A novel X-linked variant c.1772delG (p.G591fs*20) in IRS4 in two related patients with central hypothyroidism
Year: 2025
Type: article
Study design: Case Report
Abstract: Introduction: Central hypothyroidism (CeH) is characterized by thyroid hormone deficiency due to impairment of pituitary thyroid stimulating hormone (TSH) or hypothalamic TRH biosynthesis. It is extremely rare and affects approximately 1:16,000-100,000 individuals. Diagnosis, especially of isolated CeH, may be challenging. CeH is often seen as a part of multiple pituitary hormone deficiencies, but it can also be seen as isolated CeH. To date, some variants that can cause CeH have been identified; although in a number of patients the cause has not been clarified. Recently, variants of the insulin receptor substrate 4 (IRS4) gene have been reported to be the cause of isolated CeH. Herein, we report two related patients and their family with carriers with a novel X-linked frameshift variant in the IRS4 gene. It has also been shown that thyroid function may be slightly affected in the heterozygous female carriers in our study. Case Presentation: Herein, we reported two Turkish male patients with CeH due to a hemizygous variant in IRS4. The index case was a 15-year-and-2-month male who presented with a low serum free thyroxin level, which was incidentally detected. Conclusion: Isolated CeH should kept in mind in insistent low fT4 levels without an increase in TSH levels. Genetic testing can aid in identifying the underlying cause of CeH in such cases. This report demonstrates the significance of providing comprehensive laboratory and molecular features of the patients and carriers with the IRS4 variants.
Source: Molecular Syndromology
DOI: 10.1159/000543796
Authors: Özge Köprülü, Hilmi Tozkir
Institution: Tekirdağ Namık Kemal University
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4406864286