Peter C. Hauser

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 (TR ) 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 [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. 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. Methods Patients and Controls 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), -subunit of TSH (RIA, Hazelton-Washington, Vienna, Virginia), prolactin (TOSOH AIA-1200, Hazelton), and thyroxine-binding globulin (TBG) (Cornings 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. 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, -subunit of TSH, and prolactin were measured 0 and 30 minutes after intravenous injection of 500 g (for adults) or 7 g/kg body weight (for children) of TSH-releasing hormone. 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 actionlevels 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. Table 1. Criteria for Tissue Assessment of Thyroid Hormone Action 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 acco

Dissociating neural subsystems for grammar by contrasting word order and inflection

An important question in understanding language processing is whether there are distinct neural mechanisms for processing specific types of grammatical structure, such as syntax versus morphology, and, if so, what the basis of the specialization might be. However, this question is difficult to study: A given language typically conveys its grammatical information in one way (e.g., English marks “who did what to whom” using word order, and German uses inflectional morphology). American Sign Language permits either device, enabling a direct within-language comparison. During functional (f)MRI, native signers viewed sentences that used only word order and sentences that included inflectional morphology. The two sentence types activated an overlapping network of brain regions, but with differential patterns. Word order sentences activated left-lateralized areas involved in working memory and lexical access, including the dorsolateral prefrontal cortex, the inferior frontal gyrus, the inferior parietal lobe, and the middle temporal gyrus. In contrast, inflectional morphology sentences activated areas involved in building and analyzing combinatorial structure, including bilateral inferior frontal and anterior temporal regions as well as the basal ganglia and medial temporal/limbic areas. These findings suggest that for a given linguistic function, neural recruitment may depend upon on the cognitive resources required to process specific types of linguistic cues.

Deafness and visual enumeration: Not all aspects of attention are modified by deafness

Previous studies have demonstrated that early deafness causes enhancements in peripheral visual attention. Here, we ask if this cross-modal plasticity of visual attention is accompanied by an increase in the number of objects that can be grasped at once. In a first experiment using an enumeration task, Deaf adult native signers and hearing non-signers performed comparably, suggesting that deafness does not enhance the number of objects one can attend to simultaneously. In a second experiment using the Multiple Object Tracking task, Deaf adult native signers and hearing non-signers also performed comparably when required to monitor several, distinct, moving targets among moving distractors. The results of these experiments suggest that deafness does not significantly alter the ability to allocate attention to several objects at once. Thus, early deafness does not enhance all facets of visual attention, but rather its effects are quite specific.

The Importance of Early Sign Language Acquisition for Deaf Readers

Researchers have used various theories to explain deaf individuals’ reading skills, including the dual route reading theory, the orthographic depth theory, and the early language access theory. This study tested 4 groups of children—hearing with dyslexia, hearing without dyslexia, deaf early signers, and deaf late signers (N = 857)—from 4 countries using both shallow and deep orthographies (American English, Hebrew, German, and Turkish) to evaluate which of these theories best describes variances in deaf childrens reading development. Results showed that deaf participants were unlike participants with dyslexia, suggesting that they do not have a phonological processing deficit. Rather, the early language access theory more readily explained the similarities between hearing and deaf early signer participants, stressing the importance of early access to visual language.

Reliability and Validity of the BRIEF-A for Assessing Deaf College Students' Executive Function.

This study investigated the reliability and validity of the Behavior Rating Inventory of Executive Functions–Adult Form (BRIEF-A) when used with deaf college students. The BRIEF-A was administered to 176 deaf and 184 hearing students of whom 25 deaf students and 56 hearing students self-identified as having an Attention Deficit Hyperactivity Disorder (ADHD) diagnoses. Cronbach’s alpha internal consistency reliabilities for the deaf participants ranged from .55 to .96, similar to the published BRIEF-A normative sample. Differential Item Function analysis revealed that only 3 of the 75 items showed evidence of item bias for deaf students. The participants with ADHD had significantly higher scores on all nine scales. Discriminant analysis revealed comparable sensitivity and specificity of the BRIEF-A for discriminating ADHD from non-ADHD individuals for deaf and hearing groups. Finally, the deaf and hearing ADHD groups exhibited score profiles across the nine BRIEF-A scales that followed the pattern of the BRIEF-A ADHD clinical sample profile. The results suggest that the BRIEF-A is a reliable, largely unbiased diagnostic tool for deaf college students, with comparable discriminant and predictive validity for ADHD.

Response bias reveals enhanced attention to inferior visual field in signers of American Sign Language.

Abstract Deafness results in cross-modal plasticity, whereby visual functions are altered as a consequence of a lack of hearing. Here, we present a reanalysis of data originally reported by Dye et al. (PLoS One 4(5):e5640, 2009) with the aim of testing additional hypotheses concerning the spatial redistribution of visual attention due to deafness and the use of a visuogestural language (American Sign Language). By looking at the spatial distribution of errors made by deaf and hearing participants performing a visuospatial selective attention task, we sought to determine whether there was evidence for (1) a shift in the hemispheric lateralization of visual selective function as a result of deafness, and (2) a shift toward attending to the inferior visual field in users of a signed language. While no evidence was found for or against a shift in lateralization of visual selective attention as a result of deafness, a shift in the allocation of attention from the superior toward the inferior visual field was inferred in native signers of American Sign Language, possibly reflecting an adaptation to the perceptual demands imposed by a visuogestural language.

A Comparison of the Letter-Processing Skills of Hearing and Deaf Readers: Evidence From Five Orthographies

This study was designed to examine the letter-processing skills of prelingually deaf and hearing students recruited from five different orthographic backgrounds (Hebrew, Arabic, English, German, and Turkish). Participants were 128 hearing and 133 deaf 6th-7th graders. They were tested with a same/different paradigm that assessed their ability to process letters under perceptual and conceptual conditions. Findings suggest that the letter-processing skills of deaf readers from some orthographic backgrounds may be underdeveloped in comparison to hearing counterparts. The finding that such letter-processing deficits were restricted to readers of some but not all of the tested orthographies warrants the conclusion that prelingual deafness, per se, does not impede the development of effective letter processing. Evidence for this study is discussed with reference to potential orthography-inherent and educational factors that may explain the existence of letter-processing deficits found in some of the prelingually deaf readers examined in this study.