ESPE Abstracts (2018) 89 P-P2-387

Phenotype and Genotype of Four Patients with Thyroid Hormone Resistance Syndrome due to Mutations in the THRB Gene

Meropi Toumbaa,b, Vassos Neocleousb, Pavlos Fanisb, Nicos Skordisb,c,d, Leonidas A Phylactoub,e, George A Tantelesf, Marinella Kyriakidou-Himonasg & Michalis Picolosh


aPediatric Endocrine Clinic, IASIS Hospital, Paphos, Cyprus; bDepartment of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; cDivision of Pediatric Endocrinology, Paedi Center for specialized Pediatrics, Nicosia, Cyprus; dSt George’s, University of London Medical School at the University of Nicosia, Nicosia, Cyprus; eCyprus School of Molecular Medicine, Nicosia, Cyprus; fDepartment of Clinical Genetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; gLarnaca Endocrinology Center, Larnaca, Cyprus; hAlithias Endocrinology Center, Nicosia, Cyprus


Background: Resistance to thyroid hormone (RTH) is a dominantly inherited rare disorder (1:40000) mainly due to mutations in the THRB gene that lead to a decreased end-organ responsiveness to thyroid hormone. Clinical and molecular characteristics of four patients with RTH are described.

Patients and methods: Four patients from three non-related families were studied; two boys (8.3 and 9.2 years old) and 2 adults (35 year old male and 27 year old female, the mother of the younger boy). RTH diagnosis was confirmed by sequencing analysis of the THRB gene.

Results: The four patients presented with various phenotypes. All individuals had persistently elevated circulating free thyroxine (FT4) and/or free triiodothyronine (FT3) associated with non suppressed thyroid stimulating hormone (TSH). They were clinically euthyroid and all had non-autoimmune goiters of various sizes. Antithyroid drugs were previously administered in both adults without successful suppression of the thyroid hormones. The 35 year old male was initially diagnosed with atrial fibrillation and treated with beta blockers. He had mild degree of cognitive impairment. The 27 year old female had resting tachycardia with no other symptoms of thyroid dysfunction. Her 8.3 year old son was investigated because of positive family history for RTH. He had been diagnosed with attention deficit disorder and also had resting tachycardia. The oldest boy underwent thyroid function tests as a part of investigation for obesity, learning difficulties and hyperactivity disorder. Direct sequencing analysis of the THRB gene revealed three previously reported mutations: p.Arg438Cys mutation was found in the two related patients, p.His435Leu was found in the 35 year old male and p.Pro453Thr was found in the oldest boy.

Conclusions: Common mutations in the THRB gene are characterized by various phenotypes; clinically asymptomatic, thyroid hormone deprivation suggestive symptoms or thyroid hormone excess symptoms. RTH can be suspected in both children and adults with elevated thyroid hormones and not suppressed TSH. Prompt molecular diagnosis and genetic counseling could prevent unnecessary tests and inappropriate treatments.

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