K S Alatzoglou1, A Azriyanti, N Rogers, F Ryan, N Curry, C Noakes, P Bignell, G W Hall, A S Littooij, D Saunders, P Thomas, H Stewart, M T Dattani. 1. Developmental Endocrinology Research Group (K.S.A., M.T.D.), Clinical and Molecular Genetics Unit, University College London Institute of Child Health, London WC1N 1EH, United Kingdom; Department of Pediatric Endocrinology and Diabetes (A.A., F.R.), Oxford University Hospitals National Health Service (NHS) Trust, Oxford OX3 9DU, United Kingdom; School of Molecular and Biomedical Science (N.R., P.T.), The University of Adelaide, Adelaide SA 5005, Australia; Oxford Hemophilia and Thrombosis Centre (N.C., P.B.), and Departments of Clinical Genetics (C.N., H.S.) and Paediatric Hematology and Oncology (G.W.H.), Oxford University Hospitals NHS Trust, Oxford OX3 9DU, United Kingdom; Department of Radiology (A.S.L., D.S.), Great Ormond St Hospital for Children NHS Trust, London WC1N 1EH, United Kingdom.
Abstract
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.
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.
Authors: Anna Szeliga; Michal Kunicki; Marzena Maciejewska-Jeske; Natalia Rzewuska; Anna Kostrzak; Blazej Meczekalski; Gregory Bala; Roman Smolarczyk; Eli Y Adashi Journal: Int J Mol Sci Date: 2021-12-08 Impact factor: 5.923
Authors: Caiqi Du; Feiya Wang; Zhuoguang Li; Mini Zhang; Xiao Yu; Yan Liang; Xiaoping Luo Journal: BMC Med Genomics Date: 2022-02-03 Impact factor: 3.063