Endocrine Abstracts

Introduction: Mutations in IRS4 have recently been shown to cause X-linked congenital central hypothyroidism in males. We present two brothers with IRS4 mutation who presented to the endocrine service in adolescence.

Case description: The younger brother presented with suspected vitiligo to paediatric dermatology at age 12. Thyroid function was performed to rule out autoimmune primary hypothyroidism, but detected low FT4 (6.7 pmol/l) and normal TSH. Height SDS was +0.10. Given the diagnosis of central hypothyroidism, combined pituitary function test was performed with normal growth hormone and cortisol status. Pituitary MRI did not identify any abnormalities. Genetic testing revealed a pathogenic, frameshift mutation in IRS4. Progression through puberty was normal with pubertal staging of G5P5 15ml testes aged 13.6 years. Adult height was 172.9 cm (within mid-parental height). The older brother presented with concerns regarding lack of puberty to adult endocrinology at age 16.3 years during the COVID-19 pandemic (not formally examined but subsequent self-assessment noted to be G1P2). There was no clear family history of delayed puberty. Testosterone was 0.5 nmol/l, LH 2.2U/l in keeping with early puberty but delayed for his age. Height Z-score was -2.3 SDS, bone age 12.2 years. He was commenced on testosterone and responded well (pubertal staging of G3P3 8 ml testes age 16.9 years). Following diagnosis of IRS4 mutation in the younger brother, it was noted that he also had low FT4 (8.4 pmol/l) with normal TSH. Genetic testing confirmed he carried the same pathogenic mutation in IRS4. Adult height was 174 cm. Both brothers had normal oral glucose tolerance tests (IRS4 may have an impact on glucose homeostasis). DXA fat mass index Z-score for younger brother was 0 and for older brother was -0.4. Genetic testing of the mother revealed she was a heterozygous carrier of the IRS4 mutation.

Conclusion: IRS4 mutations have recently been reported to cause central hypothyroidism in a small number of patients. The IRS4 protein is known to bind to insulin, IGF-1 and leptin receptors and has been found to be expressed in human pituitary and hypothalamus. The exact role of IRS4’s impact on puberty remains unclear and warrants further research.