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Extreme Thyroid Hormone Resistance in a Patient with a Novel Truncated TR Mutant

Diabetes and Molecular Regulation and Neuroendocrinology Sections, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; University of Maryland School of Medicine (J.L.), Baltimore, Maryland 21201; Portland Veterans Affairs Medical Center, Department of Psychiatry, Oregon Health Sciences University (P.H.), Portland, Oregon 97201; and Department of Medicine, Centre Hospitalier, Universite de Nice (F.B.-D.), Nice, France

Address all correspondence and requests for reprints to: Paul M. Yen, M.D., Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, National Institutes of Health, Building 10, Room 8D12, Bethesda, Maryland 20892. E-mail: pauly{at}intra.niddk.nih.gov

Abstract

Resistance to thyroid hormone (RTH) is a syndrome in which patients have elevated thyroid hormone (TH) levels and decreased sensitivity to its action. We describe a child with extreme RTH and a severe phenotype. A 22-month-old female presented to the NIH with goiter, growth retardation, short stature, and deafness. Additionally, the patient had hypotonia, mental retardation, visual impairment, and a history of seizures. Brain magnetic resonance imaging showed evidence of demyelination and bilateral ventricular enlargement. The patient had markedly elevated free T₃ and free T₄ levels of more than 2000 pg/dl (normal, 230–420 pg/dl) and more than 64 pmol/liter (normal, 10.3–20.6 pmol/liter), respectively, and TSH of 6.88 mU/liter (normal, 0.6–6.3 mU/liter). These are the highest TH levels reported for a heterozygous RTH patient. A T₃ stimulation test confirmed the diagnosis of RTH in the pituitary and peripheral tissues. Molecular analyses of the patient’s genomic DNA by PCR identified a single base deletion in exon 10 of her TRß gene that resulted in a frameshift and early stop codon. This, in turn, encoded a truncated receptor that lacked the last 20 amino acids. Cotransfection studies showed that the mutant TR was transcriptionally inactive even in the presence of 10^-6 M T₃ and had strong dominant negative activity over the wild-type receptor. It is likely that the severely defective TRß mutant contributed to the extreme RTH phenotype and resistance in our patient.

PATIENTS WITH RESISTANCE to thyroid hormone (RTH) have elevated serum thyroid hormone (TH) levels, inappropriately normal or elevated serum TSH levels, and decreased tissue responsiveness to TH. Since its first description by Refetoff et al. in 1967 (1), more than 600 subjects with RTH have been reported (2, 3, 4). Classic features include attention deficit hyperactivity disorder, growth delay, tachycardia, and goiter; however, other features, such as frequent ear nose and throat infections, hearing deficit, and decreased bone mass, have recently been recognized (2, 3, 4). The phenotype of RTH is variable, with most patients presenting with mild to moderate symptoms.

TRs are encoded by two genes, TR and TRß, located on chromosomes 17 and 3, respectively (5). Most patients with RTH have mutations in the TRß gene whereas none have been found to date in the TR genes. Most mutations have clustered in three hot spots encoding the T₃-binding domain (exons 8–10) (5). RTH is generally inherited in an autosomal dominant manner. Cotransfection studies have shown that the mutant TRß blocks the transcriptional activity of wild-type TR (dominant negative activity) (2, 6, 7). A likely mechanism for the dominant negative activity is formation of inactive wild-type TR/mutant TR dimers on thyroid hormone response elements of target genes (2). Additionally, it was recently shown that there is a strong correlation between the dominant negative activity and release of corepressors from mutant TRs (9, 10, 11). The dominant negative activity by mutant TRßs probably account for the decreased responsiveness of target genes to TH and contributes to the phenotypic expression of RTH.

We now report a novel case of extreme thyroid hormone resistance in a 22-month-old girl with markedly elevated levels of TH associated with mental retardation, failure to thrive, seizures, and severe visual and auditory deficits. A deletion/frameshift mutation in TRß was identified in the patient that generated a truncated TRß that had severely impaired transcriptional activity and strong dominant negative activity. This mutant TRß probably plays a key role in the severe phenotype of the patient.

Case Report

N.M. is a Hispanic female from Puerto Rican female born at 35 wk gestation to healthy nonconsanguinous parents. The patient’s birth weight was at the 25th percentile; length and head circumference were at the 50–75th percentiles for gestational age. Newborn screening showed elevated T₄. At 10 months of age, she was hospitalized for seizures associated with failure to thrive (weight and height below the 5th percentile) and developmental delay. The patient was noted to have a small goiter and elevated serum T₄ and TSH levels. She was then referred to the NIH for further evaluation.

N.M. was 22 months old at the time of her evaluation at NIH, where she was entered into a peer-reviewed NIH protocol after parental informed consent was given. She had mildly dysmorphic features, with prominent frontal bossing, high hairline, and micrognathia (Fig. 1A). She did not respond to visual or auditory cues and had limited speech. She was hypotonic, but her strength was normal. Her thyroid was enlarged to approximately 3 times normal size. Vital signs were normal.

View larger version (67K): [in this window] [in a new window]   Figure 1. Image and brain MRI of patient at 22 months of age. A, Image. A mild goiter is noted with some dysmorphic features: high hair line, depressed nasal bridge, and down-turning of the mouth. B, MRI of brain (coronal view). The images demonstrate mild bilateral ventricular enlargement and multiple focal increased signal densities in the subcortical white matter involving cerebral hemispheres. The periventricular white matter and the optic radiation region are spared.

Additional studies were performed to fully characterize the severity of N.M.’s phenotype. A skeletal survey revealed a markedly delayed bone age of 9 months (less than -3 SD from mean at chronological age of 22 months) with no evidence of epiphyseal stippling. An electreencephalogram showed multifocal seizure activity, and brain MRI demonstrated mild bilateral ventricular enlargement and focal white matter changes consistent with either leukomalacia or leukodystrophy (Fig. 1B).

Neuropsychological testing suggested developmental delay in the mentally retarded range. An audiological assessment showed severe neuroconductive hearing loss. An ophthalmological examination revealed astigmatism and severe myopia in association with marked visual impairment.

The patient was discharged from the hospital on Cytomel (12.5 µg/d) and anticonvulsant therapy.

Materials and Methods

Genetic analysis

Genomic DNA was prepared from the whole blood of the patient and her parents according to specifications in the QIAamp blood kit (QIAGEN, Valencia, CA). PCR was performed essentially as previously described with 200 ng genomic DNA amplified for 30 cycles (11). Exon 10 of the human TRß1 was amplified with two sets of primers. The first primer pair was: forward (A1) primer, 5'-GGCTTGCCTGTGTTGAGAGAATA, starting 9 bp into exon 10; and reverse (A2) primer, 5'-AAAGAGCTAGGCAATGGAATG, starting 71 bp downstream from stop codon. The second primer pair was: forward (B1) primer, 5'-TTCCCCGCAGATCGCCCGG, starting 10 bp upstream of the intron/exon boundary; and reverse (B2) primer, 5'-TAGGCAATGGAATGAGATGA, 64 bp downstream of the stop codon. Exon 9 primers were as follows: 5'-primer, TGT AAA ACG ACG GCC AGT GAC TGG CAT TTT GCA TTT GTT CTT; and 3'-primer, CAG GAA ACA GCT ATG ACC AGA CAA GCA AAA GCT CTT TGG ATG. PCR products were confirmed by direct sequencing. R438Xfs was generated by PCR-based mutagenesis using wild-type hTRß in pSV2 expression vector and then subcloned into pcDNA as described previously (12). The construction of wild-type human TRß and G345R was described previously (13).

Cotransfection studies

Human wild-type and TRß mutants (total receptor DNA, 1 µg) were expressed in pcDNA expression vector (Invitrogen, San Diego, CA) and cotransfected with F2-luciferase reporter vector containing the chick lysozyme TRE (1 µg) as well as ß-galactosidase expression vector (0.5 µg) into CV1 cells by the Lipofectamine Plus method (Life Technologies, Inc., Gaithersburg, MD) (13). Posttransfection, cells were maintained in DMEM with 10% FBS for 16 h, and then incubated for an additional 24 h in DMEM containing 10% charcoal-stripped FBS, supplemented with 10^-6 M T₃ (Sigma, St. Louis, MO) as needed. Cells were then harvested, and luciferase activity was measured as previously described (13). Results were normalized to ß-galactosidase activity to correct for any differences in the transfection efficiency of samples. Results were expressed as relative units of luciferase activity/ß-galactosidase activity.

Results

Identification of TRß mutation the in patient

Genomic PCR amplification of exon 10 with two sets of primers, A1/A2 and B1/B2, respectively, followed by direct sequencing of the PCR products showed heterozygous expression of a single base deletion (C) in codon 438, which resulted in a frameshift and a premature termination at codon 442. (Fig. 2). Thus, the encoded mutant receptor (R438Xfs) lacked the last 20 amino acids. PCR amplification and subsequent sequencing of exon 9 did not show any sequence abnormality in the patient (results not shown). Similar analysis of maternal and paternal DNA found no mutation in exon 9 or 10.

View larger version (24K): [in this window] [in a new window]   Figure 2. Base pair and amino acid alignment of wild-type and mutant TRß (R438Xfs). A single base deletion (C) in codon 438 resulted in a frameshift with alteration of downstream amino acids leading to a premature stop codon at codon 442. * denotes base pair deletion.

We examined the transcriptional activity of TRß by cotransfecting CV1 cells with TRß expression vectors encoding wt-TRß, R438Xfs or another natural mutant from an RTH patient (G345R), and F2-luciferase reporter. We observed that the R438Xfs repressed basal transcription in the absence of ligand and lacked transcriptional activation even in the presence of 10^-6 M T₃ similar to the mutant G345R, which previously has been shown to have virtually no T₃ binding (Fig. 3A) (6). When R438Xfs vector was transfected at a 3:1 molar ratio of mutant TRß to wild-type TRß expression vectors, it exhibited strong dominant activity, as it abolished 90% of T₃-induced transcriptional activation by wild-type TRß (Fig. 3B). Additionally, we compared the dominant negative activity of the mutant TRß to another natural mutant TRß that has a strong dominant negative activity (G345R) (6) using two different mutant/wild-type TR expression vector ratios (Fig. 3B). Both TR mutants showed similar potencies of dominant negative activity.

View larger version (26K): [in this window] [in a new window]   Figure 3. Transcriptional activity and dominant negative activity of wild-type and mutant TRs (R438Xfs and G345R). A, Transcriptional activation of wild-type and mutant TRs in the absence or presence of T3. Human wild-type and mutant TRßs, R438Xfs and G345R in pcDNA expression vector (0.3 µg), were cotransfected with F2-luciferase reporter vector containing the chick lysosyme TRE (1 µg) as well as ß-galactosidase expression vector (0.5 µg) in CV1 cells in the absence or presence of 10-6 T3 for 24 h. Cells were harvested, and luciferase activity was measured and normalized to ß-galactosidase activity. Results are shown as the fold basal luciferase activity, with 1-fold basal activity defined as luciferase activity with control pcDNA vector alone in the absence of ligand. Bars denote the mean of triplicate samples ± SD. B, Dominant negative activity of R438Xfs and G345R mutants. Human wild-type TRß and the mutants R438Xfs and G345R in pcDNA expression vectors (0.25 µg) were cotransfected as in A. Two different molar ratios of wild-type to mutant TRß, 1:1 and 1:3, also were cotransfected in the presence of 10-6 M T3. Cells were harvested, and luciferase activity was measured as described in Fig. 3A. Bars denote the mean of triplicate samples ± SD.

Our patient presented with markedly elevated thyroid hormone levels and a severe RTH phenotype. Some of her features, such as goiter, micrognathia, decreased weight and height, and delayed bone maturation, have been observed in other RTH patients (2, 3, 4). Although previously reported, the extreme severity of her hearing loss and mental retardation is atypical (2). Additionally, the clinical manifestations of hypotonia, seizures, and visual impairment are quite unusual in RTH patients.

The particular combination of neurological defects observed in this patient has not been observed previously. Hypotonia has been rarely described in RTH and is a sign of poor motor development (2). Seizures have not been described in RTH; however, they have been reported in patients with delayed myelination and hypotonia (14). Severe mental retardation is quite uncommon in RTH; at the NIH, less than 5% of patients had IQs below 70 (4).

Our patient had visual impairment, which included astigmatism, severe myopia, and strabismus. Although these are thought to be rare in RTH, they have been described in children with leukomalacia, which was noted in our patient (15). Recently, Forrest and co-workers (16) have shown that TRß may play a critical role in retinal development in mice; however, our patient did not have any evidence of retinal disease.

Varying degrees of hearing loss have been described in RTH (17); however, it is usually mild. In at least one severe case, it led to deaf-mutism (1). Our patient had severe hearing loss that was conductive and sensorineural in nature, which probably contributed to her impaired speech development. Although the patient did not have recurrent ear infections, MRI revealed bilateral middle ear effusions. Previous in situ hybridization studies of rat brain and TRß knockout mouse studies (18, 19, 20) have shown that TRß may play a critical role in the inner ear development.

One of the most striking clinical features in our patient was the lack of myelination on MRI. To the best of our knowledge this has not been reported in RTH. MRI studies performed on RTH patients showed anomalous Sylvian fissures in the left hemisphere and multiple Heschl’s gyri in male patients, which may be due to delays in myelination (21). Myelination defects are known to occur in hypothyroidism; in fact, TH is involved in the regulation of several genes that encode proteins that participate in the myelinization process (22, 23).

Our patient had a novel deletion/frameshift mutation in the TRß gene that resulted in a truncated receptor that lacks the last 20 amino acids, including part of the hormone-binding domain and could not mediate T₃-dependent trans-activation. As the patient’s parents did not have elevated TH levels, it is likely that the patient is an index case, and her mutation was not inherited. Truncated TRß have been described previously in RTH patients (2, 12, 24, 25). Miyoshi et al. (24) studied three deletion mutant TRßs from patients with RTH that led to receptors lacking 11, 13, and 16 amino acids. Similar to our mutant TRß, these receptors had negligible T₃ binding and transcriptional activation and strong dominant negative activity over the wild-type receptor. Two of the three patients had a very severe phenotype, including impaired speech development, impaired hearing, and mental retardation. The third patient, however, had a very mild phenotype and was diagnosed on routine examination when he was 16 yr old. Behr et al. (25) described a patient with a TRß lacking the last 28 amino acids with no detectable T₃ binding. This patient’s phenotype was very severe and included mental retardation and short stature. Parilla et al. (11) also described a patient with a 13-amino acid deletion who had severe symptoms of short stature and attention deficit disorder. In these two last cases, the mutant TRßs has strong dominant negative activity as well (12, 25). Additionally, a transgenic mouse overexpressing the mutation described by Parilla et al. demonstrated a similar phenotype as the patient (26). Finally, a single point mutation of arginine to histidine at amino acid position 438 has been described, but did not cause a severe phenotype (27, 28). Thus, as might be expected, mutations that involve premature truncations of the TRß are associated with a more severe phenotype than isolated missense mutations.

Our patient had TH levels that were higher than those recorded among patients from 42 RTH kindreds previously studied at NIH (4). Her T₄ was 1088 nmol/liter and T₃ was 10.6 nmol/liter, which are the same order of magnitude as those found in a patient who was homozygous for a TRß mutation (a 3-bp deletion of the TRß gene leading to loss of threonine at amino acid position 332) reported by Bercu and co-workers (29). The Bercu patient was a member of an RTH kindred and presented with the most severe RTH phenotype described to date (29, 30). Of note, this patient had markedly delayed growth and skeletal maturation, developmental delay, mental retardation, and hyperactivity. He had a TSH level of 102 mU/liter, whereas our patient had a TSH level that was only mildly elevated at 6.88 mU/liter. Although normal TSH values are found in about 60% of patients with RTH (2, 3, 4), it is remarkable that the TSH level was detectable in our patient given her extremely high TH levels. Indeed, our patient’s TH levels are the highest observed in a patient who is heterozygous for a TRß mutation. It is not known whether this mutation alone is sufficient to cause such high TH levels and severe RTH, particularly when compared with other TRß truncation mutants.

Several previous studies have shown that dominant negative activity by mutant TR correlates with decreased release of corepressors in the presence of T₃ (9, 10, 11). We have performed protein/protein interaction cotransfection studies that showed that the mutant TRß had impaired corepressor release in the presence of T₃ similar to G345R, suggesting that this mechanism may contribute to the patient’s phenotype (Ando, S., P. Rotman-Pikielny, and P. M. Yen, unpublished results). However, our patient’s phenotype was more severe than that of the patient with the G345R mutation (32), so it is plausible that other factors may be involved. In this connection, studies of a patient with another TR mutation, R311H, showed a high level of thyroid hormone resistance, whereas other patients with this same mutation had mild or normal phenotypes (32). Recent studies with SRC-1 knockout mice have shown that deletion of coactivators can lead to mild TH resistance (33). Additionally, families with the RTH syndrome have been described that do not have any TR mutations (34, 35), again suggesting that mutations in cofactors or other genetic modifiers may be involved in RTH in some cases.

In summary, we have described a patient with extremely elevated TH levels and severe RTH phenotype with unusual neurological manifestations. The patient had a TRß truncation mutant that was transcriptionally inactive in the presence of T₃ and had strong dominant negative activity on T₃-mediated trans-activation of the wild-type TR. This case enhances our understanding of the wide range of cellular and biological processes that are regulated by THs.

Acknowledgments

We thank Dr. Samuel Refetoff (University of Chicago, Chicago, IL) for kindly performing thyroid function tests in his laboratory and providing advice on the diagnosis and management of this patient. We thank Dr. S. de Rodriguez (Puerto Rico) on referring the patient to the NIH. We also thank Dr. Ying Liu (NIH, Bethesda, MD) for her help in preparing the figures.

Footnotes

¹ S.A.P. and P.R.-P. are co-first authors.

Abbreviations: MRI, Magnetic resonance imaging; RTH, resistance to thyroid hormone; TH, thyroid hormone.

Received June 4, 2001.

Accepted August 13, 2001.

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