A rare thyroid hormone receptor beta (THRβ) gene mutation in a 15-year-old girl with thyroid hormone resistance syndrome: a case report

Resistance to thyroid hormone (RTH) is a rare disorder characterized by reduced tissue response to free thyroxine (FT₄) hormone. RTH is an inherited disorder characterized by variable tissue hyposensitivity to 3,5,3′-l-triiodothyronine (T₃), with persistent elevation of circulating free T₃ (FT₃) and FT₄ levels, along with non-suppressed serum thyrotropin (TSH) [1, 2]. Sporadic cases are common, but recessive cases are rare [1]. This syndrome was initially identified by Refetoff and colleagues, and since then 1000 cases have been identified from 339 families [2]. In 2008, Refetoff et al. reported more than 2000 individuals with RTH belonging to about 500 families [3]. RTH is associated with mutations in the thyroid hormone receptor beta (THRβ) gene; the THRβ protein is a nuclear hormone receptor for T₃. Mutations in THRβ are associated with thyroid hormone resistance. The mode of inheritance can be autosomal dominant or recessive. The majority of patients are heterozygous for the mutant THRβ allele, consistent with the autosomal dominant pattern of inheritance [3]. Mutant THRβs can interfere with the function of the wild-type receptor in a dominant negative manner [4]. Lee et al. reported that at least 137 different THRβ mutations have been associated with RTH syndrome, affecting more than 40,000 people worldwide [5]. In our study, screening by direct sequencing analysis revealed a rare mutation (A268G) in the THRβ gene in a patient with RTH.

A 15-year-old Omani girl of Arabian origin had presented with episodic palpitations since birth. At age 11 an electrocardiogram showed sinus tachycardia, whereas an echocardiogram was normal. Four years later, she presented with the episodic palpitations associated with mild dizziness. Her past medical history was normal and she reported no similar problem in any member of her family. A clinical examination showed a normal-looking girl with normal growth for her age. There was no evidence of mental retardation, but her parents reported that she had low performance at school. Her blood pressure was 124/59mmHg with a pulse rate of 108beats/min. She was not pale and her thyroid gland was not enlarged. A systemic examination was normal. Her electrocardiogram showed tachycardia with a few ventricular ectopics and an echocardiogram was once again normal.

A complete blood count was performed and her hemoglobin level was normal. Her C-reactive protein level was 97mg/L (normal range: 0 to 8mg/L), electrolytes were normal, potassium was 3.8mmol/L (normal range: 3.5 to 5.1mmol/L), sodium 139mol/L (normal range: 135 to 145mol/L), creatinine 33μmol/L (normal range: 29 to 56μmol/L), and urea 3.0mmol/L (normal range: 2.1 to 7.1mmol/L). Her FT₄ level was 30.7pmol/L (normal range: 8.7 to 13.6pmol/L), FT3 9.0pmol/L (normal range: 3.8 to 6.0pmol/L), TSH 1.56mIU/L (normal range: 0.60 to 3.70mIU/L), thyroid antibodies (anti-thyroglobulin and antimicrosomal antibodies) 1IU/mL (normal range: 0 to 50IU/mL) and thyroglobulin 13μg/L (normal range: 3 to 30μg/L). Her thyroglobulin antibody level was <0.9IU/mL (normal range: 0.0 to 4.0IU/mL) and anti-thyroid receptor antibody level was 0.30UI/L (normal range: 0.00 to 1.50UI/l). A thyroid ultrasound showed altered echo texture with normal vascular flow on Doppler study. Tiny cystic areas of 2mm to 4mm were seen on both lobes. There were no significant nodules in her thyroid gland, and no lymphadenopathy was detected in her neck. A technetium-99m thyroid scan showed a total uptake of 3.2% (normal uptake: 1% to 4%) seen on both lobes, and no cold nodules were observed. Her prolactin level was 727mIU/L (normal range: 71 to 566mIU/L). Magnetic resonance imaging scan of the pituitary gland and brain showed that both her pituitary gland and brain were normal in size and morphology.

Blood samples were collected from our patient and her deoxyribonucleic acid (DNA) was isolated. The samples were sent to an accredited laboratory in the Department of Clinical Genetics at the University of Amsterdam, Netherlands. Direct sequencing analysis of the full THRβ gene was performed. The results revealed the presence of heterozygous mutation c.803C > G in THRβ. This nucleotide change results in the amino acid change p.Ala268Gly in THRβ. Hence, this mutation indicates that our patient was most likely affected with RTH. We therefore treated her with beta-blockers to control her tachycardia.

RTH is characterized by tissue hyposensitivity to elevated levels of FT₃ and FT₄ in association with unsuppressed serum thyrotropin (TSH) [6]. Patients with congenital RTH can be clinically euthyroid, but often show increased levels of FT₄ and FT₃ with unsuppressed TSH [7]. In our patient, the elevated levels of thyroid hormones (FT₃ and FT₄) with normal levels of TSH, exclusion of a pituitary tumor by magnetic resonance imaging and the presence of a rare mutation, p.Ala268Gly, in THRβ support the diagnosis of RTH. The DNA analysis of our patient showed the presence of a heterozygous mutation c.803C > G in THRβ. An alpha subunit to TSH ratio, which would give more support to the diagnosis, will be calculated in our patient during the screening of her family. Rivolta et al. reported that 85% of patients were heterozygous for the mutant THRβ allele, consistent with the autosomal dominant mode of inheritance [6]. In our patient, the c.803C > G nucleotide change, resulting in the amino acid change p.A268G, altered the highly conserved amino acid THRβ. This mutation was not detected in 60 other index patients and 13,000 control alleles in the indexed laboratory. This rare mutation has been previously described only in a four-generation family with RTH [8] and in one South American patient [6].

The incidence of RTH is one in 40,000 [9]. The clinical presentation of this syndrome is variable. Some individuals tend to be normal and the syndrome is detected only on routine investigations, whereas others may display features such as goiter, hyper- and hypothyroidism, delayed bone maturation, short stature and attention deficit hyperactive disorder [10]. Goiter is the most common finding, reported in 66% to 95% of patients [11]. Our patient had no goiter. According to the clinical presentation, this syndrome has been divided into two entities; generalized type (GRTH) and pituitary type (PRTH). Patients with RTH who appear normal or hypothyroid are considered to have GRTH, and those with thyrotoxic clinical presentation are considered to have PRTH [12]. Accordingly, we would classify our patient as having PRTH, because of her sinus tachycardia. One of the most important reasons for recognizing RTH is that its management is different from other types of thyroid dysfunction. Also, it is important to distinguish GRTH from PRTH using clinical criteria as the management of these two types differ. Patients with PRTH should not be treated with anti-thyroid drugs, as any reduction of the thyroid hormone will aggravate the symptoms, reduce growth and increase the goiter size. Patients with this type, similar to our patient, are usually the most difficult to treat. Patients with GRTH can benefit from thyroxin administration, since it reduces TSH level and the goiter [5].

The alpha subunit of the TSH (α-GSU/TSH) was not measured in our patient, which is considered as a limitation of this case report, because of non-availability of the test. While the main difference between patients with TSH-producing pituitary tumors (TSHomas) and RTH is the presence of symptoms of hyperthyroidism; a minority of patients with RTH might display signs of hyperthyroidism involving some organs and not others, known as PRTH [13]. Nevertheless, the differential diagnosis between these forms of RTH and TSHomas may be difficult, and elevated α-GSU concentrations or high α-GSU/TSH molar ratio, favors TSHoma. More interestingly, similar biochemical data in relatives favors RTH. Therefore, α-GSU concentrations or high α-GSU/TSH molar ratio will be measured in the next study, which will include our patient and other members of her family.

Written informed consent was obtained from the patient’s guardian for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.