eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Aicardi Syndrome

Author: Ronald G Davis, MD, MPH, FAAP, Assistant Clinical Professor, Child Neurology, Florida State University; Owner and Medical Director of Pediatric Neurology, PA and Pediatric Neurology Epilepsy Center of Central Florida; Medical Director of Epileptology, Arnold Palmer Hospital for Women and Children in Orlando, Florida; Medical Director, Central Florida Muscular Dystrophy Association Clinic
Coauthor(s): Marc P DiFazio, MD, Associate Professor, Department of Neurology, Uniformed Services University of the Health Sciences; Director, Pediatric Subspecialty Services, Shady Grove Adventist Hospital for Children
Contributor Information and Disclosures

Updated: Jan 5, 2010

Introduction

Background

In 1965, a French neurologist, Dr Jean Dennis Aicardi, described 8 children with infantile spasm-in-flexion, total or partial agenesis of the corpus callosum, and variable ocular abnormalities.¹ This clinical scenario, already reported in 1949, was recognized as an entity distinct from congenital infections. An additional 7 patients were described in 1969, and, in 1972, Dennis and Bower established the Aicardi syndrome designation.²

Further patient study demonstrated other less consistent characteristics outside the classic triad of findings. These additional characteristics include abnormal facies, cleft lip and palate, vertebral body abnormalities, and abnormalities of neuronal migration.³ Most children have a moderate-to-severe degree of mental retardation, although less severely affected children occasionally are described. To date, only 2 affected children have been male, both with the XXY karyotype.

Pathophysiology

At present, no etiology explains all the manifestations of Aicardi syndrome. Findings are ascribed to neural tube overdistension during embryogenesis at 4-8 weeks' gestation, but experimental evidence is lacking, and the cause remains unknown.

Frequency

International

Although cases occur throughout the world, exact incidence and prevalence is unknown. In a series of children with infantile spasm, 2% had Aicardi syndrome. Given the phenotypic heterogeneity and diagnostic difficulties associated with young children, Aicardi syndrome may be a more frequent cause of mental retardation and seizure in girls than previously thought. Some children may, in fact, have normal neurodevelopment, which significantly increases the potential numbers of children with Aicardi syndrome.⁴

Mortality/Morbidity

Aicardi syndrome is often complicated by severe mental retardation, intractable epilepsy, and a resultant propensity to pulmonary complications. The condition often leads to death in the first decade. Sudden, unexplained death is common.

Race

The syndrome occurs in people of diverse racial backgrounds throughout the world with no noted racial predominance.

Sex

Aicardi syndrome is thought to be an X-linked dominant disorder lethal to males. Except for 2 male children, all reported instances have been in females. Both males had XXY genotypes, which further supports an X-linked male lethal genetic substrate. This mutation appears to be de novo.⁵

Age

Because Aicardi is a congenital syndrome, it is often first recognized during the neonatal period and infancy. Less severely affected individuals may live into childhood and adolescence, and diagnosis may be delayed. In one group of patients, diagnosis was delayed from 11-234 weeks after the onset of seizures.

Clinical

History

• Aicardi syndrome is often diagnosed in female infants only after the onset of seizures or when the presence of dysmorphic facies prompts further evaluation. Some children are diagnosed in utero with brain-structure abnormalities.
• If only visual abnormalities or developmental delays are present, the condition may not be recognized until the onset of seizures, or if ophthalmologic evaluations demonstrate characteristic chorioretinal lacunae, which are considered pathognomonic for Aicardi syndrome and are shown in the images below.
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  Cross-section of an eye in a patient with Aicardi syndrome. The arrow indicates chorioretinal lacunae.

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  Cross-section of an eye in a patient with Aicardi syndrome. The arrow indicates chorioretinal lacunae.

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  Chorioretinal lacunae.

  [ CLOSE WINDOW ]

  

  Chorioretinal lacunae.

• Presumably, asymptomatic children who have not undergone neuroimaging in utero are not recognized unless they are incidentally screened by an ophthalmologist or brain imaging specialist.
• Seizures are a common initial manifestation, most frequently infantile spasm. Chevrie et al reported 97% of patients had infantile spasm, and most of these had seizures when younger than 3 months.⁶ Additional seizure types noted include hemiconvulsions, complex partial seizures, and focal motor seizures.
• Electroencephalogram (EEG) findings are not consistent. In the relevant clinical scenario, a burst suppression pattern arising independently from each hemisphere suggests Aicardi syndrome. The most common EEG tracing is bursts of high-amplitude slow and sharp waves separated by intervals of low amplitude.
• Global developmental delay is uniform, and most patients have moderate-to-severe mental retardation. This characteristic is probably due to the combination of brain dysgenesis and intractable epilepsy, although some children may walk and, in rare cases, develop expressive language.
• Most of these children are unable to walk, due to spastic hemiplegia, and are bedridden. Children with Aicardi syndrome typically lack even rudimentary abilities to interact with their environments.
• Ocular abnormalities limit visual ability, blinding some children. Certain malignancies develop more frequently, including embryonic soft tissue carcinoma, hepatoblastoma, and angiosarcoma.

Physical

• Ocular
  • Pathognomonic lesions, called chorioretinal lacunae, commonly cluster around the optic disc of the eye and are described as punched-out, white- or yellow-colored defects. These lesions characteristically lack pigment, a characteristic that helps to distinguish them from lesions seen in infectious chorioretinitis. Classic chorioretinal lacunae do not enlarge or progress. Although other ocular lesions are present in Aicardi syndrome, this manifestation is pathognomonic for diagnosis.⁷
  • Other common ocular lesions include the following:
    • Microphthalmos
    • Retrobulbar cyst
    • Cataract
    • Coloboma
    • Retinal detachment
    • Iris synechiae
    • Remnants of fetal pupillary membrane
• Craniofacial
  • Microcephaly, hemifacial asymmetry, microphthalmia, or plagiocephaly may be present.
  • Cleft lip and palate also occur with increased frequency.
• Musculoskeletal
  • Skeletal malformations are common but are not uniform in all patients.
  • Costovertebral abnormalities, such as hemivertebrae, fused or butterfly vertebrae, and rib abnormalities, may be present.
  • Scoliosis resulting from these deformities can be disfiguring and disabling.
• Neurodevelopmental
  • Patients typically have profound mental retardation; however, the disease course may have a milder expression in some than was thought historically.
  • Some children may walk and speak, although rarely. One of the few studies to examine natural history indicates that 21% of patients could ambulate, and 29% could communicate. These abilities appeared independent of seizure frequency, EEG findings, or other clinical features studied during the first year of life.
  • If present, hypotonia, spasticity, or hemiplegia may complicate gross motor development.

Causes

• Causes of various clinical manifestations are unknown.
• Events early in gestation, probably in weeks 4-8, are suspected causes. The exact etiology of these events remains elusive, although considerations have included in utero exposure to toxins, mild hypoxia, and infections. Investigation of these potential etiologies has been unrevealing.
• A genetic basis for the syndrome is favored, specifically an X-linked dominant mutation with lethality in male hemizygotes. Spontaneous mutation is most likely because siblings appear to be spared, but parental gonadal mosaicism could be the basis for a reported pair of sisters with the condition.
• The only male patients have been described with an XXY genotype.
• Skewed X chromosome inactivation may account for some clinical heterogeneity.⁸ However, one center has reported no evidence of skewing in 10 patients studied, suggesting that an alternative reason for differences in the phenotype may exist.

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