DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives

Abstract

Congenital hypothyroidism (CH) may be primary, due to a defect affecting the thyroid gland itself, or central, due to impaired thyroid-stimulating hormone (TSH)-mediated stimulation of the thyroid gland as a result of hypothalamic or pituitary pathology. Primary CH is the most common neonatal endocrine disorder, traditionally subdivided into thyroid dysgenesis (TD), referring to a spectrum of thyroid developmental abnormalities, and dyshormonogenesis, where a defective molecular pathway for thyroid hormonogenesis results in failure of hormone production by a structurally intact gland. Delayed treatment of neonatal hypothyroidism may result in profound neurodevelopmental delay; therefore, CH is screened for in developed countries to facilitate prompt diagnosis. Central congenital hypothyroidism (CCH) is a rarer entity which may occur in isolation, or (more frequently) in association with additional pituitary hormone deficits. CCH is most commonly defined biochemically by failure of appropriate TSH elevation despite subnormal thyroid hormone levels and will therefore evade diagnosis in primary, TSH-based CH-screening programmes. This review will discuss recent genetic aetiological advances in CH and summarize epidemiological data and clinical diagnostic challenges, focussing on primary CH and isolated CCH.

Molecular defects in thyroid dysgenesis

“…The Gruss group showed that Pax8 −/− mice developed smaller thyroid glands with absence of follicles, concluding that the aberration creates a defect in competent endoderm primordia differentiation into thyroxin‐producing follicular cells . Additionally, the disappearance of the thyroid cell precursors in Pax8 −/− mice at about E11‐11.5 suggest a putative role for PAX8 in thyroid precursor cell survival …”

“…NKX2‐1 mutations may exhibit autosomal dominant inheritance with variable expressivity and penetrance, but frequently occur de novo . General mutational screening in three non‐syndromic TD cohorts detected no NKX2‐1 mutations …”

“…Homozygous mutations in FOXE1 were reported in patients with a syndromic form of TD, the Bamforth‐Lazarus syndrome, characterized by TD (ie, athyreosis or severe hypoplasia), cleft palate, and spiky hair. To date, at least eight biallelic TD‐associated FOXE1 point mutations have now been reported . Inheritance of FOXE1 mutations is autosomal recessive and all described mutations cluster in the forkhead DNA‐binding domain.…”

“…TSHR mutations are known to cause partial TSH resistance. In this context, hormonal replacement remains controversial because elevated TSH levels are sufficient to maintain normal circulating thyroid hormone concentrations …”

“…It is expressed in human thyroid tissue during embryonic development and in vitro transfection of mutant CDCA8 resulted in altered cellular migration and adhesion through the decrease in the expression of focal adhesion‐related genes . A recent WES approach on familial cases with TD allowed to highlight biallelic mutations of CDCA8 in two cases of one consanguineous family, and monoallelic mutations in two other sporadic cases …”