A Novel Familial Variation of the Thyroid Hormone Receptor Beta Gene (I276N) Associated with Resistance to Thyroid Hormone

Dear Editor:

Resistance to thyroid hormone (RTH) occurs in about 1:40,000 births (1). The most frequent defect in RTH is a mutation in the thyroid hormone receptor beta gene (THRB); more than 100 mutations were identified (2). Typical hormonal findings are an elevated serum free T4 (fT4) and nonsuppressed thyroid-stimulating hormone (TSH), usually accompanied by high serum levels of free T3 (fT3). The phenotype is heterogeneous (1). We report a child and her mother with RTH, both carrying the same THRB mutation, reported here for the first time.

A 3-year-old girl was seen for growth impairment of about 30 months duration. She was born at 35 weeks gestation. Birth weight and length were appropriate, and newborn TSH levels were normal. There was no appetite loss, stool frequency anomalies, or abdominal pain. Weight and height were at the 6th percentile for sex and age, −1.7 standard deviation (SD) based on parents' height. Physical examination was normal, blood pressure was 100/65 mmHg (83rd and 93rd centile for age and height, respectively), and pulse was 110. She had negative serology for celiac disease, normal circulating creatinine, hemoglobin, glucose, and IGF-1, and normal urinalysis. Serum TSH was 3.34 mIU/L (normal=0.450–3.500) with elevated fT3 and fT4 of 7.10 pg/mL (normal=2.3–4.2) and 2.32 ng/dL (normal=0.89–1.76), respectively. Anti-thyroglobulin antibodies and anti-TSH antibodies were negative, with slightly elevated anti-thyroperoxidase antibodies to 70 IU/mL (normal=0–60). Thyroid ultrasound was normal, and neuropsychiatric evaluation showed normal cognitive development. We identified, in the heterozygous state, a novel missense variation of THRB in exon 8. This variation, a transition T to A at nucleotide 827 resulting in an Isoleucine to Asparagine substitution at codon 276 (I276N), has not been reported in the Online Mendelian Inheritance in Man (OMIM) or and HGMD^® databases (for more details see Supplementary Data, available online at www. liebertonline.com/thy).

Information regarding the girl's father was not available. The child's 42-year-old mother had a history of tachycardia, hyper-defecation, and goiter since age 25. Thyroid hormone levels had been elevated but TSH was normal, with positive anti-thyroid peroxidase and anti-thyroglobulin antibodies, and negative anti-TSH receptor antibodies. A thyroid ultrasound and thyroid cytology suggestive of lymphocytic thyroiditis was reported, and she was treated with methimazole for short periods. When seen at age 42, her blood pressure was 120/70 mmHg, pulse was 125 and regular, body temperature was 36.9°C, and the body mass index was 27.7 kg/m². The thyroid was not enlarged or nodular to palpation. The fT3 was elevated to 5.5 pg/mL, and the fT4 was slightly elevated to 1.90 ng/dL. TSH was 3.47 mIU/L, with high serum anti-thyroperoxidase (890 IU/mL) and anti-thyroglobulin antibodies (334 IU/mL). Analysis of THRB showed the same I276N variation in the heterozygous state as was present in her daughter.

The features of the mother and her daughter are consistent with the extreme variability in the clinical expression of RTH. A possible explanation for the different phenotype in the child and her mother may be their different age. Temporal variation in the clinical expression RTH in the same patient has been reported (1,2), but signs and symptoms often vary between patients harboring the same mutation, even if they are in the same kindred.

The mother reported here developed clearly positive anti-thyroglobulin and anti-thyroid peroxidase antibodies, while the daughter had borderline positive anti-thyroid peroxidase antibodies. Gavin et al. (3) suggested that chronic TSH stimulation in RTH activates intra-thyroidal lymphocytes to produce the pro-inflammatory cytokine TNF-alpha, leading to thyroid cell destruction by binding to its receptors on thyrocytes, or indirectly by potentiating antibody formation or cytotoxic T lymphocyte production. Recently, Barkoff et al. (4) demonstrated a role for autoimmunity in RTH, involving the stimulation of the immune system at the level of TR-alpha.

The I276N variation reported here is located in cluster 3 (residue 234–282) of the ligand-binding domain and could impair receptor function indirectly by defective corepressor release. Most of the disease-causing mutations are clustered in the ligand-binding domain of the receptor, because a dominant-negative effect requires the preservation of DNA-binding and heterodimerization functions in mutant receptors. We used bioinformatics tools SIFT (http://blocks.fhcrc.org/sift/SIFT.html) and PolyPhen (http://genetics.bwh.harvard.edu/pph) to predict I276N substitution effects on protein structure and function, and it predicted the likely disruption of the ligand-binding domain of the receptor.

In conclusion, we report a novel variation of THRB as a cause of RTH. Similar to other THRB mutations associated with RTH, the clinical phenotype is probably variable, but more information regarding affected patients of the same age, gender, and environmental settings is needed to confirm this.