Within the past year, we had the pleasure of seeing a young woman who was referred to us in early pregnancy with a strong family history of “X-linked hydrocephalus.” Indeed, she was known to be a carrier of a mutation in the cell adhesion molecule L1 (L1CAM) gene, located on the X-chromosome at Xq28, which is commonly the culprit. As in other X-linked conditions, such as hemophilia, this meant that any male child she conceives has a 50% chance of getting the X-chromosome that carries the mutation and therefore of being affected by the condition. In most instances, female babies are not affected by X-linked conditions because they have the benefit of one normal X-chromosome and, indeed, our patient had already had two perfectly normal little girls.
At the time of her first visit at 12 weeks, there were no abnormalities seen in her baby, but we did suspect that the baby was male. We also knew that the condition may not manifest itself until midtrimester or even later, so follow-up was arranged. When she was seen at 19 weeks, no abnormalities were seen again and the baby was confirmed to be male. We also confirmed that a structure called the cavum septum pellucidum was present in the baby’s brain, a finding that often rules out agenesis of the corpus callosum that frequently accompanies L1CAM-associated, X-linked hydrocephalus syndromes. With these reassuring findings, we were all beginning to feel more optimistic about the pregnancy. To be on the prudent side, however, she was scheduled to return again.
At 25 weeks, the sonographer informed me that everything still looked fine, but she admitted the head had not been well-visualized because of its position in the pelvis. So I took my turn at looking. After a few minutes, I managed to elevate the fetal head, the head suddenly turned, and my sonographer took an audible deep breath as it was very apparent to both of us the baby had developed severe hydrocephalus in the 6 weeks between visits. Both lateral ventricles were symmetrically enlarged, as well as the third ventricle situated between the thalami, findings consistent with acqueductal stenosis typically associated with X-linked hydrocephalus. We all had tears in our eyes as we told our patient that her only son was affected by the condition…
“X-linked hydrocephalus” is associated with diverse mutations in the L1CAM gene and the locations and the types of the mutations play a significant role on the expression and severity of the syndromes associated with them. Indeed, at least four phenotypes accompany mutations in the L1CAM gene:
X-linked hydrocephalus (HSAS) MASA syndrome Complicated spastic paraplegia type 1 (SPG1) X-linked agenesis of the corpus callosum
The main clinical features of these have been given the acronym CRASH and this has the following components:
Corpus callosum hypoplasia Retardation Adducted thumbs Spastic paraplegia Hydrocephalus
Expression of these varies both between and within families, so even if a specific mutation is identified, there may be variable expression of the same.
In our next post, we will elaborate on HSAS/MASA syndromes and provide a little more information about the significance of L1CAM mutations in the pathogenesis of these conditions…