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Year : 2017  |  Volume : 4  |  Issue : 2  |  Page : 144-146

Thyroid hormone resistance misdiagnosed as Graves' disease

1 Department of Medicine, King George's Medical College, Lucknow, Uttar Pradesh, India
2 Department of Radiodiagnosis, King George's Medical College, Lucknow, Uttar Pradesh, India
3 Department of Endocrinology, LLRM Medical College, Meerut, Uttar Pradesh, India

Date of Web Publication14-Mar-2017

Correspondence Address:
Dr. Manish Gutch
Department of Medicine, King George's Medical College, Lucknow, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cjhr.cjhr_122_16

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Resistance to thyroid hormone (RTH) syndrome is a very rare disorder characterized by mutations of the thyroid hormone receptor beta and is usually inherited as an autosomal dominant trait. Patients with RTH are usually euthyroid but rarely may present with signs and symptoms consistent with hyperthyroidism. Here, we describe the case of a young girl with goiter who was previously misdiagnosed to have hyperthyroidism and was subsequently diagnosed to be suffering from RTH.

Keywords: Hyperthyroidism, neurophysiologic abnormalities, resistance to thyroid hormone syndrome, thyroid hormone receptor beta

How to cite this article:
Gutch M, Bhattacharya A, Kumar S, Razi SM, Singh RS, Pahan RK. Thyroid hormone resistance misdiagnosed as Graves' disease. CHRISMED J Health Res 2017;4:144-6

How to cite this URL:
Gutch M, Bhattacharya A, Kumar S, Razi SM, Singh RS, Pahan RK. Thyroid hormone resistance misdiagnosed as Graves' disease. CHRISMED J Health Res [serial online] 2017 [cited 2022 Aug 17];4:144-6. Available from: https://www.cjhr.org/text.asp?2017/4/2/144/201989

  Introduction Top

Thyroid hormone resistance (RTH) is a rare autosomal dominant disorder characterized by reduced target tissue responsiveness to thyroid hormones despite their high serum levels and associated with a nonsuppressed serum thyroid-stimulating hormone (TSH). First described by Refetoff in 1967, over 1000 cases have been identified till date.[1]

Thyroid hormone secretion is stimulated by TSH whose levels are regulated via negative feedback by thyroid hormone. RTH is characterized by high levels of circulating thyroid hormone and inappropriately normal or elevated value of TSH.

Previously, thyroid hormone resistance was classified into generalized RTH (GRTH) and pituitary RTH (PRTH). PRTH is very rare and is diagnosed on the basis of the presence of the clinical signs and symptoms of hyperthyroidism.[2]

The most common clinical features of thyroid hormone resistance syndrome include attention deficit hyperactive disorder, delayed growth, tachycardia, and goiter; other less common features include frequent ear nose infection, hearing impairment, and decrease bone mass.

Most patients with RTH have a mutation in thyroid hormone receptor beta (TRβ) gene; no mutation in TRa has been described till now.[3] Autoantibodies against thyroglobulin and thyroid peroxidase (TPO) are usually absent.

We are describing the case of a 6-year-old girl with goiter who was misdiagnosed as hyperthyroidism and was subsequently found to be suffering from RTH.

  Case Report Top

A 6-year-old girl presented to us for the evaluation of goiter which had been previously attributed to Grave's disease. She was being treated as a case of primary hyperthyroidism. She was born at 35 weeks gestation off a healthy, nonconsanguineous marriage. She had cried immediately after birth, and her developmental milestones were within normal limits. On her first visit to our OPD, she weighed 15 kg, and her height was 110 cm. Her thyroid gland was enlarged, but she did not have any clinical symptoms suggestive of hyperthyroidism (tachycardia, finger tremor, and moist skin) nor any ocular signs or symptoms. Her parents had noticed that she had become more lethargic and dull after being treated by anti-thyroid medications as prescribed by a local practitioner. She had no family history of thyroid diseases. Her thyroid function tests which were ordered 15 days ago revealed T4 = 17.9 µg/dl (normal range 5.01–12.45), T3 = 1.97 ng/ml (normal range 0.60–1.81), and TSH = 28.4 µIU/ml (normal range 0.35–5.50) while free T4 and T3 were 2.1 ng/dl (normal: 0.8–1.8 ng/l) and 5.6 pg/ml (normal: 2.4–4.2 pg/ml). Anti-TPO antibodies titre = 20 (normal <65 IU/mL). Ultrasonography showed diffusely enlarged thyroid gland with no signs of nodularity or increased vascularity.

These were the baseline values of thyroid function tests based on which patient was diagnosed as a case of hyperthyroidism and was started on carbimazole and propranolol 15 days back by the local practitioner. However, her symptoms persisted, and there were no signs of regression of goiter. Moreover, she became more lethargic with each passing day.

With the provisional diagnosis of RTH in our mind, we reordered a thyroid hormone profile of the patient along with her parents' [Table 1] along with Anti-TPO antibody titer, radioiodine uptake (RAIU) study [Figure 1] and magnetic resonance imaging (MRI) scan of the brain [Figure 2]. MRI study of the pituitary gland and sellar region showed no abnormality. Genetic analysis could not be performed due to finance constraints.
Table 1

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Figure 1: Increased radio-iodine uptake

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Figure 2: Sagittal T2-weighted magnetic resonance imaging image showing normal pituitary gland

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After analyzing all her reports, we stopped antithyroid medications and followed the patient for 6 months. At present, her condition has improved, and she continues to visit for regular follow-up.

To summarize the case, a 6-year-old girl child presented with high levels of FT3, FT4 with the inappropriate lack of TSH suppression, and goiter. In view of positive family history (her mother also affected with RTH), elevated levels of T3, T4, and TSH, negative anti-TPO, increased RAIU and a normal MRI study of the pituitary gland, we could exclude the possibility of a TSH-producing pituitary adenoma and diagnose her as a case of RTH.

  Discussion Top

The prevalence of RTH is about 1 case/40,000–50,000 live births. This condition is found with equal frequency in both genders and has wide geographic distribution having been reported in Caucasians, Africans, and Asians. The prevalence may vary among different ethnic groups. Familial occurrence of RTH has been documented in approximately 75% of cases. Inheritance is usually autosomal dominant.[1]De novo mutation occur approximately 17% of cases with equal gender predilection.

RTH is subclassified into two phenotypes: GRTH and PRTH. Patients with GRTH are typically euthyroid or hypothyroid, whereas patients with PRTH usually are in a hypermetabolic state. There are no differences in the absolute levels of TSH or free thyroid hormone in GRTH patients as opposed to PRTH patients. A molecular mechanism to explain these two clinical phenotypes has proven elusive. Many authors have concluded that they are part of a spectrum of the same disorder.[2] RTH should be differentiated from other thyroid related disorders which present with a detectable TSH despite high levels of T4 and/or T3 [Table 2].
Table 2: Causes of detectable thyroid-stimulating hormone with elevated thyroid hormones (T4 and/or T3)

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Sinus tachycardia is very common in patients with RTH, some studies reporting frequency as high as 80%. The liver and pituitary express predominantly TRβ1 and TRβ2 receptors respectively, whereas myocardium expresses TRα1 receptor. Therefore mutations in the TRβ gene in RTH are associated with resistance in the pituitary and liver, as exemplified by normal serum sex-hormone-binding globulin and nonsuppressed TSH levels, while the occurrence of tachycardia in many RTH cases may represent retention of cardiac sensitivity to elevated thyroid hormones acting through a normal TRα.[4] Most cases of RTH are caused by mutations in the THRB gene encoding the TRβ1 receptor.

Neurophysiological abnormalities such as attention deficit hyperactivity disorder in childhood or language-related developmental problems such as poor reading skills, dyslexia, and problems with articulation have been documented in a large number of patients with RTH.[5]

Treatment of RTH is difficult because the use of Levothyroxine to suppress TSH may result in worsening of cardiovascular effects due to the intact functional TRα1 receptor in the myocardium.[6] At present, efforts are being made to develop thyroid hormone analogs that selectively bind to TRβ receptors which might simplify the treatment of this rare disorder.

In conclusion, thyroid function testing by sensitive TSH assays may help in detecting more number of patients in outpatient's clinics. However, it is important to remember that patients with RTH may have an only minimal elevation of serum TSH despite high thyroid hormone levels.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Refetoff S. Resistance to thyroid hormones. In: Braverman LE, Utiger RD, editors. The Thyroid. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 1109-29.  Back to cited text no. 1
Beck-Peccoz P, Chatterjee VK. The variable clinical phenotype in thyroid hormone resistance syndrome. Thyroid 1994;4:225-32.  Back to cited text no. 2
Usala SJ, Bale AE, Gesundheit N, Weinberger C, Lash RW, Wondisford FE, et al. Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbA beta gene. Mol Endocrinol 1988;2:1217-20.  Back to cited text no. 3
Mitchell CS, Savage DB, Dufour S, Schoenmakers N, Murgatroyd P, Befroy D, et al. Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. J Clin Invest 2010;120:1345-54.  Back to cited text no. 4
Kaplan MM, Swartz SL, Larsen PR. Partial peripheral resistance to thyroid hormone. Am J Med 1981;70:1115-21.  Back to cited text no. 5
Weiss RE, Refetoff S. Treatment of resistance to thyroid hormone – primum non nocere. J Clin Endocrinol Metab 1999;84:401-4.  Back to cited text no. 6


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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