Jorge Alexander Augusto de Lima, Andrade Nathalia L M, Rezende Raissa C, Crisostomo Lindiane G, Dantas Naiara C B, Cellin Laurana P, de Souza Vinicius, Quedas Elisangela P S, Lerario Antonio M, Vasques Gabriela A, Jorge Alexander A L
Unidade de Endocrinologia Genética (LIM 25), Hospital Das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil.
Departamento de Pediatria, Faculdade de Medicina do Centro Universitário São Camilo, São Paulo, Brazil.
Horm Res Paediatr. 2025;98(5):457-464. doi: 10.1159/000539348. Epub 2024 May 14.
Mutations in the thyroid hormone receptor alpha (THRA) gene are a rare cause of thyroid hormone resistance, which leads to a pleomorphic phenotypic spectrum. Hormonal profiles are variable and subtle, making laboratory diagnoses challenging. Genetic evaluation can be a helpful tool in diagnosing these cases.
Three patients (P1, P2, and P3) from unrelated families presented to their endocrinologists with short stature and abnormalities in thyroid function results. P1 showed hypoactivity and mild thyroid-stimulating hormone (TSH) elevation. P2 presented with a mild developmental delay and a hormonal profile initially interpreted as central hypothyroidism. Patient P3 had severe symptoms, including hypotonia, developmental delay, normal TSH, hypercholesterolemia, severe hypertriglyceridemia, high amylase levels, and mild pericardial effusion. All the patients had low free thyroxine (FT4) levels, mild constipation, and short stature. The patients underwent exome sequencing analysis that identified three different heterozygous variants in the THRA gene (P1 and P2 had missense variants, and P3 had a stop codon variant). All patients were treated with levothyroxine replacement, improving their clinical symptoms, such as constipation, and neurological symptoms. P1 and P2 were also treated with the recombinant human growth hormone (rhGH). The improvements in growth velocity and height standard deviation scores (SDS) were remarkable. Notably, P1 had a total height gain of 2.5 SDS, reaching an adult height within the normal range.
THRA gene defects can lead to growth disorders with different phenotypes. Children with THRA mutations can benefit from adequate treatment with levothyroxine and may respond well to rhGH treatment.
甲状腺激素受体α（THRA）基因突变是甲状腺激素抵抗的罕见原因，可导致多形性表型谱。激素水平变化多样且细微，给实验室诊断带来挑战。基因评估可能是诊断这些病例的有用工具。
来自无关家庭的三名患者（P1、P2和P3）因身材矮小和甲状腺功能检查结果异常就诊于内分泌科医生。P1表现为活动减少和轻度促甲状腺激素（TSH）升高。P2表现为轻度发育迟缓，其激素水平最初被解释为中枢性甲状腺功能减退。患者P3有严重症状，包括肌张力减退、发育迟缓、TSH正常、高胆固醇血症、严重高甘油三酯血症、高淀粉酶水平和轻度心包积液。所有患者游离甲状腺素（FT4）水平均低，有轻度便秘和身材矮小。患者接受了外显子测序分析，在THRA基因中发现了三种不同的杂合变异（P1和P2有错义变异，P3有一个终止密码子变异）。所有患者均接受左甲状腺素替代治疗，改善了便秘等临床症状和神经症状。P1和P2还接受了重组人生长激素（rhGH）治疗。生长速度和身高标准差评分（SDS）有显著改善。值得注意的是，P1的身高总共增加了2.5个SDS，达到了正常范围内的成人身高。
THRA基因缺陷可导致不同表型的生长障碍。患有THRA突变的儿童可从左甲状腺素的充分治疗中获益，且可能对rhGH治疗反应良好。
