ESPE Abstracts

Background & aim: Biallelic thyroglobulin (TG) gene variants can cause congenital hypothyroidism (CH), usually presenting with neonatal goiter and permanent in duration. In cases where biallelic truncating TG variants are present, serum TG levels are undetectable, while monoallelic or biallelic missense mutations manifest with circulating TG. Here, we present a case of transient CH resulting from TG deficiency, stemming from compound heterozygosity for a missense and a splice site mutation.

Case presentation: The infant, delivered vaginally at term, underwent regular fetal ultrasound scans, which had been normal. Throughout the pregnancy, his mother did not take iodine-containing vitamins. Both parents, of white descent, were healthy and non-consanguineous. At birth, the boy weighed 3640g (0 SDS), measured 53cm (+1.1 SDS), and had a head circumference of 36cm (+0.6 SDS). Upon examination, a goiter and respiratory distress were noted. Serum thyroid-stimulating hormone (TSH) levels measured at 72h were elevated (57mIU/L; 0.7-15.2mIU/L), while free thyroxine (fT4) levels were reduced (5.35 pmol/L; 11.0-32.0pmol/L), and TG levels were elevated (164ng/mL; 3.5-77ng/mL). Ultrasound imaging revealed an enlarged, homogenous, hyporeflective thyroid, with MRI documenting posterior expansion of the thyroid. A targeted CH gene panel analysis, including classical dyshormonogenesis genes, identified a previously reported, likely pathogenic missense variant NM_003235.5(TG):c.113G>A, p.(Arg38Lys) and a splice site variant of unknown significance NM_003235.5(TG):c.3634+5G>T, p.?. Each parent carried one of the variants. Treatment with thyroxin was started at 37.5 µg on day 3, resulting in rapid normalization of TSH and fT4 by day 5. TSH levels remained below 10mIU/L during subsequent months of treatment. At 3.5 years old, thyroxine was discontinued when the child was receiving a dose of 25µg (= 1.9µg/kg/day). Over the next two years, normal growth in length and weight, as well as stable thyroid function tests, were observed, albeit with a consistently slightly enlarged thyroid.

Conclusion: We report the first case in Europe of a newborn with compound heterozygosity for causal TG variants associated with a transient goitrous CH. We hypothesize that in newborns with at least one missense TG mutation, resulting in detectable TG levels, there may be only a transient insufficiency in thyroid hormone synthesis during the first months of life, particularly when there is an increased thyroxine demand and/or maternal iodine levels are low. We advocate for a reassessment of thyroid function in newborns carrying compound heterozygous TG variants.