ESPE Abstracts

Background: Inherited forms of congenital hypothyroidism (CH) account for approximately one quarter of all causes of CH. These include biosynthetic defects and developmental and morphological abnormalities.

Objective: Describe the Scottish experience of genetic testing in CH.

Method: Retrospective study over 37 years up to March 2016. Patients were selected on the basis of imaging findings or strong family history of CH.

Results: From 970 infants referred by Scottish neonatal screening, 649 cases of permanent CH were identified. DNA was analysed in 66 cases of suspected dyshormonogenesis. Mutations or variants were found in 28 patients (43.8%; M:F 12:16) 4/28 cases (14.3%) had congenital cardiac abnormalities, two associated with Down’s syndrome; one PAX8, one TSH receptor gene (TSHR). 18/28 (64.3%) had first degree relative with thyroid disease with an incidence of 54% compared with only 27% in patients with no detected mutation. Among patients with mutations there are five kindreds accounting for 11/26 individual patients. There were two additional cases of familial dysgenesis (one aplasia and one ectopia), 0.3% of all permanent CH. Mutations were identified in Thyroglobulin gene (Tg) n=10 (36%), thyroperoxidase gene (TPO) n=8 (29%), 4 in TSHR (14%) and in PAX8 (2;7%), and THOX2 (2;7%) genes. Two patients (7%) had TPO sequence variants, one with heterozygous Tg gene mutation. No significant difference was found between biochemical results at assessment for infants with TPO and Tg gene mutations; the median (range) TSH and fT4 values were 100 (21.9–385) vs 150 (7.17–401) mU/L and 5.45 (1.8–15.8) vs 7.45 (3.8–11.6) pmol/L and quantitative Tg 160(<2.0–2993) vs 5 (<2.0–3977) μg/L respectively. On ultrasound, where available, patients with TPO mutation had normal or small glands whereas 80% of Tg gene mutations had remarkably large glands. All but two had permanent hypothyroidism one had TSHR and the other had TPO.

Conclusion: Thyroid test results don’t appear to be helpful for selecting patients for genetic analysis nor for targeting mutation analysis. However thyroid imaging could be useful for targeting mutation analysis as patients with Tg mutation had markedly large glands.