不同亚型的甲状腺激素抵抗综合征二例的临床特点分析

Clinical characteristics of thyroid hormone resistance syndrome in two cases with different subtypes

目的分析2例不同亚型的甲状腺激素抵抗综合征（RTH）病例的临床特点，并对相关甲状腺激素受体（TR）基因变异进行分析。方法报道2例2015年和2017年苏州大学附属儿童医院内分泌遗传代谢科收治的RTH患者的临床表现、实验室检查及基因检测结果并复习相关文献。结果例1女，10岁，发现甲状腺肿大数天，无甲状腺毒性症状。实验室检查示：游离三碘甲状腺原氨酸15.36 pmol/L（3.1~6.8），游离甲状腺素65.77 pmol/L（12~22），促甲状腺激素水平正常。基因检测在TRβ基因发现一个杂合变异，根据2015年美国医学遗传学与基因组学学会（ACMG）指南为可能致病性变异，诊断为RTHβ。例2男，3岁，有典型的甲状腺功能低下表现（生长、发育落后，骨骼畸形），但是甲状腺激素指标接近正常范围。目标序列捕获测序分析在TRα基因发现一个新生的无义变异，根据ACMG指南为致病性变异，诊断为RTHα。结论RTHβ常见临床表现为甲状腺肿大，血游离三碘甲状腺原氨酸和游离甲状腺素明显升高，促甲状腺素正常；RTHα临床表现类似甲状腺功能低下，但甲状腺激素指标接近正常。对TRβ和TRα进行基因测定和致病性分析有助明确诊断。

ObjectiveTo analyze the clinical characteristics of children with two types of thyroid hormone resistance （RTH） syndrome, and to detect the variants of thyroid hormone receptor alpha（TRα） and TRβ gene in children.MethodTwo children with RTH were reported in regard to clinical manifestation, laboratory examination and genetic variants. Some related reports in literature were reviewed.ResultCase 1 was a girl, 10 years old, with thyroid enlargement for several days and without thyrotoxicosis. Laboratory work-up revealed that free thyroxine （FT4） was 65.77 pmol/L （reference 12-22） , free triiodothyronine （FT3） was 15.36 pmol/L （reference 3.1-6.8） and thyroid stimulating hormone （TSH） level was normal. There was a likely pathogenic missense variant detected in TRβ gene and this patient was diagnosed with RTHβ. Case 2 was a boy, 3 years old, with classic features of hypothyroidism（growth retardation, developmental retardation, skeletal dysplasia） but had only borderline-abnormal thyroid hormone levels. Targeted sequencing showed a de novo heterozygous nonsense variant in TRα gene which is a pathogenic variant and this patient been diagnosed with RTHα.ConclusionThyroid enlargement is a common clinical manifestation of RTHβ, with laboratory work-up reveals elevated FT4 and FT3 levels but TSH level is normal. The clinical manifestations of RTHα are similar to those of hypothyroidism, but the thyroid hormone levels are almost normal. The gene sequence and the pathogenicity analysis for TRα and TRβ will help to make a definitive diagnosis.