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Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism.

ABSTRACT: Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalities, anterior pituitary hypoplasia (APH), an ectopic posterior pituitary (EPP), and an absent infundibulum. This duplication contains SOX3 and sequences corresponding to two transcripts of unknown function; only Sox3 is expressed in the infundibulum in mice. Next, we identified a novel seven-alanine expansion within a polyalanine tract in SOX3 in a family with panhypopituitarism in three male siblings with an absent infundibulum, severe APH, and EPP. This mutation led to reduced transcriptional activity, with impaired nuclear localization of the mutant protein. We also identified a novel polymorphism (A43T) in SOX3 in another child with hypopituitarism. In contrast to findings in previous studies, there was no evidence of MR or learning difficulties in our patients. We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR.

SUBMITTER: Woods KS

PROVIDER: S-EPMC1199372 | biostudies-literature | 2005 May

REPOSITORIES: biostudies-literature

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Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism.

Woods Kathryn S KS Cundall Maria M Turton James J Rizotti Karine K Mehta Ameeta A Palmer Rodger R Wong Jacqueline J Chong W K WK Al-Zyoud Mahmoud M El-Ali Maryam M Otonkoski Timo T Martinez-Barbera Juan-Pedro JP Thomas Paul Q PQ Robinson Iain C IC Lovell-Badge Robin R Woodward Karen J KJ Dattani Mehul T MT

American journal of human genetics 20050330 5

Duplications of Xq26-27 have been implicated in the etiology of X-linked hypopituitarism associated with mental retardation (MR). Additionally, an expansion of a polyalanine tract (by 11 alanines) within the transcription factor SOX3 (Xq27.1) has been reported in patients with growth hormone deficiency and variable learning difficulties. We report a submicroscopic duplication of Xq27.1, the smallest reported to date (685.6 kb), in two siblings with variable hypopituitarism, callosal abnormalitie ...[more]

PMID: 15800844

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Project description:BackgroundHemangioblastomas are benign (World Health Organization Grade I), highly vascular neoplasms commonly associated with Von Hippel-Lindau (VHL) disease.[2] The VHL tumor-suppressor gene, located on chromosome 3, is implicated in sporadic cases and cases associated with VHL disease. Hemangioblastomas most commonly arise in the posterior fossa; however, they may also be found supratentorially or within the spinal cord.[3] Surgical intervention is indicated for symptomatic lesions with a goal of complete resection of the enhancing nodule.[1].Case descriptionWe demonstrate the case of a 69-year-old man with a history of multiple hemangioblastomas who had undergone two previous craniotomies and Gamma-Knife radiosurgery (Video https://drive.google.com/file/d/1lUwsb80NLmIW2Enp-DVdtM9_Oqbid3Ih/view?usp=sharing). He presented with progressive imbalance and diplopia and was found to have a new lesion within the suprasellar cistern. Digital subtraction angiography (DSA) and magnetic resonance imaging (MRI) characteristics were typical of hemangioblastoma. Surgery was determined to be indicated, with a goal of vision preservation. Preoperative embolization was not possible because preoperative DSA demonstrated vascular supply by only small perforators directly from the internal carotid artery. Hypopituitarism was identified preoperatively, although diabetes insipidus was not present. The patient underwent a right orbitozygomatic craniotomy and extradural anterior clinoidectomy for access. The tumor was noted to encapsulate the infundibulum, which necessitated its sacrifice. Postoperatively, the patient remained at his neurologic baseline. He had a positive triphasic diabetes insipidus response and was discharged home on maintenance desmopressin. Postoperative MRI demonstrated complete lesion resection.The patient gave informed consent for treatment and video recording. Institutional review board approval was deemed unnecessary.ConclusionThis video highlights a safe and effective surgical technique for suprasellar lesions as well as the complex anatomy observed through an orbitozygomatic approach.

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Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism.

Publications

Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism.

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