Domené Horacio M, Gruñeiro-Papendieck Laura, Chiesa Ana, Iorcansky Sonia, Herzovich Viviana C, Papazian Regina, Forclaz Verónica, Prieto Laura, Sansó Gabriela, Scaglia Paula, Bre Mónica, Chamoux Alfredo, Heinrich Juan J
División de Endocrinología, Centro de Investigaciones Endocrinológicas, Hospital de Niños 'R. Gutiérrez', Buenos Aires, Argentina.
Horm Res. 2004;61(1):41-6. doi: 10.1159/000075196. Epub 2003 Nov 27.
Congenital isolated thyrotropin (TSH) deficiency is an unusual condition characterized by low levels of thyroid hormones and TSH, usually presenting early typical signs of severe hypothyroidism. Five different beta-TSH mutations have been described so far. While 4 of them affect only consanguineous families, a frameshift mutation in exon 3 (C105fs114X) has been found also in nonconsanguineous families.
The aim of the present study was to characterize beta-TSH mutations in Argentinean patients with congenital central hypothyroidism (CCH) and to emphasize the importance of early biochemical and molecular diagnosis of this disorder.
We investigated 8 Argentinean children (3 boys, 5 girls) from 7 unrelated families with CCH based upon low levels of T(4) and T(3), and low basal and stimulated TSH levels. Mutation characterizations for the beta-TSH gene were performed by PCR amplification followed by sequence and restriction enzyme analysis with SNABI in the patients, 9 parents and in 100 newborn children.
All patients presented the same homozygous mutation in exon 3 of the beta-TSH gene (C105fs114X), the 9 studied parents were heterozygous for the same mutation and 1 carrier was found in the 100 studied newborns.
Our findings show that the C105fs114X mutation is prevalent in our population and may constitute a hot spot at codon 105 in the beta-TSH gene. Since this mutation is easily demonstrable by a SNABI digestion in DNA amplified from dried blood spots, its investigation would be indicated in patients in our milieu with clinical and biochemical features of CCH, allowing early L-thyroxine (LT(4)) replacement and genetic counseling of the family.
先天性孤立性促甲状腺激素（TSH）缺乏是一种罕见病症，其特征为甲状腺激素和TSH水平低下，通常会出现严重甲状腺功能减退的早期典型症状。迄今为止，已描述了五种不同的β-TSH突变。其中4种仅在近亲家庭中出现，而外显子3中的移码突变（C105fs114X）在非近亲家庭中也有发现。
本研究旨在对阿根廷先天性中枢性甲状腺功能减退症（CCH）患者的β-TSH突变进行特征分析，并强调对该疾病进行早期生化和分子诊断的重要性。
我们对来自7个无亲缘关系家庭的8名阿根廷儿童（3名男孩，5名女孩）进行了研究，这些儿童患有CCH，其依据是T4和T3水平低下，基础及刺激后TSH水平也较低。通过聚合酶链反应（PCR）扩增，随后对患者、9名父母及100名新生儿进行序列分析和使用SNABI进行限制性内切酶分析，对β-TSH基因进行突变特征分析。
所有患者在β-TSH基因外显子3中均出现相同的纯合突变（C105fs114X），9名被研究的父母为该突变的杂合子，在100名被研究的新生儿中发现1名携带者。
我们的研究结果表明，C105fs114X突变在我们的人群中很普遍，可能是β-TSH基因第105密码子处的一个热点。由于该突变通过对干血斑中扩增的DNA进行SNABI消化很容易得到证实，因此对于我们环境中具有CCH临床和生化特征的患者进行该突变的检测是必要的，这有助于早期进行左甲状腺素（LT4）替代治疗以及为家庭提供遗传咨询。
