A New Mutation in the Promoter Region of the PAX8 Gene Causes True Congenital Hypothyroidism with Thyroid Hypoplasia in a Girl with Down's Syndrome

Background: Thyroid dysfunction is common in newborn infants with Down's syndrome (DS), but defects causing classic thyroid dysgenesis (TD) with permanent congenital hypothyroidism (CH) have not been described. Objective: We studied a girl with DS and CH who had a mutation in the promoter sequence of the PAX8 gene. Results: A female infant was found to have trisomy 21 and CH, with a venous thyrotropin (TSH) of >150mU/L and a free thyroxine (fT4) of 15.1 pmol/L (day 12). Thyroid peroxidase antibodies and thyroglobulin antibodies were elevated. Scintigraphy showed normal uptake, but ultrasound identified a small gland with heterogenous echotexture and cystic changes. Sequence analysis of the PAX8 gene revealed a new heterozygous maternally inherited mutation (-3C>T) close to the transcription initiation site. Electromobility shift assay studies of the wild type and the mutant PAX8 sequence incubated with nuclear extracts from PCCL3 cells exhibited that the sequence at position -3 is not involved in specific protein binding. However, the mutant PAX8 promoter showed a significantly reduced transcriptional activation of a luciferase reporter gene in vitro tested in HEK, PCCL3, as well as in HeLa cells, indicating that this mutation is very likely to lead to reduced PAX8 expression. Conclusions: The persistent CH in this patient with DS is likely to be attributable to the diminished PAX8 expression due to a new heterozygous mutation in the PAX8 promoter sequence. Our case shows that true CH may occur in DS, as in the general population. Furthermore, it is possible that the trisomy 21 itself may have resulted in a more severe phenotypic expression of the PAX8 mutation in the child than the mother.