ESPE Abstracts

Background: The pituitary set-point for TSH synthesis and secretion is known to be an individual parameter with a strong genetic influence. Type II iodothyronine deiodinase is a pituitary enzyme involved in local deiodination of T₄ and negative feed-back loop for TSH secretion. Defects in DIO2 have not been reported in humans; however, Dio2 knockout mouse has pituitary resistance to T₄ with elevated TSH, T₄ and TSH/T₄ ratio, with normal T₃.

Objective: To identify human phenotypes consistent with deiodination defects in DIO2.

Subjects and methods: From a pediatric cohort of patients with suspected TH resistance without THRB mutations (13/25 patients, 52%), we investigated those with elevated TSH (>5 mU/ml), fT₄ (>1.7 ng/dl) and TSH/fT₄ ratio (>0.15) with normal T₃ under high dose levo-thyroxine which was unable to decrease TSH, or decreased it at the cost of clinical hyperthyroidism. PCR and Sanger sequencing of DIO2 and TSHR genes.

Results: Five patients (three males) compatible with such phenotype were identified (38.5%). 4/5 showed severe thyroid hypoplasia on ultrasound and/or scintigraphy detected at neonatal screening and one had euplastic hypothyroidism. From 2 years of age, all patients showed persistent elevation of TSH (12±5.1 mU/ml) concomitant to elevated fT₄ (1.87±0.1 ng/dl; 4/5), normal T₃ (4/5). and high TSH/fT₄ (0.51±0.2, N:<0.13; 5/5) and fT₄/fT₃ ratios (4.16±0.5; N<3.7; 3/5), suggesting pituitary resistance to exogenous T₄. Maximum dose of levothyroxine was 5.9±1.4 μg/kg per day, which caused clinical hyperthyroidism in 3/5. No mutations were identified in the coding regions of the genes studied.

Conclusion: We describe a pediatric phenotype of pituitary resistance to exogenous LT₄ heralded by persistently elevated TSH which only normalized under biochemical or clinical hyperthyroidism. The phenotype is recognizable by high TSH/fT₄ ratio and represents an aberrant set-point for TSH secretion and feedback whose genetic determinants need to be investigated.