• By: Karen G. Zaarour, MD; Elias I. Traboulsi, MD
    A Compendium of Inherited Disorders and the Eye, Oxford University Press
    Genetics

    OMIM Numbers

    • 304050

    Inheritance

    • X-linked dominant
    • Lethal in hemizygous males
    • De novo mutation

    Gene/Gene Map

    • Xp22

    Epidemiology

    • The incidence rates of Aicardi syndrome are estimated at 1:105,000 in the US, 1:93,000 in the Netherlands, and 1:110,000 in Northern Ireland. There are more than 850 cases in the US and the worldwide estimate of prevalence is several thousand. A prevalence of 0.63 per 100,000 females was found in Norway.1
    • Kroner et al. (2008) found that the risk of death peaked at age 16 years. The probability of survival to 27 years of age was 0.62 and the risk of death by age follows other congenital neurological disorders, with a wide range in severity of functional disability.2

    Description

    • Jean Aicardi et al. first described this condition, now named after him, in 1965.3 It is a rare neurodevelopmental disorder originally characterized by the triad of:
      • Infantile spasms
      • Partial or total agenesis of the corpus callosum
      • Typical lacuna-shaped chorioretinal lesions
    • Sutton et al. (2005) proposed modified diagnostic criteria for Aicardi syndrome.4 It was suggested that if all 3 classic features of the triad were present, the diagnosis would be clinically confirmed. If 2 classic features plus at least 2 other major or supporting features were present, the diagnosis would be highly suspected.
      • Major features include:
        • Cortical malformations
        • Periventricular and subcortical heterotopia
        • Cysts around the third cerebral ventricle and/or choroid plexus
        • Optic disc/nerve coloboma or hypoplasia
      • Supporting features:
        • Vertebral or rib abnormalities
        • Microphthalmia

    Clinical Findings

    • The clinical outcome is generally severe, with poor cognitive development, moderate to severe global developmental delay, and difficult-to-treat epilepsy, although Grosso et al. (2007) reported a case of Aicardi syndrome with normal cognitive functions. In most cases, seizures manifest before one year of age, and many girls present with severe episodes during the first 3 months of life.5
    • Multiple structural central nervous system abnormalities have been documented, including: cortical migration anomalies (eg, pachygyria, cortical heterotopia and polymicrogyria), cysts around the third cerebral ventricle, pineal cyst, arachnoid cyst, cerebral hemispheric asymmetry, microcephaly, ventricular septal defect, colpocephaly, enlargement of the tectum, and a Dandy-Walker variant.
    • Aicardi syndrome may also be associated with systemic anomalies such as vertebral malformations (eg, fused vertebrae, scoliosis, spina bifida), costal malformations (eg, absent ribs, fused or bifurcated ribs), hip dysplasia, muscular hypotonia, polydactyly, cleft lip and/or palate, auricular anomalies, hiatal hernia, gastrointestinal tract dysfunction, autism traits, and precocious or delayed puberty.
    • A constellation of facial anomalies (prominent premaxilla, upturned nasal tip, decreased angle of nasal bridge, sparse lateral eyebrows, deep philtrum, upslanting palpebral fissures) has also been described in Aicardi syndrome.
    • A few patients have developed tumors such as choroidal plexus papilloma, teratoma of the soft palate, embryonal carcinoma of the cheek, hepatoblastoma, nevoid hypertrichosis of the face, oral extragonadal yolk sac tumor, orbital ectopic brain tissue, orbital cyst, arachnoid cyst, metastatic angiosarcoma with scalp lipoma, and large cell medulloblastoma.6-12

    Ocular Findings

    • In his report of a large case series in 1969, Aicardi stated that the ocular findings of chorioretinal lacunae are an essential feature of this syndrome. Although virtually pathognomonic of Aicardi syndrome, they have been seen in other conditions, including orofaciodigital syndrome type IX. The chorioretinal lacunae consist of well-circumscribed, full-thickness defects limited to the retinal pigment epithelium (RPE) and choroid, with an intact overlying retina that may appear histologically abnormal. These lesions are most commonly found around the optic nerve head and the posterior pole (Figure 1) and typically decrease in size towards the peripheral fundus (Figure 2). Previous reports have noted increased pigmentation or fading of lacunae over time. Unilateral chorioretinal lacunae do not rule out the diagnosis of Aicardi syndrome in the presence of the clinical picture of the syndrome.13

    Figure 1. Left eye of a patient with Aicardi syndrome. The optic nerve head is dysplastic and has a grayish appearance. There are 3 lacunar lesions around the disk.

    Figure 2. Left eye of another patient with Aicardi syndrome revealing an inferior para-papillary lacuna, as well as a large oval area of RPE depigmentation inferiorly. Note numerous midperipheral ovoid depigmented lesions.

    • Description of RPE structures in postmortem histopathological studies have shown variable findings ranging from absence of RPE, attenuated RPE, or hyperplasia of RPE with lacunae. The choriocapillaris vessels were found to be decreased in caliber and number at the level of lacunae. Some histopathological specimens showed well-preserved neurosensory retina, whereas others showed glial tissue replacing the neurosensory retina overlying lacunae.
    • A more recent chorioretinal architecture study by optical coherence tomography and fluorescein angiography in an 8-month-old girl with Aicardi syndrome demonstrated that lacunae are, in fact, subretinal fluid-filled cavities overlying typically absent RPE. Thin choroid and sclera form the base of these cavities. An abnormal neurosensory retina, characterized by disruption of the photoreceptors and intraretinal cysts, overlies the cavities.14
    • Other ophthalmic features include optic nerve coloboma or hypoplasia and microphthalmia. Other features have been reported more sporadically, including optic nerve aplasia, increased rate of excavated disc anomalies, morning glory abnormality, nystagmus, sixth cranial nerve palsy, persistent pupillary membrane, iris cyst, iris coloboma, aniridia, peripheral retinal dysplasia, glial tissue extending from the optic disc, hyperplastic primary vitreous, detached retina, choroidal neovascularization (treated successfully with bevacizumab), retinopathy of prematurity, severe congenital ptosis, and late onset retinoblastoma.15–20

    Neuroimaging findings

    • The diagnosis of Aicardi syndrome can be suspected by prenatal ultrasound with color Doppler identifying the agenesis or dysgenesis of the corpus callosum. In the neonatal period, dysgenesis can be identified by transfontanellar ultrasound.21
    • Hopkins et al. (2008) reported detailed brain magnetic resonance imaging (MRI) findings of 23 patients with Aicardi syndrome. Apart from corpus callosum partial or total agenesis, additional neuroimaging findings included ventriculomegaly with colpocephaly, polymicrogyria, periventricular and subcortical heterotopias, intracranial cysts, and cerebellar abnormalities.22
    • Diffusion tensor imaging at 3 Tesla performed on 2 subjects with Aicardi syndrome by Wahl et al. revealed a widespread disruption in the corticocortical white matter organization, which appeared to be specific to Aicardi syndrome and not shared by other neurodevelopmental disorders with similar anatomic manifestations.23

    Genetic studies

    • Despite a well-recognized clinical picture for more than 50 years, the etiology of Aicardi syndrome is still unknown. Considering Aicardi syndrome as a monogenic X-linked dominant disease caused by a de novo mutation in a gene in the X chromosome has been a leading hypothesis.6,24
    • Ropers et al. (1982) found a case of Aicardi syndrome in a girl in whom the breakpoint was in Xp22, between p22.2 and p22.3.25,26 Donnerfeld et al. (1989) found normal chromosomes in 17 out of 18 patients with Aicardi syndrome, except for an unbalanced X;3 translocation involving a breakpoint at Xp22.3 in a girl with chorioretinal lacunar lesions characteristic of the syndrome, in addition to developmental delay and infantile seizures. However, her brain MRI and CT failed to show any dysgenesis of the corpus callosum.27 Nielson et al. (1991) also failed to find any evidence of microdeletion in a patient with Aicardi syndrome using 5 DNA markers from the Xp22.3-p21.3 region.28
    • Astrocytic inclusions containing filamin have been found, but the molecular defect is not yet known.29,30 Genetic studies attempting to identify the mutated gene using array comparative hybridization with genome-wide DNA-microarrays31 and X –chromosome DNA-microarrays32 have not been successful to date. The variability in the severity of the Aicardi syndrome phenotype could be attributed to the presumed mutated gene undergoing X-chromosome inactivation. Studies on this topic have shown contradictory results, showing either random or skewed X-chromosome inactivation patterns. A non X-linked cause of Aicardi syndrome has been suggested, partly due to a lack in several X-inactivation studies of nonrandom X chromosome inactivation, which would be expected in a disorder with an X-linked genetic defect.33 However, this is not always present in X-linked disorders such as Rett syndrome. Furthermore, a causal mutation in an autosomal gene with a sex-limited  effect that causes Aicardi syndrome in females has also been considered.34
    • Aicardi syndrome has been reported several times in 47, XXY males35–37, which is still consistent with an X-linked dominant inheritance with a possibility of mosaic pathogenic variants in the presumed Aicardi syndrome gene. However, the affected XY males reported by Curatolo et al. (1980), Aggarwal et al. (2000) and Chappelow at al. (2008), argue against this putative hypothesis.38–40
    • Until the genetic etiology of Aicardi syndrome is confirmed, the possibility of a de novo pathogenic variant on an autosome with gender-limited expression in females remains. A recent publication identified de novo mutation in 2 affected girls: one carried a nonsense mutation in TEAD1 (OMIM 189967) and the second manifested a missense mutation in OCEL1.41 These data suggested that the clinical diagnosis of Aicardi syndrome may be genetically heterogeneous, and may be caused by mutation in autosomal genes. However, Bibiana Wong et al. (2017), sequenced TEAD1 and OCEL1 coding regions using DNA from 38 clinically well-characterized girls with the syndrome and failed to detect the previously reported variants, suggesting that these previously published variants represent either an extremely rare cause of Aicardi syndrome or an incidental finding.42
    • Peripapillary chorioretinal lacunae in a girl with 3q21.3 to 3q22.1 microdeletion with features of Aicardi syndrome was described.43 A molecular characterization of a monosomy 1p36, presented as an Aicardi syndrome, raised the question of whether to consider the monosomy 1p36 in the differential diagnosis of the syndrome. However, the girl lacked typical chorioretinal lacunae.44
    • Nemos et al. (2009) excluded mutations in the CDLK5 gene (300203) previously attributed to early infantile epileptic encephalopathy and the development of Rett syndrome-like features in 10 French patients with Aicardi syndrome.45

    Differential diagnosis

    • Agenesis of the corpus callosum in isolation or in association with other brain malformations or syndromes.
    • Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) (OMIM 152950).
    • Neuronal migration disorders, such as polymicrogyria, pachygyria and heterotopia.
    • Oculocerebrocutaneous syndrome (OCCS) (OMIM 164180).
    • Infantile spasms in isolation or as part of other syndromes.
    • Orofaciodigital syndrome type IX (OFD 9) (OMIM 258865) also may manifest chorioretinal lacunae.
    • Goltz syndrome (microphthalmia and other developmental eye defects) and microphthalmia with linear skin (MLS) defects syndrome.

    Therapeutic considerations

    • Treatment generally consists of multiple antiepileptic medications and general supportive measures. Chau et al. (2004) demonstrated a role of early treatment with vigabatrin in improving outcome in Aicardi syndrome.46 However, seizures are frequent, of different types (predominantly spastic flexion seizure) and typically refractory to medical therapy.
    • Palliative epilepsy surgery such as corpus callostomy of a partial corpus callosum, vagus nerve stimulator implantation and hemispherectomy, showed variable outcomes ranging from near complete resolution of seizures to worsening of seizure profile.47
    • Associated health issues, such as tumors or aspiration pneumonia, should be treated promptly to improve prognosis.
    • Physical therapy, speech therapy, occupational therapy, and vision therapy should be started as soon as possible to ensure the maximum functionality and quality of life.
    • Appropriate musculoskeletal therapy for management of scoliosis-related complications and spasticity is of high importance.
    • Genetic counseling is advocated.

    References

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