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L1 Syndrome

Synonyms: L1 Spectrum, L1 Disease

, MD, PhD and , PhD.

Author Information

Initial Posting: ; Last Update: March 5, 2015.

Estimated reading time: 17 minutes


Clinical characteristics.

The phenotypic spectrum of L1 syndrome includes:

  • X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS);
  • MASA syndrome (mental retardation [intellectual disability], 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).


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. Detection of a hemizygous pathogenic variant in L1CAM confirms the diagnosis of L1 syndrome.


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 (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 L1CAM pathogenic variant in each pregnancy. Sons who inherit the L1CAM pathogenic variant will be affected; daughters who inherit the pathogenic variant will be carriers. Affected males do not reproduce. Carrier testing of at-risk female relatives and prenatal testing are possible if the L1CAM pathogenic variant has been identified in an affected family member.

GeneReview Scope

L1 Syndrome: Included Phenotypes 1
  • X-linked hydrocephalus with stenosis of the aqueduct of Sylvius
  • MASA syndrome (mental retardation, adducted thumbs, shuffling gait, and aphasia)
  • SPG1 (X-linked complicated hereditary spastic paraplegia type 1)
  • X-linked complicated corpus callosum agenesis

For synonyms and outdated names see Nomenclature.


For other genetic causes of these phenotypes see Differential Diagnosis.


Suggestive Findings

L1 syndrome involves a phenotypic spectrum ranging from severe to mild. L1 syndrome should be suspected in individuals with any of the following clinical phenotypes or neuroimaging findings.

Clinical Phenotypes

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 increased occipital-frontal circumference and imaging findings including increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid
    • Increased intraventricular pressure based on [Schrander-Stumpel & Fryns 1998]:
      • Specific clinical signs and symptoms depending on age, such as progressive increase of OFC (occipital frontal circumference), headache, nausea and vomiting, irritability; and/or
      • Ultrasound and/or brain imaging; or
      • Intracranial pressure measurements with ventricular catheter or lumbar puncture
  • 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

Neuroimaging Findings

Hydrocephalus with or without stenosis of the aqueduct of Sylvius is found 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, Váradi et al 1987, Yamasaki et al 1995].

Establishing the Diagnosis

The diagnosis of an L1 syndrome is established in a male proband with the identification of a hemizygous pathogenic variant in L1CAM (see Table 1).

Molecular testing approaches can include the following:

  • Single-gene testing beginning with sequence analysis of L1CAM and followed by deletion/duplication analysis if no pathogenic variant is found
  • Use of a multigene panel that includes L1CAM and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing including exome sequencing if single-gene testing (and/or use of a multigene panel) has not confirmed a diagnosis in an individual with features of L1 syndrome
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in L1 Syndrome

Gene 1MethodProportion of Probands with a Pathogenic Variant Detectable by Method
Affected malesCarrier females
L1CAMSequence analysis detecting sequence variants 299% 398% 4
Deletion/duplication analysis 5See footnote 6.Unknown

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.


Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Deletion analysis can be used to confirm a putative exon/whole-gene deletion in males after failure of DNA to amplify by PCR in the sequence analysis. The frequency of deletions and duplications is low: to date eight large deletions or duplications (including one deletion of the entire gene) have been described [Vos & Hofstra 2010, Adle-Biassette et al 2013] (see Molecular Genetics).

Table 2.

Probability of Detecting an L1CAM Pathogenic Variant in Probands Based on Number of Age-Independent Clinical Findings

Family HistoryVariant Detection Frequency by Number of Clinical Findings 1
<3 findings≥3 findings
≥2 affected family members32%85%

Adapted from Vos et al [2010]. Note: The test method used was scanning for pathogenic variants; sequence analysis may have a slightly greater sensitivity.


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

Clinical Characteristics

Clinical Description

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 (mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs), 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 within the same family.

Other findings of unknown significance in individuals with L1CAM pathogenic variants and L1 syndrome. At least 15 individuals with an L1CAM pathogenic variant 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, Griseri et al 2009, Jackson et al 2009, Fernández et al 2012, Takenouchi et al 2012]. 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] and Griseri et al [2009] hypothesized that L1CAM may modify the effects of a Hirschsprung disease-associated gene to cause aganglionosis. An L1CAM pathogenic variant alone does not result in HSCR.

Basel-Vanagaite et al [2006] reported two sibs with an L1CAM pathogenic missense variant, corpus callosum hypoplasia, and Hirschsprung disease. This family expands the phenotypic spectrum of L1CAM-associated disease. Additional studies are necessary to understand this association.

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 pathogenic variant had been detected.

Carrier females. Females heterozygous for an L1CAM pathogenic variant 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 pathogenic missense variants in extracellular domains or pathogenic variants in cytoplasmic regions cause milder phenotypes than those resulting from truncation in extracellular domains or from nondetectable L1 protein.

Pathogenic missense variants 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].

A statistical analysis was performed on 33 individuals with L1 syndrome in whom a pathogenic variant was identified to detect any possible genotype-phenotype correlation. Children harboring a pathogenic truncating variant were more likely to die before age three years (52%) than children with a pathogenic missense variant (8%), indicating a relationship between the seriousness of the disease and the type of pathogenic variant. These results are statistically significant (Fisher exact p=0.02) [Vos et al 2010].

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


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.


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 pathogenic variants in PLP1 include spectrum range of phenotypes 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. Life span is shortened. SPG2 manifests as spastic paraparesis with or without CNS involvement and usually normal life span. Intrafamilial variation of phenotypes can be observed, but the signs are usually fairly consistent within families. Female carriers may manifest mild to moderate signs of the disease.

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.


Evaluations Following Initial Diagnosis

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

  • Head imaging study
  • Complete neurologic evaluation
  • Developmental evaluation
  • Evaluation for Hirschsprung disease if there is a history of constipation
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Optimal management involves a multidisciplinary team with expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and clinical 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 educational programming is important.
  • Adducted thumbs. Surgical intervention is not generally indicated. A splint may help reduce the degree of adduction. In some milder cases, tendon transfer may improve thumb function.
  • Spastic paraplegia. Neurologic features should be monitored. Follow up and treatment is nonspecific; general guidelines can be followed.

Prevention of Secondary Complications

Physiotherapy is recommended.


Evaluation by a child neurologist at regular intervals is appropriate.

Evaluation of Relatives at Risk

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

Pregnancy Management

Prenatal recognition of an affected fetus in case of an ungoing pregnancy requires multidisciplinary planning for a safe delivery for both mother and infant and for early evaluation and possible treatment for hydrocephalus shortly after birth.

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe 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 of the proband has an L1CAM pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and may have some manifestations (see Clinical Description, Carrier females)
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the L1CAM pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal 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 pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote (Carrier) Detection

Identification of female carriers requires either (a) prior identification of the L1CAM pathogenic variant 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 pathogenic variant is identified, by deletion/duplication analysis.

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 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the L1CAM pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

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.


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.

  • National Library of Medicine Genetics Home Reference
  • Hydrocephalus Association
    870 Market Street
    Suite 705
    San Francisco CA 94102
    Phone: 888-598-3789 (toll-free); 415-732-7040
    Fax: 415-732-7044

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 from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for L1 Syndrome (View All in OMIM)


Gene structure. L1CAM consists of 29 exons, 28 of which are coding [Kallunki et al 1997]. The noncoding exon (exon 1A) of 125 bp is about 10 kb upstream of exon 1, the first coding exon. The mRNA is alternatively spliced. The neuronal mRNA (NM_000425.3 encodes the full-length isoform) of L1CAM contains exon 2 and exon 27, while they are excluded from the non-neuronal mRNA. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Missense variants that are benign or of unknown pathogenic relevance have also been reported [Finckh et al 2000, Weller & Gärtner 2001, Vos et al 2010].

Pathogenic variants. L1CAM pathogenic variants, the majority of which appear to be private, are scattered throughout the gene. All types of pathogenic variants are found: nonsense, frameshift, splicing, and missense variants, but also large duplications and deletions. The nonsense and frameshift variants lead to truncation of the L1 protein.

To date, about 350 different pathogenic variants associated with L1 syndrome have been reported (see L1CAM Mutation Database and Table A). See Vos & Hofstra [2010], Adle-Biassette et al [2013] and the L1CAM database, National Genetics Reference Laboratory, Manchester (LOVD).

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 pathogenic nonsense variant 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 variants in the cytoplasmic domain act on a highly conserved domain that contains binding and phosphorylation sites. Abnormal proteins resulting from pathogenic missense variants 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].


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Chapter Notes

Author Notes

Connie 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

  • 5 March 2015 (me) Comprehensive update posted live
  • 23 December 2010 (me) Comprehensive update posted live
  • 20 October 2006 (me) Comprehensive update posted live
  • 28 April 2004 (me) Review posted live
  • 14 October 2003 (css) Original submission
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