Fatma DURSUN, Metin ESER, Murat Hakkı YARAR, Irmak Dicle SARGIN, Ayşe YAŞAR, Esma Ebru ALTUN, Fatma Güliz ATMACA, Şerife Ece ULU, Heves KIRMIZIBEKMEZ
Trends in Pediatrics - 2026;7(3):167-175
Objective: This study aimed to investigate the genetic etiology of congenital hypothyroidism (CH) with gland-in-situ (GIS) by screening 23 candidate genes using next-generation sequencing (NGS) in a cohort of Turkish patients. Methods: A total of 44 patients diagnosed with GIS-CH were enrolled. Genetic analysis was performed using a targeted gene panel including 23 genes related to thyroid development and function. Clinical and demographic features were compared between permanent CH (PCH) and transient CH (TCH) groups. Patients with thyroid dysgenesis, central hypothyroidism, syndromic features, or insufficient follow-up were excluded. Results: Genetic variants were identified in 43.1% (19/44) of patients, with similar frequencies in PCH (46.1%) and TCH (38.8%) groups. Ultrasonography revealed hyperplasia in two patients, hypoplasia in 10, and normal-sized gland-in-situ (GIS) in 32 patients. The most frequently identified variant was in the TSHR gene (15.9%), followed by DUOX2 (11.3%), PAX8 (6.8%), TG (4.5%), and DUOXA2 (2.2%). Homozygous or compound heterozygous variants were consistently associated with PCH. In contrast, heterozygous variants showed variable clinical outcomes, ranging from transient disease to persistent hypothyroidism requiring ongoing L-thyroxine therapy. An oligogenic variant (DUOX2+TG) was identified in one patient and was associated with a milder clinical course. Thyroid hypoplasia was predominantly observed in patients with TSHR and PAX8 variants and was strongly associated with the need for continued treatment, even in heterozygous cases. Conclusions: The most common genetic causes of GIS-CH in our cohort were mono- and biallelic TSHR, DUOX2, and monoallelic PAX8 variants. Thyroid hypoplasia was observed predominantly in patients with TSHR and PAX8 variants and was consistently associated with the continued requirement for L-thyroxine therapy, even among heterozygous cases. The main limitations of this study include the relatively small sample size and lack of functional validation of identified variants.
