IGSF1 deficiency is the most common genetic cause of X-linked isolated central congenital hypothyroidism. In addition to central congenital hypothyroidism, IGSF1 deficiency in males leads to a heterogeneous phenotype, including macroorchidism, delayed pubertal testosterone rise (but a normal timing of testicular growth) and in some cases other pituitary hormone deficiencies, namely low serum prolactin and growth hormone (GH) deficiency (in childhood). Adult males exhibit increased growth hormone secretion, and as a result acromegalic features. While IGSF1 deficiency segregates in a recessive X-linked pattern, females carrying a pathogenic variant present with varying FT4 concentrations, ranging from moderately reduced to normal. Other characteristics in female carriers include delayed menarche, low prolactin and increased BMI.
IGSF1