Endocrine Abstracts

Introduction: Congenital hypothyroidism (CH) occurs 1 in 3,000-4,000 live-births. The causes of CH can be divided into two groups: thyroid developmental defects (thyroid dysgenesis) and inborn errors of thyroid hormone biosynthesis (dyshormonogenesis). Although mutations in paired box gene 8 (PAX8) usually cause thyroid dysgenesis, they have been reported in association with eutopic thyroid gland without function. PAX8 has been described to have a role in regulating the expression of sodium/iodine symporter in humans. We describe a rare case of CH with eutopic thyroid gland due to a heterozygous PAX8 mutation.

Case report: The proband was born at term by normal vaginal delivery to non-consanguineous parents. Her birth weight was 3390grams. Mother had gestational diabetes and antenatal (26 weeks) scan showed polyhydramnios. There was no family history of thyroid disease. She presented on day 5 of life with reduced feeding and excessive weight loss. On examination she had low muscle tone and soft distinctive facial features which prompted the paediatric team to perform thyroid function tests (TFTs). The result showed normal free thyroxine (fT4) - 21.8 pmol/l (normal 11.0-21.2) and elevated Thyroid Stimulating Hormone (TSH) - 29.5 mIU/l (normal 0.27- 4.2). Persistently elevated TSH (19.6 mIU/l) with normal fT4 (19.2 pmol/l) on repeat bloods a week later, triggered Technetium thyroid uptake scan. No uptake of Technetium in the neck region, suggestive of thyroid aplasia. Normal serum free T4 and detectable serum thyroglobulin (128 mg/l) was inconsistent with thyroid aplasia. Subsequent neck ultrasound confirmed a normal shape, size, position and morphology of thyroid gland. Suspecting iodine transport defect due to discrepancy in Technetium scan and thyroid ultrasound results, genetic testing was performed. Targeted next generation sequencing identified a pathogenic heterozygous mutation in PAX8 (c.619C>T, p.Arg207*). Genetic testing for parents is in progress to determine if the variant has arisen de novo. Levothyroxine (25 mg) was commenced at two weeks of age and follow up TFTs have been normal.

Conclusion: Although detection rate of pathogenic mutations in thyroid dysgenesis is low, it is important to consider genetic analysis of atypical presentations as increased mutation detection rate is likely. Identification of genetic mutations help in screening for conditions associated with CH.