ESPE Abstracts

Introduction: Resistance to Thyroid Hormone (RTH) is a clinical syndrome characterized by impaired end-organ responsiveness to Thyroid Hormone (TH). The cardinal features of this syndrome are elevated serum levels of free THs with normal or high TSH, often with goiter and no clear symptoms of thyrotoxicosis. Mutations in the Thyroid Hormone Receptor beta (THRB) gene constitute the most frequent cause of RTH, defined as RTHβ.

Patient and methods: The patient was referred after neonatal screening for congenital hypothyroidism due to elevated TSH levels. Thyroid function test revealed markedly elevated levels of TSH, T3, freeT4, while on physical examination tachycardia (140-170 beats/minute), increased head circumference and insufficient weight gain was observed. During hospitalization, impairment in hearing capacity, dilation of brain ventricles without the need for peritoneal drainage and a marked goiter were noted. Molecular genetic analysis was carried out employing Whole Exome Sequencing (WES) on an Illumina NextSeq 500. After variant filtration patient’s and his parents’ DNA underwent Sanger sequencing of exon 10 of the THRB gene.

Results: WES revealed the presence of a novel heterozygous THRB gene variant, c.1301_1301delG, p.C434Sfs*9. The presence of this variant was verified by Sanger sequencing exon 10 of the THRB gene in the patient’s DNA, but not in his parents, indicating that it is a de novo variant. The c.1301_1301delG results in a frameshift and a premature stop codon 9 amino acids further down rendering the THRB protein 20 amino acids shorter than the wild type. According to the ACMG criteria this variant is classified as pathogenic (PVS1, PM2, PP3). A heterozygous variant in the same codon, the c.1302C>A [p.Cys434*] has been previously reported in a RTH patient who presented with both hypothyroid and hyperthyroid features, severe mental retardation (ID<50) and short stature. During hospitalization the patient continued to show inadequate weight gain and non-response to auditory stimuli. Tachycardia was initially treated with β-blocker, but due to vagotonic symptoms, treatment was modified to α-blocker. Thyrostatic treatment, as expected, did not improve the symptoms, while the administration of high doses of T3 on every other day basis resulted in a decrease in TSH values and a slight remission of the goiter.

Conclusions: Early diagnosis of the rare thyroid hormone resistance syndrome as well as molecular confirmation of the clinical diagnosis allows both the timely investigation and treatment of the comorbidities of the syndrome and the appropriate genetic counseling.