Correspondence

Congenital Hypothyroidism Caused by Mutations in the Thyrotropin-Receptor Gene

N Engl J Med 1997; 336:1390-1391May 8, 1997

Article

To the Editor:

The causes of congenital hypothyroidism are poorly understood. Recently, two different missense mutations in the extracellular domain of the thyrotropin receptor were identified in three siblings who had elevated serum thyrotropin concentrations but were euthyroid and had thyroid glands of normal size.1 We describe a patient with congenital hypothyroidism and thyroid hypoplasia due to two loss-of-function mutations in exon 10 of the thyrotropin-receptor gene.

At birth the patient, the firstborn infant of nonconsanguineous parents, had a blood thyrotropin concentration of 89 mU per liter. Reexamination revealed a serum thyrotropin concentration of 82 mU per liter (normal, <10) and a low serum free thyroxine concentration, confirming the diagnosis of congenital primary hypothyroidism. Ultrasonography revealed a small thyroid gland. The infant was treated with thyroxine. Discontinuation of thyroxine at the age of two years resulted in an increase in the serum thyrotropin concentration and a fall in the serum free thyroxine concentration. The thyroid volume was 0.8 ml (normal, 1.5 to 4.0). Thyroxine therapy was reinstituted.

Two years before becoming pregnant with this child, the mother was found to have a slightly elevated serum thyrotropin concentration (5.5 mU per liter) and a low serum free thyroxine concentration. She was treated with thyroxine. The father had normal serum thyrotropin and free thyroxine concentrations.

DNA was obtained from leukocytes for polymerase-chain-reaction and single-strand conformation polymorphism studies of a 376-bp segment of exon 10 of the patient's thyrotropin-receptor gene. The analysis revealed differences in electrophoretic mobility. Studies of maternal and paternal thyrotropin-receptor genes identified the parents as heterozygous carriers of two different mutations in the extracellular region of the receptor. The mother had an 18-bp deletion (nucleotide positions, 1217 to 1234) and a 4-bp insertion in one allele, which resulted in a frame shift and a coding sequence for 14 novel amino acids followed by a premature stop codon after amino acid 419. The father had a transversion of thymidine to guanine at nucleotide position 1170 (codon 390) in one allele, resulting in the substitution of a tryptophan for a cysteine residue.

COS-7 cells transiently expressing the wild-type receptor and the mutant paternal allele responded to thyrotropin with an increase in the formation of cyclic AMP, but cells expressing the mutant maternal allele did not respond. However, as compared with the amount needed to stimulate the wild-type receptor, 20 times more thyrotropin was required to stimulate the mutant paternal allele. Similarly, the concentration of thyrotropin required to reduce binding of ¹²⁵I-labeled bovine thyrotropin to the mutant receptor was 16 times as high as the amount needed with the wild-type receptor.

In this infant the combination of two different germ-line loss-of-function mutations in the thyrotropin-receptor gene resulted in persistent congenital hypothyroidism. Mutations of this gene may be the cause of a substantial number of cases of congenital hypothyroidism.

Heiki Biebermann
Annette Grüters, M.D., Ph.D.
Medizinische Fakultät der Humboldt Universität zu Berlin, D-13353 Berlin, Germany

Torsten Schöneberg, M.D.
Thomas Gudermann, M.D.
Freie Universität Berlin, D-14195 Berlin, Germany

1 References

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   Full Text | Web of Science | Medline

Citing Articles (12)

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   Jan Haavik, Anne Halmøy, Tor-Arne Hegvik, Stefan Johansson. (2011) Maternal genotypes as predictors of offspring mental health: the next frontier of genomic medicine?. Future Neurology 6:6, 731-743
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   Annette Grüters, Heiko Krude. (2011) Detection and treatment of congenital hypothyroidism. Nature Reviews Endocrinology
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   Pere Berbel, Juan Bernal. (2010) Hypothyroxinemia: a subclinical condition affecting neurodevelopment. Expert Review of Endocrinology & Metabolism 5:4, 563-575
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   P. Berbel, D. Navarro, E. Auso, E. Varea, A. E. Rodriguez, J. J. Ballesta, M. Salinas, E. Flores, C. C. Faura, G. Morreale de Escobar. (2010) Role of Late Maternal Thyroid Hormones in Cerebral Cortex Development: An Experimental Model for Human Prematurity. Cerebral Cortex 20:6, 1462-1475
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   J. H. Robben, M. L. A. Kortenoeven, M. Sze, C. Yae, G. Milligan, V. M. Oorschot, J. Klumperman, N. V. A. M. Knoers, P. M. T. Deen. (2009) Intracellular activation of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus by nonpeptide agonists. Proceedings of the National Academy of Sciences 106:29, 12195-12200
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   Stefano Stagi, Giuseppe Bindi, Anna Silvia Neri, Elisabetta Lapi, Stefania Losi, Rita Jenuso, Roberto Salti, Francesco Chiarelli. (2005) Thyroid function and morphology in patients affected by Williams syndrome. Clinical Endocrinology 63:4, 456-460
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   Torsten Schöneberg, Angela Schulz, Heike Biebermann, Thomas Hermsdorf, Holger Römpler, Katrin Sangkuhl. (2004) Mutant G-protein-coupled receptors as a cause of human diseases. Pharmacology & Therapeutics 104:3, 173-206
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   O. E. Janssen, Beate Quadbeck, S. Refetoff. (2003) Resistenz gegen TSH/Resistance to Thyrotropin. LaboratoriumsMedizin 27:1-2, 60-66
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   Malgorzata Wasniewska, Filippo De Luca, Sergio Siclari, Giuseppina Salzano, Maria Francesca Messina, Fortunato Lombardo, Mariella Valenzise, Caterina Ruggeri, Teresa Arrigo. (2002) Hearing loss in congenital hypothalamic hypothyroidism: a wide therapeutic window. Hearing Research 172:1-2, 87-91
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    P. Bretones, L. Duprez, J. Parma, M. David, G. Vassart, P. Rodien. (2001) A Familial Case of Congenital Hypothyroidism Caused by a Homozygous Mutation of the Thyrotropin Receptor Gene. Thyroid 11:10, 977-980
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    Laurence Duprez, Jasmine Parma, Jacqueline Van Sande, Patrice Rodien, Jacques E. Dumont, Gilbert Vassart, Marc Abramowicz. (1998) TSH Receptor Mutations and Thyroid Disease. Trends in Endocrinology & Metabolism 9:4, 133-140
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    AKIRA HISHINUMA, JUNTA TAKAMATSU, YUMIKO KANNO, SHIGERU YOSHIDA, TAMIO IEIRI. (1998) Analysis of the Promoter of the Thyrotropin Receptor Gene and the Entire Genomic Sequence of Thyroid Transcription Factor-1 in Familial Congenital Hypothyroidism due to Thyrotropin Unresponsiveness. Thyroid 8:4, 305-309
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