Bonomi M, Proverbio M C, Weber G, Chiumello G, Beck-Peccoz P, Persani L
Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore Istituto de Ricovero e Cura a Carattere Scientifico, Italy.
J Clin Endocrinol Metab. 2001 Apr;86(4):1600-4. doi: 10.1210/jcem.86.4.7411.
Inheritable isolated central hypothyroidism (ICH) due to mutations of TSH beta gene has been reported in few patients. For this reason the diagnostic criteria are vague. The disorder is usually characterized by undetectable TSH levels, although low/normal serum TSH, depending on TSH measurement methods, has been documented in some patients. Here we report an Egyptian girl with ICH due to a novel nonsense mutation of the TSH beta gene (Q49X). She was referred at 75 days of age for severe clinical signs of hypothyroidism, whose central origin was documented by normal serum TSH, low free T(4) and free T(3) levels, impaired TSH response to TRH, absence of (99)Tc thyroidal uptake, and antithyroid autoantibodies. Ultrasound revealed a hypoplastic thyroid, whereas magnetic resonance imaging showed a hyperplastic pituitary. All other pituitary hormones, including PRL, were normally secreted. A diagnosis of idiopathic ICH was made, and substitutive L-T(4) treatment was started at 81 days of age. At the age of 7 yr the patient had normal thyroid hormone levels, but was severely mentally retarded. Interestingly, the sella computed tomography scan had completely normalized. At 8 yr of age the patient was reinvestigated after 6-week L-T(4) withdrawal. TSH values were highly variable depending on the measurement method used, whereas extremely high levels of circulating free glycoprotein alpha-subunit were recorded. Despite the fact that mutant TSH beta lacks 60% of the C-terminal amino acid sequence, it forms with the alpha-subunit a heterodimer with preserved immunoreactivity in some TSH measurement methods, but the mutant heterodimer is completely devoid of bioactivity. In conclusion, high circulating free glycoprotein alpha-subunit levels, variable TSH levels, and, possibly, hyperplastic pituitary gland are the hallmark of ICH due to mutations of the TSH beta gene.
少数患者中曾报道过因促甲状腺激素β基因（TSHβ）突变导致的遗传性孤立性中枢性甲状腺功能减退症（ICH）。因此，其诊断标准尚不明确。该疾病通常表现为促甲状腺激素水平检测不到，不过根据促甲状腺激素检测方法的不同，部分患者的血清促甲状腺激素水平可呈低/正常。在此，我们报告一名患有因TSHβ基因新的无义突变（Q49X）导致的ICH的埃及女孩。她在75日龄时因甲状腺功能减退的严重临床症状前来就诊，通过正常的血清促甲状腺激素水平、低游离T4和游离T3水平、促甲状腺激素对促甲状腺激素释放激素（TRH）反应受损、无（99）锝甲状腺摄取以及抗甲状腺自身抗体，证实其甲状腺功能减退源于中枢。超声检查显示甲状腺发育不全，而磁共振成像显示垂体增生。包括催乳素（PRL）在内的所有其他垂体激素分泌均正常。诊断为特发性ICH，并于81日龄开始进行左甲状腺素（L-T4）替代治疗。7岁时，患者甲状腺激素水平正常，但存在严重智力发育迟缓。有趣的是，蝶鞍计算机断层扫描已完全恢复正常。8岁时，在停用L-T4 6周后对患者进行复查。促甲状腺激素值因所使用的检测方法不同而差异很大，同时记录到循环中游离糖蛋白α亚基水平极高。尽管突变的TSHβ缺乏60%的C末端氨基酸序列，但在某些促甲状腺激素检测方法中，它与α亚基形成了具有保留免疫反应性的异二聚体，不过该突变异二聚体完全没有生物活性。总之，循环中游离糖蛋白α亚基水平升高、促甲状腺激素水平多变以及可能存在的垂体增生是TSHβ基因突变导致的ICH的特征。
