Clinical characteristics: L1 syndrome involves a phenotypic spectrum ranging from severe to mild and includes three clinical phenotypes:
X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS)
MASA (mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs) syndrome including X-linked complicated hereditary spastic paraplegia type 1
X-linked complicated corpus callosum agenesis
Males with HSAS are born with severe hydrocephalus, adducted thumbs, and spasticity; intellectual disability is severe. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay; intellectual disability ranges from mild (IQ: 50-70) to moderate (IQ: 30-50). It is important to note that all phenotypes can be observed in affected individuals within the same family.
Diagnosis/testing: The diagnosis of L1 syndrome is established in a male proband with suggestive findings and a hemizygous pathogenic variant in L1CAM identified by molecular genetic testing. The diagnosis of L1 syndrome in a female is unusual but not impossible (most likely in the setting of general delay and/or hydrocephalus) and is established with the identification of a heterozygous pathogenic variant in L1CAM by molecular genetic testing.
Management: Treatment of manifestations: It is best to involve a multidisciplinary team with expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and clinical genetics. Shunting of the cerebrospinal fluid should be performed as needed to reduce intracranial pressure. Individual educational programming is indicated for developmental delay and intellectual disability. Standard treatment guidelines should be followed for spasticity. A splint may help reduce the degree of thumb adduction; surgery is not generally indicated.
Surveillance: Neurologic evaluation at regular intervals to monitor hydrocephalus, developmental progress, and spastic paraplegia.
Genetic counseling: L1 syndrome is inherited in an X-linked manner. If the mother of the proband is heterozygous for an L1CAM pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the L1CAM pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually not be affected but may have a range of (typically mild) clinical manifestations. Once the L1CAM pathogenic variant has been identified in an affected family member, heterozygote detection, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
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