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

Abstract

-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 p resent with lissencephaly, agenesis of the corpus callosum, re f r a c t o ry epilepsy of neonatal onset, acquire d m i c rocephaly and male genotype with ambiguous genitalia. Case re p o rt: 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 micro c e p h a l y, 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. K a ryotype 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.Lisencefalia, genitália ambígua e epilepsia refratária: relato de caso da síndrome XLAG RESUMO -I n t rodução: Lisencefalia com genitália ambígua ligada ao X (XLAG) é doença genética re c e n t emente descrita, causada por mutação no genea r i s t a l e s s -related homeobox (ARX) (Xp22.13). Os pacientes a p resentam lisencefalia, agenesia de corpo caloso, epilepsia refratária com início no período neonatal, m i c rocefalia 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.

A Child with a Novel de novo Mutation in the Aristaless Domain of the Aristaless-Related Homeobox <b><i>(ARX)</i></b> Gene Presenting with Ambiguous Genitalia and Psychomotor Delay

“…The undervirilization of the external genitalia and low basal serum testosterone levels in this patient are likely to be the result of defective testicular development. The association between ARX mutations and cardiac anomalies such as ventricular septal defect and patent ductus arteriosus, which were documented in this case, has been described in several previously reported cases [Ogata et al, 2000;Uyanik et al, 2003;Spinosa et al, 2006].…”

Clinical Benefit of New Targeted Agents in Phase I Trials in Patients with Advanced Colorectal Cancer

“…These pathways are often overexpressed, amplified or mutated in patients with ACRC, and many of these targets play a fundamental role in the regulation of cell proliferation, differentiation and survival [24]. …”

X-Linked Lissencephaly With Absent Corpus Callosum and Abnormal Genitalia

“…Chronic diarrhea has previously been reported in at least half of the reported patients with X-linked lissencephaly with abnormal genitalia. 7 , 9 - 10 , 14 The congenital intestinal diarrheal diseases group of diseases are classified into 4 broad etiological groups based on the underlying pathophysiology; (1) defects of digestion, absorption, and transport of nutrients and electrolytes; (2) defects of absorptive enterocyte differentiation or polarization; (3) defects of the enteroendocrine cells; and (4) defects of the immune system affecting the intestine. 20 …”

“… 1 More than 20 affected males have subsequently been reported. 1 – 12 Consistent clinical features (see Table 1 ) include the following: (1) a brain malformation characterized by lissencephaly and agenesis of the corpus callosum, (2) perinatal encephalopathy with an intractable seizure disorder, (3) hypothalamic dysfunction manifest by poor temperature regulation, (4) ambiguous or underdeveloped genitalia, and (5) death in early infancy, usually within 3 months of age. 4 Common neuroanatomical features of X-linked lissencephaly with abnormal genitalia include the following: (1) mildly increased cortical thickness of approximately 6 to 10 mm, (2) distinctive histopathology reflecting defective tangential migration of precursor γ-aminobutyric acid (GABA)-producing interneurons, (3) a posterior–anterior gradient of severity, (4) complete agenesis of the corpus callosum with or without associated interhemispheric cyst, (5) basal ganglia dysplasia, (6) enlarged posterior temporal horns of the lateral ventricles (colpocephaly), and (7) normal brain stem and cerebellar development.…”