ESPE Abstracts

Objective: Congenital isolated thyrotropin (TSH) deficiency is a rare condition due to autosomal recessive defects in TSHβ, TBL1X, IGSF1, TRHR genes. There are a few patients described with TSHβ mutations to date. These patients display the typical manifestations of severe untreated congenital hypothyroidism. Most patients are unrecognized, even in newborns screening settings due to unelevated TSH levels, which results in severe growth failure and intellectual disability. We describe a baby boy with isolated congenital central hypothyroidism (ICCH) due to a novel homozygous TSHβ gene mutation.

Case: A 53-day-old male was admitted for investigation of severe hypotonia, prolonged jaundice, and constipation which began around 4 weeks of age. Parents were third degree cousins. Following a normal delivery with birth weight of 4230 g (+3.4 SDS), he had been hospitalized for 8 days in a neonatal care unit for hypotonia and transient tachypnea of the newborn. There was no jaundice, umbilical hernia or macroglossia noted in the newborn period. At referral to our clinic, he was 5940 g in weight (+0.9 SDS), 60.5 cm in height (+1.29 SDS), and 40.5 cm (+0.89 SDS) in head circumference. He had severe hypotonia, jaundice, dry skin with, macroglossia, and coarse facial features. Anterior fontanelle was 2×2 cm, and posterior fontanelle was closed. His physical examination was otherwise unremarkable. On laboratory testing, free T4 was <0.25 (normal range, 0.61–1.12 ng/dl); TSH was, 0.06 μIU/ml (0.34–5.6 μIU/ml). To rule out multiple pituitary hormone deficiencies, additional hormone tests were performed which revealed a spot GH level of 5.8 ng/dl (0–1 ng/ml), IGF-1 33.1 ng/ml (15–189 ng/ml), IGFBP-3 1.53 μg/ml (0.7–3.6 μg/ml), FSH: 2.65 mIU/ml, LH 1.75 mIU/ml, total testosterone 0.93 ng/ml and PRL 26 ng/ml. Sufficient cortisol response detected in the low-dose ACTH stimulation test. An MRI of the head and pituitary was unremarkable. He was started on levothyroxine replacement. After 4 weeks of treatment, he was much more alert, active, and feeding better.

Conclusion: We identified a novel homozygous mutation c.217 A>C (p.T73P) of the TSHβ gene responsible for a severe isolated TSH deficiency in male infant missed from neonatal screening. Its should be remembered that clinical features of hypothyroidism related to TSHβ mutations can be as severe as in cases with primary hypothyroidism.