The phenotypic spectrum associated with OTX2 mutations in humans.

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.

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.

Agenesis of the septum pellucidum: Prenatal diagnosis and outcome.

OBJECTIVE: The purpose of this study is to describe the imaging findings in a group of fetuses with suspected agenesis of the septum pellucidum (ASP) and to evaluate their clinical outcome. METHODS: This is a retrospective multicenter study on a cohort of fetuses diagnosed with suspected ASP, between 2008 and 2017. The records of each patient, including ultrasound (US) and magnetic resonance studies, were reviewed and compared with the postnatal findings. RESULTS: Forty-seven patients were included in the study at a mean gestational age of 26.6 weeks. In 17 patients, the ASP was considered isolated. Fourteen patients delivered live-born, and all 14 are developing normally. Three were lost to follow-up. Twenty-four patients had associated malformations involving the central nervous system (CNS); 13 were delivered (normal development [5], abnormal [6] and no follow-up [2]). Nine patients opted for termination, and two pregnancies were lost to follow-up. Six patients had non-CNS associated findings, two were delivered with normal neurological development and four had a termination. CONCLUSIONS: Isolated ASP is usually associated with a favorable outcome; but in the presence of associated malformations, there is at least a 50% risk of abnormal development. Current imaging techniques can provide an accurate prognosis in cases when ASP appears isolated.

Septo-optic dysplasia caused by a novel FLNA splice site mutation: a case report.

BACKGROUND: Septo-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 PRESENTATION: To 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. CONCLUSIONS: We 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.

Further delineation of Malan syndrome.

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.

Clinical and Radiologic Spectrum of Septo-optic Dysplasia: Review of 17 Cases.

We retrospectively reviewed the clinical and radiologic characteristics of 17 individuals with septo-optic dysplasia (SOD) and attempted to identify correlations between imaging findings, clinical features, and neurodevelopmental outcome. Surprisingly, only 1 (6%) individual was classified as classic SOD (with septum pellucidum/corpus callosum dysgenesis), 3 (18%) as SOD-like (with normal septum pellucidum/corpus callosum) and the majority, 13 (76%), as SOD-plus (with cortical brain malformation). Cortical abnormalities included schizencephaly, polymicrogyria, and gray matter heterotopias. All individuals had optic nerve hypoplasia, 11 (65%) had endocrinologic deficits, and 13 (76%) had abnormal cerebral midlines. Seven individuals (41%) had all 3 features. Neurodevelopmental outcome was abnormal in 13 (78%), ranging from mild to severe developmental delay. Individuals with SOD-plus did not have more severe neurologic deficits than individuals with classic or SOD-like subgroups. Thus, SOD is clinically and radiologically heterogeneous, and cortical abnormalities are very common. Neurodevelopmental deficits are very prevalent, and of wide-ranging severity.

Increased Intraocular Pressure in a Patient With Septooptic Dysplasia: A Case Report.

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.

Septo-Optic Dysplasia: A Case Study.

Septo-optic dysplasia (SOD) is a rare congenital heterogeneous malformation. SOD was formerly known as de Morsier syndrome, which associated a midline brain defect such as an absent septum pellucidum with optic nerve hypoplasia. The diagnosis of SOD is made when there are two or more characteristics of the classic triad. The triad consists of optic nerve hypoplasia, pituitary hormone abnormalities, and midline brain defects, although it can vary in the severity of clinical presentation and phenotype. The purpose of this article is to review a case and analyze the literature regarding prevalence, etiology, clinical presentation, diagnosis, and management of SOD.

Spectrum of clinical presentations and endocrinological findings of patients with septo-optic dysplasia: a retrospective study.

BACKGROUND: Septo-optic dysplasia (SOD) is a rare condition with variable clinical pictures and spectrum of findings. OBJECTIVE: To analyze the spectrum of findings, frequency and age of onset of hypothalamic-pituitary dysfunctions in children with SOD. METHOD: A retrospective electronic medical record (EMR) chart review was done for patients with SOD seen in a tertiary care center's pediatric endocrinology clinic between January 1, 2012, and March 31, 2014. The diagnostic criteria for SOD included presence of ≥ 2 of the following: (i) optic nerve hypoplasia, (ii) agenesis/hypoplasia of septum pellucidum and/or corpus callosum and (iii) hypothalamic-pituitary dysfunction. RESULTS: Eighty patients fitting the diagnostic criteria of SOD were included in this study. The majority of patients (96%) had optic nerve hypoplasia on magnetic resonance imaging and were diagnosed due to visual issues including nystagmus (36%) or strabismus (13.8%). Hypothalamic-pituitary dysfunction was most common (51%) when optic nerve hypoplasia was present with (36%) or without (15%) dysgenesis of septum pellucidum and/or corpus callosum compared to dysgenesis of septum pellucidum and/or corpus callosum alone (4%). Hypothalamic-pituitary dysfunction was noted in 55% of patients, and most (86%) were diagnosed ≤ 2 years of age. Central hypothyroidism and growth hormone deficiency were most common followed by secondary/tertiary adrenal insufficiency and diabetes insipidus. CONCLUSIONS: The risk of hypothalamic-pituitary dysfunction in SOD is highest ≤ 2 years of age and when both optic nerve hypoplasia and dysgenesis of septum pellucidum/corpus callosum are present, suggesting a need for more frequent follow-up and screening tests for hypothalamic-pituitary dysfunction in these patients.

Septo-optic dysplasia plus: a case report.

BACKGROUND: Septo-optic dysplasia, also referred to as de Morsier syndrome, is a congenital condition characterized by classic triad features: midline brain abnormalities, optic nerve hypoplasia and pituitary endocrine dysfunction. Sometimes, other various malformations appear within syndrome. CASE PRESENTATION: An 11 and 1/2-year-old Caucasian Southeast European female patient with earlier established diagnoses of growth hormone deficiency, diabetes insipidus, seizures, mental retardation, optic nerve atrophy and right ptosis, was directed to us for consultative examination.The girl of short stature and low weight for her age had bilateral optic nerve hypoplasia, poor vision, nystagmus and right eye oculomotor palsy. Electroencephalogram revealed epileptic changes. Magnetic resonance imaging showed an empty sella syndrome, partial hypoplasia of corpus callosum, cavum of pellucid septum and diffuse polymicrogyria of the left temporal lobe. We found all elements of septo-optic dysplasia plus syndrome with right oculomotor nerve involvement. CONCLUSION: By earlier findings and evaluation, we established a diagnosis of septo-optic dysplasia plus. The case confirms the existence of various malformations within the syndrome and the need for the cooperation of several specialists in the diagnosis and treatment of children with the syndrome.

Septo-optic dysplasia: fitting the pieces together.

A 7-year-old boy was admitted for a general tonic-clonic seizure with severe hypoglycaemia (1.39 mmol/l). His medical history was remarkable for a congenital left eye strabismus, unilateral cryptorchidism and three previous episodes of hypoglycaemic seizures with inconclusive metabolical and neurological investigations. Physical examination revealed a hoarse tone voice, dry skin, cold extremities and height in the third percentile (target height between 50th and 85th percentile). Left wrist radiography revealed a bone age of 4.5 years ±6 months Laboratory studies confirmed growth hormone deficiency and central hypothyroidism. The brain MRI showed an ectopic neurohypophysis. Neuroophthalmology investigation revealed left optic nerve hypoplasia and septo-optic dysplasia was then diagnosed. Thyroid and recombinant growth hormone replacement were started showing clinical improvement. A detailed clinical history and a careful physical examination in children presenting with multiple clinical signs of hypopituitarism may lead to a timely diagnosis, avoiding clinical morbidity associated to untreated hormonal abnormalities.

Septo-optic dysplasia in childhood: the neurological, cognitive and neuro-ophthalmological perspective.

AIM: We set out to describe 17 patients with septo-optic dysplasia (SOD), focusing on the little-explored neurological, cognitive, and neuro-ophthalmological components. A further aim was to identify possible clinical correlations and phenotypic characteristics within the diagnostic spectrum. METHOD: We collected clinical-instrumental data (from the history, general and neurological examination, developmental assessment, and neuro-ophthalmological, neuroradiological, neurophysiological, and endocrinological evaluations) on nine males and eight females (mean age 34.4mo, SD 31.6; range 4mo-9y 6mo) diagnosed with SOD who were referred to our Centre of Child Neuro-ophthalmology between 1999 and 2010. RESULTS: We observed a heterogeneous clinical spectrum characterized by nervous system, visual, and endocrine dysfunctions; optic nerve involvement was present in all 17 children, midline brain defects in 14, and cortical developmental malformations in seven. Developmental/cognitive delay and relational and communication difficulties were observed in eight and seven children, respectively, and reduced visual acuity and oculomotor dysfunction were observed in all. Pituitary hormone deficiencies were present in nine children. INTERPRETATION: Nervous system involvement emerged as a key feature of SOD. As part of a holistic approach to the disease, particular attention should be paid to this aspect. The emergence of new clinical correlations and correlations between clinical features and three SOD subtypes opens the way for better clarification of this disease and, therefore, more targeted diagnosis, follow-up, and care of affected children.

Reappraisal of the optic nerve hypoplasia syndrome.

BACKGROUND: Optic nerve hypoplasia (ONH) has been described as an increasingly prevalent cause of congenital blindness. Its association with hypopituitarism and absent septum pellucidum has been recognized for more than 40 years as "septo-optic dysplasia" or "de Morsier syndrome." More recent studies have suggested that these associations are independent of one another. This review was designed to assess the historical and recent evidence for associations of neuroradiologic, endocrinologic, and developmental problems in patients with ONH. EVIDENCE ACQUISITION: Historical and contemporary literature review. RESULTS: The medical literature does not support the notion that Georges de Morsier ever described a case of ONH or recognized its association with hypopituitarism or missing septum pellucidum. Recognition of the critical association of ONH with hypopituitarism should be attributed to William Hoyt. Hypopituitarism and other more recently identified associations with ONH, such as developmental delay, hypothalamic dysfunction, and autism, are independent of septum pellucidum development. Other common neuroradiographic associations, such as corpus callosum hypoplasia, gyrus dysplasia, and cortical heterotopia, may have prognostic significance. CONCLUSIONS: Children with ONH need to be monitored for many systemic, developmental, and even life-threatening problems independent of the status of the septum pellucidum. "Septo-optic dysplasia" and "de Morsier syndrome" are historically inaccurate and clinically misleading terms that should be abandoned.

Posterior pituitary (PP) evaluation in patients with anterior pituitary defect associated with ectopic PP and septo-optic dysplasia.

OBJECTIVE: Controversies exist about posterior pituitary (PP) function in subjects with ectopic PP (EPP) and with cerebral midline defects and/or their co-occurrence. We investigate water and electrolyte disturbances in patients at risk for PP dysfunction. DESIGN: The study was conducted in a single Pediatric Endocrinology Research Unit. METHODS: Forty-two subjects with childhood-onset GH deficiency were subdivided into five groups: normal magnetic resonance imaging (n=8, group 1); EPP (n=15, group 2); septo-optic dysplasia (SOD) with normal PP (n=4, group 3); EPP and SOD without (n=7, group 4), and with additional midline brain abnormalities (n=8, group 5). At a mean age of 16.0±1.1 years, they underwent a 120 min i.v. infusion with hypertonic 5% saline and evaluation of plasma osmolality (Posm), arginine vasopressin (AVP), thirst score (in groups 1 and 2), and urinary osmolality were performed. RESULTS: Mean Posm and AVP significantly increased from baseline scores (284.7±4.9 mosm/kg and 0.6±0.2 pmol/l) to 120 min after saline infusion (300.5±8.0 mosm/kg and 10.3±3.3 pmol/l, P<0.0001). Group 5 showed higher mean Posm and lower mean AVP at all time points (P<0.0001). Mean thirst score did not show a significantly different trend between the groups 1 and 2. Urine osmolality was above 750 mosm/kg in all but seven patients after osmotic challenge. CONCLUSIONS: Patients with midline brain abnormalities and EPP have defective osmoregulated AVP. Patients with EPP and congenital hypopituitarism have normal PP function.

Septo-optic dysplasia.

Septo-optic dysplasia is a rare disorder characterized by optic nerve hypoplasia; midline developmental defects including agenesis of the septum pellucidum, thinning or absence of the corpus callosum, or both; and deficiencies of pituitary hormones. The majority of cases are sporadic but rare familial cases occur. The clinical manifestations include poor visual function in one or both eyes, developmental delay, seizures, sleep disturbances, and precocious puberty. A life-long multidisciplinary approach is crucial in the management of these patients to optimize their growth and development and to help them lead as normal lives as possible.

Rest-activity disturbances in children with septo-optic dysplasia characterized by actigraphy and 24-hour plasma melatonin profiles.

INTRODUCTION: A trial of melatonin treatment in children with septo-optic dysplasia (SOD) and sleep disruption is accepted clinical practice in many centers. However, no objective measurements of sleep/activity patterns with 24-h melatonin profiles have been published for these individuals, and the pathophysiological basis underlying sleep disorders in SOD remains largely unknown. METHODS: We studied six children with rest-activity disturbances and SOD. All wore an Actiwatch-Mini (a noninvasive method of detecting and recording movement intensity) for 2 wk and were admitted to hospital for a 24-h period during which hourly measurements of serum melatonin were taken. Sleep data were analyzed in conjunction with a detailed sleep diary. Ethical approval was obtained for these studies. RESULTS: Two children produced virtually no melatonin throughout the 24-h period of measurement and had fragmented sleep patterns with no evidence of a non-24-h sleep-wake disorder or delayed sleep-phase disorder. One child had a normal melatonin profile despite actigraphy showing an arrhythmic sleep pattern. The remaining three children had fragmented sleep, with two having normal melatonin profiles and one having a modest increase in daytime melatonin concentrations, making the timing of dim-light melatonin onset difficult to discern. CONCLUSIONS: There is considerable variation in timing and amount of melatonin secretion in these children. Surprisingly, none of the children had either actigraphic or melatonin profile evidence of a non-24-h sleep-wake disorder or delayed sleep-phase disorder. Understanding the heterogeneous nature of underlying sleep disorders in this group of children is important and has implications for their management.

A patient with septo-optic dysplasia plus.

Septo-optic dysplasia (SOD) is an uncommon developmental disorder involving variable midline brain structures, characterized by optic nerve hypoplasia, dysgenesis of septum pellucidum, and pituitary-hypothalamic dysfunction such as growth hormone deficiency. The phenotype is highly variable and the clinical presentation may be mild or extremely severe. Other distinct features, which occur especially when cerebral cortical abnormalities are also present (SOD-plus), consist of significant generalized developmental delay and/or spastic motor deficits. We report a case of SOD-plus with mild cortical dysplasia which was revealed to be thickening of bilateral insular cortex without schizencephaly by MRI, and there was no sign or symptom of cortical dysfunction except for one episode of brief seizure.