Endocrine Abstracts (2006) 11 P823

Etiology of congenital hypothyroidism in children with a normal located thyroid gland

C Di Cosmo, M Tonacchera, G De Marco, P Agretti, ME Banco, A Perri, H Ramos, C Ceccarelli, P Vitti & A Pinchera


Department of Endocrinology, Pisa, Tuscany, Italy.


Congenital hypothyroidism (CH) with a normal located thyroid gland may be transient or permanent and environmental, iatrogenic, immunologic or genetic factors can be involved. PAX-8, TSH receptor and THOX2 gene mutations have been identified in cases of CH with a gland of normal size.

In this study we performed genetic analysis of PAX8, TSH receptor and THOX2 genes in 14 children with CH and a normal sized eutopic gland. Genomic DNA was extracted from lymphocytes and the coding-region of the genes was analyzed by direct sequencing. No mutations were identified in PAX8 and TSHr genes, but only polymorphisms of the TSHr gene. With respect to the THOX2 gene, in 3 children a monoallelic deletion of a GTTC at position 2895–2898 in exon 21 was identified. This deletion introduces a frame shift generating a termination signal in exon 22. The same deletion was found in all 3 fathers who were euthyroid. 1 of the fathers showed a mild organification defect at the perchlorate discharge test (KCLO4). This deletion was also present in 1/60 euthyroid adult subjects who was affected by nodular goiter. When the 3 children were 3 yr old, the L-T4 was stopped to perform the KCLO4. 1 child was euthyroid with a borderline test, 2 were hypothyroid with no organification defect. 3 other children had 2 heterozygous point mutations at exon 16 of THOX2 gene, causing a H678R substitution and a R701Q substitution. The same mutations were found in 8/60 controls. In another child we found a C1052Y substitution at exon 23, together with a S911L substitution at exon 20. These mutations were not present in any of the 60 controls.

In conclusion, in 14 children with CH and normal eutopic thyroid gland, THOX2 gene modifications were the most frequent alterations identified. The phenotypic variability of THOX2 gene alterations may be explained by the presence of other genes involved in the iodine organification process.

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