• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

L1 Syndrome

Synonyms: L1 Spectrum, L1 Disease. Includes: X-Linked Hydrocephalus with Stenosis of the Aqueduct of Sylvius (HSAS, Aqueductal Stenosis, X-linked), MASA Syndrome (Mental Retardation, Adducted Thumbs, Shuffling Gait, and Aphasia), SPG1 (X-Linked Complicated Hereditary Spastic Paraplegia Type 1), X-Linked Corpus Callosum Agenesis

, MD, PhD and , PhD.

Author Information
, MD, PhD
Department of Clinical Genetics
Academic Hospital Maastricht
Research Institute Growth & Development (GROW)
Maastricht University
Maastricht, The Netherlands
, PhD
Department of Genetics
University Medical Center Groningen
Groningen, The Netherlands

Initial Posting: ; Last Update: December 23, 2010.

Summary

Disease characteristics. The phenotypic spectrum of L1 syndrome includes X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), MASA syndrome (Mental retardation, Aphasia [delayed speech], Spastic paraplegia [shuffling gait], Adducted thumbs), SPG1 (X-linked complicated hereditary spastic paraplegia type 1), and 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).

Diagnosis/testing. The diagnosis of L1 syndrome can be established in males with characteristic clinical and neuropathologic findings and a family history consistent with X-linked inheritance. Of note, bilateral absence of the pyramids detected by MRI or autopsy is an almost pathognomonic finding. L1CAM is the only gene in which mutation causes L1 syndrome.

Management. Treatment of manifestations: It is best to involve a multidisciplinary team with expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and medical genetics. Shunting of the cerebrospinal fluid (CSF) should be performed as needed to reduce intracranial pressure. Surgery for adducted thumbs is not indicated; in some milder cases, tendon transfer and/or splint may improve thumb function.

Surveillance: Monitoring of developmental progress and neurologic findings.

Genetic counseling. L1 syndrome is inherited in an X-linked manner. Women who are carriers have a 50% chance of transmitting the disease-causing mutation in each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation will be carriers. Affected males do not reproduce. Carrier testing of at-risk female relatives and prenatal testing are possible if the L1CAM disease-causing mutation has been identified in an affected family member.

Diagnosis

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].

Molecular Genetic Testing

Gene. L1CAM is the only gene associated with L1 syndrome.

Clinical testing

Note: In males, deletions are inferred by absence of a PCR product in mutation scanning and sequence analysis; duplication analysis is necessary for confirmation (see Table 1 footnote 5).

Table 1. Summary of Molecular Genetic Testing Used in L1 Syndrome

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
Affected Males Carrier Females
L1CAMSequence analysisSequence variants 2 100%100%
Partial- and whole-gene deletions0% 3
Deletion / duplication analysis 4Partial- and whole-gene deletionsSee footnote 5Unknown

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Sequence analysis cannot detect exonic or whole-gene deletions on the X chromosome in carrier females.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Deletion analysis can be used to confirm a putative exonic/whole-gene deletion in males after failure of DNA to amplify by PCR in the sequence analysis.

Table 2. Detection of L1CAM Mutations in Probands by Mutation Scanning

Family HistoryMutation Detection Frequency by Number of Clinical Findings 1
<3 Findings3 Findings
Negative9%50%
≥2 affected family members32%85%

Adapted from Vos et al [2010]

1. Age-independent clinical characteristics: hydrocephalus, aqueduct stenosis, adducted thumbs, agenesis/dysgenesis of the corpus callosum

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband, L1CAM molecular genetic testing is performed:

1.

Initially sequence analysis

2.

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.

Clinical Description

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 potentially offensive and not causally focused [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.

Differential Diagnosis

The differential diagnosis of males with developmental delay or intellectual disability and early hypotonia evolving into spastic paraplegia during childhood, with or without adducted thumbs, includes many conditions.

In newborns with hydrocephalus, other causes of hydrocephalus should be excluded [Schrander-Stumpel & Fryns 1998]. Hydrocephalus is often divided into nonsyndromic forms and syndromic forms:

Nonsyndromic congenital hydrocephalus

  • As part of a neural tube defect
  • Isolated hydrocephalus:
    • Congenital aqueductal stenosis
    • Autosomal recessive hydrocephalus
  • As part of a CNS malformation:
    • Arnold-Chiari malformation
    • Dandy-Walker malformation
    • Hydranencephaly
    • Vein of Galen malformation
    • Midline hyperplasia with malformation of the fornical system
    • Congenital cyst
    • Other midline abnormalities
  • Congenital communicating hydrocephalus secondary to hemorrhage

Syndromic congenital hydrocephalus

PLP1-related disorders (including SPG2). The PLP1-related disorders of central nervous system myelin formation caused by mutations in PLP1 include the spectrum of phenotypes ranging from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. SPG2 can be “complicated” or “uncomplicated” (pure) spastic paraparesis. Complicated SPG2 often includes autonomic dysfunction (e.g., spastic urinary bladder), ataxia, and nystagmus; pure SPG2 does not have other significant CNS signs; however, autonomic dysfunction including spastic urinary bladder may also occur. A wide range of phenotypes can be observed in members of the same family. Clinical diagnosis depends on the typical neurologic findings, X-linked recessive inheritance pattern, and, usually, diffusely abnormal myelin on MRI.

Because of clinical overlap between the SPG1 phenotype of L1 syndrome and the SPG2 phenotype of the PLP1-related disorders, it may be difficult to make the diagnosis of the L1 syndrome on clinical grounds alone especially when hydrocephalus is absent in affected males.

See also Hereditary Spastic Paraplegia Overview.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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.

Evaluation 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

L1 syndrome is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

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.

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 approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 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 an option for some families in which the disease-causing mutation has been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Hydrocephalus Association
    870 Market Street
    Suite 705
    San Francisco CA 94102
    Phone: 888-598-3789 (toll-free); 415-732-7040
    Fax: 415-732-7044
    Email: info@hydoassoc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. L1 Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for L1 Syndrome (View All in OMIM)

303350MASA SYNDROME
307000HYDROCEPHALUS DUE TO CONGENITAL STENOSIS OF AQUEDUCT OF SYLVIUS; HSAS
308840L1 CELL ADHESION MOLECULE; L1CAM

Normal allelic variants. L1CAM consists of 29 exons, 28 of which are coding [Kallunki et al 1997]. The non-coding exon (exon 1A) of 125 bp is about 10 kb upstream of exon 1, the first coding exon. The mRNA has been shown to be alternatively spliced. The neuronal form (NM_000425.3 includes a neuron-specific exon in the 3' region and encodes the full-length isoform) of L1CAM contains exon 2 and exon 27, while they are excluded from the non-neuronal mRNA. Missense mutations that are non-pathogenic polymorphisms and mutations of unknown pathogenic relevance have also been reported [Finckh et al 2000, Weller & Gärtner 2001].

Pathologic allelic variants. L1CAM mutations, the majority of which appear to be private, are scattered throughout the gene. All types of disease-causing mutations are found: nonsense, frameshift, splice site, and missense mutations. The nonsense and frameshift mutations lead to truncation of the L1 protein.

To date, 247 different mutations in about 300 families with L1 syndrome have been reported (www.l1cammutationdatabase.info). See Vos & Hofstra [2010].

Normal gene product. The protein consists of 1257 amino acids with a molecular weight of 200 kd (including carbohydrates). The L1 cell adhesion molecule (L1CAM) is a cell surface (transmembrane) glycoprotein. It belongs to the large class of immunoglobulin superfamily proteins with an extracellular part consisting of six immunoglobulin-like (Ig-like) domains and five fibronectin type III-like (FNIII) domains, a single-pass transmembrane domain, and a short cytoplasmic domain [Weller & Gärtner 2001].

L1 is expressed on neurons, both in the central nervous system and the peripheral nervous system. On differentiated neurons, L1 is found at regions of contact between neighboring axons and on the growth cones. The L1 protein mediates cell-cell adhesion through homophilic and heterophilic interactions with other L1 protein molecules and with various ligands. L1 ligand binding is linked to intracellular signaling pathways and the L1 protein is involved in modification of cytoskeleton interactions [Kenwrick et al 2000].

Abnormal gene product. Truncated proteins caused by a nonsense mutation in the extracellular part of the protein lack the transmembrane domain and thus contact between neurons is impaired. The truncated proteins are either secreted into the extracellular space or degraded quickly [Kamiguchi & Lemmon 1997, Brümmendorf et al 1998].

Truncating or missense mutations in the cytoplasmic domain act on a highly conserved domain that contains binding and phosphorylation sites. Abnormal proteins resulting from missense mutations in the extracellular domain may lose function by altered folding or trafficking or by altered ligand binding [Kenwrick et al 2000, De Angelis et al 2002, Rünker et al 2003].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. Basel-Vanagaite L, Straussberg R, Friez MJ, Inbar D, Korenreich L, Shohat M, Schwartz CE. Expanding the phenotypic spectrum of L1CAM-associated disease. Clin Genet. 2006;69:414–9. [PubMed: 16650080]
  2. Bateman A, Jouet M, MacFarlane J, Du JS, Kenwrick S, Chothia C. Outline structure of the human L1 cell adhesion molecule and the sites where mutations cause neurological disorders. EMBO J. 1996;15:6050–9. [PMC free article: PMC452426] [PubMed: 8947027]
  3. Bianchine JW, Lewis RC. The MASA syndrome: a new heritable mental retardation syndrome. Clin Genet. 1974;5:298–306. [PubMed: 4855169]
  4. Bott L, Boute O, Mention K, Vinchon M, Boman F, Gottrand F. Congenital idiopathic intestinal pseudo-obstruction and hydrocephalus with stenosis of the aqueduct of sylvius. Am J Med Genet A. 2004;130A:84–7. [PubMed: 15368500]
  5. Boyd E, Schwartz CE, Schroer RJ, May MM, Shapiro SD, Arena JF, Lubs HA, Stevenson RE. Agenesis of the corpus callosum associated with MASA syndrome. Clin Dysmorphol. 1993;2:332–41. [PubMed: 8305964]
  6. Brümmendorf T, Kenwrick S, Rathjen FG. Neural cell recognition molecule L1: from cell biology to human hereditary brain malformations. Curr Opin Neurobiol. 1998;8:87–97. [PubMed: 9568396]
  7. Chow CW, Halliday JL, Anderson RM, Danks DM, Fortune DW. Congenital absence of pyramids and its significance in genetic diseases. Acta Neuropathol (Berl). 1985;65:313–7. [PubMed: 3976367]
  8. De Angelis E, Watkins A, Schafer M, Brummendorf T, Kenwrick S. Disease-associated mutations in L1 CAM interfere with ligand interactions and cell-surface expression. Hum Mol Genet. 2002;11:1–12. [PubMed: 11772994]
  9. Finckh U, Schroder J, Ressler B, Veske A, Gal A. Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease. Am J Med Genet. 2000;92:40–6. [PubMed: 10797421]
  10. Fransen E, Lemmon V, Van Camp G, Vits L, Coucke P, Willems PJ. CRASH syndrome: clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene, L1. Eur J Hum Genet. 1995;3:273–84. [PubMed: 8556302]
  11. Gigarel N, Frydman N, Burlet P, Kerbrat V, Steffann J, Frydman R, Munnich A, Ray PF. Single cell co-amplification of polymorphic markers for the indirect preimplantation genetic diagnosis of hemophilia A, X-linked adrenoleukodystrophy, X-linked hydrocephalus and incontinentia pigmenti loci on Xq28. Hum Genet. 2004;114:298–305. [PubMed: 14673643]
  12. Griseri P, Vos Y, Giorda R, Gimelli S, Beri S, Santamaria G, Mognato G, Hofstra R, Gimelli G, Ceccherini I. Complex pathogenesis of Hirschsprung's disease in a patient with hydrocephalus, vesico-ureteral reflux and a balanced translocation t(3;17)(p12;q11). Eur J Hum Genet. 2009;17:483–90. [PMC free article: PMC2986215] [PubMed: 19300444]
  13. Jackson SR, Guner YS, Woo R, Randolph LM, Ford H, Shin CE. L1CAM mutation in association with X-linked hydrocephalus and Hirschsprung’s disease. Pediatr Surg Int. 2009;25:823–5. [PMC free article: PMC2734257] [PubMed: 19641926]
  14. Kaepernick L, Legius E, Higgins J, Kapur S. Clinical aspects of the MASA syndrome in a large family, including expressing females. Clin Genet. 1994;45:181–5. [PubMed: 8062435]
  15. Kallunki P, Edelman GM, Jones FS. Tissue-specific expression of the L1 cell adhesion molecule is modulated by the neural restrictive silencer element. J Cell Biol. 1997;138:1343–54. [PMC free article: PMC2132545] [PubMed: 9298989]
  16. Kamiguchi H, Lemmon V. Neural cell adhesion molecule L1: signaling pathways and growth cone motility. J Neurosci Res. 1997;49:1–8. [PubMed: 9211984]
  17. Kenwrick S, Watkins A, De Angelis E. Neural cell recognition molecule L1: relating biological complexity to human disease mutations. Hum Mol Genet. 2000;9:879–86. [PubMed: 10767310]
  18. Knops NB, Bos KK, Kerstjens M, van Dael K, Vos YJ. Nephrogenic diabetes insipidus in a patient with L1 syndrome: a new report of a contiguous gene deletion syndrome including L1CAM and AVPR2. Am J Med Genet A. 2008;146A:1853–8. [PubMed: 18553546]
  19. Landrieu P, Ninane J, Ferriere G, Lyon G. Aqueductal stenosis in X-linked hydrocephalus: a secondary phenomenon? Dev Med Child Neurol. 1979;21:637–42. [PubMed: 574474]
  20. Nakakimura S, Sasaki F, Okada T, Arisue A, Cho K, Yoshino M, Kanemura Y, Yamasaki M, Todo S. Hirschsprung's disease, acrocallosal syndrome, and congenital hydrocephalus: report of 2 patients and literature review. J Pediatr Surg. 2008;43:E13–7. [PubMed: 18485929]
  21. Okamoto N, Del Maestro R, Valero R, Monros E, Poo P, Kanemura Y, Yamasaki M. Hydrocephalus and Hirschsprung's disease with a mutation of L1CAM. J Hum Genet. 2004;49:334–7. [PubMed: 15148591]
  22. Okamoto N, Wada Y, Goto M. Hydrocephalus and Hirschsprung's disease in a patient with a mutation of L1CAM. J Med Genet. 1997;34:670–1. [PMC free article: PMC1051030] [PubMed: 9279760]
  23. Panayi M, Gokhale D, Mansour S, Elles R. Prenatal diagnosis in a family with X-linked hydrocephalus. Prenat Diagn. 2005;25:930–3. [PubMed: 16088863]
  24. Parisi MA, Kapur RP, Neilson I, Hofstra RM, Holloway LW, Michaelis RC, Leppig KA. Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease? Am J Med Genet. 2002;108:51–6. [PubMed: 11857550]
  25. Pinckert TL, Golbus MS. Fetal surgery. Clin Perinatol. 1988;15:943–53. [PubMed: 3061709]
  26. Rünker AE, Bartsch U, Nave KA, Schachner M. The C264Y missense mutation in the extracellular domain of L1 impairs protein trafficking in vitro and in vivo. J Neurosci. 2003;23:277–86. [PubMed: 12514225]
  27. Schrander-Stumpel C, ed. Clinical and Genetic Aspects of the X-Linked Hydrocephalus/MASA Spectrum. Maastricht, Netherlands: Datawyse/University Press; 1995.
  28. Schrander-Stumpel CT. What's in a name? Am J Med Genet. 1998;79:228. [PubMed: 9788567]
  29. Schrander-Stumpel C, Legius E, Fryns JP, Cassiman JJ. MASA syndrome: new clinical features and linkage analysis using DNA probes. J Med Genet. 1990;27:688–92. [PMC free article: PMC1017259] [PubMed: 2277384]
  30. Schrander-Stumpel C, Fryns JP. Congenital hydrocephalus: nosology and guidelines for clinical approach and genetic counselling. Eur J Pediatr. 1998;157:355–62. [PubMed: 9625330]
  31. Schrander-Stumpel CT, Krijne-Kubat B, Vandevijver N, Offermans J, Blanco C, Blackburn W, den Hartog J, Cooley NR. Studies of congenital hydrocephalus with special emphasis on the X-linked type: the need for a protocol. Proceedings of the Greenwood Genetic Center. 2000;19:74.
  32. Sermon K, Van Steirteghem A, Liebaers I. Preimplantation genetic diagnosis. Lancet. 2004;363:1633–41. [PubMed: 15145639]
  33. Tegay DH, Lane AH, Roohi J, Hatchwell E. Contiguous gene deletion involving L1CAM and AVPR2 causes X-linked hydrocephalus with nephrogenic diabetes insipidus. Am J Med Genet A. 2007;143:594–8. [PubMed: 17318848]
  34. Van Camp G, Vits L, Coucke P, Lyonnet S, Schrander-Stumpel C, Darby J, Holden J, Munnich A, Willems PJ. A duplication in the L1CAM gene associated with X-linked hydrocephalus. Nat Genet. 1993;4:421–5. [PubMed: 8401593]
  35. Varadi V, Csecsei K, Szeifert GT, Toth Z, Papp Z. Prenatal diagnosis of X linked hydrocephalus without aqueductal stenosis. J Med Genet. 1987;24:207–9. [PMC free article: PMC1049996] [PubMed: 3295245]
  36. Vits L, Chitayat D, Van Camp G, Holden JJ, Fransen E, Willems PJ. Evidence for somatic and germline mosaicism in CRASH syndrome. Hum Mutat. 1998 Suppl 1:S284–7. [PubMed: 9452110]
  37. Vits L, Van Camp G, Coucke P, Fransen E, De Boulle K, Reyniers E, Korn B, Poustka A, Wilson G, Schrander-Stumpel C, Winter RM, Schwartz C, Willems PJ. MASA syndrome is due to mutations in the neural cell adhesion gene L1CAM. Nat Genet. 1994;7:408–13. [PubMed: 7920660]
  38. Vos YJ, Hofstra RM. An updated and upgraded L1CAM mutation database. Hum Mutat. 2010;31:E1102–9. [PubMed: 19953645]
  39. Vos YJ, de Walle HE, Bos KK, Stegeman JA, Ten Berge AM, Bruining M, van Maarle MC, Elting MW, den Hollander NS, Hamel B, Fortuna AM, Sunde LE, Stolte-Dijkstra I, Schrander-Stumpel CT, Hofstra RM. Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis. J Med Genet. 2010;47:169–75. [PubMed: 19846429]
  40. Weller S, Gärtner J. Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): Mutations in the L1CAM gene. Hum Mutat. 2001;18:1–12. [PubMed: 11438988]
  41. Willems PJ, Brouwer OF, Dijkstra I, Wilmink J. X-linked hydrocephalus. Am J Med Genet. 1987;27:921–8. [PubMed: 3425602]
  42. Yamasaki M, Arita N, Hiraga S, Izumoto S, Morimoto K, Nakatani S, Fujitani K, Sato N, Hayakawa T. A clinical and neuroradiological study of X-linked hydrocephalus in Japan. J Neurosurg. 1995;83:50–5. [PubMed: 7782849]

Chapter Notes

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
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1484PMID: 20301657
PubReader format: click here to try

Views

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...