Novel germline mutation (Leu512Met) in the thyrotropin receptor gene (TSHR) leading to sporadic non-autoimmune hyperthyroidism

J Pediatr Endocrinol Metab. 2017 Mar 1;30(3):343-347. doi: 10.1515/jpem-2016-0185.


Background: Primary nonautoimmune hyperthyroidism is a rare cause of neonatal hyperthyroidism. This results from an activating mutation in the thyrotropin-receptor (TSHR). It can be inherited in an autosomal dominant manner or occur sporadically as a de novo mutation. Affected individuals display a wide phenotype from severe neonatal to mild subclinical hyperthyroidism. We describe a 6-month-old boy with a de novo mutation in the TSHR gene who presented with accelerated growth, enlarging head circumference, tremor and thyrotoxicosis.

Methods: Genomic DNA from the patient's and parents' peripheral blood leukocytes was extracted. Exons 9 and 10 of the TSHR gene were amplified by PCR and sequenced.

Results: Sequencing exon 10 of the TSHR gene revealed a novel heterozygous missense mutation substituting cytosine to adenine at nucleotide position 1534 in the patient's peripheral blood leukocytes. This leads to a substitution of leucine to methionine at amino acid position 512. The mutation was absent in the parents. In silico modeling by PolyPhen-2 and SIFT predicted the mutation to be deleterious.

Conclusions: The p.Leu512Met mutation (c.1534C>A) of the TSHR gene has not been previously described in germline or somatic mutations. This case presentation highlights the possibility of mild thyrotoxicosis in affected individuals and contributes to the understanding of sporadic non-autoimmune primary hyperthyroidism.

MeSH terms

  • Adult
  • Biomarkers / metabolism*
  • Female
  • Germ-Line Mutation / genetics*
  • Humans
  • Hyperthyroidism / congenital*
  • Hyperthyroidism / genetics
  • Hyperthyroidism / pathology
  • Infant
  • Male
  • Prognosis
  • Receptors, Thyrotropin / genetics*


  • Biomarkers
  • Receptors, Thyrotropin

Supplementary concepts

  • Hyperthyroidism, Nonautoimmune