Thyroid Hormone Resistance Due to Thyroid Hormone Receptor Beta (THRB) p.I431T Gene Mutation

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 449-497-Thyroid Neoplasia & Case Reports
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-490
Ameer Khowaja*1, Pernia Latif2 and Sidney A Jones3
1University of Minnesota, Minneapolis, MN, 2Hennepin County Medical Center, Minneapolis, MN, 3Ridgeview Medical Center, Waconia, MN
Background: Generalized resistance to thyroid hormone (GRTH) is a rare inherited disorder characterized by elevated circulating thyroid stimulating hormone (TSH) and thyroid hormones (thyroxine, tri-iodothyronine)  along with  reduced responsiveness of target tissues to thyroid hormone action. Patients with GRTH typically present with signs and symptoms of hypothyroidism, the severity of which is dependent on homo- or heterozygosity of inherited mutation. Several causative mutations have been described in the THRB gene. We present a case of THRB p.I431T mutation resulting in generalized thyroid hormone resistance.  

Clinical Case: 28 year old female presented to endocrinology clinic for follow up of her “hypothyroidism”. She was diagnosed with Graves’ disease at the age of 20. Her thyrotoxicosis symptoms at that time included weight loss, tremors and palpitations. Of note, her lowest TSH during this time was low but not fully suppressed. She was initially treated with methimazole for 18 months followed by radioiodine (RAI) treatment. She was subsequently started on levothyroxine replacement for elevated TSH and apparent hypothyroidism. Since initiation of levothyroxine she has never had TSH within normal range despite progressively increasing doses of levothyroxine. Her TSH levels generally remained between 20-30 uIU/mL. Her most recent value was 48.50 uIU/mL with a free T4 of 1.5 ng/dL and total T3 of 132 ng/dL.  The patient continued to experience fatigue, dry skin, constipation and inability to lose weight. Because of her elevated TSH and upper normal thyroid hormone levels mutation analysis for THRB gene was performed. This demonstrated a heterozygous mutant allele of p.I431T which leads to replacement of Threonine by Arginine at c.1292 T>C in exon 10 of THRB gene. Her levothyroxine dose is presently being titrated to correct her signs and symptoms of hypothyroidism. Currently, mutation analysis of other first degree relatives is being performed.

Conclusion: Mutation of THRB gene is a rare condition with an incidence of 1:50,000 live births. Several mutations have been described causing variable severity of thyroid hormone resistance. The mutation at p.I431T is associated with severe generalized resistance to thyroid hormone. Treatment of this condition includes high doses of levothyroxine with dose titration depending upon clinical signs and symptoms. It is of paramount importance to provide genetic counseling to the patients and their families.

Nothing to Disclose: AK, PL, SAJ

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