Objectives: Pregnancy and early infancy are periods when increased demand for thyroid hormone can result in subclinical hypothyroidism (SH). SH is frequently a prodrome to autoimmunity, but may be a compensation mechanism for an underlying genetic defect. The W546X mutation of the thyrotropin receptor (TSHR) is present at a frequency of 1 in 180 in a Caucasian population. We aimed to investigate whether W546X was the cause of SH presenting in pregnancy and early infancy.
Patients studied: A pregnant woman was recruited to the Controlled Antenatal Thyroid Screening study. She had an elevated TSH 3.75 U/L (based on the ranges of 400 women of known gestational age, adjusted following recruitment of the first 1000 women) whilst FT4, at 12.7 pmoles/L, was within the normal range. Her son was normal at newborn screen for congenital hypothyroidism. Investigations at 3 months of age revealed a TSH of 7.3 U/L, FT4 of 17.3 pmoles/L and a slightly exaggerated TRH release test. He commenced thyroxine (25 ug/day). The womans mother also has a history of hypothyroidism, commencing postpartum.
Methods: The entire coding region of the womans TSHR was genotyped using intronic and overlapping exonic primers. The PCR amplicon of TSHR exon 10 was analysed by Bfa1 restriction in the woman, her mother and son.
Results: Direct sequencing revealed that the woman is heterozygous for a G to A transition producing the missense mutation, W546X. The same genotype was confirmed in her son, on the basis of the pattern of restriction fragments generated following Bfa1 digestion. The womans mother is also heterozygous for W546X.
Conclusions: The results provide clinical confirmation of our earlier study of the frequency of W546X in the local population. They also indicate that the genotype can result in SH and raise interesting questions as to the optimal management of such patients.