Molecular diagnosis of neonatal hyperthyroidism. A contribution to translational medicine.

ADROVER, EZEQUIELA; MOLINA MARICEL; DUJOVNE NOELIA; AGUINAGA, MARÍA AGUSTINA C; OLCESE, MARÍA C; LAZZATI JUAN M; GAZEK NATALIA; ZAIDMAN VERÓNICA; FELIPE LAURA; AYARZABAL VICTOR; MACEIRAS MERCEDES; BELGOROSKY ALICIA; HERZOVICH, VIVIANA; TARGOVNIK , HÉCTOR M; RIVOLTA CARINA M

Ciudad Autónoma de Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias. LXII Reunión Anual de la Sociedad Argentinta de Investigación Clínica; 2017

Sociedad Argentina de Investigación Clínica

Neonatal hyperthyroidism occurs in 1:25,000 to 1:45,000 births. Primary nonautoimmune hyperthyroidism is a rare cause of neonatal hyperthyroidism. This results from an activating mutation in the thyrotropin-receptor (TSHR). Germline mutations, inherited in an autosomal dominant pattern, cause familial nonautoimmune hyperthyroidism, whereas de novo mutations cause sporadic congenital non-autoimmune hyperthyroidism. Sporadic cases tend to have a more severe course. To date, approximately 21 familial and 12 sporadic gain-of-function mutations have been described. The TSHR gene resides on the chromosome 14 and carries 10 exons. We report a case of severe congenital hyperthyroidism without family history of thyroid disease. At 21 days of life the thyroid function test of the female patient, confirmed the diagnosis of hyperthyroidism. TSHR and TPO antibodies were not detected. She was treated with methimazole and propranolol with poor response. Currently, she is two years old. Then a TSHR mutation was suspected. Genomic DNA was isolated from blood cells of the patient, parents and her brother and all exons of the TSHR gene, including the flanking intronic regions, were amplified by PCR. Each amplified fragment were sequenced with the Taq polymerase-based chain terminator method. Sequence analysis revealed a de novo, heterozygous and germinal activating mutation: c.1897G>C; p.Asp633His. In silico studies were performed to elucidate a correlation between structural disturbances and putative functional commitment. The p.Asp633His mutation has been identified previously in the heterozygous state in thyroid nodules (somatic mutation) from two children with benign folicular adenoma and an adult woman with thyroid insular carcinoma. Since this mutation in children could be a higher risk factor for malignancy in adulthood, a thyroidectomy has been performed on our patient. Molecular techniques lead to an early diagnosis and adequate treatment of this pathology.