L1 syndrome (ORPHA:275543)
A rare, 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.
Epidemiology
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.
Clinical description
Presentation is commonly in the antenatal or neonatal period but, depending on the severity of condition, may present later in life with developmental delay and other neurological features such as spasticity. Affected males have varying degrees of hydrocephalus (frequently present 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. Female carriers may have minor features such as adducted thumbs or mild intellectual deficit but they rarely have the severe manifestations of the syndrome.
Etiology
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.
Diagnostic methods
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 (corticospinal tract) 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.
Differential diagnosis
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.
Antenatal diagnosis
Prenatal testing can be performed in female carriers if an L1CAM disease-causing mutation has been identified in a family member. Genetic counseling is important; fetal gender determination can be part of the prenatal workup. Fetal cells, obtained by chorionic villus sampling or by amniocentesis, can be studied 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.
Genetic counseling
L1 syndrome is inherited in an X-linked manner. Genetic counseling should be provided to affected families. For carrier females, there is a 50% chance that male offspring will be affected; for female offspring there is 50% risk of inheriting the mutation. Carrier females may be asymptomatic or express a milder phenotype.
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.
Prognosis
Hydrocephalus may result in stillbirth or death in early infancy. Prognosis is dependent on the severity of the manifestations.

                            Last update: 
                            November 2020


                            - Expert reviewer(s): 
                            Pr C.T.R.M. [Connie] STUMPEL | ITHACA* - Dr Y.J. [Yvonne] VOS 


                                * European Reference Network