Clinically Symptomatic Resistance to Thyroid Hormone β Syndrome Because of THRB Gene Mosaicism

Abstract

Context Resistance to thyroid hormone β syndrome (RTHβ) is caused by pathogenic variants in the THRB gene, but such variants are found in only 85% of cases. We report the case of a patient with RTHβ phenotype but for whom we found a pathogenic variant of the THRB gene in a mosaic state. Case Description The patient is a 52-year-old woman with clinical and biological signs of RTHβ. Symptoms included asthenia, cardiac palpitations, and diarrhea. Repeated thyroid function tests showed an elevated serum TSH, elevated serum free T4, and variably normal or slightly elevated serum fT3. Pituitary magnetic resonance imaging was normal, and the thyrotropin-releasing hormone test result was compatible with the diagnosis of RTHβ syndrome. Initial Sanger sequencing on blood samples could not highlight the presence of a mosaic variant because of insufficient sensitivity. When next-generation sequencing became accessible, blood samples were retested and we found a known pathogenic variant: c.949G > A; p.(ala317Thr), with an allelic frequency of 12%. Other samples from tissues of different embryological origin were also tested and found an allelic frequency of 5.7%, 17.9%, 9.9%, 6.4%, and 0% on urine tests, oral swab, nasal mucosa swab, skin biopsy, and conjunctival swab, respectively. Cloning confirmed the allelic frequency observed. Conclusions We highlight that a pathogenic variant in a mosaic state in the THRB gene may be the cause of an authentic RTHβ syndrome. High-throughput sequencing of multiple tissues eases the detection of pathogenic variant in a mosaic state and allows the correct diagnosis of patients with true RTHβ, thus avoiding patient mismanagement.

Concurrent <i>THRB</i> and <i>DUOX2</i> variants in a patient detected via newborn screening for congenital hypothyroidism: a case of resistance to thyroid hormone

“…The mosaicism ratio of the variant in peripheral blood was 8.6% (32). Another patient, with the p.Ala317Thr variant, exhibited signs of RTH such as goiter, tachycardia, and diarrhea, with 12% mosaicism in peripheral blood (31).…”

“…The father of the patient carried a THRB variant in a somatic mosaic state. To date, only two patients with somatic mosaic THRB variants have been described ( 31 , 32 ). One patient, diagnosed with RTH through a family study (p.Arg338Trp), remained asymptomatic despite having high FT4 levels without suppression of TSH levels.…”

“…The mosaicism ratio of the variant in peripheral blood was 8.6% ( 32 ). Another patient, with the p.Ala317Thr variant, exhibited signs of RTH such as goiter, tachycardia, and diarrhea, with 12% mosaicism in peripheral blood ( 31 ). The father of our patient exhibited 23% mosaicism for p.Gly345Cys in peripheral blood and was diagnosed with symptomatic RTH based on mild tachycardia.…”