Grüters A, Köhler B, Wolf A, Söling A, de Vijlder L, Krude H, Biebermann H
Department of Pediatrics, Humboldt University Berlin, Germany.
Exp Clin Endocrinol Diabetes. 1996;104 Suppl 4:121-3. doi: 10.1055/s-0029-1211718.
While congenital hypothyroidism in 80-90% of the affected individuals is caused by thyroid dysgenesis (athyrosis, ectopy or hypoplasia), hypothyroidism in patients with a thyroid gland of normal position and size can be due to regulatory or enzymatic defects of thyroid hormone biosynthesis. Beside defects of thyroglobulinsynthesis, defects of the sodium-iodide-transporter or the TSH-receptor, a defect of the thyroidperoxidase, the key-enzyme of thyroid hormone biosynthesis, can cause a total iodide organification defect and thereby congenital hypothyroidism. We screened 14 of 103 patients (13.6%) with non familial congenital hypothyroidism and a normally developed thyroid gland detected by the newborn screening program with the PCR-SSCP (single-stranded-conformational-polymorphism) technique for mutations in the exons 2, 8, 9, 10 and 14 of the human thyroperoxidase gene, and in which mutations had been described previously in Dutch and Brazilian families with total organification defects. Most of the previously reported mutations were found in exons 8, 9 and 10 which code for the caralytic part of the enzyme. In two patients a GGCC-duplication in exon 8 was detected leading to a premature stop codon in exon 9. While one patient without neonatal goiter was homozygous for this mutation, the second patient was only heterozygous thus demanding another mutation on the second TPO-allel to explain the phenotype. Since the GGCC duplication is easily demonstrable by a NaeI digestion, because it creates a restriction site for this enzyme, screening for this mutation is indicated since it is easy to perform. In contrast to the perchlorate discharge test molecular genetic studies are less invasive, but as useful in making a definitive diagnosis in the individual patient. Furthermore it is the first feasible step to study the etiology and epidemiology of the so far only putative defects of thyroid hormone biosynthesis leading to congenital hypothyroidism.
虽然80% - 90%的先天性甲状腺功能减退症患者是由甲状腺发育不全（无甲状腺、异位或发育不全）引起的，但甲状腺位置和大小正常的患者出现甲状腺功能减退症可能是由于甲状腺激素生物合成的调节或酶缺陷。除了甲状腺球蛋白合成缺陷、钠碘转运体或促甲状腺激素受体缺陷外，甲状腺过氧化物酶（甲状腺激素生物合成的关键酶）缺陷可导致完全碘有机化缺陷，进而引起先天性甲状腺功能减退症。我们对103例非家族性先天性甲状腺功能减退症患者中的14例（13.6%）进行了筛查，这些患者通过新生儿筛查项目检测出甲状腺发育正常，采用聚合酶链反应 - 单链构象多态性（PCR - SSCP）技术检测人类甲状腺过氧化物酶基因外显子2、8、9、10和14中的突变，此前在荷兰和巴西患有完全有机化缺陷的家族中已描述过这些突变。大多数先前报道的突变存在于编码该酶催化部分的外显子8、9和10中。在两名患者中检测到外显子8中的GGCC重复，导致外显子9中出现提前终止密码子。一名无新生儿甲状腺肿的患者对此突变为纯合子，而另一名患者仅为杂合子，因此需要第二个TPO等位基因上的另一个突变来解释其表型。由于GGCC重复通过NaeI消化很容易证明，因为它为该酶创造了一个限制位点，因此鉴于其易于操作，对该突变进行筛查是有必要的。与高氯酸盐释放试验相比，分子遗传学研究创伤性较小，但在对个体患者进行明确诊断方面同样有用。此外，这是研究迄今为止仅有的可能导致先天性甲状腺功能减退症的甲状腺激素生物合成缺陷的病因和流行病学的第一步可行措施。
