Intrauterine death following intraamniotic triiodothyronine and thyroxine therapy for fetal goitrous hypothyroidism associated with polyhydramnios and caused by a thyroglobulin mutation

Abstract

In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother's second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (TG) mutations which are the likely cause of fetal goitre in the deceased sibling. TG mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases.

Learning points: CH due to biallelic, loss-of-function TG mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery.CH due to TG mutations may manifest with variable phenotypes, even within the same kindred.Treatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise.Genetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring.

Figure 1

Pedigree diagram for the affected family. Black bars denote those individuals who have been genotyped; black and grey shading denotes confirmed (P1) and presumed (P2) compound heterozygous genoypes, heterozygotes for one of the two mutations are denoted by a central black dot.

Figure 2

Technetium-99m pertechnetate thyroid scintigraphy performed in P1 aged 29 days, demonstrating appropriate radionuclide uptake in a normally-sited thyroid gland, consistent with dyshormonogenesis. (A) Anterior and (B) lateral images.

Figure 3

Sequential fetal ultrasound images with gestational age annotated demonstrating progressive fetal goitre (white arrow). A coronal view at 23 + 3 weeks gestation demonstrates a goitre measuring 42.8 mm × 26.6 mm which persists aged 24 + 4 weeks (sagittal view) and has enlarged to 54 mm × 36 mm × 52 mm aged 29 + 2 weeks gestation (sagittal view), 48 h prior to intrauterine liothyronine therapy.

Figure 4

Sequencing electropherograms from the proband (P1), mother and father, illustrating compound heterozygous TG mutations, comprising a novel, paternally-inherited single nucleotide deletion (c.5178delT, p.A1727Hfs*26), and a maternally-inherited missense mutation (c.7123G > A, p.G2375R).