X-linked lissencephaly with abnormal genitalia

X-linked lissencephaly with abnormal genitalia (XLAG), also known as X-linked lissencephaly with ambiguous genitalia, is a rare and severe brain malformation disorder caused by mutations in the ARX (Aristaless-Related Homeobox) gene located on the X chromosome. The condition predominantly affects males and is characterized by lissencephaly (a smooth brain surface due to absent or incomplete development of the normal folds and grooves of the cerebral cortex), which leads to profound intellectual disability and intractable epilepsy. The brain malformation in XLAG typically presents as a posterior-predominant lissencephaly with an abnormally thick cortex and absent corpus callosum (agenesis of the corpus callosum). In addition to the central nervous system involvement, affected males have abnormal genitalia, which can range from ambiguous genitalia to micropenis and cryptorchidism, reflecting disrupted development of the hypothalamic-pituitary-gonadal axis. Affected infants typically present in the neonatal period with severe seizures that are often refractory to treatment, poor feeding, hypothermia, and chronic diarrhea. Additional features may include neonatal hypoglycemia, pancreatic dysfunction with exocrine insufficiency, and hypothalamic dysfunction leading to temperature dysregulation. The prognosis is very poor, with most affected males dying in infancy or early childhood due to the severity of the neurological impairment and associated complications. Female carriers may be asymptomatic or may present with milder features such as agenesis of the corpus callosum, mild intellectual disability, or epilepsy. There is currently no cure or disease-modifying treatment for XLAG. Management is supportive and symptomatic, focusing on seizure control (though seizures are often highly resistant to antiepileptic medications), nutritional support, management of endocrine abnormalities, and palliative care. Genetic counseling is important for affected families, as carrier females have a 50% chance of transmitting the ARX mutation to their offspring.

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