X-linked hydrocephalus (L1 syndrome) …

William D Graf MD

Developmental Malformations

Updated 12.13.2023
Released 06.17.1996
Expires For CME 12.13.2026

X-linked hydrocephalus (L1 syndrome)

Author: William D Graf MD

See Contributor Disclosures

Editor: Harvey B Sarnat MD FRCPC MS

X-linked hydrocephalus (L1 syndrome)

In This Article

Quick Link

Introduction

Overview

Cell adhesion molecules (CAMs) are a diverse family of extracellular (eg, laminin) and cell surface (eg, NCAM) glycoproteins involved in cell-cell and cell-extracellular matrix adhesion, recognition, activation, and migration. The L1 family of CAMs is found primarily in the developing nervous system. These membrane glycoproteins guide neurite outgrowth, neuronal cell migration, fasciculation, and the development of the cortical spinal tract. L1 syndrome results from various mutations in the gene encoding the neuronal CAM L1. The clinical spectrum comprises three major disorders, namely X-linked hydrocephalus (XLH), MASA syndrome (mental retardation, adducted thumbs, shuffling gait, aphasia) and spastic paraplegia type I (SPG1). L1CAM mutations are the cause of most cases of “congenital absence of pyramids” and the most common genetic cause of hydrocephalus and hereditary spastic paraplegia in boys. Both L1CAM gene mutation analysis and chromosomal microarray (array comparative genome hybridization, aCGH) should be considered in every patient with congenital hydrocephalus.

Key points

	• Congenital hydrocephalus accounts for approximately 50% of all forms of hydrocephalus, and neurogenetic disorders account for about half of all congenital hydrocephalus.
	• X-linked hydrocephalus (L1 syndrome) is the most common genetic cause of congenital hydrocephalus, accounting for about 10% of congenital hydrocephalus in boys, and is a common cause of X-linked spastic paraplegia (SPG1) in boys.
	• L1 syndrome is caused by mutations in the neural cell adhesion molecule L1 (L1CAM) gene at Xq28 and comprises a broad clinical spectrum of disorders, including X-linked hydrocephalus (XLH), MASA syndrome (mental retardation, adducted thumbs, shuffling gait, aphasia), spastic paraplegia type I (SPG1), and “congenital absence of pyramids.”
	• Cell adhesion molecules (CAMs) are a diverse family of extracellular (eg, laminin) and cell surface (eg, NCAM) glycoproteins involved in cell-cell and cell-extracellular matrix adhesion, recognition, activation, and migration.
	• The L1 family of CAMs is found primarily in the developing nervous system. These membrane glycoproteins guide neurite outgrowth, neuronal cell migration, fasciculation, and the development of the cortical spinal tract. L1CAM spectrum disorders result from various mutations in the gene encoding the neuronal CAM L1.

Historical note and terminology

Initially termed "hereditary stenosis of the aqueduct of Sylvius," this rare genetic disorder is characterized by hydrocephalus, macrocephaly, flexion-adduction thumb deformity, spasticity, mental retardation, and cerebral malformations. Bickers and Adams first provided a detailed account of a newborn boy with stenosis of the cerebral aqueduct and a family history of congenital hydrocephalus in two brothers and four maternal uncles (04). Edwards and colleagues further characterized this family (11), and later Jouet and colleagues performed gene mutation analysis (32). Other investigators subsequently described clinical and pathologic characteristics of the "syndrome of sex-linked hydrocephalus" (11; 27; 30) and recognized the strong association the disorder had with congenital absence of the pyramids (09).

A similar but less severe X-linked recessive disorder, MASA syndrome, is characterized by mental retardation, adducted thumbs, shuffling gait, aphasia, and, in some cases, hydrocephalus (03) or agenesis of the corpus callosum. In X-linked complex spastic paraplegia type I, arrested hydrocephalus with spasticity and cognitive impairment is prominent. Linkage analysis has demonstrated that X-linked hydrocephalus, MASA syndrome, and spastic paraplegia type I loci were located in subchromosomal region Xq28 (62) and result from mutations in the gene encoding the neuronal cell adhesion molecule L1 (44; 32). Because the most frequent and typical findings in individuals with L1 mutations include corpus callosum agenesis, mental retardation, adducted thumbs, spastic paraplegia, and hydrocephalus, this clinical spectrum has also been referred to as the CRASH syndrome (18).

Because this developmental disorder might begin as communicating hydrocephalus followed by brainstem compression, the designation "X-linked aqueductal stenosis" may be a misnomer (34; 61). The terminology "X-linked congenital hydrocephalus" was later proposed (43). “X-linked hydrocephalus” and “L1 syndrome” are now the most commonly used terms (36).

Clinical manifestations

Presentation and course

The clinical spectrum of this X-linked recessive disorder is broad, and there is notable interfamilial and intrafamilial phenotypic heterogeneity (45). Moderate to severe hydrocephalus, macrocephaly, spastic paraparesis or quadriparesis, and flexion-adduction thumb deformities are commonly present. Affected boys with severe hydrocephalus may be stillborn, or they may die shortly after birth or in childhood (04; 11; 27; 61). Other abnormalities include nystagmus with visual impairment, short stature, bilateral syndactyly of the second and third toes, hyperreflexia, gait disturbances, and intellectual disability. The degree of cognitive impairment ranges from mild to profound (40). Congenital aganglionic megacolon (Hirschsprung disease), confirmed by rectal biopsy, has also been reported in boys with X-linked hydrocephalus and L1CAM mutations (29; 41). Learning problems or mild intellectual disability may be seen in obligate female carriers (24).

In a large family with 22 known affected boys with the MASA syndrome, Kaepernick and colleagues described a wide variation of clinical features among family members (33). Some of the affected males had characteristics of the MASA syndrome, and others had features of X-linked hydrocephalus. In this large family, female carriers displayed a variety of features including adducted thumbs, cognitive impairment, and hydrocephalus.

Neuroimaging and gross pathologic studies reveal diverse characteristics in X-linked hydrocephalus, notably bilateral enlargement of the lateral ventricles, diffuse white-matter hypoplasia, absence of the corticospinal tract, agenesis of the corpus callosum, and atrophy of the anterior vermian lobe (09; 64; 05). A patent cerebral aqueduct is observed in most cases on magnetic resonance imaging (64).

Prognosis and complications

Many boys with X-linked hydrocephalus are stillborn or die in infancy or early childhood. Certain L1CAM mutations, especially those that result in a truncation of the extracellular domain of the protein, are associated with the severe phenotype of congenital hydrocephalus, marked developmental motor and cognitive disabilities, and shorter survival (65; 37). Boys harboring a truncating mutation are significantly more likely to die before three years of age (52%) than boys with a missense mutation (8%), indicating a correlation between the severity of the developmental encephalopathy and the type of mutation (57). Most L1 nonsense and frameshift mutations lead to truncation of the protein prior to the transmembrane domain eliminating L1- expression on the cell surface. Such mutations interrupt the effects of cell adhesion and interfere with the intracellular signaling pathways producing severe phenotypes. Missense mutations in the extracellular domains can lead to both severe or mild phenotypes whereas mutations in the cytoplasmic domain tend to produce the mildest form of the neurodevelopmental disorder (Weller and Gartner).

In boys with longer survival, severe motor and cognitive neurologic deficits are invariably present. Intellectual outcome is notably poorer in cases of X-linked hydrocephalus compared to non-X-linked, shunted congenital hydrocephalus. School performance is generally poorer in mothers of X-linked patients as well (24). Recurrent seizures are present in most affected boys (21). Because hydrocephalus alone does not account for seizures, the coexpression of epilepsy implies focal cerebral cortical dysgeneses or secondary neuroblast migratory disturbances that may be microscopic and below the resolution of neuroimaging.

Clinical vignette

Prenatal diagnosis of hydrocephalus and macrocephaly was made in this male fetus by ultrasound at 36 weeks’ gestation. Subsequently, a 3.8 kg boy was delivered by elective cesarean section. Occipitofrontal circumference at birth was 39.5 cm. Physical findings at birth included mild diffuse spasticity and abnormal fisting of the hands with fixed flexion deformities of the thumbs. A ventriculoperitoneal shunt was placed on the second day of life. A CT scan performed after surgery demonstrated a peripheral 1.5 cm mantel of brain parenchyma and marked hydrocephalus. Seizures developed postoperatively and were adequately managed with phenobarbital.

By one year of age the infant showed signs of severe developmental disabilities. He could support his head in the prone position and roll over, but he could not sit independently. He made babbling sounds and had a social smile to some stimuli. Spontaneous nystagmus, minimal ocular tracking, and signs of severe cerebral visual impairment were noted. A follow-up CT scan showed mildly increased cerebral parenchyma without discernible gray or white matter differentiation.

The boy died unexpectedly in sleep shortly after his second birthday. Postmortem neuropathologic assessment showed aqueductal stenosis, irregularly dilated lateral and third ventricles, absence of septum pellucidum, marked atrophy of the corpus callosum, marked cerebral white matter hypoplasia, diffuse polymicrogyria, hypoplastic and poorly differentiated hippocampi, and marked hypoplasia of medullary pyramids.

L1CAM mutation and diffuse polymicrogyria (CT)

CT scan of 5-week-old patient with a L1CAM mutation shows a 1 cm cortical mantle (1a). CT scan at 20 months of age reveals a typical decrease in size of the hydrocephalus with increased thickness of brain parenchyma (1b). Lateral ...
Transverse section of medulla comparison shows normal pyramids

Transverse section of the medulla from an 80-year-old comparison shows the normal pyramids (right outlined in solid white line in a). The medial lemniscus is outlined by the white dashes (a and b). Transverse section of medulla fr...

Biological basis

Etiology and pathogenesis

X-linked hydrocephalus is associated with mutations in the gene for the neural cell adhesion molecule L1, which is located on the subchromosomal region Xq28 (32). L1 is a transmembrane glycoprotein involved in cell adhesion, axonal guidance, fasciculation, and synapse formation (15; 07; 20). Various human L1CAM mutations can be responsible for a wide spectrum of neurologic abnormalities with intellectual disability including X-linked hypogammaglobulinemia, MASA syndrome, SPG1, and X-linked agenesis of the corpus callosum (18; 17). Phenotypic heterogeneity occurs within individual families.

Over 115 different L1CAM gene mutations have been reported (http://www.L1CAMmutationdatabase.info/references.aspx); however, this online database was last updated on October 19, 2012. A registry of specific small deletions, insertions and indels, nucleotide substitutions (nonsense and missense, regulatory, and splicing), gross deletions, and a single gross duplication is obtainable with references via the Internet in the Human Gene Mutation Database, in association with Celera. Approximately half of the currently known mutations cause disruption of the overall L1 structure, and the remaining mutations are missense mutations (18). Milder neurologic disabilities in obligate female carriers may be related to nonrandom X-chromosome inactivation (33).

SPG1 and other hereditary spastic paraplegias are clinically diverse, but all have characteristic leg spasticity and motor dyspraxia caused by either abnormal development or progressive degeneration of corticospinal tracts. A large and rapidly expanding list of at least 83 hereditary spastic paraplegias genes are known to cause this heterogeneous condition (46). The molecular genetic diagnosis of a patient suspected of having hereditary spastic paraplegias may require genetic sequencing using a targeted gene panel, whole-exome sequencing, or whole-genome sequencing, depending on the clinical circumstances and level of diagnostic suspicion.

L1 syndrome is caused by the loss of L1-protein structure and function during the development of the nervous system, which impairs neuronal cell migration, neurite elongation, and axon fasciculation. Congenital hydrocephalus generally occurs by obstruction of the cerebrospinal fluid circulation. In some cases of X-linked hydrocephalus, the obstruction of the cerebral aqueduct may result from a primary CNS malformation. Communicating hydrocephalus followed by secondary aqueductal stenosis was initially postulated to be a cause (63; 34).

X-linked hydrocephalus and two clinically milder disorders, MASA syndrome and spastic paraplegia type I, are associated with mutations of the L1 gene. L1 is a member of the immunoglobulin super family of cell adhesion molecules. Neural cell adhesion proteins play an important role in neural development (07; 20). Mutations in L1 are thought to result in disruption of neuroblast migration, axonal guidance, and axon-fascicle formation (06). Homophilic interactions between L1 family proteins are essential for neural system development through signal transduction-activated cell growth signaling. Various models for homophilic interaction have been proposed for cell adhesion proteins, including zipper, domain-swapped monomer, domain-swapped multimer, 2-fold symmetry-related surface interaction, and 2-fold symmetry-related edge interaction models based on the structures of axonin-1, hemolin, Dscam, and TAG-1/neurofascin (an L1 family protein) (59). It is believed that some cancer progression may involve the homophilic interaction of L1.

The L1-protein is a transmembrane glycoprotein with six immunoglobulin-like and five fibronectine type III domains on the extracellular surface, a single-pass transmembrane segment, and a short but highly conserved cytoplasmic C terminal region. Although the natural distribution of mutations over the functional L1 protein domains are variable, mutations are most common in the second, third, and fourth immunoglobulin-like domain and in the second fibronectin domain (65).

In mice that do not express L1 (L1-Y hemizygous males), there are defects in the guidance of corticospinal tract axons. In this mouse model, the pathway to the caudal medulla appears normal, but a major portion of axons fail to cross the midline to the opposite dorsal column. These defects in medullary or cervical decussation and axon guidance arise during early stages of development (10).

In other experimental models, a novel L1 syndrome mouse with an extracellular L1 mutation and a cell surface-exposed L1 can be remediated through L1 mimetic compounds such as duloxetine, crotamiton, and trimebutine, which rescue impaired cell migration and neuritogenesis in culture (35).

L1CAM receptors are a subfamily of the immunoglobulin superfamily of transmembrane receptors, which include L1, CHL1 (close homologue of L1), NrCAM (neuron-glia-related CAM), and neurofascin. At the cellular level, the L1-CAM family is also expressed in non-neuronal tissues, often as different isoforms. For example, L1 lacking the RSLE motif is found in a variety of glial cells, and the 185 kDa isoform of CHL1 is found in astrocytes, Schwann cells, and oligodendrocyte precursors and progenitors (54; 26).

Under physiological conditions, L1 expression is absent in epithelial cells, but L1 is detectable in precursor lesions, or epithelial cells under inflammatory conditions. L1-CAM proteins expressed outside of the nervous system have also been heavily implicated and are involved in tumor initiation, progression, and migration, as well as in chemoresistance in diseases, including cancers of the lung, pancreas, kidney, and colon (25; 02). L1 expression is a poor prognostic biomarker for cancer patients and is regarded as a potential target for cancer therapy (14).

In humans, postmortem neuropathologic examination reveals polymicrogyria, pachygyria and leptogyria, hypoplasia of the medullary pyramids, hypoplasia of the corpus callosum, small anterior commissure, and poorly differentiated hippocampi. Despite the extensive cerebral malformations, the cortex shows normal-appearing laminar cortical neuronal architecture, further suggesting an underlying disturbance of neuronal connectivity, fasciculation, and synapse formation rather than abnormal neuroblast migration or secondary changes from aqueductal stenosis and increased intracranial pressure (21; 48).

L1CAM mutation shows regions of thick, large gyri

Low power photomicrograph of the occipital lobe from a patient with a L1CAM mutation shows regions of relatively thick, large gyri (a). Medium power photomicrograph representative of Figure a shows normal appearing laminar cortica...
L1CAM mutation showing paucity of white matter and slit-like ventricle remnants

Low (a) and medium (b) power photomicrograph of temporal lobe from a patient with a L1CAM mutation showing a paucity of white matter and slit-like ventricle remnants and fused ependyma. Arrow notes hypoplastic hippocampus. (Contri...

Some nonneuronal cells express a short isoform of L1, in contrast to the complete L1 gene expressed exclusively in neurons (55). L1CAM-mediated cell adhesion may also alter ganglion cell precursors in the development of intestinal aganglionosis (29; 41).

Differential diagnosis

Numerous developmental disorders may present with hydrocephalus or ventriculomegaly, such as 13 or 18 trisomy, arrhinencephaly, Apert syndrome, oro-facio-digital syndrome, Hurler syndrome, achondroplasia, thanatophoric dysplasia, osteogenesis imperfecta, and incontinentia pigmenti (51).

Strain and colleagues described a separate form of X-linked hydrocephalus in a family that displayed the typical clinical features of X-linked hydrocephalus but lacked the linkage to region Xq28 markers (53). In their family, linkage to the FRAXA region of Xq27.3 was demonstrated. Thus, clinical criteria alone are not sufficient in discriminating between genetic types of X-linked hydrocephalus.

Other less common X-linked and autosomal genetic disorders may cause congenital hydrocephalus. Pathological variants in the X-linked AP1S2 gene cause Fried and Pettigrew syndromes, which include congenital hydrocephalus in their phenotype spectrums (19; 08). The AP1S2 gene encodes the sigma-2 subunit of the heterotetrameric adaptor protein 1 (AP1) complex found in the cytosolic side of coated vesicle in the Golgi compartment and mediates the recruitment of clathrin and the recognition of sorting signals of transmembrane receptors.

Autosomal gene variants associated with congenital hydrocephalus include the CCDC88C, MPDZ, EML1, and WDR81 genes. In 2010, the first autosomal recessive disorder causing congenital hydrocephalus secondary to a pathologic CCDC88C gene variant was reported in a consanguineous multiplex family (13). In 2013, a founder homozygous truncating variant in the MPDZ gene was the second reported autosomal recessive disorder causing congenital hydrocephalus (01). Exome sequencing, genome-wide autozygome analysis, and “Mendeliome assays” have identified additional autosomal recessive genes associated with congenital hydrocephalus including the EML1 and WDR81 genes (50).

Macrocephaly is defined as an occipitofrontal circumference (OFC) greater than the 98th percentile for age. Macrocephaly without hydrocephalus is easily diagnosed by all neuroimaging modalities. Macrocephaly without hydrocephalus occurs for many reasons, including megalencephaly, cerebral edema, neoplasia, structural anomalies, and certain neurodevelopmental disorders. Syndromic macrocephaly may also exhibit somatic overgrowth such as in Cowden syndrome (PTEN hamartoma tumor syndrome) or Sotos syndrome (NSD1-related genetic disorder).

Confusing conditions

By definition, in congenital hydrocephalus the condition should be present at birth, and, thus, a developmental etiology is implied. If the condition is diagnosed postnatally, other forms of hydrocephalus caused by overproduction of CSF, defective reabsorption, or obstruction of the CSF pathway should be considered. Overproduction of CSF may occur with increased function of choroid plexus tissue. Underabsorption of CSF most commonly occurs with obstruction of venous return, such as in venous sinus thrombosis. Blockage of the CSF pathway at the cerebral aqueduct or the foramina of Magendie and of Luschka will result in dilatation of the proximal ventricular system. Intraventricular hemorrhage is a frequent complication of prematurity and may result in blockage of the aqueduct from a blood clot. Obstruction of CSF flow secondary to prenatal or perinatal CNS infections may result in inflammatory or gliotic blocks at multiple sites.

Other identifiable developmental disorders are associated with "complicated" hydrocephalus where it is secondary to a primary malformation, such as a neural tube defect. In myelomeningocele, approximately 90% of infants will require ventriculoperitoneal shunt placement to manage hydrocephalus secondary to the Chiari II malformation.

Diagnostic workup

	• Prenatal diagnosis of L1 syndrome may be suspected by fetal ultrasound or fetal MRI.
	• Prenatal, neonatal, or postnatal diagnosis of L1 syndrome can be confirmed by targeted genetic testing or by discovered incidentally by exome sequencing.

In utero ultrasonography, performed after 20 to 24 weeks’ gestation, will reveal the fetus with hydrocephalus in most cases. Although X-linked hydrocephalus has a variable presentation of ventriculomegaly and hydrocephalus, fetal ultrasound and fetal MRI remains a useful tools for prenatal diagnosis (23). Postnatally, computerized tomography or magnetic resonance imaging provides morphologic detail needed to identify other distinct CNS malformations. Because the neuroanatomy of X-linked hydrocephalus secondary to L1CAM gene mutations includes the distinct finding of brainstem corticospinal tract hypoplasia, diffusion-weighted imaging of the brainstem can be used to demonstrate lack of anisotropy in the corticospinal tracts of the basis pontis. Thus, diffusion-weighted imaging may be useful in screening boys thought to have L1 syndrome (22).

Despite the distinct phenotype of L1 syndrome congenital hydrocephalus, its prenatal and neonatal presentation may suggest a broader differential diagnosis. Advances in genetic technologies have led to higher expectations and standards in clinical practice. L1CAM gene mutation analysis is indicated in boys, and chromosomal microarray (chromosomal microarray analysis or array comparative genome hybridization, [aCGH]) should be strongly considered in every patient with congenital hydrocephalus—especially syndromic hydrocephalus (56).

Clinical recognition of phenotypes along with a series of “first-line” and “second-line” genetic tests provide an approach to diagnose both the type and cause of various cerebral malformations. Chromosomal microarray analysis (including both microarray-based comparative genomic hybridization and single nucleotide polymorphism microarray) has become the first-line genetic test in the etiological evaluation of CNS malformations identified pre- or postnatally (52). The widespread use and high diagnostic yield of chromosomal microarray analysis provides the awareness of the unpredictability of human genomic gains and losses as a major cause of cerebral malformations, including those disorders initially described as “developmental delay”, microcephaly, intellectual disability, and multiple congenital anomalies that often include ventriculomegaly. With wide application of next-generation sequencing methods, genes related to cerebral malformations have been identified and more discoveries will be anticipated. In current practice, the combination of “first-line” chromosomal microarray analysis followed by next-generation sequencing should provide an etiological diagnosis in approximately 30% to 40% of major cerebral malformations. Variability in diagnostic rates depends on the differences in the types of patients included in different studies (39). Thus, chromosomal microarray analysis followed by next-generation sequencing testing technology might enable the “genotype first” screening approach ahead of the traditional “phenotype first” patient-examination approach, but pretesting patient selection is essential to exclude patients who are not likely to have a genetic condition.

Obligate female carriers have no reliable clinical marker. Accurate prenatal diagnosis is feasible by L1 gene mutation analysis (49; 47; 31). Using genomic DNA obtained from a blood sample, all coding exons and intron/exon boundaries of the L1CAM gene can be screened by bi-directional sequence analysis. L1CAM gene testing is currently by commercial laboratories in North America and Europe.

Media

References

01: Al-Dosari MS, Al-Owain M, Tulbah M, et al. Mutation in MPDZ causes severe congenital hydrocephalus. J Med Genet 2013;50(1):54-8. PMID 23240096
02: Altevogt P, Ben-Ze’ev A, Gavert N, Schumacher U, Schäfer H, Sebens S. Recent insights into the role of L1CAM in cancer initiation and progression. Int J Cancer 2020;147:3292-6. PMID 36570468
03: Bianchine JW, Lewis RC. The MASA syndrome: a new heritable mental retardation syndrome. Clin Genet 1974;5:298-306. PMID 4855169
04: Bickers DS, Adams RD. Hereditary stenosis of the aqueduct of Sylvius as a cause of congenital hydrocephalus. Brain 1949;72:246-62. PMID 18136715
05: Bousquet I, Bozon M, Castellani V, et al. X-linked partial corpus callosum agenesis with mild intellectual disability: identification of a novel L1CAM pathogenic variant. Neurogenetics 2021;22(1):43-51. PMID 33415589
06: Brummendorf T, Kenwrick S, Rathjen FG. Neural cell recognition molecule L1: from cell biology to human hereditary brain malformations. Curr Biol 1998;8:87-97. PMID 9568396
07: Burden-Gulley SM, Pendergast M, Lemmon V. The role of cell adhesion molecule L1 in axonal extension, growth cone motility, and signal transduction. Cell Tissue Res 1997;290:415-22. PMID 9321705
08: Cacciagli P, Desvignes JP, Girard N, et al. AP1S2 is mutated in X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome). Eur J Hum Genet 2014;22(3):363-8. PMID 23756445
09: Chow CW, Halliday JL, Anderson RM, Danks DM, Fortune DW. Congenital absence of pyramids and its significance in genetic diseases. Acta Neuropathol 1985;65:313-7. PMID 3976367
10: Cohen NR, Taylor JS, Scott LB, Guillery RW, Soriano P, Furley AJ. Errors in corticospinal axon guidance in mice lacking the neural cell adhesion molecule L1. Curr Biol 1997;8:26-33. PMID 9427628
11: Edwards JH. The syndrome of sex-linked hydrocephalus. Arch Dis Child 1961;36:486-93. PMID 13889295
12: Edwards JH, Norman RM, Roberts JM. Sex-linked hydrocephalus. Report of a family with 15 affected members. Arch Dis Child 1961;36:481-5. PMID 13889294
13: Ekici AB, Hilfinger D, Jatzwauk M, et al. Disturbed Wnt signalling due to a mutation in CCDC88C causes an autosomal recessive non-syndromic hydrocephalus with medial diverticulum. Mol Syndromol 2010;1(3):99-112. PMID 21031079
14: Ernst AK, Putscher A, Samatov TR, et al. Knockdown of L1CAM significantly reduces metastasis in a xenograft model of human melanoma: L1CAM is a potential target for anti-melanoma therapy. PLoS One 2018;13(2):e0192525. PMID 29432466
15: Fields RD, Itoh K. Neuronal cell adhesion molecules in activity-dependent development and synaptic plasticity. Trends Neurosci 1996;19:473-80. PMID 8931273
16: 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. PMID 10797421
17: Fransen E, Van Camp G, Vits L, Willems PJ. L1-associated diseases: clinical geneticists divide, molecular geneticists unite. Hum Mol Genet 1997;6:1625-32. PMID 9300653
18: Fransen E, Vits L, Coucke P, Van Camp G, Willems PJ. The clinical spectrum of mutations in L1, neuronal cell adhesion molecule. Am J Med Gen 1996;64:73-7. PMID 8826452
19: Fried K. X-linked mental retardation and/or hydrocephalus. Clin Genet 1972;3(4):258-63. PMID 5054319
20: Goodman CS, Tessier-Lavigne M. Molecular mechanisms of axon guidance and target recognition. In: Cowan WM, Jessell TM, Zipursky SL, editors. Molecular and cellular approaches to neural development. New York: Oxford University Press, 1997:108-78.
21: Graf WD, Born DE, Sarnat HB. The pachygyria-polymicrogyria spectrum of cortical dysplasia in X-linked hydrocephalus. Eur J Pediatr Surg 1998;8(Suppl 1):10-4. PMID 9926316
22: Graf WD, Born DE, Shaw DW, Thomas JR, Holloway LW, Michaelis RC. Diffusion-weighted magnetic resonance imaging in boys with neural cell adhesion molecule L1 mutations and congenital hydrocephalus. Ann Neurol 2000;47:113-7. PMID 10632110
23: Graf WD, Cohen BH, Kalsner L, et al. Fetal anomaly diagnosis and termination of pregnancy. Dev Med Child Neurol 2023. [Epub ahead of print] PMID 36732680
24: Halliday J, Chow CW, Wallace D, Danks DM. X-linked hydrocephalus: a survey of a 20 year period in Victoria, Australia. J Med Genet 1986;23:23-31. PMID 3950933
25: Herron LR, Hill M, Davey F, Gunn-Moore FJ. The intracellular interactions of the L1 family of cell adhesion molecules. Biochem J 2009;419:519-31. PMID 19356150
26: Hillenbrand R, Molthagen M, Montag D, Schachner M. The close homologue of the neural adhesion molecule L1 (CHL1): patterns of expression and promotion of neurite outgrowth by heterophilic interactions. Eur J Neurosci 1999;11:813-26. PMID 10103075
27: Holmes LB, Nash A, ZuRhein GM, Levin M, Opitz JM. X-linked aqueductal stenosis: clinical and neuropathological findings in two families. Pediatrics 1973;51:697-703. PMID 4121400
28: Hortsch M, Nagaraj K, Mualla R. The L1 family of cell adhesion molecules: a sickening number of mutations and protein functions. Adv Neurobiol 2014;8:195-229. PMID 25300138
29: Ikawa H, Kawano H, Takeda Y, et al. Impaired expression of neural cell adhesion molecule L1 in the extrinsic nerve fibers in Hirschsprung's disease. J Pediatr Surg 1997;32:542-5. PMID 9126750
30: Jansen J. Sex-linked hydrocephalus. Dev Med Child Neurol 1975;17:633-40. PMID 1183743
31: Jouet M, Kenwrick S. Gene analysis of L1 neural cell adhesion molecule in prenatal diagnosis of hydrocephalus. Lancet 1995;345:161-2. PMID 7823673
32: Jouet M, Rosenthal A, Armstrong G, et al. X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet 1994;7:402-7. PMID 7920659
33: Kaepernick L, Legius E, Higgins J, Kapur S. Clinical aspects of the MASA syndrome in a family, including expressing females. Clin Genet 1994;45:181-5. PMID 8062435
34: 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. PMID 574474
35: Loers G, Appel D, Lutz D, et al. Amelioration of the abnormal phenotype of a new L1 syndrome mouse mutation with L1 mimetics. FASEB J 2021;35(2):e21329. PMID 33484186
36: McKusick VA. Mendelian inheritance in man: catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes. 11th ed. Baltimore: Johns Hopkins Univ Pr, 1994:2406-8.
37: Michaelis RC, Du YZ, Schwartz CE. The site of a missense mutation in the extracellular Ig of FN domains of L1CAM influences infant mortality and the severity of X linked hydrocephalus. J Med Genet 1998;35:901-4. PMID 9832035
38: Moya GE, Michaelis RC, Holloway LW, Sanchez JM. Prenatal diagnosis of L1 cell adhesion molecule mutations. Capabilities and limitations. Fetal Diagn Ther 2002;17(2):115-9. PMID 11844917
39: Need AC, Shashi V, Hitomi Y, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet 2012;49(6):353-61. PMID 22581936
40: Opitz JM, Segal AT, Klove H, Mattews CH, Lehrke RC. S-linked mental retardation. Study of a large kindred with 20 affected members. J Pediatr 1965;67:713-4.
41: Parisi MA, Kapur RP, Neilson I, et al. Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease. Am J Med Genet 2002;108:51-6. PMID 11857550
42: Piccione M, Federico M, Fichera M, et al. A novel L1CAM mutation in a fetus detected by prenatal diagnosis. Eur J Pediatr 2010;169:415-9. PMID 19685344
43: Renier WO, Ter Haar BG, Sloof JL, et al. X-linked congenital hydrocephalus. Clin Neurol Neurosurg 1982;84:113-23. PMID 6288305
44: Rosenthal A, Jouet M, Kenwrick S. Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus. Nature Genet 1992;2:107-12. PMID 1303258
45: Ruiz JC, Cuppens H, Legius E, et al. Mutations in L1CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS. J Med Genet 1995;32:549-52. PMID 7562969
46: Saputra L, Kumar KR. Challenges and controversies in the genetic diagnosis of hereditary spastic paraplegia. Curr Neurol Neurosci Rep 2021;21(4):15. PMID 33646413
47: Schrander-Stumpel C, Meyer H, Merckx D, et al. The spectrum of "complicated spastic paraplegia, MASA syndrome and X-linked hydrocephalus." Contribution of DNA linkage analysis in genetic counseling of individual families. Genet Couns 1994;5:1-10. PMID 8031529
48: Senner V, Kismann E, Puttmann S, Hoess N, Baur I, Paulus W. L1 expressed by glioma cells promotes adhesion but not migration. Glia 2002;38(2):146-54. PMID 11948808
49: Serville F, Benit P, Saugier P, et al. Prenatal exclusion of X-linked hydrocephalus-stenosis of the aqueduct of Sylvius sequence using closely linked DNA markers. Prenat Diagn 1993;13:435-9. PMID 8372068
50: Shaheen R, Sebai MA, Patel N, et al. The genetic landscape of familial congenital hydrocephalus. Ann Neurol 2017;81(6):890-7. PMID 28556411
51: Smith DW. Recognizable patterns of human malformation. 3rd ed. Philadelphia: WB Saunders, 1982.
52: South ST, Lee C, Lamb AN, Higgins AW, Kearney HM, Working Group for the American College of Medical Genetics and Genomics Laboratory Quality Assurance Committee. ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med 2013;15(11):901-9. PMID 24071793
53: Strain L, Gosden CM, Brock DJ, Bonthron DT. Genetic heterogeneity in X-linked hydrocephalus: linkage to markers within Xq27.3. Am J Hum Genet 1994;54:236-43. PMID 8304340
54: Takeda Y, Asou H, Murakami Y, Miura M, Kobayashi M, Uyemura K. A nonneuronal isoform of cell adhesion molecule L1: tissue-specific expression and functional analysis. J Neurochem 1996;66:2338-49. PMID 8632156
55: Uyemura K, Takeda Y, Asou H, Hayasaka K. Neural cell adhesion proteins and neurologic diseases. J Biochem 1994;116:1187-92. PMID 7706205
56: Verhagen JM, Schrander-Stumpel CT, Krapels IP, et al. Congenital hydrocephalus in clinical practice: a genetic diagnostic approach. Eur J Med Genet 2011;54(6):e542-7. PMID 21839187
57: Vos YJ, de Walle HE, Bos KK, et al. Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis. J Med Genet 2010;47(3):169-75. PMID 19846429
58: Vos YJ, Hofstra RM. An updated and upgraded L1CAM mutation database. Hum Mutat 2010 31(1):E1102-9. PMID 19953645
59: Wei CH, Ryu SE. Homophilic interaction of the L1 family of cell adhesion molecules. Exp Mol Med 2012;44:413-23. PMID 22573111
60: Weller S, Gartner J. Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): mutations in the L1CAM gene. Hum Mutat 2001;18:1-12. PMID 11438988
61: Willems PJ, Brouwer OF, Dijkstra I, Wilmink J. X-linked hydrocephalus. Am J Med Genet 1987;27:921-8. PMID 3425602
62: Willems PJ, Dijkstra I, Van der Auwera BJ, et al. Assignment of X-linked hydrocephalus to Xq28 by linkage analysis. Genomics 1990;8:367-70. PMID 1979056
63: Williams B. Is aqueductal stenosis a result of hydrocephalus. Brain 1973;96:399-412. PMID 4577076
64: Yamasaki M, Arita N, Hiraga S, et al. A clinical and neuroradiological study of X-linked hydrocephalus in Japan. J Neurosurg 1995;83:50-5. PMID 7782849
65: Yamasaki M, Thompson P, Lemmon V. CRASH syndrome: mutations in L1CAM correlate with severity of the disease. Neuropediatr 1997;28:175-8. PMID 9266556

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

William D Graf MD

Dr. Graf of Connecticut Children's Medical Center has no relevant financial relationships to disclose.
See Profile

Editor

Harvey B Sarnat MD FRCPC MS

Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.
See Profile

Former Authors

Adeeb Ahmed MD

Patient Profile

Age range of presentation: 0-1 month
Sex preponderance: male>female, >2:1
Heredity: heredity typical

heredity may be a factor

X-linked recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Congenital hydrocephalus: 742.3

Obstructive hydrocephalus: 331.4

Hereditary spastic paraplegia: 334.1

Unspecified mental retardation: 319
ICD-10: Congenital hydrocephalus, unspecified: Q03.9

Obstructive hydrocephalus: G91.1

Hereditary spastic paraplegia: G11.4

MASA syndrome: F79.9
OMIM: X-linked hydrocephalus: #307000

MASA syndrome: #303350

SPG1: #303350

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

X-linked hydrocephalus (L1 syndrome)

Associated Disorders

MASA syndrome
Complex spastic paraplegia
CRASH syndrome

Differential Diagnosis

hydrocephalus due to overproduction of CSF
hydrocephalus due to defective reabsorption
hydrocephalus due to obstruction of the CSF pathway
neural tube defect
myelomeningocele
- Chiari malformation type II
- 13 trisomy
- 18 trisomy
- Fried and Pettigrew syndromes (X-linked AP1S2 gene variants)
- Autosomal recessive congenital hydrocephalus associated with the CCDC88C, MPDZ, EML1, and WDR81 genes
- arrhinencephaly
- Apert syndrome
- oral-facial-digital syndromes
- Hurler syndrome
- achondroplasia
- thanatophoric dysplasia
- osteogenesis imperfecta
- incontinentia pigmenti

X-linked hydrocephalus (L1 syndrome) …

X-linked hydrocephalus (L1 syndrome)

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Vein of Galen malformations

Epileptic lesions due to malformation of cortical development

Norrie disease

Klippel-Feil syndrome

Megalencephaly

Hydrocephalus

Collagen VI-related dystrophies: Ullrich congenital muscular dystrophy, Bethlem muscular dystrophy, and intermediate COL6-RD

Andermann syndrome

X-linked hydrocephalus (L1 syndrome)

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Vein of Galen malformations

Epileptic lesions due to malformation of cortical development

Norrie disease

Klippel-Feil syndrome

Megalencephaly

Hydrocephalus

Collagen VI-related dystrophies: Ullrich congenital muscular dystrophy, Bethlem muscular dystrophy, and intermediate COL6-RD

Andermann syndrome

This is an article preview.
Start a Free Account
to access the full version.