Endocrine Abstracts

JOINT3741

Introduction: The transcription factor PAX8 is essential for thyroid development and function, acting as a key regulator in gene transcription. More than 50 variants in the PAX8 gene have been identified, which can be de “novo” or autosomal inheritance. These variants are associated with a wide range of clinical phenotypes, ranging from mild forms of hypothyroidism to more severe situations, such as congenital hypothyroidism accompanied by structural thyroid malformations. In some cases, these variants are also associated with renal or urogenital tract anomalies. We present two clinical cases of non-autoimmune subclinical hypothyroidism with PAX8 gene varians.

Clinical Patients description: Patient 1: A 5-year-old male with normal neonatal growth and a history of treated cryptorchidism presented with weight gain and asthenia. Laboratory results showed thyroid-stimulating hormone (TSH) levels of 37.2mUI/ml and thyroxine (T4) levels of 0.94ng/dl in two occasions with negative antibodies, diagnosing non-autoimmune subclinical hypothyroidism (NASHT). Levothyroxine treatment was initiated, and thyroid ultrasound was normal. High-throughput sequencing of a gene panel revealed a heterozygous variant in the PAX8 gene (c.80C>T p.(Pro27Leu)), classified as a variant of uncertain significance (VUS). The patient’s mother has a history of hypothyroidism, but family segregation analysis was not possible. At age 15, due to poor treatment adherence, lab results showed TSH of 52.2mUI/ml and T4L of 0.68 ng/dl. At age 18, the patient weighs 129 kg, is 183 cm tall, and has a BMI of 38.5. He continues treatment with levothyroxine 250 mg/day (0.5 mg/kg). Patient 2: A 6-year-old male diagnosed with NASHT, with TSH of 7mUI/ml, T4 of 0.83ng/dl, and negative thyroid antibodies. Levothyroxine was started at an external center. Thyroid ultrasound showed a reduced size for his age (3rd percentile). Molecular study revealed a pathogenic heterozygous variant in the PAX8 gene (c.1033_1036dupTTTC), inherited from the mother, causing a premature stop codon. At 13 years old, prepubertal, he is on 50 mg/day of levothyroxine (1.4 mg/kg/day).

Conclusions: These cases highlight the importance of PAX8 in thyroid function, showing that PAX8 gene variants can lead to a broad spectrum of clinical manifestations, including NASHT. Functional studies are needed to confirm the role of VUS variants in the PAX8 gene in thyroid gland formation and function.