Heterogeneous phenotype in children affected by non-autoimmune hypothyroidism: an update

In the last decades, a higher incidence of congenital hypothyroidism (CH) has been recorded in Italy (1:1940) and worldwide, mainly due to the shift to lower screening TSH cutoffs. Although CH can also be caused by dysgenetic defects, most CH cases have recently been found to be more frequently associated with functional defects of an in situ thyroid gland. Although the clinical phenotype is milder with high prevalence of transient forms, some cases eventually prove to be permanent.

Possible explanations of the raised incidence of CH are ethnic modifications of the screened population and the increasing incidence of preterm birth and multiple pregnancies. These findings are important in terms of public health and standardization of screening programmes for special at-risk categories such as preterms, acutely ill term neonates, low birth weight and very low birth weight infants, and newborns with specific drug exposure. Other environmental factors have contributed to the increased incidence of hypothyroidism, including thyroid disrupting chemicals, iodine supply (excess/deficiency), and drugs interfering with thyroid function. Finally, an increased prevalence of hypothyroidism has been documented in obese children and patients with syndromic forms (Williams, Down, Turner, pseudohypoparathyroidism). The clinical and molecular phenotype of patients with CH will be better defined thanks to novel genetic approach based on the systematic analysis of a panel of genes (TSHR, DUOX2, DUOXA, TPO, PDS, TG, NKX2.1, JAG1, GLIS3, FOXE1, PAX-8).

This review summarizes significant advances in the epidemiology and aetiology of non-autoimmune hypothyroidism, with a focus on thyroid dysfunction in preterm infants.