New Cases of Isolated Congenital Central Hypothyroidism Due to Homozygous Thyrotropin Beta Gene Mutations: A Pitfall to Neonatal Screening

Abstract

Background:

Congenital central hypothyroidism (CCH) is a rare condition that is often diagnosed in late childhood in countries where neonatal screening programs rely solely on detecting thyrotropin (TSH) elevation. TSHβ gene mutation is one of the causes of CCH. We describe two cases of c.Q49X mutation and three cases of c.C105Vfs114X mutation in exon 3 of the TSH β-subunit gene.

Summary:

We found two different TSHβ gene mutations in two families. In one family, we identified a missense mutation in exon 3 leading to a premature stop at position 49 (c.Q49X) in the two affected twins. In the other family, the three affected siblings had a 313delT nucleotide deletion leading to a frame shift responsible for premature termination at codon 114 (c.C105Vfs114X); neonatal screening showed very low TSH levels in all three patients. The presence of inappropriately low TSH levels at birth in the three affected members of the second family raises questions about the value of the TSH level for CCH screening.

Conclusions:

The marked phenotypic variability in patients with the c.Q49X mutation suggests modulation by interacting genes and/or differences in the genetic background. TSHβ gene mutations should be suspected in neonates with inappropriately low TSH levels.