Chorioretinal Lacunae Research Articles

Teaching Neuroimage - Aicardi Syndrome: A Triad of Epileptic Spasms, Agenesis of Corpus Callosum, and Chorio-Retinal Lacunae.

Teaching Neuroimage - Aicardi Syndrome: A Triad of Epileptic Spasms, Agenesis of Corpus Callosum, and Chorio-Retinal Lacunae.

Microcephaly and Chorioretinopathy Relevance as a Differential Diagnosis.

Microcephaly and chorioretinopathy are genetic disorders that are inherited in an autosomal recessive manner. The most frequent ocular manifestation is the presence of lacunar atrophy in the retina and choroid. The diagnosis of this condition can be challenging as several potential causes and related syndromes need to be ruled out. We present two cases of microcephaly and chorioretinopathy in Mexican patients, their clinical characterization, and discuss the differential diagnoses that should be considered. An 8-year-old girl was examined due to a history of decreased vision in both eyes. Fundus examination showed excavated, well-defined, sectorial, bilateral, and symmetrical areas of chorioretinal atrophy. An 18-year-old male had a history of poor vision since childhood. Previous ophthalmological examinations reported bilateral symmetric chorioretinal atrophy with pigment accumulation. Both patients had a prior diagnosis of microcephaly and language delay. Blood tests and a comprehensive systemic evaluation ruled out intrauterine infections. The electroretinogram showed decreased amplitude and increased implicit time in the photopic and scotopic responses. Genetic tests revealed mutations in the TUBGCP4 gene, leading to a diagnosis of microcephaly and chorioretinopathy. As observed in these cases, there was variability in retinal lesions. The presence of chorioretinal lacunae and genetic testing can help to correctly diagnose this disorder.

Aicardi Syndrome Is a Genetically Heterogeneous Disorder.

Aicardi Syndrome (AIC) is a rare neurodevelopmental disorder recognized by the classical triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile epileptic spasms syndrome. The diagnostic criteria of AIC were revised in 2005 to include additional phenotypes that are frequently observed in this patient group. AIC has been traditionally considered as X-linked and male lethal because it almost exclusively affects females. Despite numerous genetic and genomic investigations on AIC, a unifying X-linked cause has not been identified. Here, we performed exome and genome sequencing of 10 females with AIC or suspected AIC based on current criteria. We identified a unique de novo variant, each in different genes: KMT2B, SLF1, SMARCB1, SZT2 and WNT8B, in five of these females. Notably, genomic analyses of coding and non-coding single nucleotide variants, short tandem repeats and structural variation highlighted a distinct lack of X-linked candidate genes. We assessed the likely pathogenicity of our candidate autosomal variants using the TOPflash assay for WNT8B and morpholino knockdown in zebrafish (Danio rerio) embryos for other candidates. We show expression of Wnt8b and Slf1 are restricted to clinically relevant cortical tissues during mouse development. Our findings suggest that AIC is genetically heterogeneous with implicated genes converging on molecular pathways central to cortical development.

Aicardi syndrome

ABSTRACT Aicardi syndrome is a rare neurodevelopmental disorder occurring primarily in female children. It is thought to have X-linked dominant inheritance and the affected male foetuses do not survive to term. A 3-year-old girl child with refractory infantile spasms and corpus callosal agenesis was found to have chorioretinal lacunae in the left eye on fundus examination. A clinical diagnosis of Aicardi syndrome was made which was confirmed with intracranial imaging.

Full Mouth Rehabilitation of a Child with Aicardia-Goutières: A Rare Syndrome

Aicardi-Goutières Syndrome (AGS) is a rare genetic disorder with autosomal recessive inheritance. AGS is characterised by an earlyonset encephalopathy that usually, but not always, results in severe intellectual and physical disability. Involuntary muscular spasms between the ages of four months and four years are the typical starting point for Aicardi syndrome. Hepatosplenomegaly, increased liver enzymes, thrombocytopenia, and abnormal neurologic signs in a subgroup of AGS children at birth strongly imply congenital infection. Agenesis of the corpus callosum, chorioretinal lacunae, and seizures are all symptoms of Aicardi syndrome. They frequently exhibit the subacute onset of a severe encephalopathy that is characterised by intense irritability, sporadic sterile pyrexias, loss of abilities, and slowed head growth. In 40% of cases, skin lesions like chilblains can appear on the fingers, toes, and ears. This disease can be diagnosed with Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) scans with the appearance of calcification of the basal ganglia. The associated behavioral challenges with syndromic patients demand pharmacological management of oral rehabilitation. The literature is scarce regarding the oral manifestations of this syndrome. Hence, authors present the successful fullmouth rehabilitation of severe Early Childhood Caries (ECC) in a 3-year-old child with AGS under General Anaesthesia (GA).

Basal Ganglia Dysmorphism in Patients With Aicardi Syndrome.

Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed. Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed. Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported). The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome. This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.

3D facial morphometry in Italian patients affected by Aicardi syndrome

Aicardi syndrome (AIC) is a rare congenital neurodevelopmental disorder of unknown etiology, that affects almost exclusively females, originally characterized by corpus callosum agenesis, chorioretinal lacunae, and infantile spasms. The current diagnostic criteria also include qualitative facial features (prominent premaxilla, upturned nasal tip, decreased nasal bridge angle, sparse lateral eyebrows, and microphthalmia) that still need quantification. A three-dimensional (3D) photogrammetric assessment of 11 Italian females, age 7-32 years, who satisfied AIC criteria, was performed. Linear distances and angles were computed from soft-tissue facial landmarks coordinates. The z-score values were calculated using data of 850 healthy reference females matched for age and compared by Mann-Whitney test (p < .01). Patients showed a shorter philtrum and right side orbital height (mean z-scores: -1.7, -0.9), shorter superior, middle, and inferior facial depths (mean z-scores: -1.3, -2.2, -2.3), and a smaller length of mandibular ramus (mean z-score: -2.1); conversely, they showed larger nasal and lower facial widths, and lower facial convexity (mean z-scores: 1.7, 1.4, 2.4). The inclinations of the orbit versus the true horizontal were increased bilaterally (mean z-scores: 1.8, 1.1). Some common facial abnormalities were quantified in AIC patients using a noninvasive instrument. They may help clinicians in performing a definite AIC diagnosis in atypical or doubt cases.

Morning glory optic nerve in Aicardi syndrome: Report of a case with fluorescein angiography

Aicardi syndrome is an X-linked condition that is associated with multiple ophthalmic malformations. Here, we report the first published fluorescein angiography (FA) study of a morning glory optic nerve in a patient with Aicardi syndrome and contralateral persistent fetal vasculature (PFV). A 12-day old full-term baby girl with a normal neurological exam was referred for evaluation of microphthalmia. The posterior segment of the right eye demonstrated chorioretinal lacunae typical of Aicardi syndrome and microphthalmos with a stalk consistent with PFV. The right eye imaging could not be captured due to the severe microphthalmos and cataract, however, fluorescein angioscopy was performed. The left eye demonstrated a morning glory appearing optic disc with peripapillary chorioretinal lacunae. Fluorescein angiography of the eye showed and late staining in the areas of ellipsoid chorioretinal lacunae emanating from the optic nerve and extensive peripapillary staining and late leakage of the optic nerve. Patients with Aicardi syndrome can have morning glory optic nerve anomaly and PFV. Using FA under anesthesia to detect these abnormalities help in estimating the extend of the disease and its complications, which allows for better management of the complications.

Aicardi syndrome, an unsolved mystery: Review of diagnostic features, previous attempts, and future opportunities for genetic examination.

Aicardi syndrome is a rare, severe neurodevelopmental disorder classically characterized by the triad of infantile spasms, central chorioretinal lacunae, and agenesis of the corpus callosum. Aicardi syndrome only affects females, with the exception of a few males with a 47, XXY chromosome constitution. All cases are de novo and the only cases of definitive recurrence in families are in identical twins. It is now recognized that individuals with Aicardi syndrome commonly exhibit a variety of other neuronal migration defects, eye anomalies, and other somatic features, including skin, skeletal, and craniofacial systems. The etiology of Aicardi syndrome remains unknown despite an international effort exploring different genetic mechanisms. Although various technologies examining candidate genes, copy number variation, skewing of X-chromosome inactivation, and whole-exome sequences have been explored, no strong genetic candidates have been identified to date. New technologies that can detect low-level mosaicism and balanced rearrangements, as well as platforms examining changes at the DNA and chromatin level affecting regulatory regions are all potential avenues for future studies that may one day solve the mystery of the etiology of Aicardi syndrome.

Seizures and chorioretinal lacunae in an infant.

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EP01.13: Prenatal diagnosis of Aicardi syndrome: a case report

Aicardi syndrome (AS) is a rare neurogenic disorder characterised by the triad of corpus callosum dysgenesis (ACC), chorioretinal ‘lacunae’, and infantile spasms. The diagnosis of ACC is feasible by sonography, yet chorioretinal lacunae are very difficult to diagnose. There are also some additional brain abnormalities including: malformation of the cortical development (MCD), interhemispheric cyst and heterotopia. Therefore the diagnosis of AS largely dependent on neurosonography (NSG). A 24–year-old woman, para 0, was referred to our hospital due to a suspicion of fetal brain anomaly at 22 weeks of gestation. Multiple cysts of the fetal brain were noted on axial plane. NSG revealed a complete ACC, interhemispheric arachnoid cysts, a choroid plexus cyst, asymmetry between 2 cerebral hemispheres and suspected MCD. The diagnosis of AS was made according to our NSG findings. The findings of the fetal MRI do not contribute to the final diagnosis because our radiologist overlooked the MCD. The couple chose to terminate the pregnancy. A female abortus was born. Necropsy was declined. The karyotype was normal female and the arrays CGH was normal. The first clue in making the diagnosis in our case was the finding of ACC. Either complete or partial type can be diagnosed by NSG. Intracranial cysts were easily found by both the fetal MRI and by NSG. Asymmetry between 2 cerebral hemispheres with irregular folds led us to suspect MCD and make the diagnosis of AS. Although most authors think fetal MRI is the gold-standard imaging modality for diagnosing AS, MCD is easily overlooked by the fetal MRI in early gestation like in our case. Because AS is mostly present in the female fetus, the prenatal exam should include gender. If there is a ACC with intracranial cysts in the female fetus, AS should be on the list of differential diagnosis. Subsequent NSG and fetal MRI should be used to scrutinise fetal brain anatomy.

Seizures and chorioretinal lacunae in an infant.

Seizures and chorioretinal lacunae in an infant.

Independent variant analysis of TEAD1 and OCEL1 in 38 Aicardi syndrome patients.

BackgroundAicardi syndrome is a severe neurodevelopmental disorder characterized by infantile spasms, typical chorioretinal lacunae, agenesis of the corpus callosum, and other neuronal migration defects. It has been reported recently that de novo variants in TEAD1 and OCEL1 each may cause Aicardi syndrome in a single individual of a small cohort of females with this clinical diagnosis. These data were interpreted to suggest that the clinical diagnosis of Aicardi syndrome may be genetically heterogeneous.MethodsTo investigate this further, we sequenced TEAD1 and OCEL1 coding regions using DNA from 38 clinically well‐characterized girls with Aicardi syndrome.ResultsWe did not detect the previously reported or any other deleterious variants in any of the analyzed samples.ConclusionsThis suggests that the published variants represent either an extremely rare cause of Aicardi syndrome or an incidental finding.

Iris cyst in a child with Aicardi syndrome: a novel association

Aicardi syndrome is a rare X-linked cerebro-retinal disorder characterized by agenesis or dysgenesis of the corpus callosum, seizures, and chorioretinal lacunae; microphthalmia or optic nerve coloboma may also be observed. We report the case of an infant born with severe ocular malformations, including an anterior chamber cyst in one eye, which was surgically removed.

A clinical study of Aicardi syndrome in Northern Ireland: the spectrum of ophthalmic findings

PurposeAicardi syndrome is a rare disorder, affecting ~1 in 100 000 live births. Chorioretinal lacunae feature alongside agenesis of the corpus callosum and spasms in flexion to make up a diagnostic triad. Recently ophthalmic findings such as microphthalmia and optic disc anomalies have been recognised in association with Aicardi syndrome. This population study aims to determine the presence of ocular findings and identifies some novel associations in these patients.MethodsA retrospective review of charts for seven patients with Aicardi syndrome was carried out.ResultsThe incidence of Aicardi syndrome in Northern Ireland was found to be 1 in 110 000 live births. Four patients who had microphthalmus also had iris abnormalities; two patients with bilateral microphthalmus had partial aniridia and two patients with unilateral microphthalmus had iris coloboma in the same eye. Optic disc abnormalities were found in 11 eyes of six patients. Two patients were found to have areas of fibrovascular proliferation with a thickened white ridge and avascular zone beyond. Both of these patients developed retinal detachments.ConclusionsOur review of patients with Aicardi syndrome in Northern Ireland has revealed some novel clinical findings, including aniridia in two cases. We also found a higher than previously reported rate of excavated disc anomalies of 50% in our cohort. We found two cases of peripheral retinal dysplasia, which has not been previously reported. This finding was associated with microphthalmus and severe optic disc abnormalities, and we feel this warrants early EUA to enable early treatment and hopefully result in better visual prognosis.

Professor Jean Aicardi

Professor Jean Aicardi

Aicardi syndrome with type 2b interhemispheric cyst

Agenesis of corpus callosum is a rare malformation of the brain. In Aicardi syndrome, it is associated with retinal lacunae and infantile spasms. Once Aicardi syndrome is diagnosed, one should look for other central nervous system malformations. We report a child who presented with developmental delay, chorioretinal lacunae and infantile spasms, due to Aicardi syndrome, associated with a type 2b interhemispheric cyst diagnosed on magnetic resonance imaging.

A De Novo Mutation in TEAD1 Causes Non-X-Linked Aicardi Syndrome.

Aicardi syndrome (AIC) is a congenital neurodevelopmental disorder characterized by infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae. Variation in phenotype and disease severity is well documented, but chorioretinal lacunae represent the most constant pathological feature. Aicardi syndrome is believed to be an X-linked-dominant disorder occurring almost exclusively in females, although 46, XY males with AIC have been described. The purpose of this study is to identify genetic factors and pathways involved in AIC. We performed exome/genome sequencing of 10 children diagnosed with AIC and their parents and performed RNA sequencing on blood samples from nine cases, their parents, and unrelated controls. We identified a de novo mutation in autosomal gene TEAD1, expressed in the retina and brain, in a patient with AIC. Mutations in TEAD1 have previously been associated with Sveinsson's chorioretinal atrophy, characterized by chorioretinal degeneration. This demonstrates that TEAD1 mutations can lead to different chorioretinal complications. In addition, we found that altered expression of genes associated with synaptic plasticity, neuronal development, retinal development, and cell cycle control/apoptosis is an important underlying potential pathogenic mechanism shared among cases. Last, we found a case with skewed X inactivation, supporting the idea that nonrandom X inactivation might be important in AIC. We expand the phenotype of TEAD1 mutations, demonstrate its importance in chorioretinal complications, and propose the first putative pathogenic mechanisms underlying AIC. Our data suggest that AIC is a genetically heterogeneous disease and is not restricted to the X chromosome, and that TEAD1 mutations may be present in male patients.

Aicardi Syndrome: An Epidemiologic and Clinical Study in Norway

BackgroundAicardi syndrome is a rare neurodevelopmental disorder. The main diagnostic features are agenesis of corpus callosum, chorioretinal lacunae, and infantile spasms. The outcome is in general severe, with poor cognitive development and difficult-to-treat epilepsy. The aim of this study was to perform a nationwide epidemiologic survey of patients with Aicardi syndrome and describe their clinical features. Norway is a small country with a well-developed health system, making epidemiologic studies of rare diseases feasible and reliable. MethodsWe aimed at identifying all patients diagnosed with Aicardi syndrome in Norway. Prevalence of Aicardi syndrome was calculated for January 1, 2011. All available patients were examined, and their medical records were scrutinized. ResultsSix females aged 7 to 27 years with the diagnosis of Aicardi syndrome were identified. With a female population of 949,578 in ages 0 to 29 years, we found an age-adjusted prevalence of 0.63 per 100,000 females. One patient never had epileptic seizures. The other five had all experienced infantile spasms, all had at some point hypsarrhythmia in electroencephalography, two had a clear picture of suppression burst, whereas three had periods of suppression. Four of the five patients with seizure disorders experienced a marked improvement with time. ConclusionWe found an age-adjusted prevalence of 0.63 per 100,000 females with Aicardi syndrome and that their seizure disorder appeared to improve with age.

Aicardi syndrome in a 47 XXY male – A variable developmental phenotype?

BackgroundAicardi syndrome (AS) is a rare neurodevelopmental disorder characterized by the triad of corpus callosum agenesis, chorioretinal lacunae, and infantile spasms. Most patients with AS also have intractable epilepsy, moderate to severe learning disability, and a reduced life expectancy. An X-linked dominant inheritance caused by de novo mutations pattern, lethal in males, is postulated, but the gene has not yet been isolated. There are three case reports of 47 XXY males with classic features of AS who all had severe developmental disability. Case reportWe report a case of a 3.5-year old 47 XXY male with the classic triad of Aicardi syndrome but with good seizure control and mild learning disability.