|Year : 2012 | Volume
| Issue : 2 | Page : 64-67
Spectrum of thyroid hormone resistance
Deep Dutta, Rajesh Jain, Ajitesh Roy, Sujoy Ghosh, Satinath Mukhopadhyay, Subhankar Chowdhury
Department of Endocrinology and Metabolism, IPGMER and SSKM Hospital, 244, AJC Bose Road, Kolkata, India
|Date of Web Publication||12-May-2012|
Department of Endocrinology and Metabolism, IPGMER and SSKM Hospital, 244, AJC Bose Road, Kolkata-700 020
Source of Support: None, Conflict of Interest: None
Thyroid hormone resistance (THR) is a rare disorder with a prevalence of 1:40,000 and is commonly due to mutation in thyroid receptor β-isoform. Goiter is the most common presenting feature in patients of THR (66-95%) followed by behavioral abnormalities (60%). Severe mental retardation and short stature are uncommon. We present three patients of THR, all of whom presented with short stature and goiter. Patient-1 had attention deficit hyperkinetic disorder with severe mental retardation (IQ-52). Patient-2 presented with bleeding and non-palpable purpura and was diagnosed to have immune thrombocytopenic purpura (ITP). This is the first report of ITP in a patient of THR. Patient-3 in contrast had normal intelligence and presented with only short stature and goiter. Patients-1 and 2 had tachycardia which improved with propranolol. Propranolol can be a useful agent in the management of thyrotoxic symptoms in THR patients when thyroid hormone analogues are not available. Unlike previously reported case series of THR, short stature and goiter were the universal presenting features in our patients, probably reflecting the fact that such patients are more likely to seek medical care.
Keywords: Immune thrombocytopenic purpura, propranolol, short stature, thyroid hormone resistance
|How to cite this article:|
Dutta D, Jain R, Roy A, Ghosh S, Mukhopadhyay S, Chowdhury S. Spectrum of thyroid hormone resistance. Thyroid Res Pract 2012;9:64-7
|How to cite this URL:|
Dutta D, Jain R, Roy A, Ghosh S, Mukhopadhyay S, Chowdhury S. Spectrum of thyroid hormone resistance. Thyroid Res Pract [serial online] 2012 [cited 2020 Jan 24];9:64-7. Available from: http://www.thetrp.net/text.asp?2012/9/2/64/96060
| Introduction|| |
Thyroid hormone resistance (THR) is a rare disorder with a prevalence of 1:40000  and is characterized by elevated free thyroxine (FT4) and free tri-iodothyronine (FT3), with inappropriately normal or elevated thyrotropin (TSH). THR can be either generalized THR, pituitary THR or peripheral THR, in which the patients are clinically euthyroid, hyperthyroid or hypothyroid respectively. 
We present three patients of THR with different clinical presentations to highlight the heterogeneity of the disorder and its varied clinical presentation.
| Case Reports|| |
A five-year, six-month girl, born preterm with low birth weight, of a consanguineous marriage with delayed motor, language milestones and decreased hearing presented with short stature. Examination revealed poor dentition [Figure 1], short stature [Table 1], Grade-Ib soft diffuse goiter, tachycardia which persisted even during sleep [Table 1]. Psychological assessment revealed that her mental age was 2 years (Seguin form board test), developmental age 2 years 9 months (developmental screening test) and social age 3 years 4 months (Vineland social maturity scale). Her intelligence quotient (IQ) was 52. She was hyperkinetic and had difficulty to concentrate. Her investigations are elaborated in [Table 1], and were suggestive of pituitary and hepatic thyroid hormone resistance [Table 1]. Her tachycardia improved with propranolol which was started at 10 mg per day and increased to 40 mg/day.
|Figure 1: Facial profile of patient-1 showing poor dentition (absence of incisors and canine teeth in upper and lower jaws)|
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|Table 1: Clinical and biochemical profile of patients with thyroid hormone resistance|
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A nine-year-old girl born term of normal milestones and intelligence presented with bleeding from nose and ears and non palpable purpura. There was no history of recent infections. Laboratory evaluation was significant for low hemoglobin (8.6 g/dl) with low platelets (10000/cc). Bone marrow was normocellular and showed active megakaryocytes with mild megakaryocytosis. Direct Coomb's test and serum anti-nuclear antibody were negative. Thrombocytopenia responded to intravenous immunoglobulins for 2 days followed by oral prednisolone (30mg/day) for 6 weeks and subsequently tapered over 3 months. Her platelet count was 40,000/cc on day 4 of therapy, 155,000/cc after 2 weeks of therapy and remained normal thereafter. Short stature and goiter (Grade-2) [Figure 2] detected during admission lead to evaluation of thyroid function which was suggestive of THR [Table 1]. She too had daytime and sleeping tachycardia [Table 1]. Trial of levothyroxine at 50μg/day (for short stature, delayed bone age and goiter) resulted in worsening of tachycardia. Levothyroxine was stopped and tachycardia improved with propranolol at 40mg/day. This is perhaps the first report of immune thrombocytopenic purpura (ITP) occurring in a patient with THR.
|Figure 2: (a) Profile of patient-2 with immune thrombocytopenic purpura and thyroid hormone resistance, (b) Grade-2 goiter in patient-2|
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An eight-year-old girl with normal milestones presented with lack of height gain and goiter of 2 years duration [Figure 3]. Examination was significant for short stature [Table 1] and grade-2 goiter. Her intelligence was normal and she did not have tachycardia. Biochemical evaluation revealed resistance to thyroid hormones at pituitary and liver [Table 1].
|Figure 3: Profile of patient-3 with thyroid hormone resistance showing grade-2 goiter|
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Biochemical screening of all first degree relatives for thyroid dysfunction in all three cases was normal.
| Discussion|| |
In humans there are two subtypes of TR, TRα and TRβ (encoded by genes on chromosomes 17 and 3, respectively).  THR is due to mutation in the β isoform of thyroid hormone receptor (TRβ), predominantly expressed in pituitary, leading to resistance of pituitary to inhibitory effects of thyroxine, resulting in inappropriately high TSH levels leading to increased thyroid hormone production by the thyroid.  Pituitary resistance is often associated with hepatic resistance characterized by normal levels of sex hormone binding globulin (SHBG) and ferritin, which should have normally increased in the background of biochemical hyperthyroidism. , Hepatic resistance to thyroid hormone was seen in all the patients in our series [Table 1].
THR usually is dominantly inherited.  Recessive transmission is very rare and was demonstrated only in the first family reported by Refetoff. De novo mutation in TR β accounts for about 22.5% of THR.  Thyroid function was normal in all the first degree relatives of all the 3 patients with THR in our series; hence, the mutation in our patients is likely to be de novo.
This resistance is not seen in peripheral tissues like heart which express predominantly α-isoform.  This explains the persistent tachycardia seen in our patients 1 and 2. Goiter is seen in 65-95% patients of THR.  All the 3 of our patients had goiter. A combination of goiter, palpitations and tachycardia often led to a misdiagnosis of Graves' disease in patients with THR, before the advent of sensitive TSH assays. 
Short stature is seen only in 18% of patients with THR. In contrast, all the 3 patients in our series had short stature. It is likely that patients of THR with short stature are more likely to seek medical care and hence are more likely to be diagnosed. Delay in bone age is variable in patients with THR varying from 29 to 47%.  Bone age delay was seen in all our patients with THR [Table 1].
Attention deficit hyperactivity disorder (ADHD) is common in children with THR (75%).  Mixson et al showed that both children and adults with THR exhibited problems with language development characterized by poor reading skills and problems with articulation.  Frank mental retardation (IQ<60) is quite uncommon.  Patient-1 in our series had ADHD with severe mental retardation (IQ-52).
Patient -2 had ITP who was diagnosed with THR during evaluation of associated short stature and goiter. This is perhaps the first report of occurrence of THR with ITP, the association is likely incidental.
The main differential diagnosis is inappropriate TSH secretion from pituitary adenoma (TSHoma). Pituitary imaging may help to differentiate the two conditions. Pituitary adenoma can be differentiated from THR with the help of the Werner test. Circulating TSH is suppressed following T3 administration (80-100 mg orally for 8-10 days) in patients with THR in contrast to TSHomas where TSH secretion is autonomous.  MRI pituitary was normal in all of our patient ruling out TSHomas.
Management is difficult in patients with THR and depends on the presenting symptoms. Clinically hypothyroid patients can be treated by the administration of supraphysiological doses of thyroid hormone, but with careful monitoring to avoid thyrotoxic symptoms. Developmental delay and growth retardation in children may warrant the administration of supraphysiological doses of levothyroxine. Trial of levothyroxine in patient-2 of our series resulted in thyrotoxic symtoms and worsening of tachycardia, leading to stoppage of levothyroxine. Tachycardia improved with propranolol therapy.
Antithyroid drugs are not preferred in patients with predominant thyrotoxic symptoms as they can further raise the TSH with consequent worsening of goiter and a risk of autonomy both at pituitary and thyroid.
Agents which inhibit pituitary TSH secretion and are devoid of peripheral thyromimetic effects can be used to reduce thyroid hormone values like tri-iodothyroacetic acid (TRIAC), tetratiodothyroacetic acid (TETRAC) or dextrothyroxine.  However these drugs are not commonly available in our country. Tachycardia in patients 1 and 2 of our series was effectively managed with propranolol.
One of the limitations of this report is the lack of genetic analysis to establish the mutations responsible for this THR.
To summarize, short stature followed by goiter was the predominant presenting symptom in patients with THR in our series. One of them had ADHD with severe mental retardation. To the best of our knowledge, this is the first report of the simultaneous occurrence of immune thrombocytopenic purpura and THR. Pituitary resistance with hepatic resistance was the pattern of THR in all of our patients. Propranolol can be effective in managing thyrotoxic symptoms like tachycardia in the absence of thyroid hormone analogues like TRIAC or TETRAC.
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[Figure 1], [Figure 2], [Figure 3]