Aicardi Syndrome

Description

Aicardi syndrome is characterized by a triad of callosal agenesis, infantile spasms, and chorioretinal lacunae ('holes'). Flexion spasms in the infant represent the usual mode of clinical presentation (Aicardi, 1999).

Clinical Features

Aicardi et al. (1969) reported 15 cases, all in females.

Dennis and Bower (1972) described a female patient who, in addition to infantile spasms, mental subnormality, specific chorioretinopathy, and 'split brain,' had evidence of heterotopia of the brain by pneumoencephalogram, vertebral anomalies, and characteristic EEG changes.

Molina et al. (1989) reported the disorder in 2 sisters, the first observation of affected sibs. The parents were healthy. Germinal mosaicism is a possible explanation.

McPherson and Jones (1990) observed cleft lip and palate in Aicardi syndrome and referred to 2 similar previously reported cases. Jones and McPherson (1992) noted that one of the 2 previously reported cases (McPherson and Jones (1990)) had been reported by Robinow et al. (1984). In addition, Robinow had brought to their attention another case of Aicardi syndrome with cleft lip and palate (Sato et al., 1987), bringing the total number of such patients to 4. The patient of Sato et al. (1987) also had holoprosencephaly, another midline defect that may occur occasionally in Aicardi syndrome.

In an infant girl with Aicardi syndrome, Tsao et al. (1993) found associated scalp lipomas and a cavernous hemangioma of the leg which became malignant at 11 months, with distant metastases from metastatic angiosarcoma causing death at age 19 months.

Trifiletti et al. (1995) reported a 5-year-old girl with choroid plexus papilloma and multiple gastric hyperplastic polyps, and referred to previous cases of Aicardi syndrome associated with brain tumors, especially choroid plexus papilloma.

Menezes et al. (1994) described unusually mild Aicardi syndrome in a 10-year-old girl whose symptoms included poorly controlled seizure disorder, typical lacunar retinopathy, partial hypoplasia of the corpus callosum, and developmental delay of 4 to 5 years with marked inattentiveness. King et al. (1998) described an even milder case: a 49-year-old woman who was not severely mentally disabled and whose epilepsy had been well-controlled. She had dysgenesis of the corpus callosum and chorioretinal lacunae, which are typical of Aicardi syndrome. She had previously been diagnosed with cerebral and retinal toxoplasmosis, but there were no intracranial calcifications to support that diagnosis.

Sutton et al. (2005) studied 40 girls with Aicardi syndrome and determined that consistent facial features appeared in over half of them, including a prominent premaxilla, upturned nasal tip, decreased angle of the nasal bridge, and sparse lateral eyebrows. Externally apparent microphthalmia was seen in 10 (25%). Sutton et al. (2005) concluded that Aicardi syndrome has a distinctive facial phenotype.

Kamien and Gabbett (2009) reported a girl with features of Aicardi syndrome, including infantile spasms, chorioretinal lacunae, partial agenesis of the corpus callosum, and neuronal migration abnormalities, including nodular heterotopia and polymicrogyria. Dysmorphic features included upslanting palpebral fissures, an upturned nasal tip, deep philtrum, and large ears. In addition, she had a hepatoblastoma and intralobar pulmonary sequestration with congenital cystic adenomatoid malformation.

Neuroradiologic Findings

Hopkins et al. (2008) reported detailed brain MRI findings of 23 patients with Aicardi syndrome, performed at ages 1 day to 7.2 years. There were 22 girls and one 47,XXY male. All patients had polymicrogyria and periventricular heterotopia. Polymicrogyria was mainly in the frontal or perisylvian regions. Widening of the operculum was observed in 13 (72%) of 18 patients. Twenty (95%) patients had intracranial cysts, and 20 (95%) had cerebellar abnormalities, including superior foliar prominence of the vermis, inferior vermian hypoplasia, and dysplastic or hypoplastic cerebellar hemispheres. An enlarged cisterna magna was present in 11 (55%), and 4 (20%) had cerebellar cysts. Ten patients had tectal enlargements. The findings were consistent with a neuronal migration disorder and asymmetric brain development.

Cytogenetics

Ropers et al. (1982) reported a case of Aicardi syndrome in a girl with presumably balanced X/3 translocation. They postulated that the clinical picture was due to chromosome breakage in the Aicardi locus. The breakpoint was in Xp22, between p22.2 and p22.3. This is the same region as steroid sulfatase, XG (300879), and a gene controlling a serologically defined, male-specific antigen, SDM (Wolf et al., 1980). According to Frezal (1987), Aicardi doubted the validity of the diagnosis in the case of Ropers et al. (1982). Neidich et al. (1988) found 2 new patients with Aicardi syndrome and Xp22 abnormalities. They stated that all patients have been either XX female or 47,XXY Klinefelter syndrome.

Nielsen et al. (1991) used 5 DNA markers from the Xp22.3-p21.3 region to study the DNA from a patient with Aicardi syndrome. No evidence for a microdeletion was observed.

Ballabio and Andria (1992) analyzed deletions and translocations involving the distal short arm of the X chromosome. Their Figure 2 showed the order of genes in the region Xp22.3-p22.2: short stature (SS; 312865), X-linked recessive chondrodysplasia punctata (CDPX1; 302950), mental retardation (MRX2; 300428), X-linked ichthyosis (XLI; 308100), Kallmann syndrome (KAL; 308700), and, in the most proximal area, Aicardi syndrome and focal dermal hypoplasia (FDH; 305600). The last 2 lyonize, and with deletions males are nullisomic, a presumably lethal state. Females with monosomy show a mosaic pattern. The first 5 loci, which escape lyonization, behave as recessive traits. Schmidt and Du Sart (1992) presented evidence suggesting that in some X/autosomal translocations, the phenotype results from the functional disomy of the region of the X chromosome that is translocated to the autosome.

Bursztejn et al. (2009) reported an 8-year-old girl with an initial clinical diagnosis of Aicardi syndrome who was subsequently found to carry a de novo 11.73-Mb terminal deletion of chromosome 1p36 (607872), thus revising the diagnosis. She had onset of infantile spasms at age 3 months, bilateral pupillary coloboma, agenesis of the corpus callosum, and delayed psychomotor development. The report emphasized the phenotypic overlap between the 2 disorders.

Inheritance

The inheritance of Aicardi syndrome is probably X-linked dominant with lethality in the hemizygous male. All cases would, on this hypothesis, be new mutations (Aicardi et al., 1969; Aicardi, 1999).

Hopkins et al. (1979) described the Aicardi syndrome in a 47,XXY male. This is, of course, consistent with the above suggested inheritance.

The affected male reported by Curatolo et al. (1980) argues against X-linked dominant inheritance with male lethality.

In 18 girls with Aicardi syndrome identified through a survey of neurologists, geneticists, and ophthalmologists, Donnenfeld et al. (1989) found complete agenesis of the corpus callosum in 72% and partial agenesis in 28%. Costovertebral defects including hemivertebrae, scoliosis, and absent or malformed ribs were present in 39%. Chromosomes in all patients and their parents were normal. An unbalanced X;3 translocation involving a breakpoint at Xp22.3 was discovered in a girl with chorioretinal lacunar lesions characteristic of Aicardi syndrome, developmental delay, and infantile seizures. Because the child had a normal-appearing corpus callosum on CT and magnetic resonance scans, she did not meet the criteria for inclusion in the study. Family studies showed a ratio of unaffected male:female sibs of 1:1.7 and a 14% spontaneous abortion rate. The findings were considered consistent with the view that Aicardi syndrome is an X-linked dominant disorder with early embryonic lethality in hemizygous males and that all cases represent new mutations. The finding in the atypical case is consistent with location of the gene in the Xp22.3 area.

X-Inactivation Studies

Neidich et al. (1990) studied X inactivation in peripheral lymphocytes in 7 patients by means of 2 methods: methylation-sensitive restriction analysis and segregation of the active X chromosome in somatic cell hybrids. They found that 3 of the 7 cytogenetically normal girls with Aicardi syndrome had profoundly skewed X inactivation in their lymphocytes, supporting the concept that Aicardi syndrome is X-linked. Three of the 5 girls with the greatest degree of psychomotor retardation and the poorest seizure control had skewed X inactivation. In contrast, the 2 highest functioning children had random X inactivation. No evidence of deletion was found with 8 polymorphic DNA probes from the Xp22 region.

Using the highly polymorphic, differentially methylated androgen receptor gene (313700), Hoag et al. (1997) found a random X-inactivation pattern in 10 female patients with Aicardi syndrome. This finding was unexpected because skewed X inactivation had been observed in at least one other condition, incontinentia pigmenti, in which the mode of inheritance has been thought to be X-linked dominant mutation, de novo in females and lethal in males. This would be predicted if there were a selection against cells in which the X chromosome carrying the mutant allele was active.

Costa et al. (1997) reported monozygotic twins who were discordant for Aicardi syndrome. Methylation-sensitive RFLP analysis showed a very similar pattern of X inactivation in both twins with no evidence of preferential expression of one particular X chromosome. Costa et al. (1997) concluded that the abnormalities in the affected twin were probably due to a postzygotic event.

In informative samples from 33 girls with Aicardi syndrome, Eble et al. (2009) found that 11 (33%) had nonrandom X inactivation, with a greater than 80:20 skewed ratio. Six (18%) of these, had an extremely skewed ratio of greater than 95:5. There was a correlation between X-inactivation patterns and clinical severity, such that nonrandom X inactivation was associated with higher neurologic severity. Conversely, random X inactivation was correlated with vertebral anomalies.

Molecular Genetics

Exclusion Studies

Nemos et al. (2009) excluded mutations in the CDKL5 gene (300203) in 10 French patients with Aicardi syndrome.