Neurodevelopmental impairments in children with septo-optic dysplasia spectrum conditions: a systematic review.

BACKGROUND: Septo-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. METHODS: The 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. RESULTS: From 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. LIMITATIONS: Importantly, 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. CONCLUSIONS: This 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.

Patients with septo-optic dysplasia: General ophthalmologic assessment and retinal imaging.

BACKGROUND: To evaluate the functional development and, retinal and optic disc morphology using OCT in patients with septo-optic dysplasia (SOD). METHODS: This retrospective case series included patients diagnosed with SOD between 2007 and 2020. Ophthalmologic assessment included visual acuity (VA) and funduscopy at the initial and last presentation. Retinal imaging included OCT of the macula analyzing the retinal morphology, central retinal thickness volume (CRT) and ganglion cell layer (GCL). Also, scans of the optic nerve head were taken to evaluate the retinal nerve fiber layer (RNFL) and global value. RESULTS: 38 eyes of 19 children with a mean age 6.3 ± 5.3 years were included. 31.6% showed all 3 characteristics of SOD, whereof ONH, midline defects and endocrine dysfunctions were found in 94.7%, 89.5% and 47.4% respectively. The mean VA was 0.70 ± 0.66logMar in the right eye (RE) and 0.40 ± 0.55logMar in the left eye (LE) at the initial presentation. No change of vision (RE: 0.69 ± 0.71logMar; LE: 0.31 ± 0.57logMar) was found after a follow-up period of 6.3 ± 4.5years. Funduscopy showed an ONH in 79% (n = 30/38), tortuous retinal vessels in 36.8% (n = 14/38) and a double-ring sign in 15.8% (n = 6/38). Retinal imaging showed variable morphology. 6 eyes of 4 patients showed temporal retinal thinning with corresponding GCL attenuation. The optic nerve head appearance varied between no changes, sectoral and hemispherical reduction. CONCLUSIONS: Patients suffering from SOD show diverse expression of retinal changes such as retinal, GCL and RNFL thinning in OCT. Furthermore, visual function remained stable during follow-up examinations, indicating no further alteration due to underlying pathology.

Novel Genetic Diagnoses in Septo-Optic Dysplasia.

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.

[Septo optic dysplasia plus: about a case]. / Dysplasie septo optique plus: à propos d'un cas.

Septo optic dysplasia plus is a rare disease seen in children. Its diagnosis is radiological, based on brain magnetic resonance imaging (MRI). We report the case of a child aged 2 years and 4 months, with no particular pathological history; who consulted for psychomotor retardation, strabismus and low vision behavior. An endocrine biological assessment exploring the hypothalomo-pituitary function was carried out, revealing no abnormality. The diagnosis of septo-optic dysplasia plus was retained on the brain MRI data, in front of the agenesis of the septum pellucidum and of the splenium of the corpus callosum, the hypoplasia of the optic pathways and of the pituitary stalk as well as in front of the agenesis of the posterior pituitary. It was associated with a closed schizencephaly. Septo-optic dysplasia is a rare congenital malformation. Our objective is to recall its semiology in imaging and to underline the importance of MRI to establish the diagnosis. Septo-optic dysplasia is a rare clinical entity typically involving midline brain abnormalities, optic nerve hypoplasia, and pituitary insufficiency. The association with cortical malformations such as schizencephaly and polymicrogyria denotes the term septo-optic dysplasia plus. Advances in imaging currently allow early diagnosis, which is essential for adequate management. Antenatal ultrasound may suspect dysplasia, and brain MRI confirms the diagnosis.

Septo-optic dysplasia presenting with nystagmus, pseudo-disc edema, and fovea hypoplasia.

BACKGROUND: Septo-optic dysplasia (SOD) is a condition that affects the early development of the brain and eyes. It presents with a combination of optic nerve hypoplasia, brain midline structure abnormalities, and pituitary gland hypoplasia. METHODS: This is a case report of a 4-year-old male who presented with low amplitude horizontal nystagmus and decreased visual acuity 20/60 OU. Further imaging and electrophysiology were conducted to classify the ocular presentation. RESULTS: No iris transillumination was noted, but foveal hypoplasia and disc edema were evident on fundus examination. This prompted neurology consultation and MRI imaging. The MRI was consistent with the diagnosis of SOD showing hypoplasia of the optic nerves, chiasm, and tracts and an absent septum pellucidum, but with normal pituitary development and function. Lumbar puncture and intracranial pressure were normal. Genetic testing identified one pathogenic variant in the SLC45A2, indicating carrier status for oculocutaneous albinism type 4 (OCA4). Flash Visual Evoked Potentials (VEPs) were consistent with chiasm dysfunction or hypoplasia rather than the chiasmal misrouting of OCA. CONCLUSION: This case report further elaborates the phenotypic variation of SOD, with the finding of blurred disc margins, in the absence of the typical optic nerve double ring sign and with normal intracranial pressure. The findings of fovea hypoplasia and blond fundi lead to the suspicion of OCA either as a separate diagnosis with a second pathogenic variant in SCL45A2 not yet identified or in association with SOD. This case highlights the importance of electrophysiology to help distinguish chiasmal hypoplasia or dysfunction from OCA misrouting.

Septo-optic dysplasia: Ophthalmological abnormalities in a series of 5 cases.

Septo-optic dysplasia (SOD) is a rare congenital condition of unknown cause, with a characteristic triad that includes optic nerve hypoplasia, pituitary function abnormalities and midline brain defects, in addition to a broad spectrum of symptoms and associations. A total of five clinical cases are presented, four of which met the complete classic triad. All of them showed a wide variety of ophthalmological, endocrinological and neurological alterations. Within the ophthalmological spectrum of SOD, papillary hypoplasia and ocular motility alterations (nystagmus, strabismus) stand out. Other less frequent ones may also appear, such as pupillary alterations, microphthalmia and coloboma. Given the suspicion of SOD, brain MRI scan should be performed, as well as consultation with the paediatric department in order to complete the study and indicate, if necessary, systemic treatment.

A severe case of Bosch-Boonstra-Schaaf optic atrophy syndrome with a novel description of coloboma and septo-optic dysplasia, owing to a start codon variant in the NR2F1 gene.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare congenital syndrome characterized by a range of phenotypes including optic atrophy and intellectual disability among other features. Pathogenic variants in the NR2F1 (nuclear receptor subfamily 2 group F member 1) gene have been linked to this condition. A recent report has shown that pathogenic variants in the start codon lead to decreased expression of the NR2F1 protein and a relatively mild phenotype, similar to that seen in whole gene deletions, and due to the lack of the dominant negative effect. Here we describe a severe case of BBSOAS with an initiation codon missense variant. The developmental delay, seizures, optic atrophy are in keeping with features observed in this condition, however this is the first report to describe colobomas and septo-optic dysplasia as associated features potentially extending the phenotype linked to BBSOAS. In addition, this is the first description of a severe phenotype linked to a de novo missense variant in the start codon of the NR2F1 gene.

Bosch-Boonstra-Schaaf optic atrophy syndrome mimicking septo-optic dysplasia in a 10-year-old child.

We report a case of confirmed Bosch-Boonstra-Schaaf optic atrophy syndrome presenting with suspected optic nerve hypoplasia, corpus callosum agenesis, and low levels of insulin-like growth factor 1. This patient's presentation demonstrates the clinical overlap of Bosch-Boonstra-Schaaf Optic atrophy syndrome with septo-optic dysplasia and the importance of genetic testing for correct diagnosis.

Septo-optic dysplasia.

Septo-optic dysplasia (SOD) or de Morsier's syndrome is a rare congenital disorder characterized by a classic triad of: (a) optic nerve hypoplasia, (b) agenesis of septum pellucidum and corpus callosum, and (c) hypoplasia of the hypothalamic-pituitary axis. This chapter will outline the key information regarding the etiology and epidemiology of this syndrome with a focus on its comprehensive management. Particular attention will be paid to the diagnostic stage and the most relevant differential diagnosis, before moving to the complexities of its treatment. In fact, although SOD is not curable, many aspects of this syndrome can be improved through a tailored multidisciplinary approach consisting in hormonal replacement, corrective ophthalmological surgery, management of epileptic seizures, and active neuropsychological support.

Management of transient central diabetes insipidus with intravenous desmopressin in a premature infant with gastroschisis and septo-optic dysplasia: A case report.

Central diabetes insipidus (CDI) may occur in the setting of intracranial abnormalities that affect the hypothalamus-pituitary system. It occurs rarely in neonates, especially in the premature population, and represents a challenging disease process to treat pharmacologically. Little is known regarding the treatment options in premature infants, including dose and route of administration of intravenous desmopressin (DDAVP). We present a case of a late premature male infant with gastroschisis and septo-optic dysplasia who developed transient CDI. He was treated with intravenous DDAVP but required frequent laboratory monitoring and a multidisciplinary approach, and ultimately his CDI resolved. Although there are minimal guidelines regarding the appropriate formulation and dosage of DDAVP for management of CDI in infants, we initiated the lowest dose available and titrated the medication based on close monitoring of urine output and serum sodium levels in order to successfully treat his transient CDI.

Neuropathology of Septo-optic Dysplasia: A Report of 4 Autopsy Cases.

Septo-optic dysplasia (SOD) is defined by the presence of 2 or more features in a diagnostic triad: (1) optic nerve hypoplasia, (2) pituitary dysfunction, and (3) midline forebrain anomalies. SOD arises due to diverse pathogenetic mechanisms including acquired and genetic factors, and it shows considerable clinical and phenotypic variability. Our knowledge of SOD is incomplete in part because of a paucity of published neuropathology data, so we reviewed the autopsy neuropathology of 4 SOD patients. All patients met SOD criteria according to the triad. Additional neuropathologic findings included malformations involving non-forebrain structures and possible secondary phenomena. Autopsies demonstrate that SOD patients often have additional neuropathologic findings beyond the triad and we feel that use of the term SOD-complex appropriately underscores this diversity and its likely clinical impact. This study suggests that autopsies enhance our understanding of SOD and may be an asset in performing needed clinical and phenotypic correlation studies.

Malan syndrome: Extension of genotype and phenotype spectrum.

Malan syndrome and Marshall-Smith syndrome (MSS) are allelic disorders caused by mutation in NFIX gene. We report a 3-year- 6 months- old female with clinical features suggestive of Malan syndrome with mutation in exon 2 of NFIX gene. NFIX gene, where most of the mutations in Malan syndrome are located. She did not have advanced bone age. The radiographs of long bones showed metaphyseal changes which were not reported previously. This study reports the first mutation proven case from India and highlights the overlap between MSS and Malan syndrome.

The central diabetes insipidus associated with septo-optic dysplasia (de Morsier syndrome).

INTRODUCTION: Septo-optic dysplasia (SOD) is a rare congenital heterogeneous malformation with postulated genetic and environmental etiology. Septo-optic dysplasia is characterized by classic triad: optic nerve hypoplasia, midline brain malformation and hypothalamic-pituitary endocrine deficiencies. The most common hormonal deficiencies affect growth hormone and gonadotropin but it can also be lower levels of the other hormones. The rarest form of hormone deficiency is the deficiency of the antidiuretic hormone. CASE REPORT: The boy was born in 39th week of pregnancy in general good condition. Weakened suction reflex and spitting resulted in substantial difficulties with breastfeeding. After transfontanelle ultrasonography central nervous system defect was suspected. In the 5th month of life MRI confirmed septo-optic dysplasia on the basis of anterior genu of corpus callosum and septum pellucidum agenesis, both optic nerves and optic chiasm hypoplasia, pachygyria and polimicrogyria of the right frontoparietal cortex. Neurological examination revealed axial laxity, psychomotor development delay, difficulties in keeping eyes fixed as well as rotary and horizontal nystagmus. At the age of 3 years he underwent the endocrinological consultation due to polydipsia and polyuria. The tests revealed lower urine specific gravity tests results, therefore diabetes insipidus was diagnosed. The boy still receives desmopressin and there are no signs of central diabetes insipidus. Currently, the boy is under a multi-disciplinary medical care. CONCLUSIONS: The attention should be focussed on early diagnosis, mutli-specialized care and treatment SOD. Hypopituitarism ranges from isolated to multiple hormone deficits, with diabetes insipidus in a minority. Although rare, SOD is an important cause of congenital hypopituitarism and should be considered in all children with midline defects and optic nerve hyploplasia.

Septo-optic dysplasia.

A seven-month-old child with congenital poor vision was referred for evaluation. Fundus examination revealed bilateral optic nerve hypoplasia with disc macula distance of approximately ten disc diameters. Neuroimaging revealed finding consistent with septo-optic dysplasia.

[Optic nerve hypoplasia and septo-optic dysplasia]. / Optikushypoplasie und septooptische Dysplasie.

Optic nerve hypoplasia (ONH) is one of the most common causes of congenital visual impairment. It was first described in 1915 and represents a developmental disorder of the central nervous system. It is often associated with intracranial midline defects and is then referred to as septo-optic dysplasia (SOD). The symptoms of ONH range from minimal visual dysfunction to significant visual impairment with sensory defect nystagmus and even blindness. The ONH is often associated with further systemic, endocrinological and neurological abnormalities requiring a close interdisciplinary treatment of the patients.