SOX3 deletion in mouse and human is associated with persistence of the craniopharyngeal canal

Context: SOX3 is an early developmental transcription factor involved in pituitary development. In humans, over- and underdosage of SOX3 is associated with X-linked hypopituitarism with variable phenotypes ranging from isolated GH deficiency (GHD) to panhypopituitarism, with or without mental retardation and, in most cases, with reported pituitary imaging, an ectopic/undescended posterior pituitary. Patient: We present a young patient with hemophilia B and developmental delay who had a 2.31-Mb deletion on Xq27 including SOX3, F9, and eight other contiguous genes. He developed GH and gonadotropin deficiency, whilst his thyroid function was in the low normal range. Magnetic resonance imaging revealed a eutopic posterior pituitary and the unusual finding of a persistent craniopharyngeal canal that has not previously been described in patients with congenital hypopituitarism. Objective and Methods: To establish whether loss of SOX3 can account for the human phenotype, we examined in detail the hypothalamo-pituitary region of neonatal Sox3 null mice. Results: Consistent with the patient's phenotype, Sox3 null mice exhibit a ventral extension of the anterior pituitary that penetrates, and generates a mass beneath, the sphenoid bone. This suggests that the defect results from abnormal induction of Rathke's pouch, leading to a persistent connection between Rathke's pouch and the oral ectoderm. Conclusions: Our observations expand the spectrum of phenotypes observed in association with altered SOX3 dosage and may affect the approach to genetic screening. Screening for SOX3 should be advised not only for hypopituitary patients with an ectopic posterior pituitary, but also for those with a structurally normal pituitary and additional findings, including clefts and a persistent craniopharyngeal canal, with or without mental retardation.