RESUMO
Objective: The transcription factor OTX2 is implicated in ocular, craniofacial, and pituitary development. Design: We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action. Methods: We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants. Results: Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary. Conclusions: OTX2 mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with OTX2 mutations are of hypothalamic origin.
Assuntos
Hipopituitarismo/fisiopatologia , Microftalmia/fisiopatologia , Neurônios/fisiologia , Fatores de Transcrição Otx/genética , Hipófise/fisiopatologia , Displasia Septo-Óptica/fisiopatologia , Adolescente , Animais , Animais Geneticamente Modificados , Brasil , Linhagem Celular , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Hipopituitarismo/embriologia , Hipopituitarismo/genética , Hipotálamo/citologia , Lactente , Masculino , Camundongos , Microftalmia/embriologia , Microftalmia/genética , Mutação , Neurônios/patologia , Linhagem , Hipófise/embriologia , Hipófise/patologia , Displasia Septo-Óptica/embriologia , Displasia Septo-Óptica/genética , Reino UnidoRESUMO
INTRODUCTION: Previous studies have described septooptic dysplasia (SOD) to describe patients who have optic nerve hypoplasia, the absence of septum pellucidum, and pituitary hypoplasia. Other rare ophthalmic associations have been described, such as low-tension glaucoma. We report the ocular findings of a patient with SOD who had high intraocular pressure (IOP) and glaucoma as a part of the syndrome. OBJECTIVES: To report the ocular findings in a Puerto Rican patient with SOD and increased IOP. PATIENTS AND METHODS: A patient with De Morsier syndrome underwent a comprehensive eye examination, Humphrey visual fields, and Stratus optical coherence tomography, and was referred for neuroradiologic examination. The patient had increased IOP, visual field loss, and asymmetric optic nerve hypoplasia. The IOP was lowered with topical hypotensive medications. CONCLUSIONS: The patient with the De Morsier syndrome had poor visual acuity, high IOP, visual field, and optical coherence tomography results that were all compatible with glaucoma. Further studies comparing ocular findings in patients with several mutations leading to De Morsier syndrome are warranted. To our knowledge, this is the first report on a patient with glaucoma as a part of the syndrome.