Aicardi Syndrome Clinical Presentation

Updated: Nov 30, 2018
  • Author: Ravi Sunderkrishnan, MD; Chief Editor: Maria Descartes, MD  more...
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Presentation

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.

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.

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

Ocular abnormalities limit visual ability and are blinding in some children. A less common presentation is that of retro-orbital cysts and optic nerve hypoplasia. [11]

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.

Some children are diagnosed in utero with brain-structure abnormalities. Most often, the absence of the corpus callosum on the fetal ultrasonogram prompts further imaging studies.

Anomalies of the sulci and gyri, periventricular heterotopia, associated cerebellar and brain stem anomalies with absent corpus callosum, can also be evaluated with magnetic resonance imaging (MRI) to aid in the diagnosis and to better determine the prognosis in Aicardi syndrome. [11]

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. [12] Additional seizure types noted include hemiconvulsions, complex partial seizures, and focal motor seizures. A study by Govil-Dalela et al indicated that compared with children who have nonsyndromic agenesis of the corpus callosum, those in whom the agenesis is related to Aicardi syndrome suffer earlier onset of seizures and worse developmental outcomes, with neuroimaging revealing larger areas of brain abnormalities in these patients. [13]

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.

Certain malignancies develop more frequently, including embryonic soft-tissue carcinoma, hepatoblastoma, and angiosarcoma.

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Physical

Neurodevelopmental

The neurologic examination can reveal microcephaly, axial hypotonia, appendicular hypertonia with spasticity that often affects one side, and brisk deep tendon reflexes, as well as hemiparesis. [14]

Moderate to severe global developmental delay and intellectual disability are expected, but individuals with only mild or no learning disabilities or developmental delay have been reported.

Infantile spasms, seizures, or epilepsy develop before age 3 months. Electroencephalography (EEG) can reveal asynchronous multifocal epileptiform abnormalities with burst suppression and dissociation between the two hemispheres; hypsarrhythmia is sometimes identified.

Ocular

Pathognomonic lesions, called chorioretinal lacunae, commonly cluster around the optic disc of the eye and are described as punched-out, white or yellow 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. [15]

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. Short philtrum and cleft lip and palate are also seen.

Gastrointestinal

Constipation, gastroesophageal reflux, diarrhea, and feeding difficulties are perceived by parents to be the second most difficult problem to manage after seizures. [8]

Extremities

Small hands, along with an increased incidence of hand malformations, have been reported.

Musculoskeletal

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. A study by Grigoriou et al indicated that Aicardi syndrome–related scoliosis progresses rapidly and does not respond to bracing. Scoliosis was first noticed in the study’s patients at a mean age of 3.9 years, at which time the mean Cobb angle was 22.5%, while the patients’ first orthopedic visit took place at a mean age of 5.8 years, when the progressed mean Cobb angle was 39.5%. [16]

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Causes

The exact mutation and its cause in Aicardi syndrome are still unknown and disputed, although an X-linked dominant mutation in a gene on Xp22 is considered a likely source. It is suspected that events early in gestation, probably in weeks 4-8, give rise to the mutation. Because a patient with Aicardi syndrome can have an unaffected twin, the potential etiologies of prenatal hypoxia and prenatal toxin are no longer in favor. [14]

Spontaneous mutation is most likely, because siblings appear to be spared and have not been reported in parents of an affected female.

The only affected male patients have been described as having an XXY genotype. The presence of Aicardi syndrome in males with a 46,XY karyotype has been disputed, but new cases have been reported. It is possible that these cases are caused by mosaic mutations of the gene. [14]

Skewed X-chromosome inactivation may account for some clinical heterogeneity. [17]

According to one report, another etiologic possibility remains in which Aicardi syndrome is caused by a new mutation on an autosome (eg, 1p36), with sex-limited expression in females. [14]

The aforementioned study by Piras et al indicated that in patients with Aicardi syndrome, differential DNA methylation patterns exist in several neurodevelopmental and/or neuroimmunologic networks, with the investigators suggesting that these networks contribute to the syndrome’s pathogenesis. [5]  

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