPT. PHPT was firstly diagnosed at the age of 21 and the patient had two recurrences separated by extended periods of normocalcemia. This unusual history prompted us to investigate other family members and study the MEN1 and HRPT2 genes. An HRPT2 germline missense mutation in exon 3 (R91P) was found in the index case, which was associated with different HRPT2 somatic alterations in each of the three examined parathyroid tumors. These findings are consistent with Knudson's 'two hit' concept of biallelic inactivation of classical tumor suppressor genes. Screening of 15 asymptomatic relatives was negative for the R91P germline mutation. All the three abnormal parathyroid specimens showed cystic features at histology and were negative for parafibromin immunostaining. In one specimen, diffuse parafibromin staining was evident in a rim of normal parathyroid tissue surrounding the adenomatous lesion. Our study shows that different somatic genetic events at the HRPT2 locus are responsible for the asynchronous occurrence of multiple adenomas in a patient carrying an HRPT2 germline mutation. The finding of diffuse parafibromin staining in a rim of normal parathyroid tissue, but not in the contiguous adenomatous lesion, reinforces the concept that loss of parafibromin expression is responsible for the development of parathyroid tumors in this setting.
原发性甲状旁腺功能亢进症（PHPT）的早发及多腺体受累提示为家族性形式，其中常可证实PHPT相关基因的种系突变以及同一基因座的体细胞事件。我们调查了1型多发性内分泌腺瘤病（MEN1）和HRPT2基因在一名复发性PHPT的39岁男性中的作用。PHPT最初在21岁时被诊断出，该患者有两次复发，中间间隔长时间的血钙正常。这一不同寻常的病史促使我们调查其他家庭成员并研究MEN1和HRPT2基因。在索引病例中发现了外显子3中的HRPT2种系错义突变（R91P），这与三个检查的甲状旁腺肿瘤中每一个的不同HRPT2体细胞改变相关。这些发现与Knudson经典肿瘤抑制基因双等位基因失活的“两次打击”概念一致。对15名无症状亲属的筛查结果显示R91P种系突变呈阴性。所有三个异常甲状旁腺标本在组织学上均显示囊性特征，且甲状旁腺素免疫染色呈阴性。在一个标本中，腺瘤样病变周围正常甲状旁腺组织边缘可见弥漫性甲状旁腺素染色。我们的研究表明，HRPT2基因座处不同的体细胞遗传事件是携带HRPT2种系突变患者中多个腺瘤异步发生的原因。在正常甲状旁腺组织边缘而非相邻腺瘤样病变中发现弥漫性甲状旁腺素染色，强化了在这种情况下甲状旁腺素表达缺失是甲状旁腺肿瘤发生原因的概念。
