Hydrocephalus Due To Congenital Stenosis Of Aqueduct Of Sylvius

A number sign (#) is used with this entry because X-linked hydrocephalus is caused by mutation in the gene encoding the L1 cell adhesion molecule (L1CAM; 308840). MASA syndrome (303350) is an allelic disorder.

There may be a separate form of X-linked hydrocephalus; Strain et al. (1994) investigated a family with typical X-linked aqueductal stenosis in which linkage to markers in the region of the L1CAM gene was excluded and close linkage established to a more proximal site. Also see 302200 for description of congenital hydrocephalus with cataract.

Description

The X-linked recessive form of congenital hydrocephalus (HSAS) is the most common of the inherited forms of hydrocephalus. The phenotype consists of enlarged cerebral ventricles and mental retardation, and often includes spastic paraparesis and adducted thumbs. The most severe cases die pre- or perinatally with gross hydrocephalus and enlarged head circumference (Rosenthal et al., 1992).

See HYC1 (236600) for a discussion of nonsyndromic autosomal recessive forms of hydrocephalus.

Clinical Features

The hydrocephalus may become arrested and the principal manifestations may be mental deficiency and spastic paraplegia. Hypoplasia and contracture of the thumb are characteristic (Edwards, 1961) but were not present in any of the 7 affected males in the family studied by Bickers and Adams (1949) and later by Holmes and Nash (1967).

In a Norwegian family reported by Sovik et al. (1977), all but 1 of 8 affected children died at or within 10 days of birth. Thumb contracture was not noted. Howard et al. (1981) stated that about a third of cases of congenital hydrocephalus are the result of aqueductal stenosis, but not all of these are the X-linked form. At least 32 families with the X-linked form had been reported by 1981. Flexed adducted thumbs have been noted in some affected members of about half the families. Clewell et al. (1982) reported 2 male sibs with X-linked aqueductal stenosis. Adducted thumbs were not observed, but 1 of the infants showed bilateral flexion contractions of the wrists and metacarpophalangeal joints--a finding noted since the first ultrasound evaluation at gestational age 16 weeks.

In a study of noncommunicating hydrocephalus in Victoria, Australia, during a 20-year period (Halliday et al., 1986), 12 definite and 13 probable cases were found. Absence of the pyramids was found in all 9 cases in whom necropsy sections of the medulla were available. Most of the patients showed pyramidal tract signs; mental retardation was usual in survivors. Adduction of the thumb occurred in 44% of cases.

The family reported by Kelley et al. (1988) reemphasized the points that XLAS may be accompanied by a head of normal size despite severe retardation and that major CNS malformations may occur in addition to the aqueductal stenosis. The findings in the 5-generation pedigree studied by Serville et al. (1992) emphasized the phenotypic variability. Ventricular dilatation in affected males was either severe and diagnosed antenatally or moderate and consistent with long survival with little or no macrocephaly.

Schrander-Stumpel et al. (1995) reported 5 families with definite hydrocephalus accompanied by various features, including macrocephaly, mental retardation, spastic paraplegia, adducted thumbs, and agenesis of the corpus callosum.

Rehnberg et al. (2011) reported a Swedish infant in whom hydrocephalus was detected by fetal ultrasound at 36 weeks' gestation. Soon after birth, he was noted to have global hypotonia and bilateral adducted thumbs. He showed developmental delay and cognitive impairment in early childhood. Family history was notable for 2 deceased maternal uncles with hydrocephalus, cognitive impairment, spastic paraplegia, and adducted thumbs. Genetic analysis identified a splice site mutation in the L1CAM gene (308840.0018) in the proband, his unaffected mother, maternal grandmother, and sister. The proband was hemizygous for the mutation, and his female relatives were heterozygous for the mutation. Rehnberg et al. (2011) noted that the mother developed metastatic clear cell renal cell carcinoma (RCC; 144700) at age 46, and they speculated that the L1CAM mutation may have stimulated tumor migration and growth in this patient.

Diagnosis

Sajid and Copple (1968) found basilar impression (109500) as an associated feature in 2 brothers and suggested its usefulness in diagnosis.

Diagnosis of hydrocephalus is determined by brain imaging, and may be suspected if macrocephaly is present. In a Dutch family described by Willems et al. (1987), progressive increase in head circumference led to the diagnosis in 3 patients; however, in 5 with normal head size, the initial diagnosis had been 'nonspecific' mental retardation. Moderate to severe hydrocephaly was present in all macrocephalic patients and in 3 of the 5 with normal occipital frontal circumference. CT scan of the brain did not show aqueductal stenosis in any of these patients. The characteristic clasped thumb was illustrated.

Prenatal Diagnosis

Prenatal diagnosis can be determined by ultrasound examination (Schrander-Stumpel et al., 1995).

Clinical Management

Clewell et al. (1982) implanted a ventriculoamniotic shunt in a 24-week fetus with probable X-linked aqueductal stenosis. Fetal head size increased normally until after the 32nd week, when the shunt failed. After cesarean delivery at 34 weeks, a standard ventriculoperitoneal shunt was placed. Williamson et al. (1984) discussed heterogeneity in congenital hydrocephalus and the indications for fetal surgery. They suggested that X-linked aqueductal stenosis might be most appropriate for such treatment.

Population Genetics

In a Chicago study, Burton (1979) estimated that 'up to 25% of aqueductal obstruction in males may be the result of an X-linked recessive disorder.'

Rosenthal et al. (1992) noted that HSAS occurs in approximately 1/30,000 male births. In a study of internal hydrocephalus and aqueductal stenosis, Haverkamp et al. (1999) found that 13 patients (37.1%) had a genetic etiology and that 2 of 35 cases had X-linked hydrocephalus as the basis of the anomaly.

Pathogenesis

Landrieu et al. (1979) failed to find stenosis of the aqueduct in 1 affected male in a family with many cases, although some changes compatible with compression of the brainstem were present. This experience led them to suggest that aqueductal stenosis is a secondary phenomenon and that the hydrocephalus begins as the communicating form. Communicating hydrocephalus followed by aqueductal stenosis is known also in mutant mice and in virus-induced experimental hydrocephalus. Varadi et al. (1987) also reported a case of X-linked hydrocephalus without aqueductal stenosis and reviewed other observations suggesting that aqueductal stenosis is a secondary phenomenon in X-linked hydrocephalus. Willems et al. (1987) raised the possibility that aqueductal stenosis, when present, is not the cause but the result of hydrocephaly. If true, the commonly used designation X-linked aqueductal stenosis may be a misnomer. Landrieu et al. (1979) concluded that the adducted thumb, present in about a fourth of cases, is not secondary to a neurologic defect but is a developmental defect, i.e., a localized atrophy or agenesis of the abductor and extensor muscles of the thumbs. The conclusion was based on electrophysiologic findings and direct observation during surgery. The 'clasped thumb' may be difficult to distinguish from a spastic flexion of the thumb in the bipyramidal syndrome commonly associated with severe hydrocephalus.

Mapping

Willems et al. (1989) found that X-linked hydrocephalus is linked to F8C (300841) and to DNA marker DXS52 at Xq28; the maximum lod score was 2.52 and 3.23, respectively, at theta = 0.00. In their full report, Willems et al. (1990) gave the following data: DXS52, maximum lod = 6.52 at theta = 0.03; F8C, maximum lod = 4.32 at theta = 0.00; and DXS15, maximum lod = 3.40 at theta = 0.00. Serville et al. (1992) confirmed the localization of the HSAS1 gene to Xq28 in a 5-generation pedigree; maximum lod = 4.57 at theta = 0.04 for linkage to DXS52. Willems et al. (1992), who suggested that this form of hydrocephalus is the most frequent genetic type, used a panel of 18 Xq27-q28 marker loci to narrow down the localization of the HSAS gene in 13 families of different ethnic origin. Multipoint linkage analysis localized the gene to the telomeric part of Xq28, with a maximum lod score of 20.91 at 0.5 cM distal to DXS52. One crossover between HSAS and F8C suggested that the HSAS gene is proximal to F8C. Therefore, HSAS is probably located in an approximately 2-Mb region between DXS52 and F8C. Similar conclusions were arrived at by Lyonnet et al. (1992) in 5 presumably independent families and by Jouet et al. (1993) in 4 others.

Molecular Genetics

The nature of the gene defect in X-linked hydrocephalus was established by the candidate gene approach. Schrander-Stumpel et al. (1990) noted that similar linkage of HSAS and the MASA syndrome (303350) to Xq28 and overlapping features of the two disorders suggested that they may be allelic. Based on these and other observations, Rosenthal et al. (1992) examined the L1CAM gene in an HSAS family and identified a point mutation (308840.0001) that segregated with the disease.

Fryns et al. (1991) reported the findings in a 3-generation family which further suggested that X-linked complicated spastic paraplegia, MASA syndrome, and X-linked hydrocephalus due to congenital stenosis of the aqueduct of Sylvius are variable clinical manifestations of mutations at the same locus at Xq28. Ruiz et al. (1995) found a novel mutation of the L1CAM gene in 2 affected males in this family (I179S; 308840.0010).

Okamoto et al. (1997) identified a mutation in the L1CAM gene (308840.0012) in a child with features of X-linked hydrocephalus (307000) who also had Hirschsprung disease and cleft palate. The mother was heterozygous for the mutation. Okamoto et al. (1997) acknowledged that X-linked hydrocephalus and Hirschsprung disease may be independent events in this patient, but suggested that L1CAM may contribute to both phenotypes. Three additional patients with X-linked hydrocephalus and coincident Hirschsprung disease have been found to have mutations in the L1CAM gene (see 308840.0014-308840.0015).

Bott et al. (2004) described an association between X-linked hydrocephalus with stenosis of the aqueduct of Sylvius and a form of congenital idiopathic intestinal pseudoobstruction (300048) in which Cajal cells were lacking in an infant. The patient carried a mutation in exon 22 of the L1CAM gene (308840.0016), which encodes the fibronectin type III domain of the L1CAM protein; other L1CAM mutations are involved in Hirschsprung disease as a quantitative defect in the migration of neural crest cells in distal segments of the gut. Bott et al. (2004) suggested that the L1CAM mutation might cause a type of intestinal obstruction representing a defect in the differentiation of Cajal cells.

History

Hydrocephalus due to stenosis of the aqueduct of Sylvius was described by Scharli (1976) in 2 sisters who developed symptoms during puberty. One of the sisters gave birth to a girl with aqueductal atresia. All 3 were successfully treated with a ventriculoatrial shunt. They appear to have had a disorder distinct from that discussed here.