Introduction: The underlying genetic causes of congenital hypothyroidism with gland in-situ (CH GIS) and hyperthyrotropinemia (HT) remain largely a mystery. Thanks to NGS, genetic screening is now finding many novel variants. The challenge is to correctly identify which genes and which variants lead to CH and which cause only a transient HT.
Objectives: Our objectives were to evaluate the presence of variants in 14 candidate genes (TG,DUOX2, DUOXA2, TPO, TSHR, PAX8, GLIS3, SLC5A5, SLC26A4, NKX2-1, NKX2-5, JAG1, IYD, FOXE1) using NGS in patients diagnosed with CH GIS and clinically reevaluated later in life. We wanted to compare the clinical data of the patients with their genotype.
Materials and Methods: 56 pediatric patients who were initially diagnosed with CH GIS and began L-T4 replacement therapy all underwent a clinical reevaluation between 3-5 years of age and were diagnosed with either CH GIS, permanent HT, or transient HT. All 56 underwent NGS screening of 14 candidate genes.
Results: 45/56 patients (80.36%) had a variant in the candidate genes (16 had one variant, 18 had two, 11 had three or more). These variants were distributed over 73 distinct sites in 11 genes: TGhad 21 distinct variants (17 novel), DUOX2had 21 (12 novel), TPOhad 8 (7 novel), TSHRhad 6 distinct (2 novel), PAX8 4 distinct (3 novel), GLIS3had 6 distinct (all novel), SLC5A5had 3 distinct (all novel), and SLC26A4, NKX2-1, JAG1, IYDeach had 1 (all novel). DUOXA2, FOXE1, and NKX2-5 were unaffected. 54/73 (74.0%) of these variants were novel and have never been reported in literature. Only 5/73 of the variants were homozygous, the rest were heterozygous. A spectrum ranging from transient HT to CH GIS was observed however, patients with variants in genes controlling gland formation (GLIS3and PAX8) had either a transient HT or CH GIS.
Conclusions: Although a genetic screening program for CH GIS patients is still a long way off, information from studies utilizing NGS is giving clinicians a clearer picture of the underlying causes. While the etiology is mostly still unclear, studies such as this one help identify possible pathologic variants and lead to a better understanding of CH GIS.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology