Endocrine Abstracts

JOINT1716

Background: Resistance to thyroid hormone (RTH) alpha is caused by pathogenic variants in the thyroid hormone receptor alpha (THRA) gene. Diagnosis is frequently delayed due to its rarity, association with near-normal thyroid function tests and variable nature of its clinical presentation. This report describes three family members exhibiting variable clinical and hormonal manifestations of RTH due to a heterozygous missense variant in the THRA gene.

Case Presentation: Two sisters, aged 5 and 2.5 years, presented with short stature and developmental delay. The oldest sister was born at 40 weeks of gestation with an average birth weight, length, and head circumference (HC). Between 6 and 20 months, she experienced faltering growth, although weight gain remained normal. She had chronic constipation and delayed language development with dysarthric speech. The younger sister was born at 38 5/7 weeks gestation, with a birth weight of -1.4 SDS, birth length of -1.2 SDS, and HC of -0.7 SDS. Postnatally, she exhibited limited catch-up growth, but a significant BMI increase after the age of 6 months. She had delayed tooth eruption, general hypotonia, and a delayed motor and language development. The mother had a history of learning problems, dysarthric speech, heart rhythm disorder, insulin resistance with hepatic steatosis. Her height was 159 cm and weight 105 kg. Her serum TSH (0.72 U/l) and fT4 (14.8 pmol/l) were normal. Clinical examination revealed in both sisters short stature (-3.8 SDS and -2.5 SDS), relative macrocephaly (HC +0.2 SDS and +0.9 SDS), and increased BMI (+1.5 SDS and +1.3 SDS), global hypotonia and hypermobility and additionally a facial dysmorphism (round face, full cheeks, and an upturned nose) in the oldest girl. Biochemical testing showed low fT4, elevated fT3, normocytic anemia, and elevated serum copper in the youngest and normocytic anemia, normal serum FT4 but an elevated FT3/FT4 ratio and a normal serum copper in the oldest girl. Whole-exome sequencing revealed a maternally inherited, pathogenic missense variant (c.1207G>A, p.(Glu403Lys)) in the THRA gene in both sisters and the mother.

Conclusion: Missense variants in the THRA gene can result in a mild RTH phenotype with normal serum FT4 concentrations and remain undiagnosed during childhood. A familial history of delayed neurodevelopment, clinical signs such as relative macrocephaly, delayed language development and global hypotonia, and biological findings such as a persistent normocytic anemia and increased serum copper should raise suspicion for RTH due to THRA variants.