Aicardi Syndrome

A rare neurodevelopmental disorder characterized by the classic triad of agenesis of the corpus callosum (total or partial), central chorioretinal lacunae and infantile spasms that affects almost exclusively females.

Epidemiology

About 200 individuals with Aicardi syndrome have been reported in North America and Europe, but the true prevalence is unknown. Single cases in males with 47, XXY chromosome constitution have been reported.

Clinical description

Individuals typically present within the first few months of life with infantile spasms and low muscle tone. In addition to the classic triad (agenesis of the corpus callosum, central chorioretinal lacunae and infantile spasms), other characteristics have been identified. All individuals manifest additional developmental brain abnormalities, with most presenting periventricular nodular heterotopias, brain cysts and polymicrogyria or pachygyria. While infantile spasms are the most common initial seizure type, most evolve into a complex pattern of partial and generalized seizures that are typically very difficult to control. In addition to chorioretinal lacunae, microphthalmia, retinal and optic nerve colobomas can be seen. Facial features, including prominent premaxilla, upturned nasal tip, decreased angle of the nasal bridge, and sparse lateral eyebrows have been described. Scoliosis is present in up to one third of affected individuals. Gastrointestinal disorders such as reflux, discomfort and constipation are nearly universal. Less common findings include cutaneous vascular malformations and pigmentary skin lesions. Vascular tumors have been reported in a few individuals.

Etiology

It is believed that Aicardi syndrome is a sporadic disorder caused by heterozygous pathogenic variants in an X-linked gene in females, with early embryonic lethality in hemizygous males; however, a candidate region on the X chromosome has not yet been identified due to the sporadic nature of the condition. Some groups have reported potential causative genes in single individuals but these have not been confirmed in larger studies.

Diagnostic methods

Diagnosis is based on clinical features, brain imaging and skeletal findings. There is no blood test or other clinical diagnostic test to confirm the diagnosis.

Differential diagnosis

Differential diagnosis includes microcephaly-chorioretinopathy with or without lymphedema (in this disorder, the lacunae are peripheral and the microcephaly is significant ; girls with Aicardi syndrome typically do not have microcephaly), oculocerebrocutaneous syndrome, neuronal migration disorders and numerous syndromes that present with one or more of the features characteristic for Aicardi syndrome.

Antenatal diagnosis

Prenatal diagnosis may be suspected based upon fetal brain imaging.

Genetic counseling

Aicardi syndrome appears to be a de novo, X-linked dominant disorder with lethality in males. There are no confirmed cases of familial recurrence.

Management and treatment

Long-term follow-up by a pediatric neurologist is necessary for management of seizures. Seizures are often refractory to multiple medication regimens and no single medication works for all; some have reported improvement with vagal nerve stimulators. Physical, occupational, speech and vision therapy should begin at diagnosis. Appropriate musculoskeletal support and treatment for prevention of scoliosis-related complications is indicated. Immunizations, infection control measures and therapy for pulmonary toilet are important to reduce the risk of pneumonia, a major cause of mortality.

Prognosis

Difficult-to-control seizures and significant neurodevelopmental disorders are the primary challenge for individuals with Aicardi syndrome. Most are not able to sit independently, walk or speak. The 5-, 10- and 20-year survival rates are 90%, 80% and 50%, respectively. Pulmonary infections, presumed secondary to hypotonia, are the most common cause of death.