Mosaicism of a Thyroid Hormone Receptor-β Gene Mutation in Resistance to Thyroid Hormone

Context: Heterozygous mutations in thyroid hormone receptor-β (TRβ) gene are the cause of resistance to thyroid hormone (RTH) in more than 85% of families having the syndrome. In 23% of the families, TRβ gene mutations occur de novo. Of the 141 families with RTH investigated by us, 21 (15%) had no TRβ gene mutations detectable by sequencing from genomic DNA (gDNA) or cDNA (non-TR RTH). Objective: The objective of the study was to investigate the genotype of a family with RTH and correlate it to the phenotype. Design: The DNA was isolated from different tissues, and the sequence of the TRβ gene was determined. Clinical studies involved the administration of incremental doses of T3. Setting: The study was conducted at a referral pediatric endocrinology clinic in Turkey and an academic medical center in the United States. Main Outcome and Measures: Measurement included markers of thyroid hormone action and sequencing of TRβ revealing a R338W mutation. Patients and Family: We studied two siblings with short stature, panic disorder, psychosis, and high free iodothyronine concentrations with nonsuppressed TSH and their father with similar thyroid function tests without growth or psychiatric abnormalities. Results: Direct sequencing of gDNA obtained from the father’s leukocytes, buccal mucosa cells, and prostate tissue showed less amplification of the mutant allele (R338W) than the normal allele as confirmed by PCR/restriction fragment length polymorphism analysis. No sequence abnormalities were detected in gDNA from fibroblasts. Similar results were found in mRNA from the leukocytes and fibroblasts. The sensitivity of various tissues to thyroid hormone was not uniform. The progeny had equal amounts of mutant and wild-type gDNA in leukocytes and skin. Conclusions: The father has a mosaicism for the R338W mutation as it was present in some cell lineages, including his germline, because it was transferred to his children but not in fibroblasts. This indicates that the mutation occurred de novo in early embryonic life. Here is the first report of mosaicism in RTH. The possibility of mosaicism should be considered in subjects with RTH without apparent mutations in the TRβ gene.