Clinical and Biochemical Characteristics of Untreated Adult Patients With Resistance to Thyroid Hormone Alpha

Abstract

Background Thyroid hormone resistance due to pathogenic variants in thyroid hormone receptor alpha (THRA) is rare and descriptions of patients are sparse. The disorder is probably under-diagnosed as patients may have normal thyroid function tests. Treatment with thyroxine in childhood improves clinical symptoms. However, it is not clear if treatment has beneficial effects if started in adulthood. Case presentation We investigated four caucasian previously untreated adult first-degree related patients with the THRA c.788C > T, p.(Ala263Val) variant identified by a gene panel for intellectual disability in the index patient. Clinical data and previous investigations were obtained from medical reports. Results During childhood and adolescence, short stature, short limbs, metacarpals, phalanges and delayed bone age maturation were observed. Delayed motor and language development and decreased intellectual and learning abilities were described. Abdominal adiposity, round face and increased head circumference were common features. All individuals complained of tiredness, constipation and low mood. While TSH and FT4 were within the reference range, FT3 was high. FT4/FT3 ratio and reverse T3 were low. Other main features were low haemoglobin and high LDL/HDL ratio. Conclusion Investigation of four first-degree adult patients with untreated RTHα revealed more pronounced phenotype features and hypothyroid symptoms than previously described in patients treated with levothyroxine from childhood or adolescence. The delay in diagnosis is probably due to normal thyroid function tests. We suggest that THRA analysis should be performed in patients with specific clinical features as treatment in early childhood may improve outcomes.

Anaemia‐based screening for resistance to thyroid hormone alpha in children

“…8,9,14 In RTH-α, near-normal TFTs, encompassing normal TSH levels, either high or high-normal fT3 levels, as well as either low or lownormal fT4 levels are encountered. 3,5,8,13,37 Note: Data are given as median (25p-75p).…”

Normal Values for the fT3/fT4 Ratio: Centile Charts (0-29 Years) and Their Application for the Differential Diagnosis of Children with Developmental Delay

“…In contrast, a genetic defect of THRA does not result in elevated TSH since THRα is not involved in the feedback loop; instead, a local defect of THRα function within the target cells results in a local hypothyroid state that causes clinical symptoms resembling those of congenital hypothyroidism, e.g. developmental delay and cognitive dysfunction [14,15]. In addition, the defect in THRα function within the metabolizing organs like the liver and kidney results in a particular pattern of mildly elevated or high-normal T3 and inversely of mildly decreased or lownormal T4 [16,17]; again the exact mechanism of this plasma hormone changes is not known so far.…”