ESPE Abstracts (2019) 92 RFC5.5

A Novel Mutation in the Thyroglobulin Gene Leading to Neonatal Goiter and Congenital Hypothyroidism in an Eritrean Infant

Eve Stern1, Eran Kassif2, Nadia Schoenmakers3, Noah Gruber1, Orit Pinhas-Hamiel1, Yonatan Yeshayahu1,4


1Pediatric Endocrine and Diabetes Unit, Sheba Medical Center, Edmond and Lily Safra Children's Hospital, Ramat Gan, Israel. 2Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel. 3University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, United Kingdom. 4Pediatric Endocrine and Diabetes Unit, Assuta Medical Center, Ashdod, Israel


Background: Congenital hypothyroidism is a common condition with reported incidence between 1/2000 – 1/4000 live births. In approximately 85% of cases this is sporadic due to a structural abnormality of the thyroid gland. Approximately 15% of cases are hereditary and secondary to thyroid dyshormonogenesis. Most of these are due to mutations in one of the genes involved in iodine transport or organification, mutations in the thyroglobulin gene or defects in iodotyrosine deiodinase. These conditions are usually transmitted in an autosomal recessive fashion and cause hypothyroidism of varying severity.

We present a case of an infant of Eritrean origin, presenting with congenital goiter, congenital hypothyroidism and a novel mutation identified in the thyroglobulin gene.

Case report: An Eritrean woman presented at term with no antenatal follow-up.

Fetal ultrasound exam revealed a large mass in the neck and upper chest consisting of 2 lobes consistent with an enlarged thyroid gland.

A live female infant was delivered in good condition. Initial examination was notable for a large diffuse neck swelling and mild respiratory distress with no other abnormal examination findings.

Initial thyroid function: TSH 272.39 mIU/l (0.4-20) FT4 6.3 pmol/l (10-30) FT3 5.5 pmol/l (2.46-9.8)

Thyroglobulin 0.7 picg/l (0-55) Thyroglobulin antibody <20U/ml

Thyroid ultrasound demonstrated enlargement of both lobes of a hyperemic thyroid gland, with normal echogenicity. Thyroid technetium scan (Tc-99m) demonstrated a diffusely enlarged thyroid gland with diffusely increased uptake.

Due to the findings of neonatal goiter, primary hypothyroidism, low serum titer of thyroglobulin and increased uptake of technetium on nuclear scanning, a genetic defect in the thyroglobulin gene was suspected and genetic studies were undertaken.

Genetic Studies: Sequencing of the thyroglobulin gene revealed a homozygous donor splice site mutation at the exon 30-intron 31 boundary; c.5686+1delG. This is a novel rare mutation with no homozygotes reported. It affects one of the invariant residues at the donor splice site. Other mutations at this site have been shown to be pathogenic. Along with the clinical phenotype this mutation is highly likely to be pathogenic.

Summary: We present an infant of Eritrean origin presenting with a congenital goiter, primary hypothyroidism, a low serum thyroglobulin and increased uptake on thyroid technetium scanning. Sequencing of the thyroglobulin gene revealed an as yet unreported change, highly likely to be pathogenic, as a donor splice site mutation with low allele frequency in an area in which other pathogenic mutations have been identified.

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