Journal of the Neurological Sciences 278 (2009) 138–140
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Short communication
Aicardi syndrome in a 47, XXY male neonate with lissencephalyand holoprosencephaly
Tai-Heng Chen a,1, Mei-Chyn Chao b, Lung-Chang Lin a, Yuh-Jyh Jong a, San Nan Yang c,Yu-Hong Lai d, Hsiu-Lin Chen c,⁎a Division of Pediatric Neurology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwanb Division of Genetics, Endocrinology, and Metabolism, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwanc Division of Neonatology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwand Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
⁎ Corresponding author. Department of Pediatrics,Hospital, Kaohsiung Medical University, No. 100, ZihyKaohsiung City 807, Taiwan. Tel.: +886 7 3121101x6529;
E-mail address: [email protected] (H.-L.1 Tai-Heng Chen has contributed the main clinical
analyzing data and editing literature in this work.
0022-510X/$ – see front matter © 2008 Elsevier B.V. Aldoi:10.1016/j.jns.2008.12.008
a b s t r a c t
a r t i c l e i n f oArticle history:
Aicardi syndrome (AS) is a Received 25 September 2008Received in revised form 4 December 2008Accepted 9 December 2008Keywords:Aicardi syndromeMaleKlinefelter syndromeLissencephalyHoloprosencephaly
rare neuro-ophthalmic disorder first described by Jean Aicardi in 1965 with acharacteristic triadof corpus callosal agenesis (CCA), chorioretinal lacunae (CRL), and infantile spasms (IS). All knowncases ofAShavebeen sporadic and a responsible genehasnot been identified.With5exceptionalmales, potential X-linked dominant geneticmutation characterizes AS occurring almost exclusively in girls.Most ofmale AS caseswerestill debatable in diagnosis either for their 46 XY karyotype or too atypical presentations to fit the formerly stricterdiagnostic criteria. We report a 47, XXYmale neonate presenting some undisputable, but otherwise some regardedas atypical features inAS.Wecomparehis distinctively clinical pictureswithpreviously reportedmale cases andfindCRL is less pathognomonic and lissencephaly appears frequently among male AS. Because of insufficient genetic andbiochemical markers for definite diagnosis at this moment, we suggest the experience of a relatively raremale casewould help to shed light on the underlying genetic pathogenesis of AS.
© 2008 Elsevier B.V. All rights reserved.
1. Introduction
Aicardi syndrome (AS) (OMIM 304050) is an uncommon neurode-velopmental disorder affecting almost exclusively females because ofthe hypnotized genopathy of X-linked dominant mutation being lethalto hemizygous male fetus [1]. To date, only few male AS with well-described features have been reported butmost of them are refuted foreither their too atypical clinical features or 46, XY karyotype, whichcounters the postulation of heterozygousmutations in a gene on 1 of theX chromosomes. So far, lack of a candidate gene in ASmakes the definitediagnosis still based mainly on clinical and neuroradiological presenta-tions [2,3]. Herewe report a 47, XXYmale neonate not only fitting in thefeatures with a revised criteria of AS [1,4], but also sharing severalcontroversial phenotypes with previously reported male cases. Wesuggested a scarce male case would provide more valuable informationto clarify the underlying pathogenesis of AS.
Kaohsiung Medical Universityou 1st Road, Sanmin District,fax: +886 7 3208201.Chen).care of this reported patient,
l rights reserved.
2. Case report
A 2-day-old male neonate was born at full term (37 + 4 weeks ofgestation) via emergent cesarean section due to fetal distress. His Apgarscores were 6 and 8 at 1 and 5 min, respectively. He was the first child ofhealthy and nonconsanguineous parents. The antenatal ultrasonographyrevealed oligohydroamnios and intrauterine growth retardation. Assess-ment after birth showed body weight 2120 g (b10 percentile), headcircumference 29 cm (b10 percentile) and body length 47 cm (10–25percentile). Besides, camptodactyly and several facial dysmorphisms,including microcephaly, hypotelorism, diminished angle of the nasalbridge, upturned nose, sparse lateral eyebrows and cleft palate weredepicted during physical examination.
Grunting and respiratory distress developed on day 1 old then nasalcontinuous positive airway pressure was administered. However,clusters of multifocal seizures with evolving to a pattern of generalizedtonic–clonic convulsions attacked on the same day. Unstable vital signsrelated to numerous multi-focal seizures made he transferred to ourneonatal intensive care unit for further management.
After admission, intermittentmyoclonuswith particularflexor spasmscontinued even though after usage of phenobarbital and subsequentlyadded phenytoin and valproic acid. Electroencephalographic (EEG)revealed paroxysmal sharp-and-wave complexes separated by intervalsof low amplitude background with hemispheric asymmetry, which wasidentical to a characteristic “split brain with burst-suppression” tracing.Brainmagnetic resonance imaging (MRI) showed lissencephaly, semilobar
Fig. 1. (A) Saggital T1-weighted FLAIRMRI (TR: 1183ms/TE: 10.2ms) of brainmanifested agenesis of the anterior portions of corpus callosum (white arrowhead). (B) Axial T2-weighted FSEMRI (TR: 4000 ms/TE: 105 ms) of brain showed semilobar holoprosencephaly and lissencephaly with a “smooth brain” appearance.
139T.-H. Chen et al. / Journal of the Neurological Sciences 278 (2009) 138–140
holoprosencephaly, ventriculomegaly and partial agenesis of corpuscallosum (Fig. 1A,B). A chest roentgenography demonstrated dysgenesisof T6-T8 vertebrae (hemivertebrae and butterfly vertebrae) causingscoliosis and missing 12th ribs bilaterally. Echocardiography showed asmall patent ductus arteriosus and closed spontaneously on 8-day-oldafter fluid restriction. Otherwise, his complete blood cell count, serumbiochemistries, electrolytes, acid-base analysis, blood spots of tandemmass spectrometry and urine gas chromatography were all normal.Giemsa-banded prometaphase chromosome study reported 47, XXYkaryotype of Klinefelter syndrome and both of his parents had normalkaryotypes. A fundoscopic survey by the ophthalmologist revealed achorioretinopathy with “salt and pepper appearance”, characterized ashyper- and hypo-pigmentary granules around macula.
Respiratory distress resolved gradually after declined frequency ofseizure episodes managed by combined antiepileptic medications(vigabatrin, nitrazepam and oxcarbazepine). He was then dischargedwith follow-up at our neurological clinic and till now, at his 5 monthsof age, daily episodes of focal to generalized seizure, profoundhypotonia and poor oropharyngeal function were still observed.
Table 1Comparisons and descriptions of previously reported male Aicardi syndrome
Reference/year Present age Karyotype Fundoscopy
Hopkins et al. [7] 4 w/o 47, XXY Typical; CRL(+)/Coloboma
Curatolo et al. [8] 4 w/o 46, XY Atypical; CRL(−)/RetinalDepigmentation/Coloboma
Aggarwal et al. [9] 9 mo 46, XY Typical; CRL(+)
Tateno et al. [11] 3 mo 46, XY Atypical; CRL(−)/Coloboma
Saddichha et al. [10] 21 y/o Unknown Atypical; CRL(−)/ChoroidalCalcification
Present case 2008 At birth 47, XXY Atypical; CRL(−)/“Salt and pepper”Pattern of pigmentations
IS, infantile spasm; CCA, corpus callosal agenesis; CRL, chorioretinal lacunae; GTC, Generali
3. Discussion
Aicardi syndrome is a rare neuro-ophthalmic disorder with incidenceestimated1/93,000-1/167,000 [5]. It isfirst described in 1965byAicardi etal., however, due to lack of reliable genetic or biochemical markers, thediagnosis of AS is still mainly based on clinical and neuroradiologicalmanifestations [4–6]. Corpus callosal agenesis (CCA), chorioretinallacunae (CRL), and infantile spasms (IS) comprise the cardinal triad ofAS but whether the coexistences are necessary for definite diagnosis isbeing debated because in rare cases, one of the features may be missing[1,2,6]. Intriguingly, the inherited pattern of AS is still a medical mysterybecause of failure to identify the candidate gene even though variousmodern genetic studies have been applied [3]. A de novo mutationwith X-linked dominant is the most acceptable hypothesis sincecases are identified almost exclusively in girls, but whether anincreased lethality of hemizygous male conceptuses occurs and therole of skewed inactivation of the X chromosome in the phenotypicexpression of AS remain unclarified [3,5]. We review medicalliteratures regarding male AS and find only 5 surviving cases in
Neurological deficit Neuroimaging Associated anomalies
IS CCA Vertebral dysplasia/Various focal seizure /Ventriculomegaly/HypotoniaAsymmetrical IS CCA Vertebral dysplasia/Clonic seizures /Cerebellar dysgenesis/Hypotonia /Cortical
HeterotopiaIS CCA VSD/Hypotonia /Lissencephaly /Scoliosis
/Cortical heterotopiaAsymmetrical IS CCA/Multifocal seizure /Lissencephaly/HypotoniaIS /focal seizure CCA Kyphoscoliosis/Subnormal /Right frontalIntelligence Dysplasia
/ColpocephalyIS/multifocal clonic CCA (partial) Costovetebral/GTC seizure /Holoporsencephaly Defects/cleft palate/Hypotonia /Lissencephaly /PDA
/Ventriculomegaly
zed tonic–clonic, VSD, ventricular septal defec; PDA, Patent ductus arteriosus.
140 T.-H. Chen et al. / Journal of the Neurological Sciences 278 (2009) 138–140
detailed description since Hopkin et al. [7] reported the first 47 XXYmale with undisputed features of AS in 1979 [8–11]. Thereafter, theremainder four male cases were debatable in diagnosis either fortheir 46 XY karyotype or too atypical features to fit the previouslystricter diagnostic criteria [1,6]. In 46 XY male cases, although anundetected XY/XXY mosaic pattern has been suspected [12], there isstill lack of a direct evidence among other male AS cases. Since abroader diagnostic criteria have been proposed based on recentepidemiologic study [1,4,6], our case is noteworthy not only for itsconformation to the revised criteria, including partial ACC, IS with“split-brain” EEG findings, cortical malformations, costovetebralanomalies, and a dysmorphic face, but sharing with several featuresregarding controversial in previously reported male AS (Table 1).Besides, although not belonged to the criteria, his microcephaly,ventriculomegaly, cleft palate, several dysmorphic facial features andcamptodactyly are also commonly associated in AS [1,2,6,13].
Atypical phenotypic expression has been observed in a minority ofgirls presumed to have AS with the assistance of modern clinicaltechniques and neuroimaging [1,2,6]. However, through our observa-tion, a greater diversion of features seems to bemore common inmalecases. With some extreme exceptions, CRL has been regarded as themost pathognomonic feature in female AS [6,12], but is surprisinglyabsent up to 67% (4/6) in male cases. Fundoscopic pictures of ourpatient presented atypical chorioretinopathy with “salt-and-pepper”pattern, which has never been described in AS before. Nevertheless,we believe it is definitely different from the typical lacunae andsequent follow up is mandatory because this ophthalmic finding maypresent as the earliest manifestations in male cases.
Moreover, our case acquires two kinds of devastating congenitalcerebral anomalies rarely reported in female or even male AS.Lissencephaly, which has put the Aggarwal's male case in disputebefore [1,9], also occurs coincidentally in our case. Indeed, it has alsobeen described in a Japanese male by Tateno et al. [11], but wasunfortunately seldom discussed previously maybe due to its domes-tically publication. Additionally, semilobar holoprosencephaly occur-ring in our case is also an uncommon feature in female AS [13]. So far,our patient should be the male AS presenting the earliest neurologicmanifestation of seizure onset as early as in his neonatal period, whichmay be explained by these two comorbid neurologic anomalies to AS.Although severe neurological handicap is generally considered in AS
regardless of genders [2,5], one male AS with mildly metal involve-ment has been reported [10].
In conclusion, although the experiences are extremely few, we thinkit is necessary to reevaluate the previously regarded as “atypical” pic-tures in male AS. This report not only adds an additional male case butprovidesmost updated anddetailed features ofmaleAS. CRL is no longerpathognomonic and lissencephaly seems prevalent in male AS. Ourobservationpropose that diversephenotypes betweendifferent gendersof AS may facilitate a functional or protein interaction-based approachon X chromosomes to identify the responsible genes. On the other hand,whether the Y chromosome in AS acts as a compensative role inmalde-velopment of visual system or an aggravating factor of neuronalmigration defect may also offer an alternative genomic approach forthis disorder from relevant developmental pathways.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.jns.2008.12.008.
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