Severe Resistance to Thyroid Hormone Beta in a Patient with Athyreosis

Abstract

We report a patient with congenital hypothyroidism due to athyreosis complicated by a heterozygous thyroid hormone receptor beta (THRβ) gene mutation (R320L), resulting in a severe resistance to thyroid hormone beta phenotype. The proband inherited the mutant allele from his father, presenting a very mild phenotype. While the precise reason for this discrepancy remains unknown, we postulate the possibility of de novo mutation and mosaicism in the father. Correlating thyrotropin (TSH) with free thyroxine (fT4) allowed us to predict the amount of fT4 required to normalize the proband's TSH, which supported the treatment with high dose of levothyroxine.

Keywords: athyreosis; congenital hypothyroidism; levothyroxine treatment; mutation; resistance to thyroid hormone.

FIG. 1.

Clinical, biochemical, and genetic data on the proband and his family. (A) Correlation of serum TSH with fT4 during the first six months of treatment. Extension of the best fit curve predicts the LT4 required to normalize the TSH. The dashed line is from Fisher et al. (8), showing the correlation for infants with congenital hypothyroidism and relative resistance to thyroid hormone without THRβ gene mutations. (B) Pertechnetate uptake shows a lack of activity in the thyroid bed nor other foci of abnormal uptake, thereby excluding ectopic thyroid tissue. Salivary glands and SSN marker are visible. (C) Pedigree of the family and thyroid function test results aligned with each symbol representing a family member. According to Lem et al. (9), abnormal values adjusted for age are in bold numbers, low in blue, and high in red. (D) Sequencing electropherogram of exon 9 of the THRβ gene of each family member. The father and the proband harbor a heterozygous guanine-to-thymidine transition, altering codon 320 from arginine in the WT to leucine in the mutant allele (R320L). (E) Results of THRβ locus haplotyping showing that the proband inherited the mutant allele from the father and that the same maternal allele was shared by the affected and unaffected sibs. (F) Direct sequencing the ICR of the THRβ2 allele demonstrated that the proband and the father carried the same heterozygous genotype C/T in rs2596623. The lower panel shows a diagram of the THRβ gene depicting the origins of the TRβ1- and TRβ2-specific transcripts. The gray square represents the conserved 600 bp TRβ2-specific ICR. A vertical line marks the approximate location of the SNP rs2596623 present in the proband and father. ICR, intron control region; Mut, mutant; SSN, suprasternal notch; TSH, thyrotropin; THRβ, thyroid hormone receptor beta; WT, wild type.