In this research program we 1) detected novel genes that underlie isolated CCeH and aim to unravel the mechanisms involved, 2) optimized neonatal diagnostics by establishing reliable FT4 and TSH neonatal reference values, and 3) perform large-scale follow-up studies of the entire Dutch CCeH cohort.

The unique Dutch neonatal screening program allows for the detection of CCeH. This facilitated identification of patients with CCeH as part of multiple pituitary hormone deficiency (MPHD) and patients with isolated CCeH over the past decades. In a research program of the Endocrinology sections of the Depts. of Pediatrics and Internal Medicine together with the Endocrine laboratory of Amsterdam UMC, we focused on genetic causes of isolated CCeH. We detected three novel genes to be associated with isolated CCeH, i.e., IGSF1, TBL1X and IRS4. Mutations in IGSF1, which encodes a hypothalamic glycoprotein, now represent the most prevalent genetic cause of isolated CCeH.

In 2016, we identified mutations in the transducin β-like 1X (TBL1X) gene in patients with a combination isolated CCeH and sensorineural hearing loss. TBL1X is an essential subunit of the NCoR/SMRT corepressor complex involved in thyroid hormone signaling. The molecular pathogenesis of this syndrome is now studied using mouse models and iPSC in an international collaboration. In 2018, we reported mutations in the insulin receptor substrate 4 (IRS4) gene in isolated CCeH. IRS4 encodes a hypothalamic protein that is part of the insulin and leptin signaling cascade. We recently optimized neonatal CCeH diagnosis by establishing reference values for neonatal free T4 and TSH plasma concentrations with FT4 lower limits considerably higher than used to date. This will improve diagnostic accuracy and facilitate early treatment. In a follow-up study of early-treated patients we found normal full-scale IQ (FSIQ) in isolated CCeH, but not on MPHD compared to their siblings.

Amsterdam UMC researchers involved in this project:

Researchers from outside of Amsterdam UMC involved in this project:
Prof. Anthony N. Hollenberg, Department of Medicine, Cornell, New York, USA
Prof. John Schwabe, Leicester, UK