Ophthalmic Genetics, 29:181–183, 2008Copyright c© Informa Healthcare USA, Inc.ISSN: 1381-6810 (print) / 1744-5094 (online)DOI: 10.1080/13816810802320209

CASE REPORT

Aicardi Syndrome in a Genotypic Male

Aimee V. ChappelowCole Eye Institute, Cleveland Clinic, Cleveland, USA

Janet ReidRadiology Institute, Cleveland Clinic, Cleveland, USA

Sumit ParikhNeurology and Neurosurgery Institute, Cleveland Clinic, Cleveland, USA

Elias I. TraboulsiCole Eye Institute, Cleveland Clinic, Cleveland, USA

Aicardi syndrome was originally described as a triad of partial or complete agenesis of thecorpus callosum, infantile spasms, and pathognomic chorioretinal lacunae. Of approximately200 cases reported since it was originally described in 1965, there have been no undisputedreports of Aicardi syndrome in a 46 XY male. Thus a dominant X-linked inheritance, presumedlethal in males, has been proposed. Herein we report a 5 year-old 46 XY male with the classicclinical triad of Aicardi syndrome.

Keywords Aicardi syndrome; male; lacunae; seizures; corpus callosum; retina

INTRODUCTIONAicardi syndrome was originally described in 1965 as a triad

of partial or complete agenesis of the corpus callosum, infantilespasms, and pathognomic chorioretinal lacunae.1 Other featuresmay include cortical polymicrogyria, choroid plexus cyst or pa-pilloma, periventricular heterotopia, optic nerve coloboma oratrophy, microphthalmos and costovertebral anomalies.2 Prog-nosis for life is poor, with 40 to 65% survival to age 14 years.3

Typically, moderate to severe developmental delay is observed,with 91% of patients functioning at a level of 12 months oryounger.4 The report of an affected 10 year-old girl with a de-velopmental delay of 4 to 5 years5 suggests that mild expressionof Aicardi syndrome is possible.

Approximately 200 cases have been reported; all were fe-male, with only four exceptions. Two of these four cases werein phenotypic boys with 47 XXY karyotype.2,4,6 The other twocases are reported in 46 XY males.7,8 Aicardi has disputed thelatter as too atypical for classification as Aicardi syndrome duethe presence of lissencephaly2 or chorioretinal lesions not remi-

Received 17 April 2008; accepted 29 June 2008.Address correspondence to Elias I. Traboulsi, MD, Cole Eye Insti-

tute, Cleveland Clinic Foundation, 9500 Euclid Avenue, i32, Cleveland,Ohio 44195, USA. E-mail: traboue@ccf.org

niscent of lacunae.9 A dominant X-linked inheritance, presumedlethal in males, has been proposed;2 however, an X chromosomelocus has not been identified.

Herein we report a 5 year-old 46 XY male with theclassic clinical triad of Aicardi syndrome (complete agene-sis of the corpus callosum, infantile spasms and chorioretinallacunae).

CASE REPORTA 4.5–year-old Caucasian male with a history of intractable

seizures, severe global developmental delay, and multiple brainmalformations was referred for ophthalmic evaluation of a pos-sible neurogenetic or neurometabolic condition. He was bornfull-term, following uncomplicated gestation, to a 28-year-oldwoman who had received routine prenatal care. There were noknown teratogenic or infectious exposures during the pregnancy,and no history of consanguinity. Maternal and paternal grand-parents and a 7 year-old male sibling are alive and healthy.

At the age of 3 months, the patient developed seizures and anMRI revealed complete agenesis of the corpus callosum (Fig-ure 1A) with choroidal plexus cyst (Figure 1B), parallel lateralventricles, colpocephaly, interhemispheric cyst, subependymalheterotopia and bifrontal polymicrogyria (Figures. 2C, 2D). Achromosome microarray analysis failed to detect any known

181

Oph

thal

mic

Gen

et D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/03/

14Fo

r pe

rson

al u

se o

nly.

182 A. V. CHAPPELOW ET AL.

FIG. 1. A. Sagittal T1 weighted image of the brain showscomplete absence of the corpus callosum (arrows). B. Rightparasagittal T1 weighted image of the brain following intra-venous gadolinium shows a choroid plexus cyst (arrow). C . Ax-ial Fast T2 weighted image shows diffuse cortical thickeningwith multiple tiny sulci consistent with polymicrogyria (arrows).D. Axial Fast T2 weighted image shows parallel dysmorphiclateral ventricles consistent with agenesis of the corpus callo-sum, an interhemispheric cyst (large arrowheads) and multiplesubependymal heterotopia (small arrowheads).

micro-deletions or -duplications and a routine chromosome anal-ysis showed a 46 XY karyotype.

Examination revealed a flat mid-face, up-slanting eyes, dim-pling of the left nares, and microcephaly with low anterior andhigh posterior hairlines. Low muscle tone and mild to moderateweakness was noted; however, reflexes were normal and therewas no tremor or ataxic movements. Ophthalmic examinationshowed roving eye movements and failure to fix or follow. Theanterior segment was unremarkable; specifically, there was nocoloboma or cataract, and corneal diameter was 10 mm bilater-ally. Cycloplegic refraction showed mild hypermetropia in botheyes. Ophthalmoscopy revealed optic nerve hypoplasia in theright eye (Figure 2A) and an anomalous-appearing disc in theleft eye (Figure 2B). There was bilateral foveal hypoplasia. Fur-ther, two chorioretinal lacunae were noted in the left eye (Figure2B, arrowheads). The lacune nasal to the disc was approximately3/4 disc diameter across and there was pigment clumping alongits margins. A smaller paler lacune was present just inferonasalto the disc.

FIG. 2. A. Fundus photograph of the right eye illustrating opticnerve hypoplasia. B. Fundus photograph of the left eye illustrat-ing an anomalous optic nerve head and two chorioretinal lacunae(arrowheads).

DISCUSSIONNo gene for Aicardi syndrome has been identified, but several

observations support the notion that Aicardi syndrome is causedby de novo mutations of a gene on the x-chromosome that is sub-ject to x-chromosomal activation and that is lethal in males.10 Atleast six pairs of twins that are discordant for Aicardi syndromeare known. Five of these are confirmed to be dizygotic, whichexcludes the possibility that the etiology is a prenatal or otherdisruptive event.5 The only three known males with a confirmeddiagnosis have a 47XXY karyotype.2,6 Our case demonstratesthat the prevailing belief that Aicardi syndrome is lethal in malesis not without exception. It remains possible, however, that ourpatient is mosaic for 47 XXY Klinefelter, but with such a lowlevel of mosaicism that it was not detected using the tests thatwere conducted.

DECLARATION OF INTERESTThe authors report no conflicts of interest. The authors

alone are responsible for the content and writing of thepaper.

REFERENCES1. Aicardi JLJ, Lerique-Koechlin A. A new syndrome: Spasms in flex-

ion, callosal agenesis, ocular abnormalities. ElectroencephalogrClin Neurophysiol. 1965;19:609–610.

2. Aicardi J. Aicardi syndrome. Brain Dev. 2005;27:164–171.

3. Glasmacher MA, Sutton VR, Hopkins B, et al. Pheno-type and management of Aicardi syndrome: New findingsfrom a survey of 69 children. J Child Neurol. 2007;22:176–184.

4. Rosser TL, Acosta MT, Packer RJ. Aicardi syndrome: Spectrumof disease and long-term prognosis in 77 females. Pediatr Neurol.2002;27:343–346.

Oph

thal

mic

Gen

et D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/03/

14Fo

r pe

rson

al u

se o

nly.

AICARDI SYNDROME IN A GENOTYPIC MALE 183

5. Taggard DA, Menezes AH. Three choroid plexus papillomas in apatient with Aicardi syndrome. A case report.Pediatr Neurosurg.2000;33:219–223.

6. Hopkins IJ, Humphrey I, Keith CG, Susman M, Webb GC, TurnerEK. The Aicardi syndrome in a 47, XXY male. Aust Paediatr J.1979;15:278–280.

7. Curatolo P, Libutti G, Dallapiccola B. Aicardi syndrome in a maleinfant. J Pediatr. 1980;96:286–287.

8. Aggarwal KC, Aggarwal A, Prasad MS, Salhan RN, UpadhayaA. Aicardi’s syndrome in a male child: An unusual presentation.Indian Pediatr. 2000;37:542–545.

9. Aicardi syndrome in a male infant. J Pediatr. 1980;97:1040–1042.10. Van den Veyver IB. Microphthalmia with linear skin defects

(MLS), Aicardi, and Goltz syndromes: Are they related X-linked dominant male-lethal disorders? Cytogenet Genome Res.2002;99:289–296.

Oph

thal

mic

Gen

et D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/03/

14Fo

r pe

rson

al u

se o

nly.