Aicardi Syndrome

Clinical characteristics.

Aicardi syndrome is a neurodevelopmental disorder that affects primarily females. Initially it was characterized by a typical triad of agenesis of the corpus callosum, central chorioretinal lacunae, and infantile spasms. As more affected individuals have been ascertained, it has become clear that not all affected girls have all three features of the classic triad and that other neurologic and systemic defects are common, including other brain malformations, optic nerve abnormalities, other seizure types, intellectual disability of varying severity, and scoliosis.

Diagnosis/testing.

The diagnosis of Aicardi syndrome is based exclusively on clinical findings. Modified diagnostic criteria include either presence of the classic triad or the presence of two of the classic triad plus at least two other major or supporting features. A gene for Aicardi syndrome has not been identified, but several observations support a hypothesis that Aicardi syndrome is caused by de novo pathogenic variants in a gene on the X chromosome that is subject to X-chromosome inactivation.

Management.

Treatment of manifestations: Treatment is individualized and long-term management by a pediatric neurologist with expertise in management of infantile spasms and medically refractory epilepsy is essential. Physical therapy, occupational therapy, and speech therapy should begin at the time of diagnosis. Appropriate musculoskeletal support and treatment for prevention of scoliosis-related complications is indicated.

Surveillance: Includes routine monitoring of growth, nutritional status and safety of oral intake, seizure control, developmental progress and educational needs, respiratory function and aspiration risk, and the spine and degree of scoliosis.

Genetic counseling.

With the exception of affected monozygotic twin girls, all individuals with Aicardi syndrome reported to date have represented simplex cases (i.e., a single affected family member). Parent-to-child transmission of Aicardi syndrome has not been reported, and the recurrence risk to sibs is thought to be less than 1%. While prenatal ultrasound or intrauterine MRI findings of corpus callosum agenesis and neuronal migration abnormalities may be suggestive of Aicardi syndrome, no findings are diagnostic.

Clinical Description

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; however, as more affected individuals 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 (see Table 1).

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; Author, unpublished data]. Moderate-to-severe developmental delay and intellectual disability are typical, although individuals with only mild or no learning disabilities or developmental delay have been reported (reviewed in Wong & Sutton [2018]).

Many girls with Aicardi syndrome develop seizures before age three months, and most before age one year. Infantile spasms are seen early on; 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.

Brain MRI reveals dysgenesis of the corpus callosum, which is most often complete but can be partial. Polymicrogyria or pachygyria, which are predominantly frontal and perisylvian and associated with underopercularization, are typical. Periventricular and intracortical gray 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) [Fruhman et al 2012] that can cluster in the posterior pole of the globe around the optic nerve. The sensory retina overlying the lacunae is usually intact but may be disorganized or entirely absent.

Figure 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. Image courtesy of Dr Richard A Lewis

Almost all individuals have some ocular abnormalities. Fruhman et al [2012] described data on 40 females with Aicardi syndrome examined by a single expert ophthalmologist and retinal specialist. Of the 75 eyes that could be evaluated, all had chorioretinal lacunae. Other common optic nerve findings included:

• Coloboma (39% of eyes)
• Glial proliferation (19% of eyes)
• Severe dysplasia (17% of eyes)
• Pseudoadenomatous proliferation of the retinal pigment epithelium (14% of eyes)

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 one third 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. A variety of rare tumor types have been reported: benign tumors such as choroid plexus papillomas [Taggard & Menezes 2000, Pianetti Filho et al 2002] and lipomas, as well as malignant tumors including angiosarcomas, hepatoblastomas, meduloblastoma, embryonal carcinomas, and teratomas [Sutton et al 2005, Wharton et al 2018].

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 [Glasmacher et al 2007]. The weight-versus-height ratio remains similar to the general population.

Endocrine. Either precocious puberty or 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 survey by Glasmacher et al [2007], the mean age at death was 8.3 years, although the median age of death was 18.5 years. The ages of death were distributed from before age one year to older than 23 years. The oldest surviving individual reported in this survey was age 32 years. 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].

Nomenclature

Note: Aicardi syndrome is NOT related to Aicardi-Goutières syndrome, an early-onset encephalopathy.

Prevalence

Aicardi syndrome is very rare and appears to affect all ethnicities equally. Its incidence has been estimated at between 1:105,000 and 1:167,000 in the United States and between 1:93,000 and 1:99,000 in some European countries [Kroner et al 2008].

The exact prevalence of Aicardi syndrome is unknown; it has been estimated to be at least 853 in the US and over 4,000 worldwide [Kroner et al 2008].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Aicardi syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations