Endocrine Abstracts

Introduction: Worldwide incidence of Congenital Hypothyroidism is 1:3000 to 1:4000 births. 80-90% of cases of Congenital Hypothyroidism are related to defects in thyroid gland development. 10- 20% related to thyroid hormone biosynthesis due to mutations in genes involved in thyroid hormone synthesis with autosomal recessive inheritance pattern. The steps in thyroid hormone synthesis include iodine trapping, synthesis and secretion of thyroglobulin, oxidation of iodide, organification of iodides, coupling reaction and storage and secretion. Enzyme defect in any of these steps can lead to dyshormonogenesis, with implications of genetic testing in Congenital Hypothyroidism.

Case: 16-day old baby referred from Newborn Screening lab with abnormal Guthrie test. TSH on day 5- 13 mlU/l Day 12- 10.7mlU/l. Term baby girl with normal clinical examination and gaining weight. Parents from Pakistan, non-consanguineous marriage. Mother takes Thyroxine for Autoimmune Hypothyroidism, which was diagnosed 5 years ago with previous pregnancy. Thyroid function test done on day 16- TSH 10.85mlU/l (0.38-5.33) T4 14 pmol/l (11.5-22.7). Patient was not started on treatment at this stage. Repeat blood test after 2 weeks showed TSH normalised at 4.43 mlU/l. Working diagnosis- Transient Hypothyroidism. Patient had a normal clinical examination, including development and normal thyroid ultrasound scan. Thyroid function monitored every few weeks. TSH normalised quickly, but due to persistently borderline low T4, both parents consented for genetic blood testing. The patient is heterozygous for a pathogenic duox2 variant. All duox2 gene variants limit the ability of the enzyme dual oxidase 2 to generate hydrogen peroxide. Without hydrogen peroxide, thyroid production is disrupted. The patient is a carrier of Thyroid Dyshormonogenesis type 6.

Conclusion: There is a low threshold to do genetic testing in Congenital Hypothyroidism, especially with Transient Hypothyroidism. Identification of asymptomatic mutation carriers has prognostic value in differentiating from transient to permanent hypothyroidism and monitoring for associated features such as hearing loss in Pendred’s syndrome. Thyroid Dyshormonogenesis should be suspected in foetal/neonatal goitre, normal thyroid scan but needing thyroxine replacement, enlarged thyroid gland with low thyroglobulin or blunted/absent uptake in scintigraphy in normal located gland.