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Arquivos de Neuro-Psiquiatria

Print version ISSN 0004-282XOn-line version ISSN 1678-4227

Arq. Neuro-Psiquiatr. vol.64 no.4 São Paulo Dec. 2006 

Lissencephaly, abnormal genitalia and refractory epilepsy: case report of XLAG syndrome


Lisencefalia, genitália ambígua e epilepsia refratária: relato de caso da síndrome XLAG



Mônica Jaques SpinosaI; Paulo Breno Noronha LiberalessoII; Simone Carreiro VieiraI; Alaídes Susana Fojo OlmosII; Alfredo Löhr JúniorII

Unidade de Neurologia Infantil Pequeno Príncipe (UNIPP), Hospital Pequeno Príncipe, Curitiba PR, Brasil
IResidentes de Neuropediatria
IIMédicos da Unidade de Neurologia Infantil




INTRODUCTION: X-linked lissencephaly with ambiguous genitalia (XLAG) is a recently described genetic disorder caused by mutation in the aristaless-related homeobox (ARX) gene (Xp22.13). Patients present with lissencephaly, agenesis of the corpus callosum, refractory epilepsy of neonatal onset, acquired microcephaly and male genotype with ambiguous genitalia.
CASE REPORT: Second child born to healthy nonconsanguineous parents, presented with seizures within the first hour of life that remained refractory to phenobarbital, phenytoin and midazolam. Examination identified microcephaly, axial hypotonia, pyramidal signs and ambiguous genitalia. EEG showed disorganized background activity and seizures starting at the right midtemporal, central and occipital regions. MRI showed diffuse pachygyria, moderate thickening of the cortex, enlarged ventricles, agenesis of the corpus callosum and septum pellucidum. Karyotype showed a 46,XY genotype. Additional findings were hypercalciuria, vesicoureteral reflux, patent ductus arteriosus and chronic diarrhea.

Key words: corpus callosum, ambiguous genitalia, epilepsy, ARX gene.


INTRODUÇÃO: Lisencefalia com genitália ambígua ligada ao X (XLAG) é doença genética recentemente descrita, causada por mutação no gene aristaless-related homeobox (ARX) (Xp22.13). Os pacientes apresentam lisencefalia, agenesia de corpo caloso, epilepsia refratária com início no período neonatal, microcefalia adquirida e genótipo masculino com genitália ambígua.
RELATO DE CASO: Segundo filho de pais não-consangüíneos, apresentou crises na primeira hora de vida que permaneceram refratárias a fenobarbital, fenitoína e midazolam. Apresentava microcefalia, hipotonia axial, sinais de liberação piramidal e genitália ambígua. EEG demonstrou atividade de base desorganizada, crises convulsivas com início nas regiões temporal-média, central e occipital direitas. RNM demonstrou paquigiria difusa, moderado espessamento do córtex, ventrículos aumentados, agenesia de corpo caloso e septo pelúcido. Cariótipo evidenciou genótipo 46,XY. Achados adicionais foram: hipercalciúria, refluxo vésico-ureteral, ducto arterioso persistente e diarréia crônica.

Palavras-chave: corpo caloso, genitália ambígua, epilepsia, gene ARX.



In 1999, Dobyns et al.1 described 5 cases of genotypic males with lissencephaly of posterior predominance, agenesis of the corpus callosum and ambiguous genitalia. In one family affected, the authors observed a pattern of inheritance compatible with an X-linked disorder. However, since the 5 patients clinically differed from the previously described X-linked isolated lissencephaly, that was known to be linked to mutations in the doublecortin gene (Xq22.3-q23), the authors postulated that the cases reported belonged to a yet unknown syndrome, and referred to it as X-linked lissencephaly with ambiguous genitalia (XLAG). Subsequent reports further described the clinical aspects of 6 other patients2-5. In 2002, Kitamura et al.6 created an animal model for embryonic mice with mutations in the X-linked aristaless-related homeobox gene (ARX) that developed with malformations in both central nervous system and testicles. The ARX gene (Xp22.13) was sequenced in 9 patients with XLAG and 8 different mutations were found (two of them were brothers and carried the exact same mutation). Three of the patients’ mothers had their ARX gene analyzed and all three cases were found to be heterozygous with respect to their son’s mutation. In 2003, Uyanik et al.7 sequenced the ARX gene in 2 patients and their mothers, confirming Kitamura’s findings. Mutations in the ARX gene can be expressed phenotypically as XLAG, X-linked infantile spasms (West syndrome)8, X-linked myoclonic epilepsy with spasticity and mental retardation9, X-linked mental retardation10, Partington syndrome (mental retardation, dystonic movements of the hands and dysarthria)11, Proud syndrome (acquired microcephaly, mental retardation, agenesis of the corpus callosum and characteristic facies)12 or hydranencephaly with ambiguous genitalia13. All cases can be associated with autistic features14.

This case report was approved by the ethics committee of Pequeno Príncipe Hospital and parental written informed consent was obtained for publication.



Second child born to healthy nonconsanguineous parents, adequate pre-natal medical care, vaginal term delivery without complications. Seizures started within the first hour of life and remained refractory to treatment with phenobarbital 40 mg/kg/day, phenytoin 15 mg/kg/day and continuous infusion of midazolam 12 mcg/kg/min. Seizures were characterized by clonic jerks of the right hemiface and arm, recurred many times a day and frequently evolved into status epilepticus. The mother had had two previous pregnancies, which resulted in a healthy boy and a miscarriage in the first trimester. Family history revealed a maternal aunt who had two seizures in late childhood.

Clinical and neurological examination identified microcephaly, lack of visual contact, axial hypotonia, pyramidal signs and ambiguous genitalia (impalpable gonads, phallus of 1.2 cm, single medial urogenital meatus and unfused labioscrotal folds with normal skin pigmentation). A series of 3 EEG tracings (24 days, 2 and 3 months of age) demonstrated disorganized background activity. In all 3 exams electroclinical and/or electrographical seizures starting at the midtemporal, central and occipital regions of the right cerebral hemisphere were detected (Fig 1). MRI showed diffuse pachygyria, moderate thickening of the cerebral cortex, enlarged ventricles, agenesis of the corpus callosum and septum pellucidum (Fig 2). Karyotype showed a 46,XY genotype.





Additional findings were hypercalciuria, grade II vesicoureteral reflux, small patent ductus arteriosus and chronic diarrhea that responded well to a semi-elementary formula. Further investigation excluded megacolon, hyperphosphaturia, mid left lung hypoplasia, exocrine pancreatic deficiency and other cardiac malformations. Deficient temperature control was not observed.



General features of the XLAG syndrome are lissencephaly, agenesis of the corpus callosum, intractable epilepsy of neonatal onset, acquired microcephaly and male genotype with ambiguous genitalia1.

Seizures occur precociously. A case of marked fetal movements suggestive of prenatal seizures was described by Uyanik et al.7. Tonic, multifocal myoclonic and generalized tonic-clonic seizures have been reported3,7. No description of the electroencephalographic pattern was found.

Key MRI findings consist of lissencephaly with a moderately thickened cerebral cortex and agenesis of the corpus callosum. Dobyns et al.1, in the first description of the syndrome, reported a lissencephaly with a posterior-to-anterior gradient, i.e. a posterior agyria and anterior pachygyria. This finding was confirmed by some authors3,7 and refuted by others4. The spectrum of neurological phenotypes determined by mutations in the ARX gene, summoned by Kato et al.13, suggests that variations in the degree of cerebral malformation should not be viewed with surprise. Basal ganglia have been described as small7 and dysplasic3. Small subependymal cystic lesions were observed in one patient7.

Many authors described hypothalamic dysfunction with deficient control of body temperature1,2,5-7, which was not observed in our patient. Chronic diarrhea is also a common finding1-3,5. Two of the three cases reported by Bonneau et al.3 had micrognathia and prominent forehead. One case of "minor facial abnormalities" was described by Uyanik et al.7 Our patient did not possess any distinctive facial features. Additional systemic features include mid left lung hypoplasia, ventricular septal defect, patent ductus arteriosus and megacolon2; exocrine pancreatic deficiency and renal phosphate wasting5; patent ductus arteriosus and foramen ovale7. The association of hypercalciuria, vesicoureteral reflux and patent ductus arteriosus has not been previously reported.

Maternal history of miscarriage, as observed in our case, had been documented by Ogata et al.2. In his study, the patient’s mother had two pregnancies that spontaneously terminated at 32 and 18 weeks of gestation. Both were male fetuses whose ultrasound showed a hydrocephalic appearance. Even though none of the fetuses had been genetically examined to confirm the presence of the ARX mutation, it was postulated that the miscarriages represented severely malformed fetuses. Some asymptomatic mothers, heterozygous carriers of the ARX mutation, were found to have either total or partial agenesis of the corpus3,13 and in one case partial posterior agenesis of the corpus callosum associated with enlarged ventricles7. Bonneau et al. described that female carriers may present with epilepsy or mental retardation. This observation was suggested to support a semi dominant X-linked inheritance mode3.

XLAG syndrome has a poor prognosis. All cases were associated with intractable epilepsy and lacked psychomotor development. Maximum survival reported was 4 years7. Most patients die before the age of 18 months2,4,5.



1. Dobyns WB, Berry-Kravis E, Havernick NJ, Holden KR, Viskochil D. X-linked lissencephaly with absent corpus callosum and ambiguous genitalia. Am J Med Genet 1999;86:331-337.        [ Links ]

2. Ogata T, Matsuo N, Hiraoka N, Hata J. X-linked lissencephaly with ambiguous genitalia: delineation of further case. Am J Med Genet 2000; 94:174-176.        [ Links ]

3. Bonneau D, Toutain A, Laquerriere A, et al. X-linked lissencephaly with absent corpus callosum and ambiguous genitalia (XLAG): clinical, magnetic resonance imaging, and neuropathological findings. Ann Neurol 2002;51:340-349.         [ Links ]

4. Hartmann H, Uyanik G, Gross C, et al. Agenesis of the corpus callosum, abnormal genitalia and intractable epilepsy due to a novel familial mutation in the Aristaless-related homeobox gene. Neuropediatrics 2004;35:157-160.        [ Links ]

5. Hahn A, Gross C, Uyanik G, et al. X-linked lissencephaly with abnormal genitalia associated with renal phosphate wasting. Neuropediatrics 2004;35:202-205.        [ Links ]

6. Kitamura K, Yanazawa M, Sugiyama N, et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nature Genet 2002; 32:359-369.        [ Links ]

7. Uyanik G, Aigner L, Martin P, et al. ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology 2003;61:232-235.         [ Links ]

8. Bruyere H, Lewis S, Wood S, MacLeod PJ, Langlois S. Confirmation of linkage in X-linked infantile spasms (West syndrome) and refinement of the disease locus to Xp21.3-Xp22.1. Clin Genet 1999;55:173-181.         [ Links ]

9. Scheffer IE, Wallace RH, Phillips FL, et al. X-linked myoclonic epilepsy with spasticity and intellectual disability: mutation in the homeobox gene ARX. Neurology 2002;59:348-356.        [ Links ]

10. Stromme P, Mangelsdorf ME, Shaw MA, et al. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet 2002;30:441-445.         [ Links ]

11. Partington MW, Mulley JC, Sutherland GR, Hockey A, Thode A, Turner G. X-linked mental retardation with dystonic movements of the hands. Am J Med Genet 1988:251-262.        [ Links ]

12. Proud VK, Levine C, Carpenter NJ. New X-linked syndrome with seizures, acquired micrencephaly, and agenesis of the corpus callosum. Am J Med Genet 1992;43:458-466.        [ Links ]

13. Kato M, Das S, Petras K, et al. Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat 2004;23:147-159.        [ Links ]

14. Artigas-Pallares J, Gabau-Vila E, Guitart-Feliubadalo M. Syndromic autism: II. Genetic syndromes associated with autism. Rev Neurol 2005; 40:S151-S162.        [ Links ]



Received 29 March 2006, received in final form 26 June 2006. Accepted 3 August 2006.



Dra. Mônica Jaques Spinosa - Rua Johann Sebastian Bach 71 - 80820-140 Curitiba PR - Brasil. E-mail:

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