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Original Studies |
Thyroid Unit (J.D.S., F.E.W.) and the Division of Behavioral Neurology (M.G.O.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215; the Division of Cardiology, Children’s Hospital and Harvard Medical School (S.D.C., S.S.), Boston, Massachusetts 02194; and the Division of Endocrinology and Metabolism, Winthrop University Hospital and State University of New York School of Medicine (S.R.T.), Mineola, New York 11501
Address all correspondence and requests for reprints to: Joshua D. Safer, M.D., Section of Endocrinology, Nutrition, and Diabetes, Boston, University School of Medicine, Room M-958, 715 Albany Street, Boston, Massachusetts 02118. E-mail: Jsafer{at}bu.edu
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Abstract |
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Introduction |
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Clinically, RTH can be divided into two entities: generalized resistance to thyroid hormone (GRTH) and central resistance to thyroid hormone (CRTH) (4). In both syndromes there is thyroid hormone resistance at the level of the pituitary and hypothalamus, causing inappropriate TSH secretion and, in turn, elevated thyroid hormone levels. In GRTH there is also peripheral resistance, often resulting in a hypothyroid- or euthyroid-appearing patient (13). In CRTH, however, peripheral sensitivity to thyroid hormone is preserved, and the individual suffers thyrotoxic symptomatology from the elevated levels of circulating T3 (14). Previously, patients with CRTH were referred to as having pituitary resistance to thyroid hormone. Recent studies suggest, however, that both hypothalamic resistance and pituitary resistance are required to significantly raise thyroid hormone levels (15); therefore, our laboratory believes a more suitable term for this disorder is CRTH.
Many researchers maintain that both GRTH and CRTH are part of a
spectrum of the same genetic disorder (9, 16, 17). This can be
explained because the CRTH phenotype is not clearly defined in patients
with a rigorous clinical evaluation. Based on newer information, we and
others have concluded that GRTH and CRTH represent distinct disorders
(18, 19). Individuals are often assigned the GRTH or CRTH designation
based on resting pulse measurements or other parameters in the absence
of T3 suppression testing. As the effects of thyroid
hormone on the heart may be predominantly mediated by TR-
, this
defining characteristic may not be suitable to separate these disorders
(20).
Refetoff et al. used a T3 suppression protocol to distinguish GRTH individuals from normal subjects (4, 21). We have established a similar protocol to separate CRTH individuals, GRTH individuals, and normal subjects. We have begun to collect data on individuals with rigorously defined CRTH using our protocol (22). Here we present the most rigorous evaluation of an individual with CRTH to date.
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Materials and Methods |
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For clinical evaluation, the subject was admitted to the Beth Israel Deaconess Medical Center (BIDMC) General Clinical Research Center in Boston, MA. A protocol to evaluate patients with CRTH was approved by our institutional review board. Serum, urine, and other testing was performed at baseline. Subjects then commenced graded thyroid hormone (oral T3) administration as follows: 25 µg twice daily for 4 days, 50 µg twice daily for 4 days, and 100 µg twice daily for 4 days. All testing was repeated on the morning before each dose change.
On day 0, the subject was admitted to the General Clinical Research Center at BIDMC. On day 1, baseline evaluation was undertaken, including serum chemistries, thyroid function tests, urine studies, ankle jerk relaxation time measurement, TRH stimulation, resting cardiac evaluation, and psychological evaluation. The subject then began taking 25 µg T3 twice daily. On day 5, the parameters measured at baseline were remeasured. The T3 dose was raised to 50 µg twice daily, and the parameters were remeasured on day 9. Finally, the T3 dose was raised to 100 µg twice daily, and the parameters were measured a final time on day 13.
Indexes of peripheral thyroid hormone action were chosen to include tests that are routinely performed and tests that measure signs associated with abnormal thyroid hormone levels. To these ends serum tests included ferritin, sex hormone-binding globulin (SHBG), alanine aminotransferase (ALT), aspartate transaminase (AST), creatinine phosphokinase (CK), lactate dehydrogenase (LDH), total cholesterol, and fasting triglycerides.
Evaluation of central T3 action
On each testing day, baseline serum TSH was measured using a
third generation TSH assay (sensitivity, 
0.01 µU/mL; interassay
coefficient of variation, 5%). In addition, each subject underwent a
TRH stimulation test to assess further the degree of central
resistance. Subjects received 7 µg/kg BW (but never more than 500
µg) protirelin (Ferring Pharmaceuticals Ltd., Suffern,
NY) by iv push. Serum TSH and PRL were measured at baseline and 15, 30,
45, 60, 90, 120, and 180 min after receiving the TRH dose.
Evaluation of peripheral T3 action
On each study day, indexes of peripheral thyroid hormone activity were measured. Serum ALT, AST, ferritin, SHBG, cholesterol, and triglycerides were measured to determine the effect of T3 on metabolic and hepatic functions. All samples were gathered in the morning after an overnight fast. An overall assessment of relative peripheral thyroid hormone effect was made with the diagnostic index developed by Billewicz et al. (23). A weight measurement was made each study day as well.
To assess neuromuscular impact from thyroid hormone, serum CK and ankle jerk relaxation time were assessed. To obtain accurate and reproducible ankle jerk relaxation times, a high speed camera was used to film the entire reflex at each dose. The camera was programmed to track movements of the subject’s foot at 16.7-ms intervals. For increased precision of the test, the time from peak to half-maximum was measured. At each dose, five measurements were made and averaged. In normal individuals, no significant change in relaxation time was observed despite large variations in the strength and speed of reflex hammer blows.
Basal cardiac status was assessed with an echocardiogram and a sleeping heart rate measurement. Subjects were attached to a remote cardiac monitor, and minute long samples of heart rates were recorded during each hour of nighttime sleep. In the morning, an average of the samples was taken.
The echocardiographic evaluation consisted of two-dimensional and Doppler evaluation, with analysis of the stress-velocity and stress-shortening indexes (24). Two-dimensional and Doppler echocardiographies were performed for the qualitative assessment of regional wall motion, the presence of intracardiac thrombus, and evidence of valvular heart disease. An m-mode echocardiogram directed by two-dimensional imaging was recorded simultaneously with an electrocardiogram, phonocardiogram, and carotid pulse tracing. Blood pressure was measured with a Critikon automated vital signs monitor (Johnson and Johnson Company, Tampa, FL). The m-mode echocardiogram, phonocardiogram, and pulse tracing were analyzed by computer as previously described (24). End-diastolic dimension and wall thickness were taken as the measures of left ventricular size, fractional shortening was used as the index of global ventricular function, wall stress was determined as the index of afterload, and the afterload-adjusted velocity of shortening (stress-velocity index) was obtained as the index of contractility.
Neuropsychological evaluation
The subject was seen for neuropsychological testing on each of the study days. Tests focused on various aspects of attention (attention span, speed of processing, sustained attention, and selective attention) and memory. Tests that were resistant to practice effects or that had alternate forms available were chosen. To these ends, tests used included the Digit Span and Digit Symbol subtests from the Wechsler Adult Intelligence Scale-Revised (25), the Trailmaking-B test (26), the Paced Auditory Serial Addition Test (27), and the Auditory Verbal Learning Test (AVLT) (28). Testing was conducted by an examiner blind to the subject’s diagnosis.
Sequencing of DNA
DNA was extracted from whole blood using the G NOME Whole Blood Kit (BIO 101, Inc., Vista, CA). With intronic primers (29), the carboxyl-terminal exons 5, 6, 7, and 8 (formerly exons 7, 8, 9, and 10) of the TR-ß were amplified by PCR. The amplified exons were subcloned into the bacterial plasmid vector pGEM T (Promega Corp., Madison, WI). Subclones were sequenced with T7 Sequenase 2.0 (Amersham Pharmacia Biotech, Cleveland, OH).
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Results |
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A 54-yr-old white woman was referred for inappropriately elevated TSH levels. The woman reported a 20-yr history of palpitations and anxiety. She suffered spontaneous palpitations three to four times weekly and sought emergency room evaluation on several occasions. Approximately 10 yr before presentation, the woman was diagnosed with Graves’ disease and was treated twice with 131I. The woman then enjoyed a long period of "tolerable" palpitations that were treated with ß-blockers on occasion. A physician viewing her laboratory tests treated her with levothyroxine. The woman reported no impact on her symptoms from the levothyroxine treatment.
On presentation, the woman was taking 50 µg/day levothyroxine. Her
laboratory thyroid testing at this time revealed a serum TSH of 14.8
µU/mL (normal, 0.35–5.5) with a free T4 index of
4.6 (normal, 1.6–3.7). Off levothyroxine, the woman was noted to have
a serum TSH of 17.6, a free T4 by equilibrium dialysis of
0.8 ng/dL (normal, 0.8–2.7), and a free T3 by equilibrium
dialysis of 420 pg/dL (normal, 260–480). Her glycoprotein hormone
-subunit level and pituitary magnetic resonance imaging were normal.
She had no other medical problems. The woman had a normal thyroid exam.
The remainder of her physical exam was normal, except for obesity (26%
above ideal body weight) and a resting tremor.
Available family consisted of an affected sister and a normal brother
The propositus was one of four children of nonconsanguinous
parents (Fig. 1
). The father had no
record of thyroid disease. The mother reportedly suffered
hyperthyroidism, which required two rounds of radioactive iodine to
treat. Both parents are deceased. Of the three siblings, one died
accidentally at age 7 yr, and the remaining two were available for
further study. At the time of the evaluation, the brother was 58 yr old
and had no history of thyroid disease. He was healthy, and his thyroid
function tests were as follows: TSH, 2.96 µU/mL; free T4
by equilibrium dialysis, 1.5 ng/dL (normal, 0.9–2.0); and free
T3 by equilibrium dialysis, 2.2 pg/mL (normal, 2.0–4.0).
The brother was the only sibling with natural children, and both
children were healthy.
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Sequencing the C-terminus of the TR-ß of the propositus and her family revealed a mutation at amino acid 383
We isolated genomic DNA from the buffy coat of a whole blood
sample from the propositus. Carboxyl-terminus exons were amplified by
PCR, subcloned into the pGEM T vector, and sequenced. By this method an
arginine to histidine mutation was found in amino acid 383 (Fig. 2). The remainder of the C-terminus was
free of mutations. The R383H mutation has been reported once before
(19) in a patient believed to suffer CRTH. Amino acid 383 is of
interest in that it lies in a region not previously thought to contain
resistance mutations. In the crystal structure of the rat TR- (30),
residues homologous to R383 and the previously described CRTH amino
acid, R429, may interact with amino acids homologous to E311 and D382
to form a salt bridging group in a polar invagination. These residues
may define a domain important in negative transcriptional regulation by
TR.
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The propositus (C23) was enrolled in a protocol to evaluate relative central and peripheral sensitivity to thyroid hormone: she was profoundly resistant to T3 centrally
Six months after cessation of all exogenous thyroid medication,
the propositus (C23) was enrolled in the clinical resistance to thyroid
hormone protocol at BIDMC. To facilitate broad comparisons with
historical data, the protocol was written as a modification of the
protocol used by Refetoff et al. (4). C23 began the study
with TSH elevated to 15.4 µU/mL despite high normal total thyroid
hormone levels (T4, 10.0 µg/dL; T3,
136 ng/dL). More striking, C23’s basal TSH remained detectable
throughout the study. On the medium and high T3 doses, both
our normal patient and historical normal controls (21) had completely
suppressed TSH. When C23 took 200 µg T3 daily for 4 days,
her TSH could still be measured (Fig. 3).
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). Normal individuals respond to low dose
T3 (50 µg/day) with suppression of TRH-stimulated TSH
level more than 75% below the baseline TRH-stimulated TSH value (21).
Individuals with resistance to thyroid hormone fail to suppress
stimulated TSH to that degree on the low T3 dose. We
evaluated a GRTH subject in our protocol who also failed to suppress
the stimulated TSH to that degree on the low T3 dose.
Similarly, C23’s low T3 dose, TRH-stimulated TSH remained
more than 25% of her baseline TRH-stimulated TSH. On the low dose of
T3, a normal individual in our protocol had a
TRH-stimulated TSH greater than 90% below baseline TRH-stimulated TSH.
On the medium and high T3 doses, both our normal patient
and those in the original study (21) had trivial rises in TSH after TRH
stimulation. Our GRTH subject, the historical GRTH subjects, and C23
continued to exhibit detectable multifold TSH responses to the TRH
stimulus despite the escalation in the T3 dose.
RTH patients are separated from hypothyroid patients by their PRL
responses to TRH stimulation. C23’s basal PRL level was 4.3 ng/mL
(normal, 2–14). Her TRH-stimulated PRL rise to a peak of 38 was normal
and only 30% of that seen in patients with hypothyroidism (21, 31, 32). C23’s TRH-stimulated PRL fell to 42% and 29% of her baseline
TRH-stimulated PRL on the medium and high T3 doses,
respectively (Fig. 4). This did not
separate her from our normal subject, whose TRH stimulated PRL
suppressed to 52% and 48% of baseline TRH-stimulated PRL on those
T3 doses (Fig. 4). The TRH-stimulated PRL in our GRTH
subject was suppressed to 36% and 32% of baseline TRH-stimulated PRL
on the respective medium and high T3 doses. Thus, we could
not distinguish normal, CRTH, and GRTH individuals by observing their
TRH-stimulated PRLs.
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A synthesized diagnostic index of relative peripheral thyroid
hormone action was designed by Billewicz et al. (23) to
assess hypo- and hyperthyroidism before the advent of good clinical
chemistry tests. We used the diagnostic index from Billewicz on each
study day. Indeed, over the course of the evaluation, C23’s diagnostic
index rose 179%, reflecting greater peripheral T3
sensitivity than that of a normal individual similarly assessed (Fig. 5A). The normal subject noted only a 33%
rise. The GRTH subject, by contrast, reported a paradoxical
decline.
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As a surrogate for energy consumption, weight was determined
on each study day. Despite a concerted effort to maintain isocaloric
diets before and during the study, C23 lost 3% of her body weight
between the baseline measurement and that on the high dose of
T3 (Fig. 5B). This proved consistent with the experience of
our normal subject and the historical normal subjects (4). It
contrasted with our GRTH subject and the historical GRTH subjects whose
weights remained remarkably stable after T3
administration.
C23 demonstrated marked hepatic sensitivity to T3
C23’s hepatic sensitivity was demonstrated via several
common chemistry tests reflective of liver biosynthetic activity. Our
studies included the standard liver function tests, ALT and AST.
Products of liver metabolism, such as cholesterol and SHBG, and the
acute phase reactant, ferritin, were measured. Refetoff et
al. (4) used the above parameters in their similar studies of GRTH
patients and normal subjects. Although tests in normal patients
demonstrated sensitivity to administered thyroid hormone, GRTH
patients demonstrated striking stability of these
T3-sensitive parameters even at the highest daily dose
(Fig. 6).
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, A, E, and
F). In addition, C23’s fasting serum cholesterol fell 25%, and her
triglycerides fell 28% (Fig. 6, C and D). These results proved quite
consistent with those of normal individuals undergoing this evaluation
in the literature (4) and one normal individual we studied under our
specific conditions. Indeed C23’s hepatic sensitivity to thyroid
hormone proved greater than that of the normal individuals tested. Neuromuscular indexes were also dramatically altered by T3 administration
Neuromuscular activity is considered sensitive to changes in
thyroid hormone levels in normal individuals. To assess the impact of
our T3 protocol, we checked serum CK and measured the ankle
jerk relaxation time at each dose. To avoid the error introduced by a
roving baseline in ankle jerk relaxation time measurement, the time
from peak to half-maximum relaxation was used. Like that of normal
individuals and in contrast to that of GRTH individuals, C23’s serum
CK fell 36% (Fig. 7A) over the course of
the study. Although there is no quantitative assessment of ankle jerk
reflex in GRTH patients receiving T3, attempts have been
made to quantify ankle jerk relaxation times in euthyroid and
hyperthyroid individuals (33, 34, 35, 36). In these studies, the hyperthyroid
relaxation times averaged 20% faster than the euthyroid relaxation
times. Our normal subject exhibited a 15% fall in Achilles tendon
relaxation time with the 200 µg/day T3 dose (Fig. 7B). By
these criteria, the CRTH subject exhibited a supernormal decline in
Achilles tendon relaxation time (36%) while taking 200 µg
T3 daily (Fig. 7B).
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Cardiac function was not associated with other
peripheral indicators. Although the sleeping heart rate of C23 rose
with her dose of T3, the degree of rise was less than that
in either normal or GRTH subjects (Fig. 8). Further confounding matters, our
normal subject’s heart rate proved more resistant to T3
administration than in the normal subjects reported by Refetoff
et al., but was statistically equivalent to values in the
historical GRTH patients receiving 200 µg T3 daily.
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Although C23’s myocardial contractility was increased on the highest T3 dose, this did not represent a significant change, and the measurement remained within normal limits. Using our stress-velocity index as an index of contractility, C23 demonstrated a 23% increase in contractility from the baseline to the highest T3 dose. Our one normal individual demonstrated a 9% increase, and our GRTH subject demonstrated a 19% increase over the same interval. All of these changes were within the measurement error of the test itself, and all of the contractility values were within previously determined normal limits (24).
C23 exhibited improved neuropsychological conditioning in response to higher T3 doses
Although neuropsychological tests were chosen in which normal individuals would not be expected to improve over several repetitions, C23’s performance on tests of attention span, speed of processing, selective attention, mental flexibility, verbal learning (memory), and motor speed improved as her dose of T3 was raised. A test of attention span revealed a 33% improvement from baseline to the 200 µg T3 test day. The degree of change proved more dramatic than the small 6% improvement seen in our normal subject over the same period. On the test of speed of processing and selective attention (Paced Auditory Serial Addition Test), C23’s baseline score fell in the low range (20th percentile). Her performance on this test rose steadily across subsequent sessions, such that it was in the high range (80th percentile) by the 200 µg T3 test day. A similar rate and extent of improvement was noted on the test of mental flexibility (Trailmaking-B). At baseline, C23’s performance was at the 75th percentile. On high dose T3, her performance rose to the 90th percentile for the test. Our normal subject suffered a small deterioration in score over the same time period. C23’s performance on the verbal learning test (AVLT) revealed steady improvement as the T3 dose escalated. Initially, her learning was average (50th percentile). By the high T3 dose, her recall rose to the 90th percentile. Delayed recall also improved from baseline (30th percentile) to the high T3 dose (70th percentile). On the AVLT, too, C23 proved more sensitive to T3 than the normal subject, who demonstrated no change in score over the course of the protocol. Finally, on the test of motor speed, C23’s score rose from the 25th percentile initially to the 75th percentile on high dose T3. This also was quite dramatic. The normal subject tested exhibited a rise from the 9th percentile to the 25th percentile over the protocol for a similar fold improvement.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several observations are worthy of highlight. First, the existence of a discreet CRTH clinical entity is much debated. Refetoff et al. (4, 21) designed a protocol of escalating T3 administration to separate normal and GRTH individuals. In that study, individuals defined as having RTH were found to demonstrate relatively nonsuppressed TSH levels despite high doses of exogenous T3. Normal subjects in the same study had their TSH levels suppressed at significantly lower T3 doses. When parameters of peripheral thyroid hormone action were evaluated, the RTH subjects exhibited no change or even paradoxical responses in the face of high T3 doses. By contrast, the normal individuals studied exhibited marked changes in the peripheral parameters under the influence of thyroid hormone. Thus, normal and RTH subjects were well separated by both central and peripheral responses to T3.
C23’s TSH was not suppressed at the high T3 dose, evidence of more profound central resistance even than that noted in most of the historical RTH cohort. However, in our evaluation of C23, we showed that multiple peripheral tissues exhibited a normal response to T3 despite this central resistance. Normally these peripheral parameters demonstrated a sensitivity to rising T3 levels, whereas RTH individuals lacked responses to T3. Here is where C23 diverged importantly from the previously reported RTH patients. Her peripheral markers mirrored those of normal subjects, and despite the fact that C23 shared central resistance with GRTH patients, her peripheral sensitivity to T3 was normal.
C23 demonstrated clear hepatic, musculoskeletal, and neuropsychological sensitivity to T3. It is worth noting, though, that although these peripheral tissues were sensitive to changes in T3, the degree of sensitivity varied among tissues. It remains to be seen if other CRTH patients display a similar variability in peripheral sensitivity to thyroid hormone. Based on the literature, we suggest that different CRTH patients may have different degrees of peripheral thyroid hormone sensitivity. Whether the explanation for these differences can be attributable to TR mutation alone will require a better understanding of the molecular mechanisms underlying CRTH.
The cardiac evaluation raises more questions than it answers. Resting tachycardia is considered by some to be a hallmark of RTH (4). Others attempt to use heart rate to separate GRTH and CRTH (9, 37). Like the majority of subjects reported by Brucker-Davis et al. (13), we found our subject’s resting heart rate to be normal. Further, the rise of C23’s heart rate while taking T3 was less than that seen in either normal or GRTH patients in the literature. Similarly, the more sophisticated echocardiographic evaluation failed to detect T3 sensitivity in either C23 or a normal individual. It is clear that heart rate alone is both a poor indicator of RTH status and insufficient to separate individuals into GRTH and CRTH categories.
The nature of our study precluded evaluation of more chronic thyroid
hormone-mediated changes. It is possible that some cardiac sequelae of
hyperthyroid states represent chronic exposure. In addition, studies in
transgenic mice have implicated TR- in cardiac phenomena (20).
Tissue-specific expression of TR isoforms, therefore, is likely to play
a part mediating RTH in different tissues. The interplay among the TR
isoforms in this subject remains an active topic of research.
Although the neuropsychological testing demonstrated T3 sensitivity in an individual with central thyroid hormone resistance, the nature of that sensitivity was surprising. Although the normal subject experienced improvement on some tests and deterioration on others, C23 demonstrated improvement in all areas evaluated. Additional subjects will need to be studied to ascertain whether the changes measured in C23 should be interpreted simply as T3 sensitivity or whether those changes reflect an aspect of central resistance that was overcome.
TRH-stimulated PRL levels have been reported to separate RTH individuals from normal subjects (21). Sarne et al. reported that TRH-stimulated PRL levels during T3 suppression testing made a clear distinction. Normal individuals suppressed their TRH-stimulated PRL levels to 50% and 25% of their baseline TRH-stimulated PRL levels on medium and high T3 doses, respectively. RTH individuals had no suppression of TRH-stimulated PRL on those T3 doses. In contrast, Snyder et al. found no change in TRH-stimulated PRL levels when normal individuals took 30 µg T3 and 120 µg T4 daily for 3–4 weeks (31). Our data contradict those of both groups, in that C23, our normal subject, and our GRTH subject all saw similar suppression of their TRH-stimulated PRL levels on the low, medium, and high T3 doses. It is likely that the variability in suppression of TRH-stimulated PRL is such that it cannot serve as a reliable indicator of resistance status.
It is interesting to note that both the index case and her affected sister had high circulating TSH levels, with free thyroid hormone levels only in the high normal range. Although C23 underwent radioactive iodine ablation therapy, the sister did not. However, the sister did have a significant antithyroperoxidase antibody titer, suggesting the possibility of coexistent Hashimoto’s disease. It seems unlikely that the proband is hypothyroid, in that her symptoms are those of euthyroidism or hyperthyroidism. Importantly, C23’s PRL level was normal and exhibited a normal, not a hypothyroid, response to TRH stimulation. If the sister were to become frankly hypothyroid, failure to diagnose her CRTH would result in overtreatment with thyroid hormone. Conversely, the elevated TSH levels may reflect the secretion of relatively bioinactive TSH in this kindred. For example, if pituitary resistance with the R383H mutation were greater than hypothalamic resistance, more TSH would be released, but it would lack the TRH-mediated posttranslational processing required for maximal potency. Biochemical parameters in this instance would be consistent with those that we observed in our kindred.
Another aspect of this study is that it represents the first of our CRTH patients with documentation of affected family members. GRTH mutations are usually found in families. Although some researchers suggest that spontaneous CRTH mutations are more common (4), others have found that familial CRTH is as common as familial GRTH (9, 38). We have not been able to document familial involvement with our R429Q mutation (22), but both R338L mutation reports (39, 40) and the other R383H report (19) include affected family members.
In separating CRTH from GRTH, it is important to note the paucity of both baseline and T3 suppression data of thyroid hormone-responsive gene products. The literature includes references to both selectively CRTH individuals and GRTH individuals. The CRTH patients are diagnosed with subjective symptoms of thyrotoxicosis and elevated heart rates. Only the R338L mutation (39), the R338W mutation (41), and our previously reported R429Q mutation (22) are presented with T3 suppression data to confirm the CRTH diagnosis. The result of the failure to more thoroughly evaluate RTH patients is significant, because misassignment of these individuals based on the lack of clinical data is possible. C23 might easily have been assigned the GRTH diagnosis in the absence of the T3 suppression protocol. Although C23 complained of palpitations intermittently before her diagnosis, there was little else in her subjective history to indicate CRTH. Although the palpitation complaint in conjunction with elevated thyroid hormone levels has been interpreted as a sign of thyrotoxicosis, increased heart rates have also been observed in GRTH individuals (13). She was not tachycardic, and even her high normal heart rate was most consistent with deconditioning from a sedentary life style.
Delineation of CRTH from GRTH is important for two reasons. Clinically, treatment of the two conditions is quite different. Although those subjects with GRTH should receive either thyroid hormone or no treatment, those with CRTH require treatment to alleviate their thyrotoxic symptoms. Failure to correctly diagnose these patients frequently leads to radioactive thyroid ablation for presumed Graves’ disease. Although this may be helpful in patients with CRTH, it is clearly the wrong therapy for patients with GRTH.
In addition, efforts to associate molecular mechanism and phenotype require reliable phenotypic definitions. To date, two molecular mechanisms responsible for the CRTH and GRTH disorders have been offered. Using the R338L, R338W, and R429Q mutations, we found an important difference between the ß1 and ß2 isoforms of the TR (18). Although the above CRTH mutations had weak dominant negative activities in the ß1 isoform, in the ß2 isoform their dominant negative activities were high. This contrasted with the GRTH mutations tested, in which dominant negative activities were high for both isoforms. The isoform difference proved interesting, in that the ß1 isoform is found throughout the body, whereas the ß2 isoform is found primarily in the pituitary and hypothalamus. Clifton-Bligh et al. (19) used the R383H mutation to demonstrate its strong dominant negative activity on TSH and TRH promoters in contrast to its weak dominant negative activity on peripheral gene promoters. They concluded that the mutation, not the TR isoform, mediated the CRTH disorder. It is possible, however, that more than one mechanism can result in CRTH.
The drive to further associate molecular and clinical phenomena in RTH is hampered by insufficient clinical evaluation of the affected individuals. In vitro characterizations of various mutations cannot be secure without clear assignment of the clinical phenotypes. To address this issue, thorough clinical evaluation of RTH subjects will need to accompany the identification of their mutations. Then, a basis for clinical/molecular associations will be established. In this report, R383H becomes one of a small number of rigorously classified CRTH mutations. As such, its in vitro analysis will prove important in providing a molecular explanation for the difference in RTH phenotypes.
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Acknowledgments |
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Footnotes |
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Received March 16, 1999.
Revised May 4, 1999.
Accepted June 1, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1. EMBO J. 17:455–461.[CrossRef][Medline]
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