X-linked hydrocephalus (L1 syndrome)

William D Graf MD (Dr. Graf of Yale University has no relevant financial relationships to disclose.)
Harvey B Sarnat MD FRCPC MS, editor. (Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.)
Originally released June 17, 1996; last updated August 16, 2016; expires August 16, 2019

This article includes discussion of x-linked hydrocephalus (L1 syndrome), hereditary stenosis of the aqueduct of Sylvius, x-linked aqueductal stenosis, x-linked congenital hydrocephalus. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

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 3 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 2 brothers and 4 maternal uncles (Bickers and Adams 1949). Edwards and colleagues further characterized this family (Edwards et al 1961), and later Jouet and colleagues performed gene mutation analysis (Jouet et al 1994). Other investigators subsequently described clinical and pathologic characteristics of the "syndrome of sex-linked hydrocephalus" (Edwards 1961; Holmes et al 1973; Jansen 1975) and recognized the strong association the disorder had with congenital absence of the pyramids (Chow et al 1985).

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 (Bianchine and Lewis 1974) or agenesis of the corpus callosum. In X-linked complex spastic paraplegia type I, arrested hydrocephalus with spasticity and mental deficiency is prominent. Linkage analysis has demonstrated that X-linked hydrocephalus, MASA syndrome, and spastic paraplegia type I loci were located in subchromosomal region Xq28 (Willems et al 1990) and result from mutations in the gene encoding the neuronal cell adhesion molecule L1 (Rosenthal et al 1992; Jouet et al 1994). 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 (Fransen et al 1996).

Because this developmental disorder might begin as communicating hydrocephalus followed by brainstem compression, the designation "X-linked aqueductal stenosis" may be a misnomer (Landrieu et al 1979; Willems et al 1987). The terminology "X-linked congenital hydrocephalus" was later proposed (Renier et al 1982). “X-linked hydrocephalus” and “L1 syndrome” are now the most commonly used terms (McKusick 1994).

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