Yesterday we began a discussion of “X-linked hydrocephalus.” As we pointed out, this is not a single disease entity, but a spectrum of overlapping syndromes that are characterized by variable expression of Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spastic paraplegia, and Hydrocephalus, sometimes referred to as CRASH. All are the result of a variety of mutations in the cell adhesion molecule L1 (L1CAM) gene, located on the X-chromosome at Xq28 and have variable penetrance even within families. The two most common ‘syndromes’ are often considered together as the HSAS/MASA spectrum.
HSAS stands for Hydrocephalus as result of Stenosis of the Acqueduct of Sylvius. The characteristic picture of acqueductal stenosis was described in the case presented in our last post. The baby developed symmetrical enlargement of the lateral ventricles, as well as the 3rd ventricle which sits beneath the lateral ventricles and in the midline between the thalami. Under normal circumstances, the cerebrospinal fluid (CSF) drains from the lateral ventricles into the 3rd ventricle and then must pass along a very narrow canal, the Acqueduct of Sylvius, into the 4th ventricle, sitting directly in front of the cerebellum, before emptying into the large space at the back of the brain (the cisterna magna) and then the spinal canal. When the Acqueduct of Sylvius becomes obstructed (for any number of different reasons), the plumbing backs up with enlargement of both the lateral ventricles and, eventually, the 3rd ventricle. This obstruction is termed acqueductal stenosis.
Interestingly, in HSAS, acqueductal stenosis might actually be a secondary effect of the condition and not the primary cause of the ventricular enlargement, although there can be no doubt that when it occurs, the stenosis contributes to the ventriculomegaly. X-linked inheritance is thought to account for about 7 to 27% of hydrocephalus of unknown etiology in males; and, among males with acqueductal stenosis, 25% have an X-linked condition. In HSAS, the hydrocephalus can occur anytime during pregnancy, but usually will not be seen before midtrimester. Hydrocephalus may also not develop until early infancy and in some cases, not at all. Indeed, about 50% of babies do not survive the first year of life, but among those who do, 50% will have minimal or no hydrocephalus.
Central nervous system findings frequently accompanying HSAS include agenesis of corpus callosum, agenesis of the cavum septum pellucidum, fusion of thalami, and hypoplasia of the pyramids and corticospinal tracts. About 90% of cases will also have flexed adducted thumbs. Mental retardation commonly occurs and is often severe to profound, but there are instances in which the children have normal intelligence. In hydrocephalus accompanied by acqueductal stenosis from other causes, insertion of a shunt to drain the ventricles may improve developmental outcome, but this is not necessarily the case in HSAS. In other words, in HSAS, the effect of the condition on the central nervous system is more global and not simply the consequence of acqueductal stenosis when it is present.
In the MASA complex, Mental handicap occurs in 100%, Aphasia (absent speech associated with severe cognitive defect) occurs in 90%, Shuffling gait in 90%, and Adducted thumbs in 90%. Agenesis of the corpus callosum is often present as well, but the spectrum of ventricular enlargement and enlargement of the head overall is much more variable than in HSAS. Indeed, affected males may have normal head circumference and ventriculomegaly or increased head circumference and no ventriculomegaly, or typical hydrocephalus with enlargement of both.
As in many X-linked conditions, female carriers are usually asymptomatic, but concern has been raised that there they may be at risk with regard to the HSAS/MASA spectrum of conditions. Halliday and colleagues (J Med Genet 1986;23:23-31) reported not only that “the intellectual outcome was notably poorer in the X linked cases” of males compared to males with acqueductal stenosis from non-heritable conditions, but “poor school performance was also described in five of 19 mothers of X linked cases” compared to “only one of 64 mothers of the remaining cases.” Indeed, one of the developmentally delayed female carriers also had ventriculomegaly.
In another study, Kaepernick and colleagues (Clin Genet 1994;45:181-5), studied a family with 22 known affected males with the MASA syndrome. There findings not only point to the overlapping spectrum of HSAS and MASA, but also to the probable cause of some carrier females being affected: “Clinical findings varied widely amongst the affected family members, with some appearing initially to have the MASA syndrome and others to have X-linked hydrocephalus (HSAS). Important findings included the presence of adducted thumbs in two obligate carriers, learning problems or mild mental retardation in three females, two of whom were obligate carriers, and hydrocephalus with neonatal death in three females born to obligate carriers. X-inactivation analysis in lymphocytes from the two women with adducted thumbs revealed preferential inactivation of one X chromosome, suggesting that nonrandom X-inactivation may be responsible for clinical expression in females.”
In our next post on this subject, we will discuss the importance of mutations in the L1CAM gene that lead to the variety and variability of conditions accompanying the HSAS/MASA spectrum of diseases...