Resistance to Thyroid Hormone Misdiagnosed and Mistreated as Congenital Hyperthyroidism

Introduction : Resistance to thyroid hormone (RTH) is a rare genetic disorder that is often difficult to diagnose early in life, due to confusing clinical presentation and thyroid function tests (TFTs). The best management is just monitoring without specific therapy. Patients with RTH are often misdiagnosed as hyperthyroidism and subsequent treatment especially with thyroidectomy or radioactive iodine ablation results in hypothyroidism that is difficult to treat.
We present a case of RTH that was misdiagnosed as congenital hyperthyroidism in infancy, and was mistreated with Propylthiouracil (PTU) for about 7 years. We also discuss the antenatal considerations in women with RTH.

Case Description : A 39 year old woman was born with abnormal TFTs, marked by normal TSH and elevated thyroid hormones. Her main clinical manifestation was tachycardia. At the age of 7 months, she was diagnosed with congenital hyperthyroidism (referred to as neonatal Graves' disease). She was treated with PTU which normalized her T4 but caused elevation of TSH. PTU was continued until age 7 years. Her TSH remained high, at times exceeding 50 mU/ml. Over those 7 years of her early childhood, she remained asymptomatic with control of tachycardia; however, she was noticed to have slow growth of her height, remaining around the 10th percentile. Eventually, the diagnosis was revisited, in view of the notion that it was thought to be very unusual for neonatal hyperthyroidism to last that long. PTU was discontinued, and a diagnosis of RTH (Refetoff’s syndrome) was made. The patient since then has been off PTU, and her TSH has remained in the normal range with both FT4 and FT3 remaining high at about 1.5 to 2.0 the upper limits of normal. Her height and physical development progressed normally, through puberty and adulthood. At age 30 years, she was referred to Dr. Refetoff at the University of Chicago, and she, her father and mother were tested. RTH diagnosis was confirmed, and both she and her father were diagnosed with mutation R320C: single nucleotide substitution (arginine to cysteine in codon 320).
The patient is now considering starting a family and she has inquired about antenatal care. RTH has dominant inheritance, with 50% chance to have an affected child in every pregnancy. Once she gets pregnant we recommended to her to have prenatal screening: Should the baby test negative for the mutation, we recommended that she should be treated with anti-thyroid medications to keep her FT4 not higher than 20% above the ULN.

Discussion : Because RTH is characterized by confusing clinical manifestations, as well as confusing TFTs, the correct diagnosis is difficult to be made. Some patients may not be diagnosed till later in childhood, or in adulthood. The majority of patients with RTH need no specific treatment, despite elevated thyroid hormones all their lives. It is advised to treat bothersome symptoms like tachycardia with beta blocker. Many patients with RTH have been erroneously diagnosed with hyperthyroidism. Once the thyroid gland is removed or ablated, the resulting hypothyroidism is so difficult to manage. Pregnant women with RTH should be carefully monitored and co-managed by an experienced antenatal specialist.