Diagnosis Clinical Diagnosis The diagnosis of Aicardi syndrome is based on clinical features. The classically described features of Aicardi syndrome consist of the triad of agenesis of the corpus callosum, distinctive chorioretinal lacunae, and infantile spasms. However, Aicardi syndrome is now recognized to be a more complex neurodevelopmental disorder with additional neuronal and extraneuronal manifestations. Based on these, modified diagnostic criteria have been proposed. The presence of all three classic features is diagnostic for Aicardi syndrome. The existence of two classic features plus at least two other major or supporting features is strongly suggestive of the diagnosis of Aicardi syndrome [Sutton et al 2005, adapted from Aicardi 1999]:Classic triadAgenesis of the corpus callosum Distinctive chorioretinal lacunae Infantile spasms Major featuresCortical malformations (mostly polymicrogyria)Periventricular and subcortical heterotopiaCysts around third cerebral ventricle and/or choroid plexusOptic disc/nerve coloboma or hypoplasiaSupporting featuresVertebral and rib abnormalitiesMicrophthalmia"Split-brain" EEGGross cerebral hemispheric asymmetryVascular malformations or vascular malignancyTesting No single laboratory or diagnostic imaging test can definitively establish a diagnosis of Aicardi syndrome. Ophthalmologic examination, brain magnetic resonance imaging (MRI) with and without contrast, electroencephalogram (EEG), and skeletal radiographs should be done to establish the clinical diagnosis. Molecular Genetic Testing Gene. Aicardi syndrome appears to be an X-linked dominant disorder with lethality in males, but no gene or candidate region on the X chromosome has been definitively identified. Several observations support a hypothesis that Aicardi syndrome is caused by de novo mutations of a gene on the X chromosome that is subject to X-chromosome inactivation [Van den Veyver 2002]. Nearly all affected individuals are female and, except for one pair of sisters and a pair of concordant monozygotic twins, all reported cases are simplex (i.e., a single occurrence in a family). At least six pairs of twins who are discordant for Aicardi syndrome are known, five of whom are confirmed dizygotic, excluding the possibility that the etiology is a prenatal toxin or other disruptive event [Taggard & Menezes 2000].Rare known males with a confirmed diagnosis of Aicardi syndrome have a 47,XXY karyotype [Aicardi 1999, Chen et al 2009, Zubairi et al 2009]. The presence of Aicardi syndrome in males with a 46,XY karyotype has been disputed, but new cases have recently been reported. It is possible that these are caused by mosaic mutations of the putative Aicardi syndrome gene [Chappelow et al 2008, Anderson et al 2009] The variable severity and asymmetry of the Aicardi syndrome phenotype could be explained if the putative mutated gene undergoes X-chromosome inactivation. Earlier limited studies, some using older methods, had conflicting results, showing either random or skewed X-chromosome inactivation patterns. The most recent study on 35 individuals with Aicardi syndrome, the largest series examined thus far, demonstrated non-random X-chromosome inactivation in leukocyte-derived DNA in 33% of 33 informative individuals, with 18% having extremely skewed patterns. This is significantly increased compared to the general population [Eble et al 2009]. Because a subset of the clinical findings of Aicardi syndrome (including colobomas, agenesis of the corpus callosum, microphthalmia, and seizures) overlaps with those of microphthalmia with linear skin defects syndrome (MLS) and with Goltz syndrome (focal dermal hypoplasia), it was hypothesized that these three conditions were allelic and that the gene for Aicardi syndrome was located on Xp22. However, sequencing and deletion studies now indicate that Aicardi syndrome is likely not allelic to MLS syndrome [Van den Veyver 2002] or to Goltz syndrome [Wang et al 2007]. Until the genetic basis of Aicardi syndrome is known, the possibility remains that Aicardi syndrome is caused by a new mutation on an autosome with gender-limited expression in females. Interestingly, a recent report describes a girl with an 11-Mb deletion of 1p36 who presents as an Aicardi syndrome phenocopy [Bursztejn et al 2009], though it is important to note that she did not have the chorioretinal lacunae typical of Aicardi syndrome and did have facial features and cardiac defects characteristic of the 1p36 deletion syndrome. Testing Strategy for a Proband Diagnosis depends exclusively on established clinical diagnostic criteria. Genetically Related (Allelic) Disorders Because the gene in which mutation is causative has not been identified, it is unknown whether other disorders are allelic to Aicardi syndrome.

Natural History Aicardi syndrome, first described by Aicardi et al [1965], is a neurodevelopmental disorder that affects primarily females [Aicardi 1999, Van den Veyver 2002, Aicardi 2005]. Initially it was characterized by a typical triad of agenesis of the corpus callosum, typical chorioretinal lacunae, and infantile spasms [Aicardi et al 1965, Donnenfeld et al 1989]. However, as more cases have been ascertained, it has become clear that other neurologic and systemic defects are common. Indeed, not all affected girls have all three features of the classic triad. Neurologic. The neurologic examination can reveal microcephaly, axial hypotonia, and appendicular hypertonia with spasticity often affecting one side and brisk deep tendon reflexes as well as hemiparesis [Aicardi 2005; unpublished data]. Moderate-to-severe global developmental delay and intellectual disability is expected, but individuals with only mild or no learning disabilities or developmental delay have been reported [Yacoub et al 2003, Chau et al 2004, Matlary et al 2004, Prats Vinas et al 2005, Grosso et al 2007, Kroner et al 2008]. Many girls with Aicardi syndrome develop seizures prior to age three months, and most before age one year. Infantile spasms are seen early on, but ongoing medically refractory epilepsy with a variety of seizure types develops over time. Common EEG findings include asynchronous multifocal epileptiform abnormalities with burst suppression and dissociation between the two hemispheres.The MRI reveals dysgenesis of the corpus callosum, which is most often complete, but can be partial [Donnenfeld et al 1989, Aicardi 1999]. Polymicrogyria or pachygyria, which are predominantly frontal and perisylvian and associated with underopercularization, are typical. Periventricular and intracortical grey matter heterotopia are very common. Gross cerebral asymmetry, choroid plexus papillomas, ventriculomegaly, and intracerebral cysts, often at the third ventricle and in the choroid plexus, are frequently present [Aicardi 2005, Hopkins et al 2008]. Recently, posterior fossa and cerebellar abnormalities are increasingly recognized as important components of the phenotype [Hopkins et al 2008, Steffensen et al 2009]. Ophthalmologic. The pathognomonic chorioretinal lacunae of Aicardi syndrome are white or yellow-white, well-circumscribed, round, depigmented areas of the retinal pigment epithelium and underlying choroid with variably dense pigmentation at their borders (Figure 1) [Donnenfeld et al 1989, Palmer et al 2006, Palmer et al 2007] that can cluster in the posterior pole of the globe around the optic nerve. The sensory retina overlying the lacunae is usually intact but can be disorganized or entirely absent. FigureFigure 1. Classic lacunae surround the modestly dysplastic left optic disc. Note the nasal "papilla nigra" appearance and the anomalous branching patterns of the central vasculature. Donnenfeld et al [1989] surveyed ophthalmologists to determine the incidence of various ophthalmologic findings in Aicardi syndrome. While these numbers may be of some help, clinicians should be aware that these data come from multiple ophthalmologists and that historically the chorioretinal lacunae have been the sine qua non for the diagnosis of Aicardi syndrome, even in the absence of dysgenesis of the corpus callosum [Iturralde et al 2006, Palmer et al 2006, Palmer et al 2007]. The reported incidences for the ophthalmologic findings in 18 patients: Punched-out chorioretinal lacunae, 100% (18/18) Unilateral microphthalmia, 33% (6/18) Optic nerve coloboma, 17% (3/18). The colobomas typically involve the optic nerve, choroid, and/or retina, but almost never the iris. Nystagmus, 6% (1/18) Detached retina, 6% (1/18) Other ophthalmologic findings include severe optic nerve dysplasia, optic nerve hypoplasia, and persistent fetal vasculature (previously known as persistent hyperplastic primary vitreous). All eye findings can be unilateral or bilateral and asymmetric. Craniofacial. Characteristic facial features reported in Aicardi syndrome include a short philtrum, prominent premaxilla with resultant upturned nasal tip and decreased angle of the nasal bridge, large ears, and sparse lateral eyebrows [Sutton et al 2005]. Plagiocephaly and facial asymmetry, occasionally with cleft lip and palate (3%), have been reported. Pierre-Robin sequence has been reported in a single case [Jensen & Christiansen 2004]. Skeletal. Costovertebral defects, such as hemivertebrae, block vertebrae, fused vertebrae, and missing ribs, are common and can lead to marked scoliosis in up to 1/3 of affected individuals [Donnenfeld et al 1989]. Hip dysplasia has been reported. Gastrointestinal. Constipation, gastroesophageal reflux, diarrhea, and feeding difficulties are perceived by parents to be the second most difficult problem to manage after seizures [Glasmacher et al 2007]. Extremities. Small hands, along with an increased incidence of hand malformations, have been reported [Sutton et al 2005]. Dermatologic. An increased incidence of vascular malformations and pigmentary lesions has been observed [Sutton et al 2005]. Tumors/malignancies. The incidence of tumors may be increased. The most common tumors are choroid plexus papillomas [Taggard & Menezes 2000, Pianetti Filho et al 2002]; however, lipomas, angiosarcomas, hepatoblastomas, intestinal polyposis, and embryonal carcinomas have also been described [Sutton et al 2005, Kamien & Gabbett 2009]. Large-cell medulloblastoma has been reported in a single case [Palmer et al 2004]. Growth. The average heights and weights of girls with Aicardi syndrome closely follow those of the general population up to ages seven and nine years, respectively, after which the growth rate for both height and weight is lower. Growth curves for Aicardi syndrome based on parent survey data have been published. The weight-versus-height ratio remains similar to the general population [Glasmacher et al 2007]. One survey did not document microcephaly, but objective measurements at a single point in time suggest that microcephaly occurs [Glasmacher et al 2007]. Endocrine. Both precocious puberty and delayed puberty may be present [Glasmacher et al 2007]. Survival. Survival in Aicardi syndrome is highly variable and likely depends on the severity of seizures. In a recent survey, the mean age at death was 8.3 years of age, although the median age of death was 18.5 years of age. The ages of death were distributed from less than one year to over 23 years. The oldest surviving individual reported in this survey was 32 years old [Glasmacher et al 2007]. Another paper also indicated that the survival is longer than previously reported, especially in more mildly affected individuals, with the highest risk of death at age 16 years and a probability of survival at age 27 years of 0.62 [Kroner et al 2008]. A 49-year-old woman with a mild form of the syndrome has been reported.

Genotype-Phenotype Correlations No information is available on genotype-phenotype correlations.

Differential Diagnosis Agenesis of the corpus callosum may occur in isolation or in conjunction with other brain malformations or as part of a larger syndrome. It has been suggested that agenesis of the corpus callosum in association with cysts that do not communicate with the ventricles and the presence of subependymal heterotopia and polymicrogyria are relatively specific for Aicardi syndrome [Barkovich et al 2001]. Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) (OMIM 152950) has similar retinal defects; however, in MCLMR chorioretinal changes are peripheral and optic nerves are normal, whereas in Aicardi syndrome the chorioretinal lacunae are central and the optic nerves are almost always involved. The degree of microcephaly is much more severe in MCLMR than in Aicardi syndrome and neuronal migration defects that are almost universal in Aicardi syndrome are uncommon in MCLMR.Neuronal migration disorders, including polymicrogyria (see also Polymicrogyria Overview), pachygyria, and heterotopia (see also X-Linked Periventricular Heterotopia), may occur as isolated malformations or as part of the phenotype associated with other syndromes or chromosome abnormalities. Oculocerebrocutaneous syndrome (OCCS) characterized by orbital cysts and anophthalmia or microphthalmia, focal skin defects, brain malformations that include polymicrogyria, periventricular nodular heterotopias, enlarged lateral ventricles, and agenesis of the corpus callosum, is predominant in males and has a pathognomonic mid-hindbrain malformation [Moog et al 2005]. Infantile spasms are observed in most girls with Aicardi syndrome, but this type of seizure is not specific for Aicardi syndrome. Infantile spasms may occur in isolation or as part of the phenotype of other syndromes, inborn errors of metabolism, or chromosome disorders (see also Tuberous Sclerosis Complex and Rett Syndrome). Ophthalmologic findings. Although chorioretinal lacunae are virtually pathognomonic for Aicardi syndrome, they have also been reported in orofaciodigital syndrome type IX (OFD 9) (OMIM 258865).Microphthalmia and other developmental eye defects may also be seen in other X-linked dominant disorders, such as Goltz syndrome and microphthalmia with linear skin (MLS) defects syndrome. However, these two disorders have characteristic skin defects and other features not seen in Aicardi syndrome. See also Anophthalmia/Microphthalmia Overview. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management Evaluations at Initial DiagnosisThe following are appropriate: Brain MRI with and without contrast to evaluate for corpus callosum dysgenesis and to search for heterotopias and other evidence of neuronal migration defects EEG performed as indicated for seizures and to evaluate the characteristic asynchronous multifocal epileptiform abnormalities with burst suppression and dissociation between the two hemispheres Dilated ophthalmologic examination to assess for chorioretinal lacunae and colobomas of the optic nerve, choroid, and retina Spine radiographs to assess for scoliosis and segmentation abnormalities of the vertebrae and ribs Dermatologic evaluation to look for vascular malformations and pigmentary lesions at risk for malignant transformation Clinical genetic and dysmorphology evaluation to confirm mode of inheritance, assess for the presence of craniofacial characteristics, evaluate for related disorders, and provide recurrence risk counseling Treatment of Manifestations A pediatric neurologist with expertise in the management of infantile spasms and medically refractory epilepsy is essential for long-term management of seizures. Individuals with Aicardi syndrome usually require multiple antiepileptic drugs (AEDs) for adequate seizure control. Improved outcome with vigabatrin [Chau et al 2004] and vagus nerve stimulators have been reported; however, these treatments do not work for all [Van den Veyver & Sutton, unpublished observation]. Physical therapy, occupational therapy, speech therapy, and vision therapy should begin at diagnosis to ensure the best functionality and developmental outcome possible. An individualized therapy plan should be developed and implemented by the therapists and caregivers. Resection of large choroid plexus papillomas has been reported for management of hydrocephalus [Taggard & Menezes 2000]. Improvement of seizures was also noted in the individual reported. Whether this improvement was related to resolution of the hydrocephalus or whether the choroid plexus papillomas may have been epileptogenic is not clear. Prevention of Secondary Complications Spasticity can result in contractures or limited range of motion affecting not only mobility but hygiene care as well. Patients benefit from evaluation by physicians specializing in physical medicine and rehabilitation as well as physical, occupational, and speech therapists. Costovertebral defects can lead to scoliosis. Appropriate musculoskeletal support and treatment for prevention of scoliosis-related complications is indicated. Constipation and gastrointestinal problems are frequent and require ongoing management at regular physician visits. Surveillance The following are appropriate:Routine dermatologic evaluation to monitor for vascular and other malignancies Monitoring for and treating gastrointestinal complications at regular physician visits Regular monitoring of the spine to assess the degree of scoliosis Evaluation of Relatives at RiskSee Genetic Counseling for issues related to genetic counseling of relatives at risk. Therapies Under Investigation Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table B. OMIM Entries for Aicardi Syndrome (View All in OMIM) View in own window 304050AICARDI SYNDROME; AICMolecular Genetic Pathogenesis A gene for Aicardi syndrome has not been identified, but clinical and molecular evidence suggests that it is on the X chromosome: affected individuals are almost uniquely female with rare 47,XXY males and there is evidence for increased skewing of X-chromosome inactivation [Eble et al 2009]. Efforts to identify the mutated gene using array comparative hybridization with genome-wide DNA microarrays [Wang et al 2009] and X-chromosome DNA microarrays [Yilmaz et al 2007] have not been successful to date.