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 two patients with SOX2 loss of function associated with large hypothalamo-pituitary tumours.
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 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) and array-CGH revealed that she was heterozygous for a complete SOX2 deletion, with no other significant copy number variants. The second patient is a 17-month-old boy with bilateral anophthalmia, hypogonadotrophic hypogonadism and an enlarged pituitary with suprasellar expansion. The patient has a novel heterozygous mutation in SOX2 that results in a truncated protein (p.Phe48X).
Conclusion: Heterozygous SOX2 mutations are associated with hypogonadotrophic hypogonadism and anterior pituitary hypoplasia. We now describe heterozygous loss of function SOX2 mutations associated with masses suggestive of craniopharyngioma. In vitro studies suggest that SOX2 represses β-catenin-TCF mediated transcription. Since β-catenin overactivation has been associated with craniopharyngiomas, the SOX2 deletion or truncation could be associated with β-catenin gain of function. These two patients give further insights into the role of SOX2 in pituitary development and tumorigenesis.