SUN-358 Central Hypothyroidism Caused by a Novel IGSF1 Mutation

Abstract Disclosure: Z. Manan: None. E. Cooney: None. J.T. Do: None. P.D. Lee: None. Background: IGSF1 (Xq26.1) codes for a transmembrane protein that may be involved in regulation of intercellular interactions. IGSF1 variants have been associated with X-linked congenital central hypothyroidism related to decreased secretion of thyrotropin-releasing hormone, low prolactin, large birth size, delayed puberty and late onset macroorchidism. We present a case of congenital central hypothyroidism caused by a novel IGSF1 mutation.The patient is a now 11.5-year-old male born after an uncomplicated pregnancy to a 27 yo primigravida, estimated gestational age 32-6/7 weeks, birth weight 2980 g (+2.0/SD), length 49 cm (+2.3SD), head circumference 33 cm (+1.9SD). Newborn screen showed low T4. Tests at 8 weeks old: TSH 2.13 (RR 0.45−4.70) uIU/mL), FT4 0.54 (RR 0.78−2.20 ng/dL)), T3 120.00 (RR 117−209 ng/dL), T4 4.0 (RR 5.5-11.0 mcg/dL). Additional testing excluded growth hormone, cortisol and thyroxine binding globulin deficiencies; prolactin 1.3 (RR 2.6−13.1); the pituitary gland was normal on MRI. Levothyroxine treatment resulted in the normalization of T4 without TSH suppression. Growth and development have been normal, with height tracking at 95th percentile, consistent with mid-parental height 189 cm. He is non-obese and currently prepubertal with normal prepubertal testicular size. Father had normal thyroid tests, mother had an elevated TSH, maternal great-uncle and his grandson have hypothyroidism. Genetic testing (Fulgent Hypothyroidism and Resistance to Thyroid Hormone 29-gene panel) revealed a novel hemizygous variant in IGSF1 c.1884_1885del. This is a frameshift variant predicted to result in a premature stop codon in exon 12. A heterozygous FOXE1 c.743C>G variant of uncertain significance was also found. Biallelic mutations in the FOXE1 gene have been associated with congenital hypothyroidism; however, no cases have been reported with heterozygous mutations. Genetic testing has been offered to the patient’s mother, who has not yet undergone testing at the time of this report.Conclusion: As in the current case, the majority of pathogenic IGSF1 variants cluster in the C-terminal domain (exons 6 −12); the segment coded by exon 12 anchors this domain to the cell membrane. Pathogenic variants in IGFSF1 should be considered in infants born large for gestational age with thyroid tests consistent with central hypothyroidism. Presentation: Sunday, July 13, 2025