The role of SOX2 in hypogonadotropic hypogonadism

SOX2 is a transcription factor involved in early embryonic development. It plays a critical role in eye, forebrain, and hypothalamo-pituitary development. Individuals with SOX2 mutations have major eye abnormalities including anophthalmia, microphthalmia, and coloboma. Hypogonadotropic hypogonadism is a complex developmental disorder characterized by gonadotropin deficiency. Recently, a number of patients with SOX2 mutations have been shown to have hypogonadotropic hypogonadism, making SOX2 an interesting addition to the list of genes implicated in the etiology of the condition. Most of the patients demonstrate anterior pituitary hypoplasia. Surprisingly, although most patients with anterior pituitary hypoplasia manifest GH (growth hormone) deficiency, gonadotropin deficiency appeared to be the most consistent endocrinopathy in patients with SOX2 mutations. SOX2 may be involved at multiple levels during the development of the hypothalamo-pituitary-gonadal axis, and is likely to play an essential role in GnRH (gonadotropin-releasing hormone) neuronal differentiation and migration. Animal data also suggest an additional role for the gene in gonadal development. Given the critical role of Sox2 in normal hypothalamo-pituitary development in the mouse and the anterior pituitary hypoplasia observed in most human patients with SOX2 mutations, it remains to be established whether further pituitary hormone deficiencies might evolve with time.