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      Long‐term postnatal outcome of fetuses with prenatally suspected septo‐optic dysplasia

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          ABSTRACT

          Objectives

          Septo‐optic dysplasia (SOD) is a clinical syndrome characterized by varying combinations of optic nerve hypoplasia, pituitary gland hypoplasia and abnormal cavum septi pellucidi. It is suspected on prenatal imaging when there is non‐visualization or hypoplasia of the septal leaflets. Long‐term postnatal outcomes of fetuses with prenatally suspected SOD have been documented poorly. The aims of this study were to describe the natural history of deficient septal leaflets, to quantify the incidence of postnatally confirmed SOD and to document the visual, endocrine and long‐term neurodevelopmental outcomes of these infants.

          Methods

          This was an observational retrospective study of all fetuses with prenatal imaging showing isolated septal agenesis, assessed at a single tertiary center over an 11‐year period. Pregnancy, delivery and neonatal outcomes and pre‐ and postnatal imaging findings were reviewed. Neonatal evaluations or fetal autopsy reports were assessed for confirmation of SOD. Ophthalmologic, endocrine, genetic and long‐term developmental evaluations were assessed. Imaging findings and outcome were compared between infants with and those without postnatally confirmed SOD.

          Results

          Of 214 fetuses presenting with septal absence on prenatal ultrasound and magnetic resonance imaging (MRI), 18 (8.4%) were classified as having suspected isolated septal agenesis suspicious for SOD. Uniform prenatal MRI findings in cases with suspected SOD included remnants of the leaflets of the cavum septi pellucidi, fused forniceal columns, normal olfactory bulbs and tracts and a normal optic chiasm. Twelve fetuses were liveborn and five (27.8%) had postnatally confirmed SOD. Only two of these five fetuses had additional prenatal imaging features (pituitary cyst, microphthalmia and optic nerve hypoplasia) supporting a diagnosis of SOD. The other three confirmed SOD cases had no predictive prenatal or postnatal imaging findings that reliably differentiated them from cases without confirmed SOD. Visual and endocrine impairments were present in two (40%) and four (80%) cases with confirmed SOD, respectively. In those with visual and/or endocrine impairment, developmental delay (median age at follow‐up, 2.5 (interquartile range, 2.5–7.0) years) was common (80%) and mostly severe. Neonates with isolated septal agenesis and a lack of visual or endocrine abnormalities to confirm SOD had normal development.

          Conclusions

          Only a quarter of fetuses with isolated septal agenesis suggestive of SOD will have postnatal confirmation of the diagnosis. Clinical manifestations of SOD are variable, but neurodevelopmental delay may be more prevalent than thought formerly. © 2020 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

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          Most cited references25

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          Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia.

          Kallmann syndrome (KS), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) all result from development defects of the anterior midline in the human forebrain. The objective of the study was to investigate whether KS, CPHD, and SOD have shared genetic origins. A total of 103 patients with either CPHD (n = 35) or SOD (n = 68) were investigated for mutations in genes implicated in the etiology of KS (FGFR1, FGF8, PROKR2, PROK2, and KAL1). Consequences of identified FGFR1, FGF8, and PROKR2 mutations were investigated in vitro. Three patients with SOD had heterozygous mutations in FGFR1; these were either shown to alter receptor signaling (p.S450F, p.P483S) or predicted to affect splicing (c.336C>T, p.T112T). One patient had a synonymous change in FGF8 (c.216G>A, p.T72T) that was shown to affect splicing and ligand signaling activity. Four patients with CPHD/SOD were found to harbor heterozygous rare loss-of-function variants in PROKR2 (p.R85G, p.R85H, p.R268C). Mutations in FGFR1/FGF8/PROKR2 contributed to 7.8% of our patients with CPHD/SOD. These data suggest a significant genetic overlap between conditions affecting the development of anterior midline in the human forebrain.
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            Genetics of septo-optic dysplasia.

            Septo-optic dysplasia (SOD) is a highly heterogeneous condition comprising a variable phenotype of optic nerve hypoplasia, midline forebrain abnormalities and pituitary hypoplasia with consequent endocrine deficits. The majority of cases are sporadic and several aetiologies including drug and alcohol abuse have been suggested to account for the pathogenesis of the condition. However, a number of familial cases have been described and the identification of mutations in the key developmental gene HESX1 in patients with SOD and associated phenotypes suggests that a genetic causation is likely in the more common sporadic cases of the condition. More recently, we have implicated duplications of SOX3 and mutations of both SOX2 and SOX3 in the aetiology of variants of SOD. As with other developmental disorders such as holoprosencephaly, the precise aetiology is most likely multifactorial involving contributions from environmental factors in addition to an important role for crucial developmental genes. This potentially complex interaction between genetics and the environment is borne out by the variability of the penetrance and phenotypes in patients with genetic SOD, but at present, the understanding of these interactions is rudimentary. Further study of these critical factors may shed light on the aetiology of this complex disorder.
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              Absence of the septum pellucidum: a useful sign in the diagnosis of congenital brain malformations.

              In a review of more than 2000 MR images of the brain we identified 35 patients with absence of the septum pellucidum. These patients were divided into seven basic groups as follows: septooptic dysplasia; schizencephaly; holoprosencephaly; agenesis of the corpus callosum; chronic, severe hydrocephalus; basilar encephaloceles; and porencephaly/hydranencephaly. Absence of the septum pellucidum was never seen as an isolated finding. By using data gathered from the review of the MR scans of patients in this study, we devised a diagnostic algorithm to aid in the classification of these patients. Absence of the septum pellucidum can provide a valuable clue to the diagnosis of malformations of the brain.
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                Author and article information

                Contributors
                shiri.shinar@sinaihealthsystem.ca
                Journal
                Ultrasound Obstet Gynecol
                Ultrasound Obstet Gynecol
                10.1002/(ISSN)1469-0705
                UOG
                Ultrasound in Obstetrics & Gynecology
                John Wiley & Sons, Ltd. (Chichester, UK )
                0960-7692
                1469-0705
                01 September 2020
                September 2020
                : 56
                : 3 ( doiID: 10.1002/uog.v56.3 )
                : 371-377
                Affiliations
                [ 1 ] Ontario Fetal Centre, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital University of Toronto Toronto ON Canada
                [ 2 ] Department of Diagnostic Imaging, Hospital for Sick Children, Department of Medical Imaging University of Toronto Toronto ON Canada
                [ 3 ] Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital University of Toronto Toronto ON Canada
                [ 4 ] Division of Clinical and Metabolic Genetics, Hospital for Sick Children University of Toronto Toronto ON Canada
                [ 5 ] Department of Paediatrics Hospital for Sick Children and University of Toronto Toronto ON Canada
                [ 6 ] Department of Pathology and Laboratory Medicine, Mount Sinai Hospital University of Toronto Toronto ON Canada
                Author notes
                [*] [* ] Correspondence to: Dr S. Shinar, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, 700 University Avenue, M5G 1Z5 Toronto, ON, Canada (e‐mail : shiri.shinar@ 123456sinaihealthsystem.ca )
                Author information
                https://orcid.org/0000-0001-6352-4846
                https://orcid.org/0000-0002-3034-6905
                Article
                UOG22018 UOG-2020-0047
                10.1002/uog.22018
                7496228
                32196785
                d2fe2fda-038d-4046-bc04-c66c16f8fe91
                © 2020 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 January 2020
                : 07 March 2020
                Page count
                Figures: 2, Tables: 5, Pages: 7, Words: 4468
                Categories
                Original Paper
                Original Papers
                Custom metadata
                2.0
                September 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.0 mode:remove_FC converted:11.09.2020

                Obstetrics & Gynecology
                cavum septi pellucidi,csp,septal hypoplasia,septo‐optic dysplasia,sod
                Obstetrics & Gynecology
                cavum septi pellucidi, csp, septal hypoplasia, septo‐optic dysplasia, sod

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