Characterization of a novel HESX1 mutation in a pediatric case of septo-optic dysplasia.
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ABSTRACT:
SUBMITTER: Pozzi S
PROVIDER: S-EPMC5378840 | biostudies-literature | 2017 Apr
REPOSITORIES: biostudies-literature
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Characterization of a novel <i>HESX1</i> mutation in a pediatric case of septo-optic dysplasia.
Pozzi Sara S Tan Wen-Hann WH Martinez-Barbera JuanPedro J
Clinical case reports 20170302 4
Septo-optic dysplasia (SOD) is a rare condition for which the precise etiology is still unclear. Elucidating the genetic component of SOD is a difficult but necessary task for the future. We describe herein a novel <i>HESX1</i> c.475C>T (p.R159W) mutation and demonstrate its potential pathogenicity in the development of this rare disease. ...[more]
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Project description:BackgroundSepto-optic dysplasia (SOD), also known as de-Morsier syndrome, is a rare disorder characterized by any combination of optic nerve hypoplasia, pituitary gland hypoplasia, and midline abnormalities of the brain including absence of the septum pellucidum and corpus callosum dysgenesis. The variable presentation of SOD includes visual, neurologic, and/or hypothalamic-pituitary endocrine defects. The unclear aetiology of a large proportion of SOD cases underscores the importance of identifying novel SOD-associated genes.Case presentationTo identify the disease-causing gene in a male infant with neonatal hypoglycaemia, dysmorphic features, and hypoplasia of the optic nerve and corpus callosum, we designed a targeted next-generation sequencing panel for brain morphogenesis defects. We identified a novel hemizygous deletion, c.6355 + 4_6355 + 5delAG, in intron 38 of the FLNA gene that the patient had inherited from his mother. cDNA studies showed that this variant results in the production of 3 aberrant FLNA transcripts, the most abundant of which results in retention of intron 38 of FLNA.ConclusionsWe report for the first time a case of early-onset SOD associated with a mutation in the FLNA gene. This finding broadens the spectrum of genetic causes of this rare disorder and expands the phenotypic spectrum of the FLNA gene.
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Project description:This review summarises the key clinical features of septo-optic dysplasia (SOD), the significant inroads that progress in genetics has made into our understanding of the aetiology of the condition over the last decade, and the pitfalls and challenges that we face in the management of these phenotypically variable patients.
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Project description:Septo-optic dysplasia (SOD) is a developmental phenotype characterized by midline neuroradiological anomalies, optic nerve hypoplasia, and pituitary anomalies, with a high degree of variability and additional systemic anomalies present in some cases. While disruption of several transcription factors has been identified in SOD cohorts, most cases lack a genetic diagnosis, with multifactorial risk factors being thought to play a role. Exome sequencing in a cohort of families with a clinical diagnosis of SOD identified a genetic diagnosis in 3/6 families, de novo variants in SOX2, SHH, and ARID1A, and explored variants of uncertain significance in the remaining three. The outcome of this study suggests that investigation for a genetic etiology is warranted in individuals with SOD, particularly in the presence of additional syndromic anomalies and when born to older, multigravida mothers. The identification of causative variants in SHH and ARID1A further expands the phenotypic spectra associated with these genes and reveals novel pathways to explore in septo-optic dysplasia.
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Project description:Background and purposeMidbrain-hindbrain involvement in septo-optic dysplasia has not been well described, despite reported mutations of genes regulating brain stem patterning. We aimed to describe midbrain-hindbrain involvement in patients with septo-optic dysplasia and to identify possible clinical-neuroimaging correlations.Materials and methodsUsing MR imaging, we categorized 38 patients (21 males) based on the presence (group A, 21 patients) or absence (group B, 17 patients) of visible brain stem anomalies. We measured height and anteroposterior diameter of midbrain, pons, and medulla, anteroposterior midbrain/pons diameter (M/P ratio), vermian height, and tegmento-vermian angle, and compared the results with 114 healthy age-matched controls. Furthermore, patients were subdivided based on the type of midline anomalies. The associations between clinical and neuroradiological features were investigated. Post hoc tests were corrected according to Bonferroni adjustment (pB).ResultsPatients with brain stem abnormalities had smaller anteroposterior pons diameter than controls (pB < .0001) and group B (pB = .012), higher M/P ratio than controls (pB < .0001) and group B (pB < .0001), and smaller anteroposterior medulla diameter (pB = .001), pontine height (pB = .00072), and vermian height (pB = .0009) than controls. Six of 21 patients in group A had thickened quadrigeminal plate, aqueductal stenosis, and hydrocephalus; 3 also had agenesis of the epithalamus. One patient had a short midbrain with long pons and large superior vermis. There was a statistically significant association between brain stem abnormalities and callosal dysgenesis (P = .011) and developmental delay (P = .035), respectively.ConclusionMidbrain-hindbrain abnormalities are a significant, albeit underrecognized, component of the septo-optic dysplasia spectrum, and are significantly associated with developmental delay in affected patients.
| S-EPMC7964443 | biostudies-literature
Project description:Septo-optic dysplasia (SOD), also known as de Morsier syndrome, is a rare congenital disorder belonging to the group of mid-line brain malformations. Despite the highly variable phenotypic penetration, its classical triad include a) optic nerve hypoplasia (ONH), b) agenesis of septum pellucidum and corpus callosum, and c) hypoplasia of the hypothalamo-pituitary axis. SOD has stringent diagnostic criteria requiring 2 or more features of the classic triad, therefore it represents a separate entity from other conditions such as ONH and achiasmia syndromes which share only some of these aspects, or SOD plus syndrome which is characterized by additional cortical abnormalities. Starting from its etiology and epidemiology, this narrative review focuses on the management of SOD patients, including their diagnosis, treatment and follow-up. To date, SOD is not curable; nonetheless, many of its symptoms can be improved through a tailored approach, consisting of hormonal replacement, corrective ophthalmological surgery and neuropsychological support.
| S-EPMC6805786 | biostudies-literature
Project description:BackgroundSepto-optic dysplasia (SOD), also known as de-Morsier's syndrome, is a rare disorder characterized by any combination of optic nerve hypoplasia (ONH), pituitary gland hypoplasia, and midline abnormalities of the brain including absence of septum pellucidum and corpus callosum dysgenesis. It is typically diagnosed in infancy and has a variable presentation that includes visual, neurologic, and/or hypothalamic-pituitary endocrine deficits.PurposeTo demonstrate the ophthalmic, endocrine, and neurologic spectrum of SOD in five Omani children and address the crucial role of high-resolution neuroimaging for its early and accurate diagnosis.Materials and methodsA retrospective chart review was performed in 2010 of all children in the pediatric ophthalmology database of Sultan Qaboos University Hospital (SQUH) who were diagnosed to have ONH. All relevantdemographic, ophthalmic, neurologic, endocrine, and neuro-radiological manifestations were recorded in a data collection form. All previous neuroimaging results were reviewed by a neuro-radiologist.ResultsFive patients (four males, one female) with the diagnosis of ONH were included in the study. They presented during the period 1998-2008. All patients were born at term, with normal birth weights to healthy mothers with insignificant antenatal history. Age at presentation ranged from three months to one year. Manifestations at presentation included severe visual impairment (5/5), neonatal hypoglycemia (3/5), seizure disorder (2/5), and failure to thrive (4/5). ONH was bilateral in 3/5 patients and unilateral in (2/5). Brain and orbit imaging revealed varying anomalies in all patients. These included absent septum pellucidum (3/5), severe corpus callosum agenesis (1/5), ectopic pituitary (5/5), falx cerebri deficiency (1/5), optic nerve hypoplasia (5/5), optic chiasmal hypoplasia (5/5), and olfactory tract hypoplasia (1/5). Endocrine deficits were detected in 4/5 patients (3 with panhypopituitarism, and 1 with growth hormone deficiency) and necessitated replacement therapy.ConclusionSOD is a clinically heterogeneous disorder with a wide spectrum of ophthalmic, endocrine, and neurologic manifestations. All features might not be present in a single patient. A high consanguinity rate and lack of history of alcohol and drug use were observed in our cohort. Most affected children present first to the pediatrician with failure to thrive. Radiological confirmation of ONH necessitates high-resolution imaging and interpretation by an experienced neuro-radiologist. In our cohort, all patients with ONH had associated optic chiasmal hypoplasia. Early detection and treatment reduces disease-related morbidity, and can be life saving.
| S-EPMC3872571 | biostudies-literature
Project description:A four generation family (UoM1) was ascertained with Waardenburg syndrome type 1 (WS1). The proband exhibited both WS1 and septo-optic dysplasia. A G to C transversion was identified in PAX3 exon 7 in four subjects affected with WS1 in this family including the proband. This glutamine to histidine missense mutation at position 391 may also affect splicing. There are over 50 mutations characterised in PAX3 in WS1 patients; however, this is the first example of a WS1 mutation in exon 7 of PAX3.
| S-EPMC1051252 | biostudies-other
Project description:BackgroundSepto-optic dysplasia (SOD) is a rare condition diagnosed in children with two or more of the following: hypopituitarism, midline brain abnormalities, and optic nerve hypoplasia. Children with SOD experience varied visual impairment and endocrine dysfunction. Autistic-like behaviours have been reported; however, their nature and prevalence remain to be fully understood. The present systematic review aimed to explore the type and prevalence of neurodevelopmental impairments in children with SOD spectrum conditions.MethodsThe search was conducted in PubMed, EMBASE, and PsycInfo. Hand-searching reference lists of included studies was conducted. All peer-reviewed, observational studies assessing behavioural and cognitive impairments or autism spectrum disorder (ASD) symptoms in children (< 18 years) with SOD, optic nerve hypoplasia, and SOD-plus were included. Studies were excluded if they did not report standardised measures of neurodevelopmental impairments or ASD outcomes.ResultsFrom 2132 screened articles, 20 articles reporting data from a total of 479 children were included in prevalence estimates. Of 14 studies assessing cognitive-developmental outcomes, 175 of 336 (52%) children presented with intellectual disability or developmental delay. A diagnosis of ASD or clinical level of symptoms was observed in 65 of 187 (35%) children across five studies. Only five studies assessed for dysfunction across behavioural, emotional, or social domains and reported impairments in 88 of 184 (48%) of children assessed.LimitationsImportantly, high heterogeneity among the samples in relation to their neuroanatomical, endocrine, and optic nerve involvement meant that it was not possible to statistically assess the relative contribution of these confounding factors to the specific neurodevelopmental phenotype. This was further limited by the variation in study designs and behavioural assessments used across the included studies, which may have increased the risk of information bias.ConclusionsThis systematic review suggests that the prevalence of neurodevelopmental impairments in children within the SOD spectrum may be high. Clinicians should therefore consider including formal assessments of ASD symptoms and neurodevelopmental impairments alongside routine care. There is, additionally, a need for further research to define and validate a standardised battery of tools that accurately identify neurodevelopmental impairments in SOD spectrum conditions, and for research to identify the likely causal mechanisms.
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Project description:Septo-optic dysplasia (SOD) is a congenital brain anomaly that results in pituitary, optic nerve, and midline forebrain defects. The etiology of SOD is poorly understood, with the majority of cases being sporadic. In rare instances, SOD is caused by mutations in Sox2, Sox3, or Hesx1, but how this manifests in disease is not entirely certain. We demonstrate here that mouse embryos lacking Sonic hedgehog (Shh) in the prospective hypothalamus exhibit key features of SOD, including pituitary hypoplasia and absence of the optic disc. The hypothalamic source of Shh is required to maintain gene expression boundaries along the anteroposterior and mediolateral neural axes that are important for proper pituitary and eye development, respectively. We further reveal that Sox2 and Sox3 are dose-dependent regulators of Shh transcription that directly bind and activate a long-range Shh forebrain enhancer. These data indicate that reduced levels of Shh expression in the hypothalamus cause SOD.
| S-EPMC3306593 | biostudies-literature
Project description:Background:Septo-optic dysplasia (SOD) is a heterogeneous congenital condition. The aim of this study was to investigate the clinical phenotypes of a large cohort of children with SOD, Multiple Pituitary Hormone Deficiency (MPHD) and Optic Nerve Hypoplasia (ONH), with a focus on endocrine testing. Methods:Retrospective single-centre longitudinal study of children with SOD (n:171), MPHD (n:53) and ONH (n:35). SOD+ and SOD- indicate patients with or without hypopituitarism, respectively. Findings:All deficits were more frequent and occurred earlier in MPHD than SOD+ [Hazard Ratios (HR): 0·63(0·45,0·89) for GH, 0·48(0·34,0·69) for TSH, 0·55(0·38,0·80) for ACTH, 0·28(0·11,0·68) for gonadotropins], except Diabetes Insipidus (DI) [HR: 2·27(0·88,5·9)]. Severe hypothalamo-pituitary (H-P) abnormalities were more frequent in MPHD [80·0% vs 41·6%, p<0·0001 for Ectopic Posterior Pituitary (EPP)]. Stalk and PP abnormalities were associated with more severe endocrine phenotypes and placed a subgroup of SOD+ at risk of developing deficits earlier. SOD and ONH shared heterogeneous phenotypes ranging from pubertal delay to precocity and from leanness to extreme obesity, whilst MPHD had GnD and obesity only. Mortality was recorded in 4·2% (6/144) SOD and 3·2% (1/31) ONH, and only in patients with multisystem phenotypes. Interpretation:More than a single disease, SOD represents a spectrum of malformative conditions involving different brain structures and characterised by a dynamic and sequential nature of endocrine. In contrast, MPHD displays a more homogeneous phenotype of (mainly) anterior pituitary early-onset failure. Stalk and PP abnormalities place a subgroup of SOD+ at a higher risk of early-onset deficits. Additionally, there are striking differences between the SOD and MPHD cohorts in terms of pubertal progression. The shared phenotypes between ONH and SOD could be partly explained by common hypothalamic dysfunction. The differences between the cohorts are important as they may aid in planning management and preventing morbidity by dictating earlier interventions. Funding:M.C., M.G., and N.I. were supported by the European Society of Paediatric Endocrinology (ESPE) through ESPE Clinical Fellowships.
| S-EPMC7046495 | biostudies-literature