E449X mutation in the thyroid hormone receptor β associated with autoimmune thyroid disease and severe neuropsychomotor involvement

Abstract

Objective: To report the clinical and molecular aspects of a patient with a diagnosis of Resistance to Thyroid Hormone (RTH) harboring the E449X mutation associated with autoimmune thyroid disease and severe neuropsychomotor retardation. Methods: We present a case report including clinical and laboratory fi ndings, and molecular analysis of a Brazilian patient with RTH. Results: A 23-year old male presented hyperactivity disorder, attention defi cit, delayed neuropsychomotor development, and goiter. Since the age of 1 year and 8 months, his mother had sought medical care for her son for the investigation of delayed neuropsychomotor development associated with irritability, aggressiveness, recurrent headache, profuse sudoresis, intermittent diarrhea, polyphagia, goiter, and low weight. Laboratory tests revealed normal TSH, increased T 3, T 4 , antithyroglobulin and antimicrosomal antibody titers. Increasing doses of levothyroxine were prescribed, reaching 200 µg/day, without signifi cant changes in his clinical-laboratory picture. Increasing doses of tiratricol were introduced, with a clear clinical improvement of aggressiveness, hyperactivity, tremor of the extremities, and greater weight gain. Molecular study revealed a nonsense mutation in exon 10, in which a substitution of a guanine to tyrosine in nucleotide 1345 (codon 449) generates the stop codon TAA, confi rming the diagnosis of RTH. Conclusion: This patient has severe neuropsychomotor retardation not observed in a single previous report with the same mutation. This may refl ect the lack of a genotype-phenotype correlation in affected cases with this syndrome, suggesting that genetic variability of factors other than β receptor of thyroid hormone (TRβ) might modulate the phenotype of RTH. RESUMOMutação E449X no Receptor β do Hormônio Tireoidiano Associada com Doença Tireoidiana Auto-Imune e Retardo Neuropscicomotor Grave. Objetivos: Descrever aspectos clínicos e moleculares de um paciente com resistência ao hormônio tireoidiano (RHT) portador da mutação E449X associada a doença tireoideana auto-imune e retardo neuropscicomotor grave. Métodos: Relatamos um caso incluindo achados clínicos, laboratoriais e aná-lise molecular de um paciente brasileiro com RHT. Resultados: Paciente masculino, 23 anos de idade, apresentou-se com distúrbio de hiperatividade, défi cit de atenção, retardo no desenvolvimento neuropsicomotor e bócio. Desde 1 ano e 8 meses de idade, sua mãe procurou assistência médica para investigação do retardo do desenvolvimento neuropsicomotor associado com irritabilidade, agressividade, cefaléia recorrente, sudorese profusa, diarréia intermitente, polifagia, bócio e perda de peso. Avaliação laboratorial evidenciou TSH normal e aumento do T3, T4 e anticorpos antimicrossomal e

Using Mouse Genetics to Investigate Thyroid Hormone Signaling in the Developing and Adult Brain

“…However, the demonstration of a precise genotype-phenotype correlation is lacking. As an example, in a single patient the E449X mutation was associated with a severe neuropsychomotor retardation associated with irritability and aggressiveness, not observed in a previous case with the same mutation (Gurgel et al 2008 ).…”

An overview of thyroid function tests in subjects with resistance to thyroid hormone and related disorders

“…Next, we searched for RTHβ caused by a deletion, truncation, or frameshift of TRβ to compare with RTHβ caused by a single amino acid substitution on PubMed 3) [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. The degrees of SITSH in truncations and frameshifts were more severe than those in single amino acid deletions and single amino acid substitutions that were obtained in our previous study [10] (Fig.…”