Clinical Diagnosis

L1 syndrome involves a phenotypic spectrum ranging from severe to mild. Before the availability of molecular genetic testing, several of the phenotypes were thought to be distinct entities. These phenotypes, which are useful in facilitating clinical diagnosis and providing prognosis, have traditionally comprised the following:

X-linked hydrocephalus with stenosis of aqueduct of Sylvius (HSAS). Signs present in affected males:

• Severe hydrocephalus, often of prenatal onset. The clinical criteria for hydrocephalus:

  • Increased intraventricular fluid volume evidenced by an increased occipital-frontal circumference and imaging findings such as increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid

  • Increased intraventricular pressure based on: (1) specific clinical signs and symptoms depending on age, such as progressive increase of OFC (occipital frontal circumference), headache, nausea and vomiting, irritability; and/or (2) ultrasound and/or brain imaging; or (3) intracranial pressure measurements with ventricular catheter or lumbar puncture [Schrander-Stumpel & Fryns 1998]

• Adducted (clasped) thumbs caused by a developmental defect of the extensor pollicus longis and/or brevis muscles (>50% of males) [Schrander-Stumpel & Fryns 1998]

• Spasticity evidenced by brisk tendon reflexes and extensor plantar responses

• Severe intellectual disability

MASA syndrome (mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs) [Bianchine & Lewis 1974, Schrander-Stumpel et al 1990]. Findings in affected males:

• Mild to moderate intellectual disability

• Delayed onset of speech

• Hypotonia progressing to spasticity

• Adducted (clasped) thumbs caused by a developmental defect of the extensor pollicis longis and/or brevis muscles

• Variable dilatation of the third ventricle

SPG1 (X-linked complicated hereditary spastic paraplegia type 1). Findings in affected males:

• Spastic paraplegia

• Mild to moderate intellectual disability

• Normal MRI of the brain

X-linked complicated corpus callosum agenesis [Willems et al 1987, Boyd et al 1993, Schrander-Stumpel 1995, Yamasaki et al 1995]. Findings in affected males:

• Variable spastic paraplegia

• Mild to moderate intellectual disability

• Corpus callosum dysplasia, hypoplasia, or aplasia

Testing

Neuropathology and neuroimaging reveal hydrocephalus with or without stenosis of the aqueduct of Sylvius in combination with corpus callosum agenesis/hypogenesis and/or cerebellar hypoplasia, small brain stem, and agenesis of the pyramids (corticospinal tracts) [Willems et al 1987, Yamasaki et al 1995].

Bilateral absence of the pyramids detected by MRI or autopsy is an almost pathognomonic finding [Chow et al 1985, Schrander-Stumpel et al 2000].

Aqueductal stenosis is not a constant feature of L1 syndrome [Landrieu et al 1979, Varadi et al 1987, Yamasaki et al 1995].

Testing Strategy

To confirm/establish the diagnosis in a proband, L1CAM molecular genetic testing is performed: initially sequence analysis, followed by deletion/duplication analysis as needed. .

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and may manifest clinical findings related to the disorder. The features are usually minor symptoms of the clinical spectrum; however, severe hydrocephalus has been reported in a female carrier [Kaepernick et al 1994, Vos et al 2010]. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations of L1CAM.

Natural History

Affected males. In L1 syndrome, the major features are hydrocephalus, intellectual disability, spasticity of the legs, and adducted thumbs. Hydrocephalus may be present prenatally and result in stillbirth or death in early infancy. Males with hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) are born with severe hydrocephalus and adducted thumbs. Seizures may occur. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay. Mild-to-moderate ventricular enlargement is compatible with long survival.

In HSAS, intellectual disability is usually severe and is independent of shunting procedures in individuals with severe hydrocephalus. In MASA syndrome, intellectual disability ranges from mild (IQ: 50-70) to moderate (IQ: 30-50). The degree of intellectual impairment does not necessarily correlate with head size or severity of hydrocephalus; males with severe intellectual disability and a normal head circumference have been reported.

Boys initially exhibit hypotonia of the legs, which evolves into spasticity during the first years of life. In adult males, the spasticity tends to be somewhat progressive, although this finding has not been documented in a large group. Spasticity usually results in atrophy of the muscles of the legs and contractures that together cause the shuffling gait.

All phenotypes can be observed in affected individuals in the same family.

Other findings of unknown significance in individuals with L1CAM mutations and L1 syndrome. At least 13 individuals with an L1CAM mutation and a combination of L1 syndrome and Hirschsprung disease (HSCR) have been reported [Okamoto et al 1997, Vits et al 1998, Parisi et al 2002, Okamoto et al 2004, Basel-Vanagaite et al 2006, Tegay et al 2007, Nakakimura et al 2008, Jackson et al 2009, Griseri et al 2009]. HSCR is characterized by the absence of ganglion cells and the presence of hypertrophic nerve trunks in the distal bowel. It has been suggested that failure of migration of the neural crest cells underlies aganglionosis. Parisi et al [2002] hypothesized that L1CAM may modify the effects of a Hirschsprung disease-associated gene to cause aganglionosis. An L1CAM mutation alone does not result in HSCR.

Another report presents an association between X-linked hydrocephalus and a specific form of congenital idiopathic intestinal pseudo-obstruction (CIIP) in an infant [Bott et al 2004] in whom an L1CAM mutation had been detected.

Carrier females. Females may manifest minor features such as adducted thumbs and/or subnormal intelligence. Rarely do females manifest the complete L1 syndrome phenotype. Severe hydrocephalus has been reported in a female carrier [Kaepernick et al 1994, Vos et al 2010].

Genotype-Phenotype Correlations

In their review, Weller & Gärtner [2001] noted that missense mutations in extracellular domains or mutations in cytoplasmic regions cause milder phenotypes than those resulting from truncation in extracellular domains or from nondetectable L1 protein.

Missense mutations that affect 'key amino acid residues' are most likely to result in a severe phenotype. Key amino acid residues are those crucial for the structure of the immunoglobulin or fibronectin type III-like domains of the L1 protein [Bateman et al 1996].

The above generalizations about genotype-phenotype correlations notwithstanding, clinical findings in L1 syndrome can range from mild to severe even in the same family, indicating that other factors must influence the clinical presentation [Finckh et al 2000].

Nomenclature

The acronym 'CRASH syndrome' was first used in 1995 [Fransen et al 1995]. This acronym was not causally focused and had the potential to be offensive [Schrander-Stumpel 1998]; thus, L1 syndrome is the preferred name.

Prevalence

X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS or hydrocephalus with stenosis of the aqueduct of Sylvius) is the most common genetic form of congenital hydrocephalus, with a prevalence of approximately 1:30,000. It accounts for approximately 5%-10% of males with nonsyndromic congenital hydrocephalus [Schrander-Stumpel & Fryns 1998, Finckh et al 2000].

In males with complicated spastic paraplegia, the prevalence of L1 syndrome is unknown.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with L1 Syndrome, the following evaluations are recommended:

• Head imaging study

• Complete neurologic evaluation

• Developmental evaluation

Treatment of Manifestations

Optimal management involves a multidisciplinary team with expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and medical genetics.

• Hydrocephalus. Surgical treatment should be performed as needed. Shunting of the cerebrospinal fluid (CSF) is indicated to reduce intracranial pressure. Of note, prenatal shunting procedures offer no advantage [Pinckert & Golbus 1988].

• Intellectual disability. Developmental progress should be monitored and stimulated. Developmental outcome is variable and individual counseling important.

• Adducted thumbs. Surgical intervention is not indicated. In some milder cases, tendon transfer may improve thumb function. A splint helps reduce the degree of adduction is some cases.

• Spastic paraplegia. Neurologic features should be monitored. Follow-up and treatment is nonspecific; general guidelines can be followed.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

L1 syndrome is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

• The father of an affected male will not have the disease, nor will he be a carrier of the mutation.

• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.

• If a woman has more than one affected son and the disease-causing mutation cannot be detected in DNA extracted from her leukocytes, she has germline mosaicism.

• When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:

  • He has a de novo disease-causing mutation in L1CAM and his mother is not a carrier. It has been shown that approximately 7% of all mutations detected occurred de novo [Vos et al 2010].

  • His mother has a de novo disease-causing mutation in L1CAM, either (a) as a 'germline mutation' (i.e., present at the time of her conception and therefore in every cell of her body); or (b) as 'germline mosaicism' (i.e., present in some of her germ cells only).

  • His mother has a disease-causing mutation that she inherited from a maternal female ancestor.

Sibs of a proband

• The risk to sibs depends on the carrier status of the mother.

• If the mother is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers.

• If the proband's disease-causing mutation has not been identified in DNA extracted from the mother's leukocytes, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. No males with L1 syndrome are known to have reproduced.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo mutation arose, information that could help determine genetic risk status of the extended family.

Carrier Detection

• Carrier testing of at-risk female relatives is possible if the mutation has been identified in the proband.

• Fewer than 5% of females who are carriers of an L1CAM mutation manifest clinical features. The features are usually minor symptoms of the clinical spectrum; however, severe hydrocephalus has been reported in a female carrier [Kaepernick et al 1994, Vos et al 2010].

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal testing is possible for pregnancies of women who are carriers if the L1CAM disease-causing mutation has been identified in a family member. The usual procedure is to determine the fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation. While it is not possible to accurately predict the clinical course and phenotype in a male with an L1CAM mutation identified prenatally, a severe phenotype is generally expected. If the karyotype is 46,XX and the fetus is a carrier of an L1CAM mutation or the carrier status is unknown, serial ultrasound examination is offered at 20 weeks and 32 weeks to monitor for hydrocephalus.

Ultrasound examination. L1 syndrome cannot be reliably diagnosed on the basis of prenatal ultrasound only. A diagnosis of hydrocephalus often requires serial ultrasound examination and cannot be guaranteed before 20 to 24 weeks' gestation or even the third trimester of pregnancy. Furthermore, apparently normal ultrasound findings in a pregnancy with a priori increased risk are not reliable in ruling out L1 syndrome in the fetus.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) has been reported [Gigarel et al 2004, Sermon et al 2004] and may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Author Notes

Connie Schrander-Stumpel is a professor of clinical genetics in Maastricht, The Netherlands. She is head of the department of clinical genetics and head of the training program for clinical geneticists in Maastricht. She wrote her thesis on the X-linked type of hydrocephalus and is especially interested in dysmorphology, X-linked intellectual disability, and preconception care.

Yvonne J Vos is a clinical molecular geneticist and head of the department of DNA diagnostics at the University Medical Center Groningen, The Netherlands.

Revision History

• 23 December 2010 (me) Comprehensive update posted live

• 20 October 2006 (me) Comprehensive update posted to live Web site

• 28 April 2004 (me) Review posted to live Web site

• 14 October 2003 (css) Original submission