Neurocutaneous disorders: Pathology review

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Case Study0:00–1:05

At the family medicine clinic, a 17 year old male named Heath came in because of lower back pain. Clinical examination reveals lots of small growths on the face, light flat patches throughout his body, and a darker raised patch on his forehead.
Heath was adopted early in his life and his family history is unknown. Abdominal ultrasound reveals an angiomyolipoma of the left kidney.
Next to Heath, there’s an 8 year old child named Sylvia. Sylvia complains of difficulty seeing what the teacher is writing in school.
She also has a purple mark that covers the forehead and her right upper eyelid. Eye examination reveals increased intraocular pressure in the right eye.
Her medical history includes an episode of seizure when she was 5 years old. A brain MRI is ordered and reveals brain atrophy.
Finally, there’s a 45 year old male named Austin who came in because of a ringing sound in his ears and a gradual loss of hearing.
Brain MRI reveals bilateral masses on the cerebellopontine angle. Okay, so all of them have a neurocutaneous syndrome.

Pathology1:05–1:37

Neurocutaneous syndromes primarily affect the nervous system and the skin. They include Sturge-Weber syndrome, tuberous sclerosis, neurofibromatosis type I and II, and Von Hippel-Lindau disease.
For the exams remember that Sturge-Weber occurs due to sporadic mutations, while tuberous sclerosis, neurofibromatosis type I and II, and Von Hippel-Lindau disease are autosomal dominant conditions.
Alright, now let’s take a closer look at these different disorders, starting with Sturge-Weber syndrome, which is also known as encephalotrigeminal angiomatosis.

Sturge-Weber syndrome1:37–3:16

During week 6 of development, as the cephalic portion of the neural tube grows, a network of tiny blood vessels called a vascular plexus develops.
There’s a gene called the GNAQ gene which codes for a guanine nucleotide-binding protein that is involved in the development of that plexus.
Normally, around week 9, the GNAQ gene stops getting expressed, leading to the regression of the vascular plexus. But in Sturge-Weber syndrome, a sporadic mutation occurs that let some cells keep making GNAQ proteins.
The mutated cell then replicates over and over, so all of the cells that descend from it have the mutation. The earlier the mutation arises in embryological development, the more tissues will be affected, since more tissues will originate from the mutant cells.
This is an example of somatic mosaicism. This means the individuals have some cells in their body with the mutation and others with the normal gene.
Now as the GNAQ proteins accumulate, it results in the excessive growth of capillaries in tissues that derive from the ectoderm, especially the brain, eyes, and facial skin.
The most common presentation is unilateral and complete disease, meaning it affects both the brain and the face on the same side, and most often the eye is not involved.
Okay, moving onto tuberous sclerosis. This disorder occurs when there’s a mutation in either the TSC1 gene on chromosome 9, or TSC2 on chromosome 16.

Tuberous sclerosis3:16–4:26

TSC1 encodes for the protein hamartin and TSC2 for the protein tuberin. These two proteins combine to form hamartin-tuberin complex, which binds to and inhibits another protein called mechanistic target of rapamycin, or mTOR.
Normally, mTOR increases cell proliferation and so the hamartin-tuberin protein complex acts as a tumor suppressor. So when there’s a mutation in the TSC genes, it causes an altered hamartin-tuberin protein complex that’s unable to switch off mTOR.
As a result, benign tumors and growths made of a variety of cell types, called hamartomas, form throughout the body. Also, the lifetime risk of cancer is increased.
The brain and the skin are usually affected the most, along with the kidneys, heart, lungs, and eyes. Now, let’s move onto neurofibromatoses.
There are two types, type I and type II, and they’re caused by mutations in the NF1 or NF2 gene, which are found on chromosomes 17 and 22, respectively.

Neurofibromatoses4:26–5:40

For the test, remember, NF1 goes with chromosome 17 and NF2 goes with chromosome 22. Normally, these are tumor suppressor genes that code for neurofibromin and merlin proteins.
Merlin is a protein found in the cytoskeleton of neurons and its tumor inhibitory mechanism isn’t fully understood. You’re much more likely to be asked about the mechanism of type I neurofibromtaosis and neurofibromin, which inactivates the RAS pathway.
The RAS pathway takes part in many other signaling pathways responsible for cell growth, so dysregulation leads to the growth of neurofibromas which are benign, fibrous tumors that originate from neurons.
For neurofibromatosis type II, a high yield fact is that it mainly causes schwannomas which arise from schwann cells. Finally, Von-Hippel-Lindau disease is caused by a mutation of the von-Hippel-Lindau or VHL gene that is located on the short arm of chromosome 3.

Von Hippel-Lindau disease5:40–6:51

The VHL gene is a tumor suppressor gene that codes for proteins in charge of degrading a transcription factor called hypoxia-inducible-factor, or HIF.
HIF is responsible for up-regulating genes that code for platelet-derived and vascular endothelial growth factors, or PDGF and VEGF, both of which promote new blood vessel formation and cell growth.
In VHL disease, this tumor suppressor gene is mutated or deleted, causing an increase in hypoxia-inducible-growth factor, which increases the levels of PDGF and VEGF and ultimately the risk of tumor formation.
So, VHL disease is characterized by the development of benign and malignant tumors in various organs, such as the eyes, kidneys, adrenal glands, CNS, and pancreas.
Alright, now all neurocutaneous syndromes typically present with skin lesions, neurological signs, and formation of various tumors.
But each of the neurocutaneous syndromes have symptoms that are special to them and can help you identify them. Let’s start with Sturge-Weber syndrome.

Diagnosis6:51–16:29

The first high yield symptoms is the characteristic nevus flammeus, which is a non-neoplastic birthmark. This is also known as a port wine stain, and it’s a purple mark on the face in the areas innervated by the trigeminal nerve.
The trigeminal nerve, especially the ophthalmic and maxillary distributions, are involved because during embryological development, it’s one of the first cranial nerves to develop from neural crest cells.
Typically, the port wine stain covers the forehead and upper eyelid on one side of the face, but in some individuals, it covers the whole face.
Now, in the brain, some individuals develop leptomeningeal angiomas, which are vascular malformations in the meninges that lead to pooling of blood, impaired venous drainage, and brain ischemia.
Ischemia causes brain atrophy which relates to the extent of neurological deficits. These include developmental delay, seizures, and muscle weakness (or hemiplegia) on the side opposite of the port-wine stain or on both sides if the disease is bilateral.
The brain can also develop areas of calcification on brain gyri. This type of brain calcification takes on a tram-track pattern because it literally looks like tramway tracks.
Now, some individuals also have congenital trabeculodysgenesis, which is when the part of the eye responsible for draining the aqueous humor is underdeveloped.
That leads to increased intraocular pressure and glaucoma that can cause reduced vision or even blindness in the affected eye.
It is thought that the presence of episcleral hemangioma can also lead to glaucoma. Okay, moving onto tuberous sclerosis.
So in the brain, the most common growths are glioneuronal hamartomas, also known as cortical tubers, and subependymal nodules.
These lesions can cause neurological problems like seizures. Also, there’s an increased risk of developing a subependymal giant cell astrocytoma, or SEGA, which is a type of cancer that can arise from the subependymal nodules.
In the eye, hamartomas can also develop in the retina causing vision problems. On the skin, many small, red or flesh colored papules called angiofibromas can appear, especially on the face.
They might also have fibromas under the nails, known as subungual fibromas. Light, flat patches also appear on the trunk called ash leaf spots and a distinctive dark, raised patch on the forehead is a common feature.
Another classical feature is a shagreen patch, which is a large, elevated, flesh colored patch, that often appears on the lower back.
Another high yield concept is that, in the kidneys, individuals with tuberous sclerosis can also develop bilateral renal angiomyolipomas which are benign tumors comprised of blood vessels, smooth muscle, and adipose tissue.
Angiomyolipomas can get really big, putting pressure on the kidneys and causing flank pain. In addition, they can bleed spontaneously.
Individuals can also have lymphangioleiomyomatosis in the lungs, where the lung tissue is gradually replaced by cysts, and this can lead to shortness of breath.
In addition, they can develop cysts in the liver and the pancreas. Finally, in the heart, the most common cardiac manifestations are cardiac rhabdomyomas, which are benign tumors that usually affect the ventricles.
If it affects the muscles of the mitral valve, it can cause mitral regurgitation. Okay, now moving onto neurofibromatosis type I, also referred to as von Recklinghausen syndrome.
Neurofibromatosis type I typically affects the peripheral nervous system, and more specifically the nerves in the extremities and the skin.
It causes numerous neurofibromas, sometimes hundreds. Cutaneous neurofibromas typically start forming in childhood and increase in number over time.
They appear as painless, mobile lumps under the skin. Also, individuals with neurofibromatosis type I often have skin markings called café-au-lait spots, which are flat patches that are the color of milky coffee.
And they’re an important clue to make the diagnosis! These spots typically appear on the back, buttocks, and thighs in the first year of life and increase in number over time.
In the eyes, there are Lisch nodules which are tan colored bumps on the iris. These nodules almost always appear by the age of 6, but don’t usually cause any vision problems.
In addition, neurofibromatosis type I is also associated with optic nerve gliomas. There’s also an increased risk of other problems in the nervous system like seizures, learning difficulties, and malignant peripheral nerve sheath tumors.
Occasionally, large neurofibromas can develop in the abdominal cavity, and they can press against nearby organs, like the kidneys, and impair their function.
Also, pheochromocytoma, a tumor of the adrenal medulla, can develop. Because this tumor pumps out large amounts of catecholamines (like norepinephrine and epinephrine) individuals can present with symptoms of sympathetic overactivity, such as headaches, sweating, palpitations, and hypertension.
Neurofibromatosis type II is less common and presents differently. It’s often limited to the central nervous system and the cranial nerves, so skin manifestation - like subcutaneous neurofibromas and café-au-lait spots - are much less common.
Individuals typically develop schwannomas in the spinal cord or along the cranial nerves. The most common and high yield area you need to know is the cerebellopontine angle along the eighth cranial nerve.
The schwannomas here are called acoustic neuromas, and they usually arise bilaterally, which is very uncommon outside of type II neurofibromatosis.
Acoustic neuromas can cause tinnitus (or a ringing sound in the ears) and gradual loss of hearing on both sides. Also, for the exams, remember that individuals with neurofibromatosis type II develop tumors called meningiomas.
If they develop in the spinal meninges, they can compress the spinal cord, leading to pain, numbness, and weakness in the extremities.
If they develop in the cerebral meninges, they can cause seizures or visual changes and muscle weakness. In addition, individuals with neurofibromatosis type II can also develop ependymomas, which derive from ciliated cells that line the ventricles and central canal.
Ependymomas can compress nearby ventricles and obstruct CSF flow leading to obstructive hydrocephalus. Finally.
Individuals with neurofibromatosis type II can develop eye problems like cataracts or hamartomas in the retina.Alright, the last disorder is Von Hippel-Lindau disease which causes hemangioblastomas.
These are benign tumors of the blood vessels that most often occur in the retina or the central nervous system, which includes the brain and the spinal cord.
Hemangioblastomas in the retina can lead to blindness, while in the CNS, symptoms are based on the location. If the tumor is in the cerebellum, it will cause ataxia, or loss of balance.
If it’s in the spinal cord, it can lead to numbness and weakness in the limbs. Since the hemangioblastomas occupy space in the brain, they can also increase intracranial pressure, causing symptoms like headaches, nausea, and vomiting.
VHL is also associated with angiomatosis that consists of many cavernous angiomas that typically form on the skin, mucosa, or internal organs.
Individuals with VHL can have benign cysts, which can arise in various organs like the lungs and the liver; and cystadenomas which are benign, cyst-like tumors that originate from the epithelium.
One type of cystadenoma is an endolymphatic sac tumor of the inner ear, and it can lead to deafness and vertigo. For the test, also remember that cysts can develop in the kidneys and pancreas, but the more worrisome tumor associated with VHL is renal clear cell carcinomas that can appear bilaterally.
All right, as a quick recap! Neurocutaneous syndromes occur when there’s a mutation in one of the many tumor suppressor genes.
A common theme is that these disorders cause neurological deficits and cutaneous manifestations, and they often present at a young age.
Sturge-Weber syndrome is the only disorder caused mainly by sporadic mutation. Tuberous sclerosis, neurofibromatosis type I and II, and Von Hippel-Lindau disease are autosomal dominant disorders.
Okay, back to the patients! Due to the presence of angiofibromas on the face, ash leaf spots on the trunk and angiomyolipoma, Heath most probably has tuberous sclerosis.

Review16:29–17:00

Diagnosis can be confirmed with genetic testing to identify a mutation in TSC1 or TSC2. Now, Sylvia most likely has Sturge-Weber syndrome.
She has a port-wine stain on her face, glaucoma, brain atrophy, and seizures. To confirm the diagnosis, brain MRI can be done to look for leptomeningeal angiomatosis and tram-track brain calcifications.

Summary17:00–17:51

Finally, Austin probably has bilateral acoustic neuromas, which is a classic symptom of neurofibromatosis type II. Genetic testing can be used to confirm the NF2 mutation.
in tsc1 or tsc2. Now.
Sylvia, most likely has sturge-weber syndrome. She has a port-wine stain on her face glaucoma brain, atrophy and seizures to confirm the diagnosis brain.
MRI can be done to look for leptomeningeal angiomatosis and tram track brain, calcifications. Finally.
Austin probably has bilateral acoustic neuromas, which is a classic symptom of neurofibromatosis. Type 2.
Genetic testing can be used to confirm the
Neurocutaneous disorders: Video, Causes, Symptoms | Osmosis