Bakhsh A, Kirov G, Gregory J W, Williams E D, Ludgate M
Centre for Endocrine and Diabetes Sciences, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
Endocr Relat Cancer. 2006 Jun;13(2):475-83. doi: 10.1677/erc.1.01138.
We report a kindred with euthyroid multi-nodular goitre (MNG) of adolescent onset. Two of the seven subjects with MNG have progressed to papillary thyroid cancer. One affected male had nodular kidney disease, and breast cancer occurred in one affected female. Genes that were candidates on the basis of the associated kidney (PAX8) and breast diseases (sodium iodide symporter (NIS)), were sequenced. No mutations were found in the coding region, intron/exon splice sites or in the promoter sequences (from -1248 relative to the translation initiation codon) of PAX8. Similar results were obtained for NIS. Subsequently, microsatellite analyses were performed on 14 informative family members. We used 2 to 3 markers per locus for 6 loci (on chromosomes 1,2,3,14,19,X) previously reported to predispose to MNG and/or familial non-medullary thyroid cancer (FNMTC). On the basis of non-significant logarithm of the odds ratio (LOD) scores or inheritance of different alleles in affected individuals, all loci have been excluded. Thyroidectomy specimens from three members of the kindred show multiple benign lesions, with papillary cancer in two. The morphological features do not resemble those seen in familial adenomatous polyposis, Cowden syndrome, or in multiple oxyphil lesions. From these findings and from the absence of any linkage to any of the known loci associated with MNG or FNMTC, we suggest that this represents a new form of inherited MNG with a significant risk of progression to papillary carcinoma.
我们报告了一个青少年期发病的甲状腺功能正常的多结节性甲状腺肿（MNG）家系。7名患有MNG的受试者中有2人已进展为甲状腺乳头状癌。1名受影响的男性患有结节性肾病，1名受影响的女性患有乳腺癌。对基于相关肾脏疾病（PAX8）和乳腺疾病（钠碘同向转运体（NIS））的候选基因进行了测序。在PAX8的编码区、内含子/外显子剪接位点或启动子序列（相对于翻译起始密码子为-1248）中未发现突变。NIS也得到了类似的结果。随后，对14名信息丰富的家庭成员进行了微卫星分析。我们对先前报道的易患MNG和/或家族性非髓样甲状腺癌（FNMTC）的6个基因座（位于染色体1、2、3、14、19、X上）每个基因座使用2至3个标记。基于非显著的优势对数比（LOD）分数或受影响个体中不同等位基因的遗传情况，所有基因座均被排除。该家系3名成员的甲状腺切除标本显示多个良性病变，其中2例为乳头状癌。其形态学特征与家族性腺瘤性息肉病、考登综合征或多个嗜酸性细胞病变中所见的特征不同。根据这些发现以及与任何已知的与MNG或FNMTC相关的基因座均无连锁关系，我们认为这代表了一种新的遗传性MNG形式，具有进展为乳头状癌的显著风险。
