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15 October 1995 | Volume 123 Issue 8 | Pages 572-583
Objective: To determine the genetic and clinical features of resistance to thyroid hormone in a study from a single institution.
Design: Prospective, controlled study.
Setting: National Institutes of Health.
Patients: 104 patients with resistance to thyroid hormone from 42 kindreds and 114 unaffected relatives sharing the patients' environmental and genetic back-grounds.
Measurements: Thyroid, cardiovascular, psychometric, hearing, speech, and growth testing; thyroid tests done at baseline and after TSH-releasing hormone stimulation; and DNA analysis for detection of mutations in the thyroid hormone receptor ß (TR ß) gene (exons 9 and 10). Assessment of tissue-specific compensation for resistance.
Results: Inheritance was autosomal dominant in 22 families, sporadic in 14 families, and unknown in 6 families. We found mutations in 25 kindreds (64 patients); 16 mutations were in exon 9 and 9 were in exon 10 of the TR ß gene. In persons with resistance to thyroid hormone, we measured the increased incidence of goiter (65%), attention-deficit hyperactivity disorder (60%), IQ less than 85 (38%), speech impediment (35%), and short stature (18%). We also described new clinical features, such as frequent ear, nose, and throat infections (56%); low weight-for-height in children (32%); hearing loss (21%); and cardiac abnormalities (18%). Genotype, age, whether the mother had resistance to thyroid hormone, and sex influenced the phenotype. Tissue resistance varied from kindred to kindred and involved, in decreasing order, the pituitary gland, the brain, the bone, the liver, and the heart.
Conclusions: This study underscores the incidence of classic features of resistance to thyroid hormone, describes new clinical characteristics of this condition for the first time, and stresses the heterogeneity of the phenotype.
Ann Inten Med. 1995; 123:572-583.
The prevalence of resistance to thyroid hormone is unknown but is thought to be low. The phenotype is heterogeneous and ranges from highly symptomatic to subclinical [2, 3, 14]. Resistance to thyroid hormone is traditionally defined as generalized resistance and, more rarely, as pituitary resistance [15]. In generalized resistance, pituitary and peripheral tissues are not always involved to the same degree, and this creates a mosaic of hypothyroid and hyperthyroid symptoms in the patient. If the degree of resistance is similar in pituitary and peripheral tissues, high levels of thyroid hormone result in compensation, and patients are euthyroid. Patients with pituitary resistance are predominantly hyperthyroid and have hypermetabolism and tachycardia [16]. A single case of isolated peripheral resistance has been reported [17].
Since 1976, 104 patients with resistance to thyroid hormone from 42 unrelated kindreds have been studied prospectively at the National Institutes of Health (NIH), along with 114 of their unaffected relatives, who serve as a control group with environmental and genetic back-grounds similar to those of the patients. Here, we report the results of their initial evaluation. Our goals were to analyze the resistance-to-thyroid-hormone phenotype, including its newly recognized features; to assess the organ specificity of resistance to thyroid hormone; and to define factors contributing to the heterogeneity of the phenotype.
Data collected at the time of initial hospitalization at the NIH were analyzed for 218 persons (104 with and 114 without resistance to thyroid hormone, including 29 persons who had married into families that had resistance to thyroid hormone) from 42 unrelated families. Patients were referred to the NIH for the evaluation of inappropriate TSH secretion. Appropriate informed consent was obtained as approved by the National Institute of Diabetes and Digestive and Kidney Diseases institutional review board. Participants younger than 16 years of age were considered to be children.
A full personal and family history was taken from each participant, and specific information about goiter; cardiac symptoms; speech; ear, nose, and throat infections; and hearing problems was collected through interviews. Resting pulse (taken while participants were sleeping or after at least 10 minutes of rest) and goiter were recorded from physical examination, and height (an average of 10 measurements with a stadiometer), weight, and weight-for-height were plotted using charts adapted from Hamill and colleagues [18].
Diagnostic Criteria
Resistance to thyroid hormone was diagnosed on the basis of elevated free and total thyroid hormone levels in the presence of normal or elevated TSH levels. Blood was analyzed for levels of T3 (Quanticoat TM, Kallesad Diagnostic, Chasco, Minnesota), T4 (fluorescein polarization immunoassay, Abbott TDx, Abbott Park, Illinois), free T4 (Gammacoat TM two-step RIA, INC-STAR, Stillwater, Minnesota), free T3 (RIA, Becton Dickinson kit, SmithKline Beecham Laboratories, Van Nuys, California), TSH (MAIAclone, Serono Diagnostics, Walpole, Massachusetts),
Magnetic resonance imaging (MRI) of the pituitary gland was done to rule out a TSH-secreting pituitary adenoma.
Parameters of Thyroid Hormone Action
Assessment of Pituitary Resistance
In patients with no history of thyroidectomy who were not receiving thyroid medication (untreated patients), TSH-releasing hormone tests (Relefact, Ferring Laboratory, Suffern, New York) were done. Levels of TSH,
Assessment of Peripheral Resistance
Attention-deficit hyperactivity disorder and IQ were assessed using previously described methods [21, 22]. Briefly, a neuropsychologist, blinded to the diagnosis of resistance to thyroid hormone assessed IQ by using age-appropriate Wechsler intelligence tests. Attention-deficit hyperactivity disorder was diagnosed by psychiatrists, also blinded to the diagnosis of resistance to thyroid hormone, using appropriate structured psychiatric interviews.
Right-ankle reflex was measured with an achillometer (Polymed GmbH, Polymed Medical Center, Medizintechnik, Glattbugg ZH, Switzerland) connected to a 1511B electrocardiograph (Hewlett-Packard, Waltram, Massachusetts) in untreated persons. Results given are each an average of three measurements.
Audiologic evaluation included threshold tests of pure tones and speech stimuli and biochemical studies of middle-ear function (tympanometry and acoustic reflexes). Significant hearing loss was defined as a speech threshold greater than 20 decibels.
Bone age was determined in children by using a hand-wrist radiograph according to the method of Greulich and Pyle [23]. Standard deviations were calculated using the Brush foundation table [23].
Basal metabolic rate was measured at Georgetown University Hospital in Washington, D.C., in untreated persons by using a Sensor Medics 2900 metabolic cart (Sensor Medics Corp., Yorba Linda, California). Results are expressed as a ratio between observed and theoretical basal metabolic rate adjusted for age, sex, height, and weight.
Pulsed and continuous echocardiography assessed cardiac dimension and cardiac cycle intervals in 36 untreated adults with resistance to thyroid hormone and 15 untreated adults without resistance.
Indices of thyroid hormone action—levels of cholesterol, ferritin (Abbott Diagnostics), testosterone-binding globulin (TeBG) (Hazelton, Washington, Virginia), and carotene (SmithKline Beecham Clinical Laboratories)—were measured [24-27] in fasting, untreated patients. Levels of IgG, IgA, and IgM were also measured.
Criteria for Organ Assessment of Thyroid Hormone Action
Table 1 shows the variables that were selected to assess end-organ action of thyroid hormone, and it defines the hypothyroid, euthyroid, and hyperthyroid ranges. For basal metabolic rate and for cholesterol, ferritin, and TeBG levels, normal ranges were those validated at our center; for resting pulse, normal values were adapted from Cole [28]; for bone and brain, ranges were based on clinical observation in persons with congenital hypothyroidism. ARTICLE
Genetic and Clinical Features of 42 Kindreds with Resistance to Thyroid Hormone: The National Institutes of Health Prospective Study
Resistance to thyroid hormone, first described by Refetoff and coworkers in 1967 [1], is characterized by decreased pituitary and tissue responsiveness to thyroid hormone. Patients typically have elevated serum free and total triiodothyronine (T3) and thyroxine (T4) levels and inappropriately normal or elevated thyroid-stimulating hormone (TSH) levels. The phenotype is heterogeneous; classic features include attention-deficit hyperactivity disorder, growth delay, and tachycardia [2, 3]. Resistance to thyroid hormone is usually transmitted in an autosomal dominant manner, but sporadic de novo cases are common, and recessive inheritance is rare [1, 4]. Linkage between resistance to thyroid hormone and the thyroid hormone receptor ß (TR ß) gene was shown in 1988 [5]. Since then, about 100 mutations have been found in that gene [6], clustered primarily in two "hot spots" in the T3-binding domain (exons 9 and 10), respecting the integrity of the dimerization domain [7]. Mutant receptors have normal DNA binding, but T3 binding and transactivation are impaired to varying degrees [8, 9]. Moreover, the abnormal receptors antagonize the function of normal receptors in a dominant negative manner [10, 11]. Thyroid hormone action is mediated through two types of nuclear receptors, 
(TR ) and TR ß [12, 13], which have different organ distributions. Thus, resistance to thyroid hormone provides an exciting opportunity to study the in vivo, tissue-specific action of thyroid hormone.
Methods
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Methods
Results
Discussion
Author & Article Info
References
Patients and Controls-subunit of TSH (RIA, Hazelton-Washington, Vienna, Virginia), prolactin (TOSOH AIA-1200, Hazelton), and thyroxine-binding globulin (TBG) (Corning's Immunophase, TBG125 I, Corning Medical, Norwood, Massachusetts). Thyroid uptake of 123I was measured at 24 hours. Diagnosis was confirmed by DNA analysis using traditional methods in 14 families [7] or using a new strategy, a modification of single-stranded conformational polymorphism, to screen [19] and identify the other mutations [20]. We used the new consensus [6] for exon, codon, and nucleotide designation. Parents of affected persons were screened if possible; if both parents tested negative, patients were considered to have sporadic cases. -subunit of TSH, and prolactin were measured 0 and 30 minutes after intravenous injection of 500 µg (for adults) or 7 µg/kg body weight (for children) of TSH-releasing hormone.
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Statistical Analysis
Continuous variables are expressed as mean ± SE, and binary variables are expressed as proportion ± SE. We estimated SE for all variables (continuous and binary) using a bootstrap approach [29] by resampling the 42 families (not the individual persons) with replacement 1000 times and estimating the distribution of means or proportions from the 1000 replicates. Specifically, we estimated the mean (or proportion) in each replicate and estimated the SE from the sample of 1000 means (or proportions). This procedure allowed us to take into account correlations among persons within families, because we used families rather than individual persons as resampling units.
Similarly, we did statistical tests that took correlations within families into account and yielded P values that discriminated between the factor being studied [such as whether a person had resistance to thyroid hormone] and familial traits. We did four sets of statistical tests that compared 1) persons who had resistance to thyroid hormone with persons who did not; 2) persons with resistance to thyroid hormone who had exon 9 mutations with persons with resistance to thyroid hormone who had exon 10 mutations; 3) persons with resistance to thyroid hormone who had an affected mother with persons with resistance who did not have an affected mother, separately in children and in adults; and 4) children with adults, separately according to whether persons had resistance to thyroid hormone status. For these four sets of tests, we did not adjust for any variables. For continuous variables, we computed the overall difference in means and did a bootstrap test [30] based on resampling the 42 families with replacement 1000 times and estimating the distribution of the overall difference in means from the 1000 replicates. This procedure produced statistical tests and P values that took correlations within families into account. For binary variables and the comparison of persons with and without resistance to thyroid hormone, the comparison of persons with and without an affected mother, and the comparison of children with adults, we tested differences in proportions by using conditional logistic regression [31], contrasting persons within families, to take correlations within families into account. Conditional logistic models only included the variable of interest, namely, whether a person had resistance to thyroid hormone (first set of tests), whether the person's mother had resistance (third set of tests), or whether the person was a child or an adult (fourth set of tests). For binary variables and the comparison of persons who had exon 9 mutations with persons who had exon 10 mutations, we could not use conditional logistic regression [31], because all persons with resistance to thyroid hormone in a family have the same exon expression. Instead, we did a bootstrap test of the difference in proportions to take correlations within families into account.
We repeated the same four sets of tests for the whole study sample; thus, we did not restrict tests according to whether a patient was a child or an adult or whether a patient had resistance to thyroid hormone. For all comparisons, we used regression models to adjust for age (first three sets of tests) or for whether a person had resistance to thyroid hormone (fourth set of tests). All regression models therefore included age (first three sets) or whether a person had resistance to thyroid hormone (fourth set of tests) and the variable of interest. For continuous variables, we used a linear model and did a bootstrap test on the model coefficient for whether a person had resistance to thyroid hormone (first set of tests), for exon expression (second set of tests), for whether the mother had resistance to thyroid hormone (third set of tests), or for whether the person was a child or an adult (fourth set of tests). For binary variables, we used conditional logistic regression and tested the model coefficient for resistance to thyroid hormone (first set of tests), for the mother's resistance to thyroid hormone (third set of tests), and for whether the person was a child or an adult (fourth set of tests). Because we could not use conditional logistic regression for the comparison between persons with exon 9 mutations and persons with exon 10 mutations (second set of tests), we used unconditional logistic regression [31] and did a bootstrap test of the coefficient for exon expression in the model.
Results
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The mode of transmission was familial in 22 of 42 kindreds (51.4% maternal and 48.6% paternal inheritance). The incidence in offspring was 58%, consistent with autosomal dominant transmission. Resistance to thyroid hormone was sporadic in 14 kindreds; parents were not available for testing in 6 kindreds.
Table 2 shows the mutations identified in 25 kindreds (64 patients with resistance to thyroid hormone); 16 were in exon 9 and 9 were in exon 10 of the TR ß gene. All mutations were located in the two previously recognized "hot spots." Fourteen of the 20 sequenced mutations were found in single kindreds (unique mutation), and 2 were found in six unrelated, sporadic cases (non-unique mutations).
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Clinical Evaluation
The clinical features of persons with resistance to thyroid hormone are summarized in Table 3. Because of the importance of the effect of age on certain variables, the data are presented separately for adults and children. In addition, an age-adjusted P value is shown for all ages combined. Persons with resistance to thyroid hormone were slightly younger (range, 0.2 to 65 years; P = 0.04) than persons without resistance (range, 0.3 to 66 years), and there was no difference in sex ratio.
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A palpable goiter (or history of goiter in patients with thyroidectomy) was found more frequently in persons with resistance to thyroid hormone than in persons without resistance; this was particularly so in females (74% of females with resistance to thyroid hormone compared with 53% of males with resistance to thyroid hormone). Moreover, 123I uptake at 24 hours was increased in persons with resistance to thyroid hormone. Interestingly, in offspring with resistance, goiter was much less frequent when the mother had resistance to thyroid hormone (Table 4); this was particularly so in children (35% of children with affected mothers had goiter compared with 87% of children with nonaffected mothers; P = 0.04).
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Attention-deficit hyperactivity disorder was common, particularly in males (72% of males with resistance to thyroid hormone compared with 43% of females with resistance). Full-scale IQ was, on average, 13 points lower in persons with resistance; the verbal component was 91 (compared with 102), and a performance component was 95 (compared with 105). One third of persons with resistance to thyroid hormone had an IQ of less than 85 (–1 SD of the mean), but mental retardation was rare (4 persons had an IQ less than 70). There was a higher incidence of speech problems, mainly speech delay (24% of persons with resistance to thyroid hormone compared with 10% of persons without resistance) and stuttering (18% of persons with resistance compared with 4% of persons without resistance), particularly in males (28% of males with resistance compared with 10% of females with resistance). These findings also had a greater tendency to occur in patients with exon 9 rather than exon 10 mutations (Table 5). Moreover, according to history, both hearing loss and ear, nose, and throat infections occurred more frequently in persons with resistance to thyroid hormone.
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Patients with resistance to thyroid hormone, on average, were shorter and weighed less than those without resistance; 18% had short stature (defined as height no greater than the fifth percentile), and the mean IQ of this 18% was lower than that in persons with resistance to thyroid hormone who were of normal height (82 compared with 94; P = 0.0004). Bone age was delayed in 29% of children with resistance to thyroid hormone; low weight was present in one third of children with resistance. In persons with resistance to thyroid hormone, there was a negative correlation between the percentile of the weight and basal metabolic rate (r = –0.52; P < 0.01) and between the percentile of weight and free T4 levels (r = –0.34; P = 0.002). There was a positive correlation between percentile of weight and age (r = 0.45; P < 0.0001). Basal metabolic rate and ankle reflex did not differ between persons with and without resistance to thyroid hormone (Table 3).
Resting pulse tended to be faster in persons with resistance to thyroid hormone as a group, but not after adjustment for age (P = 0.11) (Table 3). Moreover, arrhythmia, including four cases of atrial fibrillation, was found in 6% of persons with resistance to thyroid hormone. Echocardiography showed an increased systolic cardiac performance in adults who had resistance to thyroid hormone with a smaller diameter of the left ventricle during systole (29 mm compared with 33 mm; P < 0.0001) and increased fractional shortening (40% compared with 35%; P < 0.001) [32]. Valvular defects were found in eight persons with resistance to thyroid hormone (seven had mitral prolapse, and one had atrial septal defect).
Resistance to thyroid hormone was coincident with other diseases: One patient had thyroid cancer, one had terminal renal failure, two had type I diabetes, two had severe skin disease (ichthyosis and eczema), two had psychotic episodes, and four had gastrointestinal disease (esophageal atresia and reflux). Furthermore, resistance to thyroid hormone did not influence age at puberty or fertility (results not shown).
Biochemical Results
The hormonal profile of untreated persons with resistance to thyroid hormone showed marked heterogeneity Table 6 with wide ranges for levels of T4 (range, 91 to 420 nmol/L [normal, 64 to 128 nmol/L]) and free T4 (range, 27 to 93 pmol/L [normal, 12.8 to 24.4 pmol/L]). Two important variables influencing thyroid hormone levels were age (levels were increased in children) and mutation location (levels were lower in persons with exon 9 mutations than in persons with exon 10 mutations, despite younger age; see Table 5). Thyroxine-binding globulin levels were lower in both adults and children with resistance to thyroid hormone. The T4:TSH ratio (used to quantify pituitary resistance) and the T4:T3 ratio were higher in persons with resistance. Baseline TSH and prolactin levels tended to be higher in persons with resistance who had a greater response to TSH-releasing hormone (> 30 mU/L in two thirds of patients with resistance); -subunit values were normal in both groups. There was no statistical difference in cholesterol, ferritin, and TeBG levels, but carotene and immunoglobulin levels tended to be lower in persons with resistance (Table 6). There was no correlation between thyroid hormone levels and affinity of the receptor for T3 when this information was available (results not shown). Free T4 levels correlated with the percentile of body weight (r = –0.39; P < 0.001), the basal metabolic rate (r = 0.55; P = 0.002), and the pulse (r = 0.32; P = 0.001) but not with height, IQ, or any other thyroid hormone end points.
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Thyroid hormone levels consistent with primary hypothyroidism were found in 10 persons who did not have resistance to thyroid hormone. We also compared thyroid hormone levels in persons without resistance, according to whether they were born into (group 1) or married into (group 2) a kindred with resistance. The mean ages of our groups were similar (group 1, 37 years [n = 21] compared with group 2, 34 years [n = 29]); there was no statistical difference for T3, T4, and TSH levels, but free T4 levels tended to be lower in group 1 (16.7 ± 0.6 compared with 18.6 ± 0.5 pmol/L).
Organ Specificity of Resistance to Thyroid Hormone
To illustrate phenotypic heterogeneity, we analyzed the degree of resistance in various organs in persons with resistance to thyroid hormone (Figure 1). Both hypothyroid and euthyroid ranges are inappropriate for the high levels of thyroid hormone; subclinical or clinical hypothyroid ranges were found in the pituitary gland (56%), the brain (33%), the bone (19%), the heart (8%), the liver (7.5%), and the metabolism (4%). Overall, heart and metabolism were the least resistant systems; they had 16% and 33%, respectively, of resistance to thyroid hormone in the hyperthyroid range.
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Discussion
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Classically Recognized Clinical Features
Our report, in which 19% of persons have had thyroidectomy, confirms that resistance to thyroid hormone is commonly mistaken for Graves disease [33]. Only one patient had thyroidectomy after resistance to thyroid hormone was diagnosed; the procedure was done because of predominant pituitary resistance. We found fewer goiters in patients with resistance to thyroid hormone (65%) than have been reported in the literature (92%) [2, 3]. However, we found goiter in 5% of persons without resistance, a rate similar to the 5% rate observed in the United States [34]; this validates our findings in persons with resistance. Goiter, increased 123I uptake, and increased thyroid hormone production, despite usually normal TSH levels, can be explained by the increased bioactivity of TSH in persons with resistance to thyroid hormone [35]. The lower incidence of goiter in children with resistance who have affected mothers suggests that transplacental thyroid hormone transfer may have a beneficial effect on fetal thyroid and that this beneficial effect is partly sustained into adulthood. Indeed, the fetus is now recognized to be dependent on maternal T4 during the first trimester of gestation [36], but the extent of maternal thyroid hormone influence later in development is unclear [37, 38].
Hauser and colleagues [21] suggested a strong association between attention-deficit hyperactivity disorder and resistance to thyroid hormone. In contrast, linkage analysis in a single family failed to show linkage between attention-deficit hyperactivity disorder and resistance to thyroid hormone, and it suggested that lower IQ may facilitate the expression of attention-deficit hyperactivity disorder [39]. This is unlikely; we found that the IQ of persons with resistance to thyroid hormone who had attention-deficit hyperactivity disorder did not differ from the IQ of persons with resistance who did not have the disorder. Given the heterogeneous causes of attention-deficit hyperactivity disorder, it is not surprising that, in some families, no linkage is found. Our study again supports the concept of an association between resistance to thyroid hormone and attention-deficit hyperactivity disorder. Furthermore, a transgenic mouse model shows a paradoxical effect of methylphenidate (Ritalin, Ciba, Summit, New Jersey) and further supports the link between the two conditions [40].
Anecdotal observations in our patients and others suggest that thyroid hormone may be beneficial. Specifically, we have found that T3 seems more efficacious than T4; this suggests the possibility of acquired deiodinase deficiency in persons with resistance to thyroid hormone (indeed, the T4:T3 ratio is higher in persons with resistance to thyroid hormone). Furthermore, preliminary data in a controlled study [41] suggest that T3 therapy may be useful in persons with resistance to thyroid hormone and attention-deficit hyperactivity disorder but not in persons without resistance who have attention-deficit hyperactivity disorder. This suggests that one mechanism of the disorder in persons with resistance to thyroid hormone could be relative hypothyroidism, and this further supports the link between attention-deficit hyperactivity disorder and resistance to thyroid hormone. Further study is necessary to define the exact role of T3 and T4 therapy in persons with resistance.
Although IQ scores are lower in persons with resistance to thyroid hormone than in persons without resistance, mental retardation is rare; furthermore, there is no correlation between attention-deficit hyperactivity disorder and IQ. Because intelligence is adversely affected in congenital hypothyroidism [42], the lower IQ found in persons with resistance to thyroid hormone may be related to relative hypothyroidism during early brain development [43, 44]. However, brain dysfunction has been anecdotally reported in congenital hyperthyroidism [45, 46], raising questions about the mechanism of lower IQ in persons with resistance to thyroid hormone.
One hallmark of hypothyroidism is a growth defect with bone age delay [47]. We found that persons with resistance to thyroid hormone are shorter than persons without resistance; 18% had short stature and no catch-up growth later in life. However, bone age is delayed in only a minority of children with resistance to thyroid hormone. The abnormal growth in persons with resistance could involve both direct and indirect (through growth hormone or insulin-like growth factor secretion or action) effects of thyroid hormone on bone [48, 49]. Moreover, the lower IQ in persons of short stature with resistance to thyroid hormone suggests relative hypothyroidism in brain and bone. Children (but not adults) with resistance are less likely to have short stature when their mothers have resistance (9% when the mother has resistance compared with 23% when the mother is unaffected; P = 0.037).
Newly Recognized Clinical Features
Among the newly recognized features of resistance to thyroid hormone is low body weight; this is particularly characteristic of children. One third of children with resistance are too thin for their age, and one third are too thin for their height. The percentile for weight correlates with free T4 levels, age, and basal metabolic rate in persons with resistance to thyroid hormone, and it may be a sign of relative hyperthyroidism. However, the percentile for weight tends to correlate with attention-deficit hyperactivity disorder, raising the possibility that hyperactivity in children results in both lower caloric intake and higher caloric expenditure. This correlation is not found in adults, in whom attention-deficit hyperactivity disorder, particularly its hyperactivity component, is much less frequent. Another contributing factor could be a specific impairment of genes involved in fat regulation or metabolism [50].
Tachycardia has been reported as a cardinal feature of resistance to thyroid hormone [2], but our results do not support this concept, at least in resting conditions. We found resting tachycardia in only 16% of persons with resistance to thyroid hormone (compared with 12.5% of persons without resistance), and the resting pulse overall was similar in persons of the same age who did and did not have resistance. However, this similarity may not occur in nonresting conditions. Moreover, the six cases of arrhythmia in persons with resistance to thyroid hormone (there were none in persons without resistance) suggest less resistance in the heart than in the pituitary for these patients. Thyroid hormones have complex direct and indirect actions on the heart [51-53], including possible non-nuclear effects [54]. Indeed, the heart is relatively less resistant than other organs Figure 1, possibly because TR and not TR ß genes are predominant in the atrial myocardium [55]. If the mother's resistance to thyroid hormone plays a minimal role, age seems to be an important factor: Adults but not children with resistance have increased cardiac contractility, as found in hyperthyroidism, but contractility is still less than that expected given the level of thyroid hormone, indicating some degree of resistance in the ventricle). This suggests that a child's heart may be more resistant to thyroid hormone [32]. One mechanism for a relative decrease in cardiovascular resistance with age could involve a decrease in the mutant:normal receptor ratio [56]. Finally, we found valve defects in eight persons with resistance (but none without resistance); seven persons had mitral valve prolapse, a condition reported to be more frequent in hyperthyroidism [57], and one child with resistance to thyroid hormone had a serious but probably incidental atrial septal defect.
We confirmed that the frequency of ear, nose, and throat infections is increased in persons with resistance to thyroid hormone; this was previously reported only anecdotally [2, 3]. The lower incidence of these infections in unaffected relatives indicates that environmental factors are not responsible. The reasons for the increased rate of infection are still unclear and could involve direct or indirect mechanisms: The presence of TR ß in granulocytes and lymphocytes [58, 59] and the tendency for immunoglobulin levels to be lower in persons with resistance suggests that these persons may have a specific immune defect. Alternatively, we can speculate about anatomic anomalies of the ear, which could result in secondary infections. Furthermore, ear, nose, and throat infections are more frequent in children with and without resistance whose mothers have resistance; further studies are needed to elucidate the underlying mechanisms.
Hearing abnormalities have long been described in congenital hypothyroidism, but their incidence is controversial [60-62]. Thyroid hormone receptor ß is now known to be restricted to the cochlea; TR is also present in the vestibule [63], and deaf-mutism in a person in whom resistance to thyroid hormone was caused by a homozygous deletion of the TR ß gene shows the importance of thyroid hormone and TR ß in inner ear development. Significant hearing loss, predominantly conductive, was noted in 21% of persons with resistance to thyroid hormone and in no persons without resistance. Frequent ear infections can explain the defect in two thirds of the patients, but about one third of persons with resistance who had hearing loss had no history of ear, nose, and throat infections; this included a few patients with isolated sensorineural deficit (results not shown). This supports the concept that mutant receptors may both directly and indirectly affect hearing.
We found an increased frequency of speech delay and stuttering in persons with resistance, particularly males and persons with exon 9 mutations, confirming our earlier findings [22]. Interestingly, subtle speech defects have also been reported in persons with congenital hypothyroidism [64].
Our analysis suggests the influence of the mother's resistance to thyroid hormone (on goiter, short stature, and resting pulse), of mutation location (on speech impediment and thyroid function), of age (on resting pulse and weight), and of sex (on goiter) on various expressions of the disorder. The differences seen in persons with resistance that depend on whether the mother has resistance seem to be related to hormonal and environmental factors and do not support the concept of imprinting in resistance to thyroid hormone [65, 66]. The change in hydrophobicity induced by a single base substitution may result in important conformational modifications of the receptor [67] and explain changes in interaction with genes and cofactors. Exon 9 and 10 mutations result in phenotypic differences, but it is clear that exonic location is an artificial distinction and that differences in phenotype are also seen in patients with neighboring mutations in the same exon [68, 69]. Moreover, variations in phenotype within the same kindred suggest the importance of other genetically determined cofactors [70].
Biochemical Diagnosis
The hormonal profile of untreated patients with resistance to thyroid hormone is typical and includes elevated free and total thyroid hormone levels and normal or elevated TSH levels. However, thyroid hormone levels can be "borderline" if pituitary resistance is mild, and such levels should not be ignored. Further genetic analysis is warranted if the phenotype suggests resistance to thyroid hormone. Levels of thyroid hormone are known to be higher in children [71], but we show for the first time a correlation with the exonic location of the mutation (persons with exon 9 mutations have lower thyroid hormone levels). Our results agree with those of a recent study [72] that showed no correlation between T3-receptor binding and thyroid hormone levels. The sharp increase in TSH levels after TSH-releasing hormone stimulation [73] recalls subclinical primary hypothyroidism; the response of the -subunit of TSH to TSH-releasing hormone was mildly increased in persons with resistance, and the response of prolactin was normal. The T4:TSH ratio was higher in persons with resistance to thyroid hormone, reflecting both resistance and the increased bioactivity of TSH seen in persons with resistance [35]. The T4:T3 ratio was higher in persons with resistance, suggesting decreased peripheral conversion of T4 to T3 [74]. In addition, we found lower (but within the normal range) TBG levels in persons with resistance, resulting in proportionally less elevation of total than of free thyroid hormone levels; this could reflect the effect of thyroid hormone on TBG expression in the liver [75, 76]. Finally, the baseline thyroid hormone action end points (cholesterol, TeBG, and ferritin levels) were in the normal range in persons with resistance and did not differ from those in persons without resistance, but carotene levels tended to be slightly lower in persons with resistance. This "normality" is characteristic of generalized resistance, because all of these variables should be in the hyperthyroid range, given the high levels of thyroid hormones.
In contrast, the biochemical diagnosis of resistance to thyroid hormone is more difficult after thyroidectomy; the main feature of resistance is the persistent elevation of TSH levels despite increasing supraphysiologic doses of thyroid hormones. Patients are suspected of poor compliance before the diagnosis is clarified. In these and other difficult cases, because baseline thyroid hormone action end points are often nondiscriminative [77], a T3 suppression test is useful. The one proposed by Refetoff and coworkers (long test) [2] uses assessment of TSH levels and thyroid hormone action end points, and one by Liu and colleagues (short test) [78] uses the measurement of TSH levels.
Our study shows no increase in thyroid hormone levels in persons without resistance to thyroid hormone who were born into the kindred compared with spouses (without resistance to thyroid hormone) of persons with resistance, whether the data were analyzed pooled or in individual large kindreds. Our results differ from those of Weiss and coworkers [79], which were based on a single Italian family and may reflect other genetic or environmental factors.
Genetic Diagnosis
When the mode of inheritance was known, resistance to thyroid hormones was seen to have been transmitted in an autosomal dominant manner in two thirds of the kindreds. It occurred sporadically in one third, a proportion greater than the 14% previously reported [2, 3]. However, we did not systematically address the paternity issue, which raises the possibility of a slight overestimation of the number of sporadic cases.
We found our modified technique of single-stranded conformational polymorphism to be a rapid screening tool for probands and relatives. The identification of a mutation confirmed the diagnosis of resistance in 64 cases from 25 kindreds. To date, all of the mutations we have found have been located within the two "hot-spots" of exons 9 and 10. The two non-unique mutations were found in six sporadic cases, confirming that certain codons are prone to de novo mutations [80, 81].
Tissue-Specific Actions of Mutant ß-Receptors
The evaluation of thyroid hormone action showed that the level of resistance varied in different tissues. The pituitary gland had the most resistance and was followed, in decreasing order, by the brain, the bone, the liver, and the heart. In addition, the metabolism was the least affected variable. Molecular study of resistance to thyroid hormone shows the complex interactions of mutant TR ß with different accessory proteins and thyroid responsive genes in various tissues or cells [82, 83]. Furthermore, the relative expression of TR ß and TR is tissue-specific [55, 85], and resistance to thyroid hormone model may aid in an understanding of the respective roles of these genes and of thyroid hormone action in general [70, 85]. The level of compensation varies; it is set by the degree of pituitary resistance and the ability of the thyroid to increase its hormone production. If pituitary resistance is dominant [16, 69, 86], the patient is predominantly hyperthyroid, but some patients do not have hyperthyroid features in every tissue, indicating the presence of resistance in at least some peripheral tissues. Thus, there seems to be a continuum in the phenotype of resistance to thyroid hormone from predominantly pituitary to predominantly peripheral forms of resistance. However, in a single case of apparently isolated pituitary resistance, the mutant receptor appeared to have a dominant negative effect restricted to the negatively regulated genes (TRH, TSH), sparing certain positively regulated genes in the periphery [87]. These data suggest the rare possibility of a distinct molecular basis for selective pituitary resistance.
In summary, resistance to thyroid hormone provides the opportunity to study thyroid hormone action in vivo. Although the clinical presentation of this condition is heterogeneous, the hormonal profile is typical and usually unambiguous in the absence of previous thyroidectomy. Family history, measurement of TSH and free T4 levels, and an MRI scan of the pituitary are usually sufficient to rule out Graves disease, thyroid hormone-binding anomalies, and TSH-secreting pituitary adenoma; therefore, the diagnosis of this heterogeneous syndrome should no longer be missed. Furthermore, techniques for genetic screening and diagnosis have greatly improved, permitting less cumbersome confirmation of the diagnosis. Resistance to thyroid hormone is often considered to be a relatively benign condition, but the existence of cardiac disorders in some families and the personal, familial, and social burden of behavioral disorders should not be underestimated. Given the potential detrimental effect of resistance to thyroid hormone on development and behavior, neonatal screening is recommended in families known to have resistance [88, 89]. This screening can be done conveniently by looking also at high T4 values on the specimen already used for neonatal screening of congenital hypothyroidism. Knowing the dramatic effect of thyroid hormone on early development, it is reasonable to postulate that early thyroid hormone therapy could be beneficial; however, a randomized controlled study is necessary to show whether thyroid hormone therapy allows children with resistance to thyroid hormone to attain their full potential of growth and intellectual development. We present evidence that maternal disease status affects the outcome of offspring with resistance, but there is currently no consensus on whether the mother, affected or not, should be treated during pregnancy. Finally, the transgenic mouse model recently developed in our laboratory [90] may help to clarify the molecular mechanisms of resistance to thyroid hormone in a more physiologic in vivo environment. Notably, these transgenic mice show decreased weight gain as seen in children with resistance. These and other, future transgenic models may also be useful in developing novel pharmacologic and genetic therapies applicable to the human disease.
Dr. Benichou: National Cancer Institute, 6130 Executive Boulevard, EPN/403, MSC 7368, Bethesda, MD 20892-7368.
Dr. Hauser: Psychiatry Service, Baltimore Veterans Affairs Medical Center, 10 North Green Street, Baltimore, MD 21201.
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