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L1 syndrome is a mild to severe congenital X-linked developmental disorder characterized by hydrocephalus of varying degrees of severity, intellectual deficit, spasticity of the legs, and adducted thumbs. The syndrome represents a spectrum of disorders including: X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), MASA syndrome, X-linked complicated hereditary spastic paraplegia type 1, and X-linked complicated corpus callosum agenesis (see these terms).
L1 syndrome primarily affects males. HSAS is the most common genetic form of congenital hydrocephalus, with a prevalence of approximately 1/30,000. The prevalence and incidence of the other disorders in the spectrum are not known.
Affected males have varying degrees of hydrocephalus (commonly already in the prenatal period) ranging from subclinical to severe. Intellectual deficit ranges from mild to severe. Patients develop generalized hypotonia and spasticity of the legs at an early age and the condition appears to progress over time, leading to leg muscle atrophy causing a shuffling gait. Adducted thumbs are a characteristic feature of the syndrome, present in about 50% of cases. Some patients also experience seizures. A small number of patients (< 20) have been reported to have a combination of L1 syndrome and Hirschsprung disease (see this term). Female carriers may have minor features such as adducted thumbs or mild intellectual deficit but they rarely have the severe manifestations of the syndrome.
L1 syndrome is caused by mutations in the L1CAM gene (Xq28) encoding the L1 cell adhesion molecule that is expressed mainly in the developing nervous system. More than 240 different mutations have been reported to date, possibly explaining the wide clinical spectrum. About 7% of mutations have been reported to occur de novo.
Diagnosis in male patients is made on the basis of the characteristic clinical and neuropathologic findings and a family history consistent with X-linked transmission. Bilateral absence of the pyramids detected by magnetic resonance imaging (MRI) or autopsy is practically a pathognomonic feature of the syndrome. The diagnosis can be confirmed by molecular genetic testing of the L1CAM gene.
The differential diagnosis is broad. Other hydrocephalus and spastic paraplegia disorders should be ruled out. A pediatric/neurologic/clinical genetics work-up enables diagnosis of the possible individual diseases.
Prenatal testing can be performed in female carriers if an L1CAM disease-causing mutation has been identified in a family member. After determination of fetal gender via chromosome analysis on cells obtained by chorionic villus sampling or by amniocentesis, fetal cells can be screened for the known disease-causing mutation. Girls may be affected, and ultrasound at 20 weeks is recommended in female fetuses. Normal fetal ultrasound at 20 weeks does not however rule out the disorder: absence of hydrocephalus at this stage does not guarantee that a male fetus is not affected.
L1 syndrome is inherited in an X-linked manner. Genetic counseling should be provided to affected families.
Management and treatment
Treatment requires a multidisciplinary team including specialists in pediatrics, child neurology, neurosurgery, rehabilitation, and medical genetics. Shunting of cerebrospinal fluid (CSF) can be carried out to lower intracranial pressure. Corrective surgery for adducted thumbs is not indicated. Monitoring should include developmental progress and neurological symptoms.
Hydrocephalus may result in stillbirth or death in early infancy. Prognosis is dependent on the severity of the manifestations.