Park S-M, Clifton-Bligh R J, Betts P, Chatterjee V K K
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Clin Endocrinol (Oxf). 2004 Feb;60(2):220-7. doi: 10.1111/j.1365-2265.2004.01967.x.
We wished to ascertain whether mutations in the TSH receptor (TSHR) gene were present in two siblings with congenital hypothyroidism with no parental consanguinity.
The pituitary-thyroid axis and thyroid gland morphology were investigated in both affected siblings and their parents. The TSHR gene was analysed in each subject.
Basal thyroid function together with circulating thyroglobulin levels were measured in each subject. In addition, a TRH stimulation test was undertaken in each parent. All family members underwent thyroid ultrasonography. The TSHR gene was amplified from genomic DNA using the polymerase chain reaction and receptor mutations were identified by sequence analysis.
Two siblings were diagnosed with severe congenital hypothyroidism (total T4 19-21 nmol/l, TSH 160-230 mU/l on neonatal screening). Although radioiodine scanning showed no tracer uptake and ultrasound imaging in both individuals failed to demonstrate thyroid tissue, suggesting complete athyreosis, circulating thyroglobulin levels were measurable. The thyroid status of the parents was discordant: in the father, baseline thyroid function (FT4 13 pmol/l, TSH 4 mU/l), the peak TSH level after TRH stimulation (30 mU/l) were normal and he exhibited an appropriate rise in circulating thyroid hormones in response to the elevated TSH; in contrast, in the mother, baseline thyroid function was abnormal (FT4 10 pmol/l, TSH 15 mU/l), the TSH response to TRH was exaggerated (110 mU/l), with no subsequent rise in circulating thyroid hormones. An eutopic, slightly hypoplastic thyroid gland was visualized on ultrasonography in the mother and her thyroid antibody status was negative. Both children were compound heterozygotes for missense (alanine to threonine at codon 553, A553T) and premature stop (tryptophan at codon 546, W546X) mutations in the fourth transmembrane domain of the TSH receptor. The mother and father were heterozygous for W546X and A553T mutations, respectively. Each mutation is known to abolish the function or cellular surface expression of the TSH receptor.
Inactivating mutations in the TSH receptor can be associated with severe TSH resistance presenting as congenital hypothyroidism with apparent athyreosis. Our observations also suggest that heterozygosity for an inactivating TSHR mutation may be associated with compensated hypothyroidism and thyroid hypoplasia.
我们希望确定在两名无父母近亲关系的先天性甲状腺功能减退症患儿中是否存在促甲状腺激素受体（TSHR）基因突变。
对两名患病患儿及其父母的垂体 - 甲状腺轴和甲状腺形态进行了研究。对每个受试者的TSHR基因进行了分析。
测量了每个受试者的基础甲状腺功能以及循环甲状腺球蛋白水平。此外，对每位父母进行了促甲状腺激素释放激素（TRH）刺激试验。所有家庭成员均接受了甲状腺超声检查。使用聚合酶链反应从基因组DNA中扩增TSHR基因，并通过序列分析鉴定受体突变。
两名患儿被诊断为重度先天性甲状腺功能减退症（新生儿筛查时总T4为19 - 21 nmol/l，TSH为160 - 230 mU/l）。尽管放射性碘扫描显示无示踪剂摄取，且两人的超声成像均未显示甲状腺组织，提示完全无甲状腺，但循环甲状腺球蛋白水平是可测量的。父母的甲状腺状态不一致：父亲的基础甲状腺功能（FT4为13 pmol/l，TSH为4 mU/l）、TRH刺激后TSH峰值水平（30 mU/l）正常，且其循环甲状腺激素随TSH升高有适当升高；相反，母亲的基础甲状腺功能异常（FT4为10 pmol/l，TSH为15 mU/l），对TRH的TSH反应过度（110 mU/l），随后循环甲状腺激素无升高。超声检查显示母亲有一个位置正常、轻度发育不全的甲状腺，其甲状腺抗体状态为阴性。两名患儿均为TSH受体第四跨膜结构域错义突变（密码子553处丙氨酸突变为苏氨酸，A553T）和提前终止突变（密码子546处色氨酸，W546X）的复合杂合子。母亲和父亲分别为W546X和A553T突变的杂合子。已知每个突变都会消除TSH受体的功能或细胞表面表达。
TSH受体的失活突变可能与严重的TSH抵抗相关，表现为先天性甲状腺功能减退症伴明显无甲状腺。我们的观察结果还表明，失活的TSHR突变杂合性可能与代偿性甲状腺功能减退症和甲状腺发育不全有关。
