Endocrine Abstracts

Background

Central hypothyroidism (CeH) is a rare condition affecting approximately 1:16000 – 100 000 individuals. Congenital forms can harm the normal development if not detected and treated promptly. The clinical and biochemical diagnosis especially of the isolated CeH can be challenging. The cases are not usually detected in the neonatal screening, which, in most countries, are focused on detection of the more prevalent primary hypothyroidism. Until now, five genetic causes for isolated CeH have been identified. Here we aimed to identify the genetic cause in two brothers with impaired growth and diagnosed with CeH at the age of 5 years. Furthermore, we evaluated the candidate gene variants in a large genetic database.

Methods

Clinical and biochemical characterization together with targeted next-generation sequencing (NGS) was used to screen the genetic etiology in a family of two brothers presenting with CeH. Screening of insulin receptor substrate 4 (IRS4) variants was carried out in the FinnGen-database.

Results

A novel monoallelic frameshift mutation c.1712_1713insT, p.Gly572Trp fs*32 in an X-linked IRS4 gene was identified in NGS analysis in both affected males and confirmed using Sanger sequencing. Their mother was an unaffected carrier. In addition to the declined growth at the presentation, central hypothyroidism and blunted TRH test, no other phenotypic alterations were found. The diagnostic tests included head MRI, thyroid imaging, bone age, and laboratory tests for thyroid autoantibodies, glucose, insulin and glycosylated hemoglobin levels. Examination of the IRS4 locus in FinnGen (R5) database revealed the strongest associations to a rare Finnish haplotype associated with thyroid disorders (P = 1.3e-7) and hypothyroidism (P = 8.3e-7).

Conclusions

Here, we identified a novel frameshift mutation in an X-linked IRS4 gene in two brothers with isolated CeH. Furthermore, we demonstrate an association of IRS4 gene locus to a general thyroid disease risk in the FinnGen-database. These findings together confirm the role of IRS4 in isolated central hypothyroidism.