Skip to
  1. Homepage
  2. Rare diseases
  3. Search
Simple search

Simple search

(*) mandatory field


Other search option(s)

X-linked lissencephaly with abnormal genitalia

Synonym(s) X-linked lissencephaly with ambiguous genitalia
X-linked lissencephaly-agenesis of the corpus callosum-genital anomalies syndrome
XLAG (X-linked lissencephaly with abnormal genitalia) syndrome
Prevalence Unknown
Inheritance X-linked recessive
Age of onset Neonatal
  • Q04.3
MeSH -
MedDRA -


X-linked lissencephaly with abnormal genitalia (XLAG) is a severe neurological disorder that only manifests in genotypic males and includes lissencephaly with posterior-to-anterior gradient and only moderate increase in thickness of the cortex, absent corpus callosum, neonatal-onset severe epilepsy, hypothalamic dysfunction including defective temperature regulation, and ambiguous genitalia with micropenis and cryptorchidism. XLAG differs considerably from classical lissencephaly, as the resulting cortical thickness is only 6-7 mm in XLAG, rather than 15-20 mm seen in classical lissencephaly due to mutations of the PAFAH1B1 or DCX genes. In 2002, mutations in the X-linked aristaless-related homeobox gene (ARX; Xp21.3) were identified in individuals with XLAG and in some of their female relatives. Mouse Arx and human ARX are highly expressed in both dorsal and ventral telencephalon, including the neocortical ventricular zone and germinal zone of the ganglionic eminence, with less intense signals in the subventricular zone, cortical plate, hippocampus, basal ganglia and ventral thalamus. Arx-deficient mice showed deficient tangential migration and abnormal differentiation of GABAergic interneurons in the ganglionic eminence and neocortex, as well as abnormal testicular differentiation. These characteristics include some of the clinical features of XLAG in humans. The ARX mutations in XLAG patients were predominantly premature termination mutations (large deletions, frameshift, nonsense mutations, splice site mutations) while the missense mutations were less common and located essentially in the homeobox domain. Patients carrying nonconservative missense mutations within the homeobox, showed less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome (ACC with abnormal genitalia). A non conservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. The ARX mutations are also associated with a spectrum of milder phenotypes, without macroscopic malformations of the brain, such as X-linked infantile spasms, a syndrome featuring mental retardation associated with distal dystonic movements (Partington syndrome; see this term), autistic features and nonsyndromicintellectual deficit.

Expert reviewer(s)

  • Pr Renzo GUERRINI
  • Dr Francesca MORO

(*) Required fields.

Attention: Only comments seeking to improve the quality and accuracy of information on the Orphanet website are accepted. For all other comments, please send your remarks via contact us. Only comments written in English can be processed.

Captcha image

Detailed information

Summary information
Get Acrobat Reader
The documents contained in this web site are presented for information purposes only. The material is in no way intended to replace professional medical care by a qualified specialist and should not be used as a basis for diagnosis or treatment.