ESPE Abstracts (2019) 92 P1-420

The Genetic and Clinical Characteristic of Pediatric Patients with Congenital Hypothyroidism Gland In-Situ

Maria Cristina Vigone1, Luca Saracco1, Gaia Vincenzi1, Silvana Caiulo1, Marianna Di Frenna1, Luca Persani2, Tiziana De Filippis2, Fabiana Guizzardi2, Maria Grazia Patricelli1, Ivana Spiga1, Giovanna Weber1

1Ospedale San Raffaele, Milan, Italy. 2Instituto Auxologico Italiano, Milan, Italy

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.