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.

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.

Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

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

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.

Epidemiology of septo-optic dysplasia with focus on prevalence and maternal age - A EUROCAT study.

Septo-optic nerve dysplasia is a rare congenital anomaly with optic nerve hypoplasia, pituitary hormone deficiencies and midline developmental defects of the brain. The clinical findings are visual impairment, hypopituitarism and developmental delays. The aim of this study was to report prevalence, associated anomalies, maternal age and other epidemiological factors from a large European population based network of congenital anomaly registries (EUROCAT). Data from 29 full member registries for the years 2005-2014 were included, covering 6.4 million births. There were 99 cases with a diagnosis of septo-optic dysplasia. The prevalence of septo-optic dysplasia in Europe was calculated to lie between 1.9 and 2.5 per 100,000 births after adjusting for potential under-reporting in some registries. The prevalence was highest in babies of mothers aged 20-24 years of age and was significantly higher in UK registries compared with other EUROCAT registries (P = 0.021 in the multilevel model) and the additional risk for younger mothers was significantly greater in the UK compared to the rest of Europe (P = 0.027). The majority of septo-optic dysplasia cases were classified as an isolated cerebral anomaly (N = 76, 77%). Forty percent of diagnoses occurred in fetuses with a prenatal diagnosis. The anomaly may not be visible at birth, which is reflected in that 57% of the postnatal diagnoses occurred over 1 month after birth. This is the first population based study to describe the prevalence of septo-optic dysplasia in Europe. Septo-optic dysplasia shares epidemiological patterns with gastroschisis and this strengthens the hypothesis of vascular disruption being an aetiological factor for septo-optic dysplasia.

Extra-Pituitary Birth Defects May Predict Diagnosis of Congenital Hypopituitarism in a Short Child.

BACKGROUND: Extra-pituitary birth defect (EPBD) in children with congenital hypopituitarism is largely unknown. OBJECTIVE: The study aims to evaluate the incidence and pattern of EPBD in children with congenital hypopituitarism and to evaluate whether it can serve as a clue to diagnose this condition. PATIENTS AND METHODS: Retrospective analysis of hospital record of patients of short stature due to various etiology from which patients with congenital hypopituitarism with age ≥18 years were recruited for the analysis. Clinical, hormonal, radiological and ocular electrophysiological studies were done in all patients and all EPBD were noted. RESULTS: Twenty seven patients (79%) had multiple pituitary hormone deficiency (MPHD) of which growth hormone was universal followed by gonadotropin (62%), TSH (59%), ACTH (44%) and prolactin (12%). Nineteen patients (56%) had multiple EPBD in various combinations. Twenty three ocular abnormalities were present in 12 patients (35%). Nine patients (26%) had other associated EPBD along with ocular abnormalities while 3 had ocular abnormalities without any other associated birth defect. Skeletal defects were present in 10 patients (29.5%). On the contrary, 5 patients in the EPBD group had total 15 visual defects. The most common abnormality of the visual system were abnormal visual evoke response (VER, 18%), followed by strabismus (15%), visual acuity (VA, 12%), electroretinogram (ERG) and electrooculogram (EOG) 8% each and visual field defect 6%. There was a trend towards early age at presentation with EPBD. CONCLUSIONS: Presence of EPBD in a short child is a sensitive marker to diagnose congenital hypopituitarism. Subtle abnormalities of visual pathway without absent septum pellucidum or midline brain defects were common.

Incidence and associated endocrine and neurologic abnormalities of optic nerve hypoplasia.

IMPORTANCE: Optic nerve hypoplasia (ONH) is an increasingly recognized cause of congenital blindness in children; however, there is significant discord regarding its incidence and the rate of associated conditions. OBJECTIVE: To determine the incidence of ONH and the rate of associated endocrine, neurologic, and developmental abnormalities among a population-based cohort of pediatric patients. DESIGN: Retrospective, population-based study. SETTING: Olmsted County, Minnesota (95.7% white in 1990). PARTICIPANTS: All pediatric residents (aged <19 years) of Olmstead County, diagnosed as having ONH from January 1, 1984, through December 31, 2008. MAIN OUTCOMES AND MEASURES: Incidence of ONH and the rate of associated endocrine, neurologic, and developmental abnormalities. RESULTS: Optic nerve hypoplasia was diagnosed in 19 pediatric patients during the 25-year study period, for an annual incidence of 2.4 (95% CI, 1.2-3.5) per 100,000 residents younger than 19 years or 1 in 2287 live births. The mean age at diagnosis was 2.1 years, and 10 (53%) patients were male. Commonly associated perinatal conditions included primiparity in 8 patients (42%), premature birth in 6 (32%), and maternal diabetes mellitus in 3 (16%). Of the 19 study patients, 16 (84%) had bilateral involvement at initial examination, 9 (47%) had decreased visual acuity, 8 (42%) had strabismus, and 5 (26%) had nystagmus. Systemic conditions included developmental delay in 12 (63%), neurologic deficits in 10 (53%), and endocrine dysfunction in 5 (26%). CONCLUSIONS AND RELEVANCE: This population-based study demonstrated an incidence of ONH of 1 in 2287 live births. More than half of the patients had developmental and neurologic deficits, and one-fourth had a diagnosis of endocrine dysfunction.

Structural pituitary abnormalities associated with CHARGE syndrome.

INTRODUCTION: CHARGE syndrome is a multisystem disorder that, in addition to Kallmann syndrome/isolated hypogonadotrophic hypogonadism, has been associated with anterior pituitary hypoplasia (APH). However, structural abnormalities such as an ectopic posterior pituitary (EPP) have not yet been described in such patients. OBJECTIVE: The aims of the study were: 1) to describe the association between CHARGE syndrome and a structurally abnormal pituitary gland; and 2) to investigate whether CHD7 variants, which are identified in 65% of CHARGE patients, are common in septo-optic dysplasia /hypopituitarism. METHODS: We describe 2 patients with features of CHARGE and EPP. CHD7 was sequenced in these and other patients with septo-optic dysplasia/hypopituitarism. RESULTS: EPP, APH, and GH, TSH, and probable LH/FSH deficiency were present in 1 patient, and EPP and APH with GH, TSH, LH/FSH, and ACTH deficiency were present in another patient, both of whom had features of CHARGE syndrome. Both had variations in CHD7 that were novel and undetected in control cohorts or in the international database of CHARGE patients, but were also present in their unaffected mothers. No CHD7 variants were detected in the patients with septo-optic dysplasia/hypopituitarism without additional CHARGE features. CONCLUSION: We report a novel association between CHARGE syndrome and structural abnormalities of the pituitary gland in 2 patients with variations in CHD7 that are of unknown significance. However, CHD7 mutations are an uncommon cause of septo-optic dysplasia or hypopituitarism. Our data suggest the need for evaluation of pituitary function/anatomy in patients with CHARGE syndrome.

Septo-optic dysplasia: antenatal risk factors and clinical features in a regional study.

BACKGROUND: Septo-optic dysplasia (SOD) is a disorder with postulated environmental and genetic aetiology. This study delineates clinical features and potential perinatal environmental factors along with epidemiology in SOD children. METHODS: Assessment of patients with SOD triad features in the UK West Midlands region. RESULTS: Of 227 patients identified between 1998 and 2009 with 1 or more feature of the triad, 55 had midline defects, 149 had optic nerve hypoplasia and 132 had hypopituitarism. Eighty-eight children (52% males; incidence 8.3/100,000 live births) had SOD defined as 2 out of 3 features and 21 (24%) had all 3. Sixty-one percent had anterior pituitary deficiency and 21.5% had diabetes insipidus. Median maternal/paternal ages in SOD were 21 and 23.5 years, compared to UK means of 29.3 and 32.4 years (p < 0.001). First trimester bleeding was markedly increased at 12/48 (25%) compared to 0.07% in the UK (p < 0.001). Ethnicity showed a non-significant higher prevalence in Afro-Caribbean and mixed race groups, and significantly lower prevalence (p = 0.004) in South Asian groups compared to West Midland and Birmingham city data: 8% versus 2.5 and 6.7%, 9% versus 1.8 and 3.2% and 3% versus 8.4 and 21%, respectively. CONCLUSIONS: SOD is associated with younger maternal and paternal age, primigravida births and ethnic differences. Increased first trimester bleeding may indicate that SOD is a vascular disruption sequence.

[Natural course of septo-optic dysplasia: retrospective analysis of 20 cases]. / Evolucion natural de la displasia septooptica: analisis retrospectivo de 20 casos.

INTRODUCTION: Septo-optic dysplasia (SOD) is the variable combination of signs of dysgenesis of the midline of the brain, hypoplasia of the optic nerves and hypothalamus-pituitary dysfunction, which is sometimes associated with a varied spectrum of malformations of the cerebral cortex. AIMS: To describe the natural history and neuroimaging findings in a series of 20 diagnosed patients. PATIENTS AND METHODS: We review the epidemiological, clinical and neuroimaging characteristics of 20 consecutive patients diagnosed with SOD between January 1985 and January 2010. Data obtained from computerised tomography, magnetic resonance imaging of the head, electroencephalogram, visual evoked potentials, ophthalmological evaluation, karyotyping and endocrinological studies were analysed. In seven patients, a study of the gene Homeobox HESX1 was conducted. RESULTS: Pathological antecedents in the first three months of gestation were presented by 60% of the cases, with normal results in the foetal ultrasound scans. Clinically, the most striking features were visual manifestations (85%), endocrine disorders (50%), mental retardation (60%) and epileptic seizures (55%). Fifty-five per cent were associated to abnormal neuronal migration. In 45%, SOD was the only finding in the neuroimaging scans. Karyotyping was performed in all cases, the results being normal. Gene HESX1 was positive in two of the seven cases studied (both with isolated SOD). None of those with mutation in gene HESX1 presented familial consanguinity. No gene study was conducted with the parents. CONCLUSIONS: SOD must be classified as a heterogeneous malformation syndrome, which is associated to multiple brain, ocular, endocrine and systemic anomalies. The most severe forms are associated with abnormal neuronal migration and cortical organisation.

Anorchia masked by septo-optic dysplasia.

Hypogonadism affecting the male pediatric population is uncommon, with that attributed to multiple unrelated etiologies being exceedingly rare. We report a case of septo-optic dysplasia, an atypical cause of delayed puberty, with subsequent workup unveiling 2 coexistent conditions: hypogonadotropic hypogonadism and anorchia. Primary and secondary etiologies must be considered in patients with undescended testes. Thorough evaluation is mandatory to ensure proper diagnosis and care, because Occam's razor can, on unique occasions, be double-edged.

The syndrome of optic nerve hypoplasia.

The congenital malformation known as optic nerve hypoplasia (ONH) has been recognized in the past 30 years as an epidemic cause of congenital blindness. It was believed to occur either as an isolated anomaly or as a component of the syndrome of septo-optic dysplasia, which has evolved to include midline brain malformations and hypopituitarism. Evidence now suggests that ONH infrequently occurs in isolation. Most afflicted children will have hypothalamic dysfunction and/or neurodevelopmental impairment, regardless of MRI findings or severity of ONH. Adverse outcomes can often be ameliorated with early intervention. Thus, the syndrome of ONH should be suspected in all infants with signs of hypothalamic dysfunction or vision impairment.

Geographical distribution of optic nerve hypoplasia and septo-optic dysplasia in Northwest England.

OBJECTIVE: To study the distribution of septo-optic dysplasia (SOD) and optic nerve hypoplasia (ONH) in the Greater Manchester and Lancashire (GM&L) region of Northwest England, and to analyze occurrence by location and over time. STUDY DESIGN: A population-based incidence study was undertaken for cases of SOD/ONH from GM&L. Standardized incidence ratio (SIR) for each district, relationships between SIRs and possible geographically varying risk factors, and spatial and space-time clustering were analyzed. RESULTS: Eighty-seven cases had a confirmed diagnosis of ONH/SOD giving an incidence of 10.9/100,000 per year in GM&L. SIRs ranged widely but were significantly elevated (lower confidence limit >100) in three districts: 167%, 192%, and 198%, respectively. All three were high population density, inner-city locations. SIRs were significantly correlated with higher rates of unemployment (r = 0.49, P = .01), dependent children in non-earning households (r = 0.47, P = .02), underage conceptions (r = 0.46, P = .02), and underage pregnancies (r = 0.44, P = .03). There was no evidence of spatial or space-time clustering. CONCLUSIONS: The incidence of ONH/SOD in GM&L was higher than that reported elsewhere. Cases were more common in areas that had higher unemployment and teenage pregnancy rates.

Maternal age in patients with septo-optic dysplasia.

AIM: To determine whether patients with septooptic dysplasia (SOD) are of normal birth weight and gestation but are born to mothers who are significantly younger than average. METHODS: Retrospective study of 30 patients with SOD attending the Royal Hospital for Sick Children, Glasgow. Birth data for the Scottish population were used for comparison. RESULTS: Mean birth weight was 3.42 (range 2.66-4.18) kg. One patient was born preterm while the rest were born at term. Data for the Scottish population were available from 1979 onwards and 26 patients born after this year were selected for analysis. Median maternal age in this group was 21 (range 16-41) years, significantly lower than the median maternal age for Scotland of 27.12 (range 25.8-28.6) years (95% CI 4.8-8.0 years). CONCLUSION: Patients with SOD are of normal birth weight and gestation but are born to mothers who are significantly younger than average.