Endocrine Abstracts

Background: SOX2 is a member of the SOX family of transcription factors (SRY-related high-mobility group (HMG) box). Heterozygous, de novo, loss-of-function mutations were initially reported in patients with bilateral anophthalmia/microphthalmia, developmental delay, male genital tract abnormalities, oesophageal atresia and sensorineural hearing loss. We have recently reported a number of SOX2 mutations in patients with anterior pituitary hypoplasia and hypogonadotrophic hypogonadism. Additional features included the association with hypothalamic hamartoma and variable defects affecting the corpus callosum and mesial temporal structures. We herein report the first patient with a heterozygous SOX2 gene deletion associated with a large hypothalamo-pituitary tumour.

Report: The proband is a female patient of non consanguineous parents who presented at the age of 18 years with pubertal delay. She had extreme microphthalmia, delayed motor milestones and severely impaired language development. At the age of 18 years, she had a height of −3.12 SDS, with a normal IGF1 (270.7 ng/ml) and GH concentration. Cortisol profile, thyroid function tests and prolactin were normal. Hypogonadotrophic hypogonadism was diagnosed with a flat LH and FSH response to GnRH stimulation. Brain MRI demonstrated a large cystic tumour consistent with a craniopharyngioma, extending into the suprasellar region. However, at the age of 24 years, she progressed to develop spontaneous but incomplete pubertal development, without change on sequential MR imaging over time. Multiple ligation probe analysis (MLPA) revealed that the patient was heterozygous for a complete SOX2 deletion.

Conclusion: Heterozygous SOX2 mutations are associated with hypogonadotrophic hypogonadism and anterior pituitary hypoplasia. We now describe loss of function of SOX2 associated with a cystic mass suggestive of a craniopharyngioma. In vitro SOX2 represses β-catenin-TCF mediated transcription. Since β-catenin overactivation has been associated with craniopharyngiomas, the SOX2 deletion could be associated with β-catenin gain of function. The case of this patient gives further insight in the role of SOX2 in pituitary development and tumorigenesis.