Click here to view next page of this article

 

Tuberous Sclerosis

Tuberous sclerosis occurs in about 1:30,000 births. The genetics are dominant inheritance but many are spontaneous mutations. So if you see a baby with tuberous sclerosis you should examine the skin of the patients family and inquire about seizure history in parents. It is certainly a dominant one but a large number of spontaneous mutations. There are two chromosomes that have been identified. One is tuberous sclerosis complex number 1 on chromosome 9 with the first linkage TSE-2, tuberous sclerosis complex 2 on chromosome 16. Interestingly this gene was cloned first, called tuberin.

So the cerebral lesions are what I am going to talk about first. They are cortical tubers, or hamartomas and this is where epilepsy comes from. Epilepsy comes from the cortex, and it’s the tubers that cause that problem. There are subependymal glial nodules that I don’t think are that big a problem, except maybe they will appear on the Board with the radiologic questions. Because they make a big issue about these things sticking into the ventricle, giving it a verrucous irregular appearance.

There are dermatologic lesions that assist in diagnosis for you clinically. A very prominent one is adenoma sebaceum, which are angiokeratomas. They can have hypopigmented macules, ash-leaf spots, shagreen patches. We saw this picture earlier, with the ash-leaf spot and several hypopigmented macules and there’s the shagreen patch. These can occur quite early in life. Later in life you may see angiofibromas or the adenoma sebaceum develop. Often you need to refer your patients to plastic surgery or dermatology for management of those. They can sometimes bleed and get messy. Periungual fibromas; all TS patients should have ultrasound of everything and ophthalmologic consult. Remember, they can also have retinal hamartomas, cardiac rhabdomyomas. Sometimes we know somebody has TS because they are having a problem in the neonatal nursery. They do a cardiac echo and find a huge intraventricular tumor. That occurs way before seizures. Interestingly, the cardiac tumors tend to regress but subsequently they can develop renal cysts and angiomyolipomas. That’s why it makes sense when I told you that this mutation seems to be in a tumor suppresser gene, they can also have problems in the liver, spleen, lungs.

Neurologic complications are: seizures, such as infantile spasms, mental retardation, autism develops very commonly. Twenty-five to thirty percent of patients with TS seem to evolve into the autistic spectrum disorders. Rarer complication could be hydrocephalus from one of the tumors obstructing the foramen of Monroe. They can rarely turn malignant. So it’s a very complex disease. 

Anencephaly is relatively common. My medical school year, the very first delivery I did as a junior medical student in the heartland of Louisiana was an anencephalic child. It’s slightly less than 1:1,000 in the United States and the recurrence rate is 3-5%. As you know probably, it can be monitored with alpha fetoprotein. Then there are encephaloceles. These are herniations of meninges with or without brain parenchyma, usually through a bony defect. Three out of four are occipital, and in the Orient there is an association with hypertelorism and short stature, and frontal encephaloceles. This illustration is there in your handout on the right side, and what it is, is to schematically show that there are two types. One is called a meningocele where the meninges are herniating. The space would be of course CSF filled and in a meningo and encephalocele there is actually some extrusion or herniation of brain parenchyma, right down here. Neural tube closure defects will continue by briefly mentioning that there is a condition called diastematomyelia. As you know, anything with myelia pertains to spinal cord.

Now we are going to disorders of cell division and migration. And here, before I go too far, let me just remind you of something from embryology. As the brain develops in early fetal stage, after the ventricular cavities are formed as you know there is a layer of cells there that are capable of cell division. These are the neuroblasts that divide in a highly orchestrated, controlled manner. When you think about the fact that we have billions of cells and each cell division doubles the number, one extra cycle or one cycle less would make a big difference. We would either end up with pinheads with very few neurons.