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 >150 mU/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.

Capillary TSH screening programme for Down's syndrome in Scotland, 1997-2009.

OBJECTIVES: To assess uptake of community-based capillary thyroid stimulating hormone (TSH) screening in Scotland and determine the optimal frequency of screening, the justification for preschool screening and strategies for treatment. METHODS: Subjects with Down's syndrome aged 1-19 years underwent capillary TSH measurement. Clinical and biochemical data were collected using proformas. RESULTS: 5742 capillary TSH tests were performed on 1329 children in 1997-2009, increasing from 183 children from two health boards tested in 1997 to 630 from 13 health boards tested in 2009. Of 132 children referred by the screening laboratory with elevated capillary TSH, 98 (M:F ratio 1:1.2, median (range) age 8.9 (0.9-17.9) years) had adequate documentation and 76 had thyroid dysfunction (defined as venous TSH >6 mU/l), giving a prevalence of not less than 5.7%. Fifty-six (57%) had tested negative during the previous year, 8 (8%) tested positive on their first screening test and 23/67 (34%) were thyroid peroxidase autoantibody negative on initial venous blood. Two of the 13 (13%) preschool children were severely hypothyroid (venous TSH 71 and 283 mU/l). Of patients with venous TSH 6-10.9 (n=27), 11.0-20.9 (n=25) and ≥ 21.0 mU/l (n=24) following referral, initial/subsequent treatment with thyroxine was given in 3/8, 15/5 and 21/1, respectively. CONCLUSION: Capillary TSH screening in Down's syndrome is eminently feasible and should be performed annually from 1 year of age. Nearly all subjects with initial venous TSH ≥ 11.0 mU/l will require thyroxine treatment but most with TSH 6-10 mU/l only require surveillance initially.