Elsevier

The Journal of Pediatrics

Volume 131, Issue 6, December 1997, Pages 899-904
The Journal of Pediatrics

Constitutively active germline mutation of the thyrotropin receptor gene as a cause of congenital hyperthyroidism,☆☆,,★★

https://doi.org/10.1016/S0022-3476(97)70040-4Get rights and content

Abstract

Congenital hyperthyroidism is a rare, transient disease usually caused by transmission of thyrotropin receptor autoantibodies from the mother with Graves' disease to her child. We report a German women and her two sons who had congenital, but persistent hyperthyroidism without any signs of autoimmunity. Direct sequencing of the polymerase chain reaction–amplified exon 10 of the thyrotropin receptor genomic DNA revealed in the mother and both sons a transition of GCC to GTC, resulting in an exchange of alanine 623 to valine. This germline mutation in a highly conserved region of the thyrotropin receptor resulted in a constitutive activation of the cyclic adenosine monophosphate–generating cascade with resulting hyperthyroidism. Analysis of the family for a corresponding BstXI restriction–site polymorphism revealed heterozygosity for this mutation in the affected family members, but not in the father or other relatives. We conclude that whenever congenital hyperthyroidism is persistent and parameters of autoimmunity are absent, a constitutively active thyrotropin receptor mutation should be considered. Treatment appears to require aggressive means such as total thyroidectomy or ablation by 131iodine because two subtotal thyroidectomies in the mother were insufficient to control the disease. (J Pediatr 1997;131:899-904)

Section snippets

Case Report

The family history was uneventful with respect to thyroid diseases (Fig. 1) except for two children and their mother, a 24-year-old woman, who received antithyroid medications since she was 3 years old. With the suspected diagnosis of Graves' disease, a partial thyroidectomy was performed, but a recurrent multinodular goiter developed, which was treated by further surgery. Thyroid autoantibodies were never detected (Table I). The mother experienced a third recurrence with clinical signs of

Methods

Lymphocytes from 10 ml heparinized blood were obtained from all family members and separated using a ficoll gradient (Ficoll-paque, Pharmacia, Germany). DNA was extracted from lymphocytes as follows: Cells were lysed overnight at 53° C in a lysis buffer (400 mmol/L NaCl, 10 mmol/L Tris, pH 8.2, 2 mmol/L EDTA, 0.2 mg/ml protease K, and 0.5% sodium dodecylsulfate). Proteins were subsequently removed using phenol/chloroform and genomic DNA was resuspended in Tris (10 mmol/L)/EDTA (1 mmol/L) buffer

Results

The levels of thyroxine, triiodothyronine, and TSH of all family members are shown in Table I. No member of the family had measurable antibody levels against the thyroid-specific antigens thyroglobulin, thyroid peroxidase, and the TSH receptor. Furthermore, stimulating TSH receptor antibodies or cytotoxic antibodies were absent. The elevation of thyroglobulin autoantibodies in the father and grandfather had no clinical relevance as shown by further investigations.

Sequence analysis of the

Discussion

The TSH receptor is a member of the large group of G protein coupled receptors characterized by seven transmembrane helices connected by three extracellular and three intracellular loops. Like two other members of the glycoprotein hormone receptors, the luteinizing hormone/human chorionic–gonadotropin receptor and the human follicle–stimulating hormone receptor, the TSH receptor has a long extracellular aminoterminal domain that has been shown to play a role in specific hormone recognition.

Acknowledgements

We acknowledge Dr. Anette Grüters, MD, Berlin, Germany, for measuring cytotoxic antibodies and Dr. Rendl, MD, Würzburg, Germany, for performing standard thyroid function tests.

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    From the Institute for Pharmacology and Toxicology and Children's Hospital of the University of Wuerzburg, University Clinic of Internal Medicine, Bochum, Germany

    ☆☆

    The study was supported by grants of the Deutsche Forschungsgemeinschaft (DFG) to KOS (Schw 573 /1-1 and 1-2) and to MD (De 407/ 7-1) and by Forum Schilddrüse.

    Reprint requests: K.O. Schwab, MD, Department of Pediatrics, University of Freiburg, Mathildenstr. 1, D-79106 Freiburg, Germany.

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