RTH 1
RTH 1
RTH 1
The syndrome of impaired sensitivity to thyroid hor- Table 1. Thyroid function panel from 2009 to 2014
mone, also known as syndrome of thyroid hormone Reference
resistance, is an inherited condition that occurs in value 12/2009 10/2010 08/2011 04/2012 02/2013 07/2014
1 of 40,000 live births characterized by a reduced TSH (mcIntUnit/mL) 0.27–4.20 10.37 42.41 46.62 37.70 26.39 39.00
responsiveness of target tissues to thyroid hor-
FT4 (ng/dL) 0.93–1.70 3.00 1.81 2.07 1.91 1.82 1.05
mone due to mutations on the thyroid hormone
receptor. Patients can present with symptoms of FT3 (pg/mL) 2.3–4.2 N/A N/A N/A N/A 8.86 3.64
hyperthyroidism or hypothyroidism. They usually FT3 indicates free triiodothyronine; FT4, free thyroxine; NA, not available; TSH, thyroid-stimulating hormone.
have elevated thyroid hormones and a normal or
elevated thyroid-stimulating hormone level. Due to
their nonspecific symptomatic presentation, these patients can be misdi- for the patient. Her family history was relevant for a son with
agnosed if the primary care physician is not familiar with the condition. “hypothyroidism.”
This can result in frustration for the patient and sometimes unnecessary The patient’s thyroid function panels from 2009 to 2014
invasive treatment such as radioactive iodine ablation, as in the case were reviewed and are presented in Table 1. During this pe-
presented herein. riod of time she was on different doses of thyroid replacement
therapy, her TSH remained elevated despite normal or elevated
free T4 levels. She also had magnetic resonance imaging of the
T
he syndrome of impaired sensitivity to thyroid head, which showed a possible right-sided pituitary microad-
hormone (ISTH) is a condition of decreased tissue enoma. A thyroid ultrasound showed a normal thyroid gland
sensitivity to thyroid hormone action usually caused with some nonspecific nodules.
by germline mutations of the thyroid hormone recep- PCR amplification of THRB gene exons 10, 9, and 8 fol-
tor beta (THRB) gene. The mutant receptor has lower binding lowed by gene sequencing showed a heterozygous missense mu-
affinity for thyroid hormone and, as a consequence, serum tation C>A located at exon 10. The mutation caused a change in
thyroid-stimulating hormone (TSH) levels remain nonsup- thyroid hormone receptor beta protein amino acid 453 proline
pressed despite elevated thyroid hormones (1–3). We present to threonine, P453T (Figure 1).
the case of a 66-year-old woman who was referred for evalu- We recommended that the patient resume thyroid hormone
ation of an abnormal thyroid function panel that suggested replacement with liothyronine 10 mg twice a day and levothy-
ISTH. roxine 75 mcg daily; unfortunately, she was lost to follow up
thereafter.
CASE REPORT
A 66-year-old woman was referred for evaluation of thyroid DISCUSSION
dysfunction. Her complaints were memory loss and intermit- We describe a case of ISTH caused by a common germline
tent gastrointestinal symptoms with alternating diarrhea and mutation located at THRB exon 10 hot spot (4). The patient
constipation attributed to irritable bowel syndrome. In 1998, went undiagnosed for many years. When reviewing her thyroid
she had been diagnosed with “a thyroid condition that no one
was able to fix.” At that time, she had a goiter and was treated
From the Department of Medicine, Division of Endocrinology and Metabolism,
with radioactive iodine (I-131) and was subsequently started Mayo Clinic, Jacksonville, Florida (Rivas); and the Department of Medicine,
on thyroid replacement therapy. For nearly 30 years, she was Division of Endocrinology, Texas Tech University Health Science Center, Lubbock,
seen by multiple physicians who continuously modified her Texas (Lado-Abeal).
thyroid hormone replacement but had been unable to “normal- Corresponding author: Ana Marcella Rivas, MD, 4500 San Pablo Road,
ize” her thyroid hormone levels, and this resulted in frustration Jacksonville, FL 32224 (e-mail: rivasmejia.ana@mayo.edu).
function tests, we noted a nonsuppressed serum TSH despite Symptoms tend to decrease with age, and patients eventually
a normal or elevated free T4 level. These abnormal values led become clinically euthyroid. Goiter is one of the most common
us to suspect THRB mutation and proceed with genetic stud- findings for which patients seek medical attention. It’s usually
ies, which confirmed the diagnosis. The diagnosis of ISTH re- refractory and recurs after surgery or treatment with radioactive
quires a high degree of suspicion, and we therefore believe it is iodine. Other common complaints include tachycardia, learning
important for the general practitioner to be able to recognize disabilities, and hyperactivity (8).
the syndrome to avoid delay in diagnosis and unnecessary in- The classic pattern of thyroid function test that these patients
vasive treatments, such as thyroid surgery or radioactive iodine present with is elevated thyroid hormones with nonsuppressed
ablation. TSH in serum. The response of TSH to thyrotropin-releasing
Thyroid hormone genomic actions are exerted by thyroid hormone is normal or exaggerated, and thyroidal radioiodine
hormone binding mostly to nuclear receptors located in the uptake may be elevated (5).
nuclei and interaction with DNA to regulate the transcription of ISTH can be difficult to differentiate from TSH-producing
target genes. Most of the cases of ISTH are caused by mutations pituitary tumors, which present with a similar thyroid func-
in the THRB gene located in chromosome 3, and these muta- tion profile. A case of coexistence of both conditions has been
tions most often clustered in three hot spots located in exons 8, reported (9). TSH-producing pituitary tumors present elevated
9, and 10. The mutant thyroid hormone receptor beta protein serum levels of T4, T3, and nonsuppressed TSH. In contrast to
has either reduced affinity for T3 or abnormal interaction with patients with ISTH who may be clinically euthyroid, patients
cofactors involved in thyroid hormone action, making the target with TSHomas usually present with symptoms of mild to severe
tissues refractory to thyroid hormones (5–7). hyperthyroidism and compression symptoms resulting from
In 15% of cases of ISTH, a gene mutation is not identi- tumor growth (7).
fied (6). Mutations affecting thyroid hormone cell membrane When treating these patients, one should concentrate on the
transporters and thyroid hormone metabolism have now been patient’s symptoms and clinical picture instead of aiming to nor-
described, and the concept of syndrome of reduced sensitivity malize thyroid hormone levels (5, 8). Most patients, if left alone,
to thyroid hormone is used to encompass any defect causing adequately overcome the resistance by increased thyroid hor-
reduced effectiveness of the thyroid hormone (3). mone secretion and therefore do not require treatment (8, 10).
The clinical presentation of patients with THRB mutations Treating patients who present with normal TSH is more chal-
is variable. Patients may present with symptoms of hyperthy- lenging; in these patients, administration of supraphysiological
roidism, hypothyroidism, or a combination of symptoms of doses of thyroid hormone might be required and, if so, should
thyroid hormone deficiency and excess depending on the level of be closely monitored. Patients who present with symptoms
THRB and THRA gene expression in the target tissues (5, 6, 8). of hyperthyroidism should be treated symptomatically with