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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 11 3879-3884
Copyright © 1997 by The Endocrine Society

Original Studies

Sporadic Congenital Hyperthyroidism due to a Spontaneous Germline Mutation in the Thyrotropin Receptor Gene*

H.-P. Holzapfel, P. Wonerow, W. von Petrykowski, M. Henschen, W. A. Scherbaum and R. Paschke

Department of Internal Medicine III (H.-P.H., P.W., W.A.S., R.P.), University of Leipzig, Leipzig; and Childrens Hospital, University of Freiburg (W.v.P., M.H.), Freiburg, Germany

Address all correspondence and requests for reprints to: Prof. Dr. Med. R. Paschke, Universität Leipzig, Zentrum für Innere Medizin, Medizinische Klinik und Poliklinik III, Philipp-Rosenthal-Straße 27, D-04103 Leipzig, Germany. * This work was supported by the Deutsche Forschungsgemeinschaft (DFG/Pa 423/3-1) and BMB+F, Interdisciplinary Center for Clinical Research at the University of Leipzig (01 KS 9504, project B5W).


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Neonatal hyperthyroidism in the absence of maternal autoimmune thyroid disease and without thyroid-stimulating antibodies in the child is rare. We here describe a boy with severe intrauterine hyperthyroidism and advanced bone age in the absence of thyroid-stimulating autoantibodies. After long term antithyroid treatment and relapse of hyperthyroidism, a near-total thyroid resection was performed. The necessity to progressively decrease postoperative thyroid hormone replacement indicates thyroid tissue regrowth in the small thyroid remnant. Analysis of the genomic DNA of the child’s peripheral leukocytes showed a G to A base exchange that led to a heterozygous Ser to Asn conversion at position 505 in the third transmembrane region of the TSH receptor (TSHR). The absence of the Ser505Asn mutation in all other family members identifies the child’s TSHR mutation as a sporadic germline mutation. Transient expression of the mutated TSH receptor in COS-7 cells showed a constitutively activated cAMP cascade. We thus identified a new constitutively activating germline mutation. Neonates with persistent nonautoimmune hyperthyroidism should be investigated for TSHR germline mutations. Because of frequent relapses, patients with sporadic congenital nonautoimmune hyperthyroidism should be treated with early subtotal to near-total thyroid resection. Moreover, postoperative radioiodine treatment should be considered.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PREDOMINANT etiology of congenital hyperthyroidism is Graves’ disease of the mother leading to transient hyperthyroidism in the child via transplacental passage of TSH receptor (TSHR) antibodies. In only a minority of patients with congenital hyperthyroidism there is no family history of Grave’s disease (1).

TSHR mutations leading to constitutive activation of the TSHR (2, 3, 4, 5) and gsp mutations that also constitutively activate the cAMP cascade (6, 7) have been identified as the molecular etiology in the majority of toxic thyroid nodules. Subsequently, constitutively activating TSHR germline mutations were identified as the molecular cause of autosomal dominant nonautoimmune hyperthyroidism in five families (8, 9). The clinical course of autosomal dominant nonautoimmune toxic hyperplasia of the thyroid is largely characterized by a variable, but mostly late-onset, development of mild clinical symptoms (8, 9, 10, 11). The earliest onset of hyperthyroidism in these five families was at the age of 18 months (8). Recently, three additional families with early and severe thyrotoxicosis were described, one with a family member showing congenital onset of hyperthyroidism (12, 13, 14). Moreover, constitutively activating TSHR mutations were identified in two patients with sporadic congenital nonautoimmune hyperthyroidism (15, 16).

We describe a boy with persistent congenital nonautoimmune hyperthyroidism caused by a new TSHR germline neomutation. Both parents, his brother, and his sister were negative for this mutation, thus characterizing it as a sporadic germline mutation.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The patient

The boy was the third child of healthy unrelated parents born at the 38th week of gestation by vacuum extraction, with a birth weight of only 2600 g (<10th percentile) and a normal length of 50 cm; head circumference was 31.3 cm (<10th percentile). In utero, the fetus had been continually active, leading to constant stress for the mother. External tococardiography before delivery showed tachycardia of 160–180 beats/min. Despite restlessness, sweating, and a great appetite, the diagnosis of hyperthyroidism was only suspected at the age of 5 months because of failure to thrive, sleeplessness, and jitteriness.

The clinical diagnosis of hyperthyroidism was confirmed by elevated plasma levels of thyroid hormones (Table 1Go). At the age of 6 months the boy was markedly underweight (length, 25th percentile; weight far below the 3rd percentile) with a small head (far below the 3rd percentile). He was agitated, trembling, with a pulse of 160 bpm, warm moist skin, sparse thin hair, bilateral pretibial edema lasting for a few weeks, mild exophthalmus without inflammatory signs or eye lid retraction lasting for only 1 month, a closed fontanel, and no thyroid enlargement. Bone age, determined at hand and leg was advanced to 4.5–6.0 yr. The scintiscan showed a homogeneous uptake (Fig. 1Go). TSHR autoantibodies (TRAK, Henning Berlin, Berlin, Germany) were repeatedly negative, just as in the mother who was euthyroid.


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  		Table 1. Thyroid function and other clinical parameters of the patient with sporadic congenital hyperthyroidism due to a constitutively activating mutation in the TSH receptor gene

 


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  		Figure 1. Thyroid scintiscan at 5 months of age showing homogeneous distribution of radionucleotide, with slight enlargement of the left thyroid lobe and a global uptake of 2.6%.

 
Treatment was initiated with propranolol and carbimazole. The latter had to be increased gradually over 6 months to 20 mg twice daily, when TSH was first measurable with 3.0 µU/mL and T4 was in the euthyroid range. T4 (25 µg) was added when thyroid function became hypothyroid, and thyroid volume, measured by ultrasound, increased (Table 1Go) at the age of 15 months. After 10 months of therapy, carbimazole had to be changed to propylthiouracil (100 mg, three times daily) because of increasing pruritus. At the age of 25 months hyperthyroidism recurred during therapy with propylthiouracil (Table 1Go) and a near-total thyroid resection was performed at the age of 27 months. The resected thyroid tissue weighed 8 g; each lobe measured 3 x 2 x 1.4 cm. Histopathological examination showed a parenchymatous goiter with signs of increased endocrine activity without any lymphocytic infiltration (Fig. 2Go). Postoperatively, the patient received 50 µg T4 daily. This dose had to be reduced to only 12.5 µg T4 daily at the age of 4 yr when T4, T3, and free T4 were in the normal range, and TSH remained below 0.04 µU/mL.



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  		Figure 2. Histology of the resected thyroid gland showing diffuse hyperplasia and small and medium-sized follicles and no lymphocytic infiltration (hematoxylin and eosin stain; magnification, x25).

 
Although the boy’s development was retarded at the time of diagnosis, he improved clinically and psychologically after starting medical treatment with propranolol and carbimazole. The bone age was considerably advanced. The boy started walking at 18 months of age. Speech was obviously retarded when he was 2 yr old. At a chronological age of 3.7 yr, his height and weight were slightly below the third percentile, and his head circumference remained markedly below the third percentile. His bone age remained at 4.5–6.0 yr since the first measurement at the age of 5.5 months. To date, motor development, perception, and social age have caught up, but his speech remains markedly disturbed.

The patient’s mother was euthyroid and there was no evidence for thyroid disease in her past history. There was also no history of any thyroid disorder in the other family members.

DNA sequencing

Genomic DNA was extracted from peripheral leukocytes (Qiagen kit, Qiagen, Chatsworth, CA) obtained from the child, his parents, his brother, and his sister. Exon 10 of the TSHR encoding the entire intracellular and transmembrane region and part of the proximal extracellular domain of the TSHR was amplified with two sets of primers by PCR. Conditions were as follows: initial denaturation for 5 min (95 C), followed by 30 cycles of denaturation for 30 s (95 C), annealing for 30 s (56 C), and elongation for 1 min and 30 s (72 C) with a final elongation step of 6 min (72 C). 5'-TGG CAC TGA CTC TTT TCT GT-3', 5'-ACT GTC TTT GCA AGC GAG TT-3', and 5'-TAT TGT TTT TGT TCT GAC GC-3' were used as forward primers, and 5'-GTC CAT GGG CAG GCA GAT AC-3', 5'-GTG TCA TGG GAT TGG AAT GC-3', and 5'-ATG TTG TGG AGA CCC TGC CT-3' were used as reverse primers. An M21-13- and M13-tail for sequencing were added to the forward and reverse primers, respectively. Sequencing was performed with Thermosequenase (Amersham, Aylesbury, UK) and dye-labeled M21-13/M13 primers. The sequencing reactions were analyzed with an automatic sequencer (ABI 373, PE Applied Biosystems, Foster City, CA). PCR and sequencing reactions were repeated, and both strands of the PCR products were sequenced.

Confirmation of the mutation by restriction fragment length polymorphism (RFLP)

For RFLP analysis, a 734-bp PCR fragment of exon 10 (positions 882-1626) was amplified using the forward primer 5'-ATCCTTGAGTCCTTGATGTGTAATGAGAG-3' and the reverse primer 5'-CAGCAAACCCAGCCCCCAACC-3' from the patient’s and his mother’s genomic DNA. The PCR products were completely digested with the restriction enzyme Cac 8I (Biolabs, Beverly, MA) for 2 h at 37 C. An adequate amount was separated in a 2% agarose gel.

Cloning of TSHR mutation

Exon 10 of the TSHR gene was amplified by PCR, using genomic DNA extracted from the patients peripheral leukocytes (described above) as template. The primers used were as follows: forward primer, 5'-ATCCTTGAGTCCTTGATGTGTAAT-3'; and reverse primer, 5'-TTACAAAACCGTTTGCATATACTCTT-3'. The PCR products were cloned in pUC57 (MBI Fermentas, Vilnius, Lithuania). Resulting recombinant vectors were sequenced with Thermosequenase (Amersham) and dye-labeled terminators, using the primer 5'-AAGTCCGATGAGTCCAACCCG-3' and analyzed with an automatic sequencer (ABI 373). Constructs, containing the mutant allele were cleaved with ScaI and BstEII (positions 1439–2169). This mutated fragment was inserted into the wild-type receptor already cloned in the expression vector pSVl. This vector with the wild-type TSH receptor was incompletely digested with ScaI (there is an additional ScaI site within pSVl) and subsequently with BstEII. The mutated TSHR constructs were generated by replacing the ScaI-BstEII segment in the wild-type receptor cloned in pSVl with the corresponding mutated segment amplified by PCR.

Expression of mutated TSHR constructs

For transient expression in COS-7 cells, the constructs were transfected in 100-mm dishes with 6 µg DNA from wild-type or mutated receptor constructs using the diethylaminoethyl-dextran method (17). Twenty-four hours after transfection, the cells were split and plated in six-well plates. Forty-eight hours after transfection, the cells were used for stimulation and detection of cAMP. Three 30-mm dishes were prepared for each condition.

Measurement of cAMP

Transfected cells (4 x 105/well) were washed with serum-free DMEM without antibiotics before preincubation for 30 min with the same medium containing 1 mmol/L isobutylmethylxanthine. Subsequently, the cells were incubated with or without bovine TSH (100 mU/mL; Sigma, St. Louis, MO) for 60 min in the presence of 1 mmol/L isobutylmethylxanthine. Thereafter, the medium was removed, and 1 mL 0.1 N HCl was added. cAMP was measured in the cell extracts with a commercial kit (Amersham, Braunschweig, Germany) according to the manufacturer’s instructions. The results from a representative experiment are expressed as the mean cAMP values ± SE per 30-mm dish.

Binding assays

Transfected cells (4 x 105/well) were washed once with Hanks’ solution without NaCl containing 280 mmol/L sucrose, 0.2% BSA, and 2.5% low fat milk (5). Thereafter the cells were incubated in the same medium in the presence of 130,000 counts/min [125I]TSH (TRAK Assays, Brahms Diagnostica, Berlin, Germany; 25 µCi/µg; 40 U/mg) and the appropriate concentrations of cold TSH at room temperature for 4 h. Before the cells were solubilized with 1 N NaOH, they were washed twice with Hanks’ solution. The bound radioactivity was determined in a {gamma}-counter. We have expressed all TSH or TSHR concentrations in milliunits per mL. The data were analyzed assuming a 1:1 stoichiometry for TSH binding to its receptor, using the fitting module (18) of SigmaPlot 2.0 for Windows (Jandel Scientific GmbH, Erkrath, Germany).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
A constitutively activating TSHR mutation was suspected as the molecular cause of the severe nonautoimmune congenital hyperthyroidism in this child. Therefore, exon 10 of the TSHR encoding the entire intracellular and transmembrane region and part of the proximal extracellular domain was screened for mutations by direct genomic sequencing. A G to A transition in position 1514 of the TSHR gene encoding the third transmembrane domain of the receptor was identified in the DNA extracted from the patient’s leukocytes. The mutation is heterozygous and results in a substitution of asparagine (AAC) for serine (AGC) at position 505 in one allele (Fig. 3aGo). The patient’s parents (Fig. 3bGo), his brother, and his sister displayed only the wild-type TSHR sequence. This mutation can, therefore, be classified as sporadic.



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  		Figure 3. A, Antisense sequence of the TSHR gene amplified from genomic DNA of the patient. A C to T base exchange in the antisense sequence, corresponding to an G to A exchange in the coding (sense) sequence at position 505 leads to a heterozygous serine (AGC) to asparagine (AAC) conversion. B, Antisense wild-type sequence of the TSHR gene amplified from genomic DNA of the patient’s mother.

 
We could confirm the presence of the heterozygous G to A transition by RFLP analysis. The mutation leads to destruction of a restriction site for Cac 8I at position 1512, resulting in an additional 332-bp fragment compared to the wild-type pattern of the patient’s mother (Fig. 4Go).



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  		Figure 4. TSHR PCR fragments amplified from genomic DNA of the patient and his mother digested with the restriction enzyme Cac 8I and separated in a 2% agarose gel.

 
The expression of the mutated receptor, with the substitution of asparagine for serine at position 505 in COS-7 cells, resulted in 5-fold higher basal values of cAMP accumulation (23.5 ± 1.2 pmol/well) compared to the wild-type receptor (4.8 ± 0.1 pmol/well). The Ser505 to Asn mutation’s maximal cAMP accumulation after stimulation with 100 mU TSH/mL was similar to that of the wild-type receptor (48.2 ± 2.0 and 47.0 ± 1.6 pmol/well, respectively; Fig. 5Go).



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  		Figure 5. Basal and stimulated cAMP levels of COS-7 cells transiently transfected with the wild-type TSHR or the construct containing the Ser505Asn mutation.

 
Simultaneous binding experiments showed similar binding capacity values for both the wild-type and mutant receptors (0.43 ± 0.09 and 0.55 ± 0.08, respectively). The binding capacities excluded overexpression of the mutant receptor as a possible reason for the increased basal cAMP accumulation. The Kd values (2.57 ± 0.5 and 1.91 ± 0.3 for the wild-type and mutant receptors, respectively) also showed similar affinities of the wild-type and Ser505Asn mutant TSHR for bTSH.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
To date, two patients have been described with congenital nonautoimmune hyperthyroidism due to a spontaneous mutation in the TSHR gene (15, 16). The TSHR mutation reported by Kopp et al. (15) was also identified in two cases with toxic solitary thyroid nodules (5), implying that the same molecular mechanism is responsible for the generation of toxic nodules in the case of somatic TSHR mutations and for toxic thyroid hyperplasia in sporadic congenital nonautoimmune hyperthyroidism caused by a TSHR germline neomutation.

The patient described by Kopp et al. (15) as well as the one described here suffered from severe recurrent hyperthyroidism requiring thyroidectomy. Moreover, a second thyroidectomy followed by radioiodine treatment was necessary (15) or thyroid tissue regrowth was noted, as indicated by the necessity to decrease the dose of thyroid hormone replacement. The description of the clinical course for the sporadic congenital nonautoimmune hyperthyroidism reported by Roux et al. (16) is limited to the postnatal period. However, fetal hyperthyroidism, goiter, and the necessity for high dose antithyroid treatment are indications that this child might also require thyroid ablation in the future for the control of severe hyperthyroidism.

The amino acid transition in the mutated thyrotropin receptor of this child (Ser505Asn) is located in a position that has previously been found mutated to a different amino acid (Ser505Arg) in a case of autosomal dominant nonautoimmune hyperthyroidism (9). This patient’s sporadic germline mutation caused a phenotype with severe recurrent hyperthyroidism and advanced bone age at delivery. Only near-total thyroid resection performed at the age of 27 months could cure the patient. This child, therefore, presents a more active phenotype compared to the relatively mild phenotype of the familial Ser505Arg mutation (9, 11). Although there are no parallel transfection data for the two mutations, the in vitro data are in agreement with these phenotypic differences. The Ser505Asn mutation showed a 5-fold increase in basal cAMP accumulation compared to the wild-type receptor, whereas the increase was only 2-fold for the Ser505Arg mutation (9). Even more significant differences were described for the in vitro activities for the Ile486Phe or Met mutations (5). Therefore, different amino acid substitutions at the same residue may cause significantly different constitutive activities of the mutated receptors.

In vitro, all three sporadic mutations showed increased basal cAMP levels in comparison to the wild-type TSH receptor (7-fold basal cAMP for Met435Thr, 5- to 6-fold basal cAMP for Phe631Leu, and 5-fold basal cAMP for Ser505Asn). The in vitro activity of the Phe631Leu mutation was directly compared with those of other sporadic and germline TSH receptor mutations in parallel transfection experiments (19). There is no clear correlation of in vitro activities with the phenotypes. The fetal onset of hyperthyroidism for the Phe631Leu sporadic germline mutation does not correlate with its lower specific constitutive activity compared to that of the Cys672Tyr mutation, for which the earliest onset of hyperthyroidism was reported at the age of 18 months. Among others, variables such as iodine, goitrogens, and genetic background are likely to modify the age of onset, the intensity, and the course of hyperthyroidism caused by constitutively activating TSHR mutations. This is also supported by the variable onset of hyperthyroidism in autosomal dominant nonautoimmune hyperthyroidism (8, 9, 10, 11). Moreover, familial germline mutations are likely to be selected for a relatively mild phenotype in order to survive and reproduce. However, there is no absolute restriction of certain constitutively activating TSHR mutations to the clinical entities of somatic and familial or sporadic TSHR germline mutations. A sporadic germline mutation has been described in toxic nodules (5, 15), and a recently described familial germline mutation (14) has also been described in a toxic nodule (3).

Site-directed mutagenesis studies of the adrenergic A2a and dopamine D2 receptors (20, 21, 22) confirm the importance of position 505 for ligand binding and agonist activation in G protein-coupled receptors. Moreover, as shown by site-directed mutagenesis of the rhodopsin receptor, the third and seventh transmembrane regions play a key role in the activation of the receptor by inducing a conformational change that results in a displacement of the transmembrane helixes 3 and 7 (23). This is in agreement with the constitutive activation of the TSHR by this and several other point mutations in the third or the seventh transmembrane domain of the TSHR (5, 8, 9).


   Acknowledgments
 
We thank N. Boehm for providing the histology of the resected thyroid gland, and T. Gudermann, T. Schöneberg, and G. Vassart for advice. We thank A. Grüters-Kieslich for providing a DNA sample and for bringing the case to our attention.

Received October 16, 1996.

Revised June 4, 1997.

Accepted July 25, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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