Central congenital hypothyroidism Early diagnosis and clinical outcome during childhood and adolescence

This thesis focuses on improving the diagnostic process for central congenital hypothyroidism (CH) and describes the long-term outcome of early-detected patients. Central CH refers to thyroid hormone (thyroxine, T4) deficiency at birth due to insufficient hypothalamic-pituitary stimulation of the thyroid gland. It may occur in isolation or combined with multiple pituitary hormone deficiency (MPHD).
Diagnosing central CH in neonates is challenging, as this relies on a low serum free T4 (FT4) concentration only. We established age-specific reference intervals for FT4 and thyrotropin (TSH) and show that the neonatal FT4 lower limit is 3 pmol/L higher than in adults.
Although worldwide most neonatal screening programs do not detect central CH, the Dutch program does. We report clinical characteristics of the largest patient group described so far and show that most patients are not identified clinically, but only after receiving an abnormal screening result. A genetic diagnosis is established in most patients with isolated central CH.
In a systematic review we show that robust studies on cognitive outcome are lacking. In a cross-sectional study we show that full-scale IQ (FSIQ) in early-detected patients with isolated central CH does not differ from siblings. In MPHD patients, FSIQ is significantly lower compared with siblings. We also show that self-reported health-related quality of life (HRQoL) is similar in central CH patients and siblings. Parent-reported HRQoL is significantly lower in MPHD patients compared with siblings.
Finally, despite a high overall mortality among early-detected central CH patients, deaths due to pituitary insufficiency are rare.