Abstract
Background: Pituitary resistance to thyroid hormone-β (RTH-β) presents with the symptoms of hyperthyroidism with inappropriate secretion of thyroid stimulating hormone (TSH). Mutation in the coding region of the TR-β gene is not observed in 10% of cases, which are termed as non-TRβ RTH. Till date, the specific contributions of co-repressors and co-activators in pituitary resistance to thyroid hormone remain unknown. Materials and Methods: We present a case of 44-year male with pituitary RTH, showing features suggestive of thyrotoxicosis, atrial fibrillation and goiter. Clinical investigations included estimation of serum FT4, T3, TSH, TRab, TPO antibodies, Tc-thyroid scan, MRI for sella. To understand the genetic cause of the disorder, we undertook the whole genome sequencing (WES) in the proband and family members, which was followed by Sanger's sequencing for confirmation. To validate the possibility of RTH due to the novel gene discovered, we undertook in-vitro functional studies using NCOR2 siRNA. Results: A 44 year old male presented with atrial fibrillation with thyrotoxicosis and elevated serum T4, FT4, and T3, and nonsuppresed TSH levels (serum total T4 24.50 ug/dl, total T3 5.22 nmol/l and TSH 5.50 uIU/ml. On treatment with PTU, he had serum TSH 16.24 uIU/ml, FT4 50 nmol/l, and total T3 6.61 nmol/l. Further clinical workup by (99m)Tc pertechnetate thyroid scan showed bilateral diffusely increased uptake, negative serum TRAb and TPO antibody. A differential diagnosis of RTH or TSH secreting pituitary adenoma was made. Gadolinium enhanced MRI of sella was normal. We observed loss of inverse correlation of serum T3 and TSH levels, signifying the loss of negative feedback mechanism. WES identified two novel mutations in the NCOR2 gene (p.Ser2304Gly, p.Ala2489Thr) in the proband. Both the mutation (p.Ala2489Thr) were confirmed in the proband and one of his children. Bioinformatics analysis suggested p.Ala2489Thr to be pathogenic. Functional studies in GH3 cell lines using NCOR2 siRNA revealed NCOR2 dependent regulation of TSH levels, further strengthening that NCOR2 mutations could cause RTH. Conclusion: We hereby describe the first case of pituitary RTH due to a novel mutation in the NCOR2 gene in a family with thyrotoxicosis.