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A Germline Mutation of the Thyrotropin Receptor Gene Associated with Thyrotoxicosis and Mitral Valve Prolapse in a Chinese Family

Department of Endocrinology, Singapore General Hospital (D.H.C. S.C.H.), and the Department of Medicine, Alexandra Hospital (C.R.), Singapore; and Institut de Recherche Interdisciplinaire, Universite Libre de Bruxelles (J.P., G.V.), Brussels, Belgium

Address all correspondence and requests for reprints to: Dr. Daphne Khoo, Department of Endocrinology, Singapore General Hospital, Block 6, Level 6, Outram Road, Singapore 169608. E-mail: daphne_khoo{at}sgh.gov.sg

	Abstract

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Activating mutations of the TSH receptor (TSH-R) have been reported to result in toxic adenomas, multinodular goiters, sporadic neonatal hyperthyroidism, and familial autosomal dominant nonautoimmune hyperthyroidism. To date, all descriptions of such mutations, whether somatic or genomic, have been confined to the Caucasian population. We describe a Chinese family in whom a germline proline to serine substitution in position 639 resulted in familial thyrotoxicosis. This constitutively activating mutation has been previously described in a hyperfunctioning thyroid nodule. The three children in this family developed thyrotoxicosis during childhood; their father was diagnosed as thyrotoxic at the age of 38 yr. Two of the children and the father had mitral valve prolapse (MVP) associated with mitral regurgitation. There was a close temporal relationship between the onset of thyrotoxicosis and the diagnosis of mitral valvular disease in these patients. An increased prevalence of MVP has been reported in Graves’ disease and chronic lymphocytic thyroiditis, but the pathophysiological mechanisms linking MVP and autoimmune thyroid disease are still not understood. This is the first report of an association between activating TSH-R mutations and MVP. We postulate that TSH-R activation may increase the clinical expression of MVP in genetically predisposed individuals.

	Introduction

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THE CLINICAL significance of activating mutations of TSH receptor (TSH-R) first became apparent in 1993 with the discovery that somatic mutations of the TSH-R gene resulted in hyperfunctioning thyroid adenomas (1). This was followed in 1994 by the description of two families with nonautoimmune autosomal dominant hyperthyroidism resulting from germline mutations of the same gene (2). Reports of activating TSH-R mutations resulting in sporadic neonatal hyperthyroidism (3) and toxic multinodular goiter (4) then followed. These reports have largely emerged from Caucasian, primarily European, populations. To date, no activating TSH-R mutations have been identified in Orientals. A Japanese study found no constitutively activating TSH-R mutations in 45 cases of autonomously functioning thyroid nodules (5). Although iodine intake in different populations may explain the discrepancy in results with regard to somatic mutations, it is not clear why there have been no reports of any sporadic or familial germline mutations in Orientals.

We report here a Chinese family in whom all three children and the father had thyrotoxicosis. Direct sequencing of the TSH-R gene revealed a P639S mutation, a substitution that has been previously described in a hyperfunctioning thyroid nodule (6, 7). There was associated mitral valve prolapse (MVP) in three of the four affected patients.

	Case Report

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Case report 1: eldest child (male)

This child, aged 7 yr, was found to have a cardiac murmur in 1976 during an examination for an upper respiratory tract infection. His development had been normal up to that point. He was delivered full term. The birth weight was normal, and no abnormalities had been detected during neonatal screening. At the time of presentation, he was noted to have a pulse rate of 100/min but no goiter or other features of thyrotoxicosis. His height was 131.0 cm (>90th percentile), and his weight was 20.0 kg (50th percentile). A pan-systolic murmur radiating to the left axilla was detected. Echo cardiography performed at the time showed MVP with mitral regurgitation. He continued to have unexplained tachycardia, but was otherwise well. In 1979, at the age of 10 yr, he developed a goiter and complained of increased sweatiness. A mild degree of proptosis was noted. By this time, his two siblings had been diagnosed to be thyrotoxic. His T₄ level was 16.0 µg/dL (normal, 4.6–12.0). Antimicrosomal and antithyroglobulin antibodies were negative. Carbimazole therapy was commenced. Two-dimensional echo cardiography was repeated when he was 18 yr of age and showed thickening of the mitral valve, a floppy anterior cusp with prolapse, and mild mitral regurgitation. Over the next 11 yr, his thyrotoxicosis remained difficult to control. Carbimazole could not be discontinued at any point. He finally underwent a subtotal thyroidectomy in 1990. Histological examination showed no evidence of lymphocytic infiltration. He remained euthyroid till 1992, at which point he defaulted follow-up.

Case report 2: second child (female)

The second child presented in 1975 at age 5 yr, 6 months with a cardiac murmur that had been detected during a routine pediatric evaluation. She weighed 3.2 kg at birth, and the neonatal as well as the pediatric assessment carried out at the age of 2 yr, 6 months had revealed no abnormalities. No murmur had been detected at either of those two examinations, and her developmental milestones were normal. Physical examination at the time of presentation revealed a harsh systolic murmur, which radiated to the axilla. Her pulse rate was 120 beats/min. Two months later, the patient was admitted for weight loss and was found to be thyrotoxic. A goiter and prominence of the eyes were noted. Antimicrosomal and antithyroglobulin antibodies were negative. Two-dimensional echo cardiography performed in 1987 was reported as normal. TSH-R antibodies measured by a RRA in 1989 were negative. She required carbimazole continuously from 1975–1990, at which time she had a subtotal thyroidectomy. The microscopic examination showed follicles of varying sizes and cystic dilatation of some follicles with scalloping of colloid. No lymphocytic infiltration was noted. She relapsed in 1992 and is currently taking carbimazole.

Case report 3: third child (male)

This patient first presented in 1977 at the age of 4 yr, 10 months with the problem of a systolic murmur that had been detected on a routine examination. There was no history suggestive of congenital heart disease or rheumatic fever. The pediatrician noted that the child was tall for his age, but was thin. There was a bounding pulse with a widened pulse pressure. Echo cardiography showed MVP. In 1978, at the age of 5 yr, 6 months, he was noted to be sweating excessively. He had tachycardia and a small goiter, and his eyes were prominent. His T₄ level was 13.1 µg/dL (normal, 5.6–11.5). Antimicrosomal and antithyroglobulin antibodies were repeatedly negative, as was a TSH-R antibody level determined in 1989. Two-dimensional echo cardiography carried out in 1987 showed thickening of the mitral valve with prolapse of the anterior cusp and mild mitral regurgitation. The patient had a subtotal thyroidectomy in 1993, and histological examination revealed follicles of varying sizes lined by hyperplastic cells. Again, no lymphocytic infiltration was demonstrated. He remains euthyroid to date.

Case report 4: father

Only a brief summary of the father’s case records was available. This patient was apparently well until 1976, when he presented with signs of mild cardiac failure at the age of 38 yr. A comprehensive preemployment medical examination conducted the year before had been normal. He was evaluated and found to have thyrotoxicosis and auscultatory findings consistent with mitral regurgitation. Satisfactory control of the thyrotoxicosis could not be achieved with carbimazole, and he underwent subtotal thyroidectomy in 1979. In 1985, cardiological assessment revealed that the cause of mitral regurgitation was MVP. He remained euthyroid until 1995, at which time he relapsed.

	Materials and Methods

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DNA was extracted from peripheral blood using standard procedures. All coding portions of the TSH-R gene were sequenced using a total of 14 fragments amplified by PCR as previously described (1). PCR was performed in a 100-µL final volume containing 1 µg DNA, 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 8.3), 1 mmol/L MgCl₂, 0.01% gelatin, 0.2 mmol/L deoxy-NTP, 5 U Taq polymerase (BRL, Gaithersburg, MD), and 100 nmol/L of each primer. The annealing temperature was 50 C. Direct genomic DNA sequencing of both strands was realized with the dye primer cycle sequencing core kit (ABI PN 402070, Applied Biosystems, Foster City, CA), and mutations were identified using the Factura and Sequence Navigator software (ABI Advanced Biotechnologies, Columbia, MD) running on an ABI 373 sequencer.

	Results

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Direct sequencing of genomic DNA extracted from peripheral leukocytes was performed for the individual indicated on the pedigree (Fig. 1). The patient (case report 3) harbored the C to T transition in the heterozygous state. This results in the substitution of a serine for proline in residue 639 in the middle of the sixth transmembrane segment of the TSH-R (Fig. 2). The same mutation has been reported recently in a toxic adenoma (6, 7). The mutant receptor was shown to activate constitutively both cAMP (6) and inositol phosphate (7) accumulation when transfected in COS cells.

View larger version (24K): [in this window] [in a new window]   Figure 1. Pedigree of the reported family.

View larger version (23K): [in this window] [in a new window]   Figure 2. Direct sequencing of PCR products from leukocyte DNA of the patient indicated in Fig. 1 shows a C to T transition in the heterozygous state, leading to the substitution of a serine for proline at position 639 (bottom lane). The normal sequence is shown for comparison (top lane).

	Discussion

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As increasing reports on germline mutations of the TSH-R have emerged, it appears that the prominence of the eyes, first highlighted by de Roux et al. (12), may be a feature in those in whom the hyperthyroidism manifests at an early age. Although a hallmark of the earlier cases was the absence of ophthalmopathy, proptosis or at least prominence of the eyes has been noted in a number of the congenital cases (8, 9, 10, 11, 12, 13). Similarly, mild proptosis was noted in our three patients at the time of diagnosis. We have followed this family up for more than 20 yr, and with time, this prominence has become less pronounced. The appearance of the children’s eyes normalized by the time they attained adulthood. Others have noted that the eye abnormalities in these cases may be transient (13) or tend to be mild (9, 10) and nonprogressive (11). The pathophysiological mechanisms responsible for these ocular manifestations are still unknown.

To date, anatomical cardiac abnormalities have not been described in either the sporadic or familial mutations. Three of the four affected members in this family had MVP associated with mild mitral regurgitation. MVP is a common disorder whose prevalence has been reported to range from 6–21% in the general population (14, 15). The inheritance of primary MVP is thought to be autosomal dominant with variable penetrance (16). The prevalence of MVP is significantly elevated in Graves’ disease (17, 18, 19) and chronic lymphocytic thyroiditis (18, 20), but not in toxic multinodular goiter (20A ). The pathophysiological mechanisms linking MVP and autoimmune thyroid disease are still not understood. It has been suggested that human leukocyte antigen genes may explain the linkage between Graves’ disease and MVP (19). However, the associations between HLA alleles and Graves’ disease reported to date have been weak and nonspecific (21).

It is not clear how a point mutation in the TSH-R gene could be related to MVP. Four possibilities exist. Firstly, the mutation itself might have caused MVP. Secondly, there may be no relationship between the two conditions, and their coexistence in this family might have been entirely coincidental. Thirdly, the TSH-R gene and the MVP gene in this family may be tightly linked. Finally, the TSH-R mutation might contribute to the clinical expression of MVP in an individual who is genetically predisposed. The detection of TSH-R messenger ribonucleic acid in the human heart by both RT-PCR (22, 23) and Northern blot analysis (22) has been reported. However, some of these results might have reflected illegitimate transcription (24, 25), and the presence of functional TSH receptor in the heart has not yet been confirmed independently. TSH stimulation of cultured mouse cardiomyocytes has been reported to result in elevated cAMP production. This effect of TSH was inhibited by inhibitory TSH-R antibodies (22). Variability in TSH-R messenger ribonucleic acid distribution (26) might explain why a constitutionally active mutation would result in MVP rather than a more generalized cardiomyopathy. Increased adenyl cyclase activity due to abnormal G_s-associated signal transduction is present in a subset of patients with MVP (27). Although the _s complementary DNA sequences in these patients appear to be normal (28), these observations suggest a possible link between G protein-coupled receptor signal transduction pathways and MVP. If TSH-R activation does, in fact, play a role in the pathogenesis of MVP, this would provide an attractive unifying hypothesis to explain the MVP in our patients as well as the increased incidence of MVP in both hyper- and hypothyroid forms of autoimmune thyroid disease. However, the fact that MVP has not been reported in any of the cases of germline mutations described to date makes it unlikely that that the TSH-R mutation on its own is sufficient to cause MVP.

Although it is possible that the two conditions in our patients are entirely unrelated, the temporal sequence of events makes this unlikely. Even if the MVP and TSH-R genes were tightly linked in this family, it would be difficult to explain why the diseases would manifest almost simultaneously. There is no significant clinical expression of MVP at birth (29, 30), and the incidence of MVP in early childhood is very low (31) even among familial cases (16). Of the four possibilities, we think that it is most probable that this family had an underlying genetic predisposition to MVP and that the coexisting TSH-R mutation contributed to the earlier clinical manifestation of disease.

The P639S mutation is known to have high constitutive activity, with activation of both the cAMP (6) and inositol phosphate (7) pathways. It is located at the C-terminal border of the major hot spot for activating mutations (1), extending from residues 629–639 in the cytoplasmic half of transmembrane segment VI. Proline 639 is a highly conserved residue in G protein-coupled receptors, which has been proposed to play a key role in the conformation change associated with receptor activation (31). Although the age of onset of hyperthyroidism has been highly variable in other cases of familial nonautoimmune autosomal dominant hyperthyroidism (2, 32, 33), all the toxic adenoma-associated germline mutations [Phe⁶³¹Leu (3), Thr⁶³²Ile (8), Ala⁶²³Val (10), and Leu⁶²⁹Phe (11)] described to date have resulted in early-onset hyperthyroidism. With these four mutations, thyrotoxicosis manifested in the neonatal period in five cases (3, 8, 10, 11) and in early childhood in the remaining two (9, 10, 11). The delayed expression of disease in our patients may be related to genetic or environmental factors. Each of our patients presented independently between the years 1975–1977, suggesting that a common infectious or environmental factor may have triggered the onset of disease in this family. Interestingly, activating TSH-R mutations have, to date, not been reported in Orientals. It has been postulated that iodine deficiency may play a role in the clinical expression of activating TSH-R mutations. The high iodine diet in countries such as Japan may therefore explain the low frequency of somatic TSH-R mutations associated with hyperfunctioning nodules in those populations. However, this would not explain the absence of germline mutations. One possibility is that a high prevalence of thyroid autoantibodies in the population may lead to these cases being mistakenly diagnosed as Graves’ disease. Alternatively, it remains to be seen whether genetic or environmental factors present in Orientals protect against the clinical expression of these mutations.

	Acknowledgments

 
The authors gratefully acknowledge the contribution of Miss Muriel Nguyen in making this work possible.

Received October 22, 1998.

Revised December 16, 1998.

Accepted December 21, 1998.

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