Hormone research in paediatrics · 2026
Intrafamilial and Age-Dependent Variability in Resistance to Thyroid Hormone Alpha: A Case Report.
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Nauwynck Elise, Ryckx Sofie, Klink Daniel, Vermaning Sietske, Meuwissen Marije, Billion Lisa, De Schepper Jean
Аннотация
INTRODUCTION: Resistance to thyroid hormone alpha (RTHα) is a rare genetic disorder caused by pathogenic variants in the thyroid hormone receptor alpha (THRA) gene, characterized by tissue-specific hypothyroidism despite often normal circulating thyroid hormone levels.
CASE PRESENTATION: In this report, we describe a family of three individuals - two sisters and their mother - carrying a heterozygous missense variant (c.1207G>A) in THRA. The variant was identified after evaluation of the daughters for short stature, increasing adiposity, and delayed bone age. Hormonal assessments revealed subtle thyroid function abnormalities, including low-normal free thyroxine (FT4), high-normal free tri-iodothyronine (FT3), an elevated FT3/FT4 ratio, and normal thyroid-stimulating hormone (TSH) levels. Additional clinical features included variably present delayed dentition, chronic constipation, and hepatic steatosis. Both sisters exhibited normocytic anemia and delayed language development.
CONCLUSION: This report adds novel insight by documenting intrafamilial variability and age-related attenuation of biochemical abnormalities in a family carrying a previously described THRA variant. It emphasizes the risk of missed diagnosis when relying solely on thyroid function tests and illustrates the importance of family-based evaluation across the lifespan, including in adults who may present with subtler biochemical or metabolic abnormalities. RTHα should be considered in patients with growth delay, disproportionate weight gain, persistent normocytic anemia, or developmental delay, even when thyroid hormone levels appear near-normal. Awareness of these patterns can prevent delayed diagnosis and support individualized clinical management.
CASE PRESENTATION: In this report, we describe a family of three individuals - two sisters and their mother - carrying a heterozygous missense variant (c.1207G>A) in THRA. The variant was identified after evaluation of the daughters for short stature, increasing adiposity, and delayed bone age. Hormonal assessments revealed subtle thyroid function abnormalities, including low-normal free thyroxine (FT4), high-normal free tri-iodothyronine (FT3), an elevated FT3/FT4 ratio, and normal thyroid-stimulating hormone (TSH) levels. Additional clinical features included variably present delayed dentition, chronic constipation, and hepatic steatosis. Both sisters exhibited normocytic anemia and delayed language development.
CONCLUSION: This report adds novel insight by documenting intrafamilial variability and age-related attenuation of biochemical abnormalities in a family carrying a previously described THRA variant. It emphasizes the risk of missed diagnosis when relying solely on thyroid function tests and illustrates the importance of family-based evaluation across the lifespan, including in adults who may present with subtler biochemical or metabolic abnormalities. RTHα should be considered in patients with growth delay, disproportionate weight gain, persistent normocytic anemia, or developmental delay, even when thyroid hormone levels appear near-normal. Awareness of these patterns can prevent delayed diagnosis and support individualized clinical management.