Neuromuscular Diseases - Strowd Flashcards
Phakomatsosi are ____ syndromes with characteristic ___, ___ and often __ manifestations
Phakomatosis are genetic syndromes with characteristic neurologic, cutaneous and often ocular manifestations
Neurofibromytosis
Neurofibromytosis is a classic example of a tumor suppressor syndrome
When someone says tumor says “tumor suppressor syndrome,” you want to think “neurofibromytosis 1 and 2”
There are 3 things we want to know:
- These are tumor syndromes: there is unregulated cell growth,
something in the body (often in the nerves) is growing too much
Cell growth is caused by a gas pedal and a brake: proto-oncogenes require one foot on the gas pedal, and that one gene causes cells to grow (these are NOT proto-oncogene syndromes)
Knudson’s Two-Hit Hypothesis of Tumor Formation
This involves the tumor suppressor genes NF1 and NF2 and there are two copes of each (2 feet on the brake)
Children can inheret an abnormal copy from parents
NF1 and NF2 are Autosomal Dominant genes
2 hits are required: The first hit comes from a germline mutation (constitutional)
The second hit comes from a somatic mutation
50% of Patients with NF1 or NF2 inherit the disease from their parents, while 50% acquire spontaneously at birth (resulting in LOH or loss of heterozygosity)
Neurofibromytosis
Neurofibromytosis is a classic example of a tumor suppressor syndrome
When someone says tumor says “tumor suppressor syndrome,” you want to think “neurofibromytosis 1 and 2”
There are 3 things we want to know:
- These are tumor syndromes: there is unregulated cell growth,
something in the body (often in the nerves) is growing too much
Cell growth is caused by a gas pedal and a brake: proto-oncogenes require one foot on the gas pedal, and that one gene causes cells to grow (these are NOT proto-oncogene syndromes)
Knudson’s Two-Hit Hypothesis of Tumor Formation
This involves the tumor suppressor genes NF1 and NF2 and there are two copes of each (2 feet on the brake)
Children can inheret an abnormal copy from parents
NF1 and NF2 are Autosomal Dominant genes
2 hits are required: The first hit comes from a germline mutation (constitutional)
The second hit comes from a somatic mutation
50% of Patients with NF1 or NF2 inherit the disease from their parents, while 50% acquire spontaneously at birth (resulting in LOH or loss of heterozygosity)
NF1 gene is a _____ gene
The base pairs in the NF1 gene contains ________+ base pairs
There is a _____ _______ rate than most genes
Where is thie chromosome located? ______
There are 1,000+ different ______ recorded in the NF1 gene, what are they? (saids)
- _____
- ____ _____ ____
- ____
- ______
- ______ _____
NF1 gene is a large gene
The base pairs in the NF1 gene contains 350,000+ base pairs
There is a HIGHER MUTATION RATE than most genes
Where is thie chromosome located? 17q
There are 1,000+ different mutations recorded in the NF1 gene, what are they? (SAIDS)
- Splice
- Amino acid substitution
- Insertion
- Deletion
- Stop codons
What are the clinical manifestations of NF1?
Skins Brain Bone Eyes Nerves
From Skin, we have:
Melanocytic findings, which include: ____ _____ ____ and _____ freckling
What are the clinical manifestations of NF1?
Skins Brain Bone Eyes NervES
From Skin, we have:
Melanocytic findings, which include: cafe au lait spots (must have more than 6) axilla and inguinal freckling
What are the clinical manifestations of NF1?
Skins Brain Bone Eyes Nerves
From Skin, we have:
- Melanocytic findings, which include: cafe au lait macules and axillae and inguinal freckling
Cafe au lait macules are flat. light, tan patches which can vary in size from less than a centimeter in diameter to several centimeters in diameter. Crowe signs refers to the presence of multiple small tan macules or freckles which can be seen in NF1 in the inguinal and axila area. Neurofibromas are flesh colored or slightly hyperpigmented soft doughy papules and nodules.
- Swchann cell skin findings include:
- Multiple ____ - tumors on the nerves on the ___
- ____ neurofibromas - tumors on the ___ nerves like on the ___ plexus and __ plexus
What are the clinical manifestations of NF1?
Skins Brain Bone Eyes Nerves
From Skin, we have:
- Melanocytic findings, which include: cafe au lait macules and axillae and inguinal freckling
Cafe au lait macules are flat. light, tan patches which can vary in size from less than a centimeter in diameter to several centimeters in diameter. Crowe signs refers to the presence of multiple small tan macules or freckles which can be seen in NF1 in the inguinal and axila area. Neurofibromas are flesh colored or slightly hyperpigmented soft doughy papules and nodules.
- Swchann cell skin findings include:
- Multiple neurofibromas - tumors on the nerves on the skin
- Plexiform neurofibromas - tumors on the deep nerves like on the brachial plexus and lumbosacral plexus
What is this?
This is a plexiform NF. It is seen on the skin of a person who has NF.
What is this?
These are Lisch Nodules. Pigmeted hamartomas on the iris. A hamartoma is a mostly benign, focal malformation that resembles a neoplasm in the tissue of its origin.
This is a very common manifestiation of NF.
What are the bone findings of NF1?
1. __ __\_
- Present in ~___% of patients
- Scoliosis
- (____) is the most common (~__%)
2. ___ __\_
- Diagnostic criterion
- Often associated with cranial nerve ___ NF
3. __ _\_
- Bony (mesodermal) dysplasia
- Possibly resulting from underlying bony weakness
- Often with posterior vertebral scalloping (depth >3-4 mm)
4. Cortical Bone Thinning +/- Pseudoarthrosis
- Commonly involves the ___
- Cortical bone ___ process
What are the bone findings of NF?
1. Spinal Deformities
- Present in ~50% of patients
- Scoliosis
- (kyphoscoliosis) is the most common (~21%)
2. Sphenoid dysplasia
- Diagnostic criterion
- Often associated with cranial nerve plexus NF
3. Dural Ectasia
- Bony (mesodermal) dysplasia
- Possibly resulting from underlying bony weakness
- Often with posterior vertebral scalloping (depth >3-4 mm)
4. Cortical Bone Thinning +/- Pseudoarthrosis
- Commonly involves the tibia
- Cortical bone dysplastic process
What is going on?
Sphenoid bone dysplasia (NF1)
What is this?
Cortical Bone Thinning +/- Pseudoarthrosis (looks like a joint, but it is not):
- common in young kids
- long bone fractures that results from the loss of NF1 gene, and there is a pseudojoint
- Commonly involves the tibia
- Cortical bone dysplastic process
What are three things that you will find in the brain of a patient with NF1?
Three things you will find in the brain of an NF1 patient.
- Normal brain - most common brain finding in NF1 is not having anything in the brain. We can see multiple dura neurofibromas, but brain itself is normal.
- UBO (bright object on the brain)
- Tumor (optic pathway glioma..a brain tumor on the optic nerve. Tumors are most commonly found on the chiasm or single nerve). It is present in 20% of NF1 patients and presents with vision loss.
Brain tumors are:
- Not universal but not uncommon
- 20% of NF1 patients will develop BT
- 70% are OPG (optic pathway gliomas)
- Extra-optic gliomas can be seen and mostly brainstem/cerebellum (67%)
- UBOs
- Scalp neurofibromas
- Stroke, moya moya (Moyamoya disease is a progressive, occlusive disease of the cerebral vasculature with particular involvement of the circle of Willis)
What nerve issues will you see in NF1?
NF-1 is a nerve syndromes - there are tumors of the nerves.
__ __ on a patient’s right foot (picture on left, this is of a foot, and he is pointing to the left side of the image). You could see this out on the skin, but extends deep into tissue to the bone of the foot.
On the right two pictures, you can see the plexiform neurofibroma invading the __ on the face. There is no normal __ __on the left side because of the ___ invading.
We need to think about the tumors that are inside the body. They present with new __ or enlarging growth. This is important because it can be a sign that these are developing into a cancer. There’s an __% chance that the DEEP ___ neurofibromas can develop into cancer.
The cutaneous neurofibromas have no ___ potential, but they can cause psychosocial stress and stigma. But the deep ones can carry a risk for ___
What nerve issues will you see in NF1?
NF-1 is a nerve syndromes - there are tumors of the nerves.
Nerve plexineurofibroma on a patient’s right foot (picture on left, this is of a foot, and he is pointing to the left side of the image). You could see this out on the skin, but extends deep into tissue to the bone of the foot.
On the right two pictures, you can see the plexiform neurofibroma invading the bone on the face. There is no normal sphenoid bone on the left side because of the tumor is invading.
We need to think about the tumors that are inside the body. They present with new pain or enlarging growth. This is important because it can be a sign that these are developing into a cancer. There’s an 8% chance that the DEEP plexiform neurofibromas can develop into cancer.
The cutaneous neurofibromas have no malignant potential, but they can cause psychosocial stress and stigma. But the deep ones can carry a risk for malignancy
Brain findings in NF1:
Most common finding in NF-1 patients: ____ on the brain, but may see cutaneous dermal neurofibromas (white spots around the scalp)
Second most common finding is in the brainstem, you see a subtle white spot (hyperintensity) in the region of the left cerebellar peduncle. We call this the “white spot on the brain” or ____ (uncharacterized bright object). These are ____, just abnormal tissue, not cancerous or precancerous.
Third most common brain finding IS a ___, an ____ ___ ____, which is a brain tumor on the optic nerve, usually on a single optic nerve or at the chiasm. Presents with __ __
Most common finding in NF-1 patients: NOTHING on the brain, but may see cutaneous dermal neurofibromas (white spots around the scalp)
Second most common finding is in the brainstem, you see a subtle white spot (hyperintensity) in the region of the left cerebellar peduncle. We call this the “white spot on the brain” or UBO (uncharacterized bright object). These are benign, just abnormal tissue, not cancerous or precancerous.
Third most common brain finding IS a tumor, an Optic Pathway Glioma (OPG), a brain tumor on the optic nerve, usually on a single optic nerve or at the chiasm. Presents with vision loss.
DIagnostic Criteria for NF1:
Need 2 or more of the following:
- > 6 __ macules..what size do they have to be?
- (>__ mm in diameter for pre-pubertal, >__ mm in diameter for post-pubertal - size of a dime) - 2 or more cutaneous ___
- ___ nodules (iris)
- ___ ___(crowes)
- ____ neurofibroma (one counts)
- 1st degree relative with diagnosis of NF (half patients with NF1 will have a first degree family)
- Bony ___ (diagnosting criteria)
•Need 2 or more of the following:
- >6 café au lait macules
- (>5 mm in diameter for pre-pubertal, >15 mm in diameter for post-pubertal)
- 2 or more cutaneous neurofibromas
- Lisch nodules
- Axillary freckling
- Plexiform neurofibroma
- 1st degree relative with diagnosis of NF
- Bony dysplasia
Clinically this is how we think of the diagnostic criteria for NF1:
Cafe au lait macules develop and are present usually very ___.
During early part of life, freckling, optic glioma, vascular abnormalities, and bony abnormalities are common.
Later in life (adults) we see different manifestations of the same disease.
After puberty, __ abnormalities do not become a problem.
The ___ ___ are present early in life, if they aren’t a problem by 12 years of life, they will never become a problem.
Later in life we find ___ all the way into adulthood. __ ___ become more common during the pubertal age and into age 21, about ___% will have this in adult patients over the age of 21, but rare in infants.
___ ___ are extremely common, but it doesn’t result from any brain abnormalities. It is present in kids and adults, but is often not disabling.
Clinically this is how we think of the diagnostic criteria for NF1:
Cafe au lait macules develop and are present usually very early!
During early part of life, freckling, optic glioma, vascular abnormalities, and bony abnormalities are common.
Later in life (adults) we see different manifestations of the same disease.
After puberty, bony abnormalities do not become a problem.
Brain tumors are present early in life, if they aren’t a problem by 12 years of life, they will never become a problem.
Later in life we find neurofibromatomas all the way into adulthood. Lische nodules become more common during the pubertal age and into age 21, about 90% will have this in adult patients over the age of 21, but rare in infants.
Learning disabilities are extremely common, but it doesn’t result from any brain abnormalities. It is present in kids and adults, but is often not disabling.
NF-2
- Less common than __
- Mutation in the: __ gene on chromosome __
- Gene encodes a protein call ____ aka ____.
Skin Findings:
NF2 has similar skin findings to NF1 but significantly ___ abundant and ___ frequent
- These patients have ____ (none or rarely neurofibromas)
- ___ __ ___macules
Bone Findings:
None
Brain Findings:
1. Bilateral vestibular schwanommas (> 90% of people have this!! very common!)
- will present with SNHL, tinnitus and imbalance
2. Intracranial Meningiomas (benign)
- Tumors on the thickened area of the dura
- They are unlike “classic” sporadic meningioma (benign) which is often a discrete, nodular lesion within the dura.
- NF2 associated meningiomas often present with diffuse dural involvement
3. Spinal ___ (benign tumor). Ependymal cells line the brain. A tumor that develops in this area are called spinal ____. They are common in the ___ part of the spinal cord.
- Multiple ependymomas present in up to ___% of NF2 patients with an ependymoma
- ___ junction (86%)
- ___ cord (62%)
- Different natural history from sporadic ependymoma
- Majority of pts are ____ (76%)
- Symptomatic ___ in ~20%
4. Nerve Findings: other tumors can develop out on peripheral nerves
- Peripheral nerve sheath schwannomas occur, often spinal or paraspinal nerve root
- Neuropathy is common, often subclinical
- ____ schwannomas are rare
NF-2
- Less common than NF1
- Mutation in the: NF2 gene on chromosome 22
- Gene encodes a protein call schwanomin/merlin
Skin Findings:
NF2 has similar skin findings to NF1 but significantly less abundant and less frequent
- Schwannomas (none or rarely neurofibromas)
- cafe au lait macules
Bone Findings:
None
Brain Findings:
1. Bilateral vestibular schwanomas (> 90% of people have this!! very common!)
- will present with SNHL, tinnitus and imbalance
2. Intracranial Meningiomas (benign)
- Tumors on the dura
- They are unlike “classic” sporadic meningioma (benign) which is often a discrete, nodular lesion within the dura.
- NF2 associated meningiomas often present with diffuse dural involvement
3. Spinal Ependymomas (benign tumor). Ependymal cells line the brain. A tumor that develops in this area are called spinal ependymomas. They are common in the center part of the spinal cord.
- Multiple ependymomas present in up to 58% of NF2 patients with an ependymoma
- cervical medullary junction (86%)
- thoracic cord (62%)
- Different natural history from sporadic ependymoma
- Majority of pts are asymptomatic (76%)
- Symptomatic progression in ~20%
4. Nerve Findings: other tumors can develop out on peripheral nerves
- Peripheral nerve sheath schwannomas occur, often spinal or paraspinal nerve root
- Neuropathy is common, often subclinical
•Plexiform schwannomas are rare
Diagnostic Criteria for NF2:
1.Bilateral __ __ (VSs)
•(By age ___ on imaging)
2.Family history of NF2 (1st degree relative)
- AND __ ___schwannoma
- AND two other characteristic NF2 tumors (1. ___, 2. ____, 3. ___ or ___ schwannoma,
- glioma, 5. juvenile posterior subcapsular ___).
- Unilateral VS + ___ other characteristic ___.
- Multiple _____ + ___ other characteristic ____
Diagnostic Criteria for NF2:
1.Bilateral vestivular schwanomma (VSs)
•(By age 30 on imaging)
2.Family history of NF2 (1st degree relative)
- AND unilateral vestibular schwannoma
- AND two other characteristic NF2 tumors (1. intracranial meningiomas, 2. spinal ependymomas, 3. spinal or peripheral schwannoma,
- glioma, 5. juvenile posterior subcapsular cateract).
- Unilateral VS + 2 other characteristic tumors.
- Multiple meningiomas + 2 other characteristic tumors
What is this?
This is a plexiform neurofibromatoma
This is commonly seen in patients with NF1.
What is this?
This is a subcapsular cateract, seen in patients with NF2.
This is NOT NF1 because in NF1, you should see Lisch nodules on the iris. This is a distinguishing factor between NF1 and NF2
What is this?
This is a bilateral vestibular schwanomma in a patient with NF2.
What is this?
This is an intercranial meningioma in NF2.
What is this?
This is a spinal ependymoma. This a benign tumor in the region of the ependymal cells in the center of the spinal cord. They are often seen in the cervical medullary and thoracic cord areas. This patient has NF2.
What is this?
This is a peripheral schwanoma, often seen in people with NF2.
1 = ___ gene (which encodes for ___)
Tuberous Sclerosis
TS is a ___ ___ genetic disease.
Typically is it ___ ____ inherited and it is a defect in one of two different genes:
Like NF, it is a tumor suppresor disease that follows the __ __hypothesis. This explains why TS will have 100% ____ but have ___ varialibltiy, In order for tumor growth to occur, you need a ___ random mutation to occur.
How does tuberous sclerosis occur?
___ and ___ are proteins that normally activate the cell ____ pathway, involving a protein called ____
When these proteins are mutated, the ___ pathway on cell proliferation is ineffective and therefore cells can grow unregulated, leading to ___ formation.
1 = TSC1 gene (which encodes for hamartin)
Tuberous Sclerosis
TS is a tumor suppressor genetic disease.
Typically is it AD inherited and it is a defect in one of two different genes:
Like NF, it is a tumor suppresor disease that follows the two hit hypothesis. This explains why TS will have 100% penetrance but have phenotypic varialibltiy, In order for tumor growth to occur, you need a 2nd random mutation to occur.
How does tuberous sclerosis occur?
hamarin and tuberin are proteins that normally activate the cell stop pathway, involving a protein called mTOR
When these proteins are mutated, the stop pathway on cell proliferation is ineffective and therefore cells can grow unregulated, leading to tumor formation.
Tuberous Sclerosis Clinical Findings:
Skin:
- __ ___ (hypomelanotic) macules - the earliest cutaneous sign are “__ ___ spots” which can be present at __.These are ___pigmented small __ on the skin, which can be easily visualized with a ___ __.
- ____ of facial skin - facial angiofibromas present as clusters of multiple small pinkish-red ___ which appear almost acneiform on the __ and ___. These lesions can be quite disfiguring in more severe cases. Treatment includes ____ (sanding of the skin), laser, or topical ___.
- ___ fibromas - these fibromas are also known as Koenen’s tumors. These are skin colored___ that grow around the ___ ___. They can be surgically excised.
- Shagreen patch - Shagreen patches present as firm larger ___ which can be skin colored or __pigmented and have a __ de ___ appearance. Classic locations include the __ __ or __ __.
Tuberous Sclerosis Clinical Findings:
Skin:
- Ash leaf (hypomelanotic) macules - the earliest cutaneous sign are “ash leaf spots” which can be present at present.These are hypopigmented small patches on the skin, which can be easily visualized with a woods lamp
- Angiofibromas of facial skin - facial angiofibromas present as clusters of multiple small pinkish-red clusters which appear almost acneiform on the nose and cheeks. These lesions can be quite disfiguring in more severe cases. Treatment includes dermabrasian (sanding of the skin), laser, or topical rapamycin.
3. Periungal fibromas - Periungual fibromas are also known as Koenen’s tumors. These are skin colored papules that grow around the nail beds. They can be surgically excised.
4. Shagreen patch - Shagreen patches present as firm larger plaques which can be skin colored or hyperpigmented and have a pea de orange appearance. Classic locations include the lower back or posterior neck.
1st picture: Ash leaf
2nd picture: Angiofibroma
1st picture on previous slide: Periungal fibromas
2nd picture on previous slide: shagreen patch/collagenoma
Brain findings of Tuberous Sclerosis
Brain Tumors
- ___ ___ - Abnormal growth of brain tissue –> cortical tubers.
___ (this is a mostly benign, focal malformation that resembles a neoplasm in the tissue of its origin) growth of the brain –> ___ often arise from cortical tubers.
(Top left picture - white spots on surface of the brain (most outside) are cortical tubers). These are highly epileptogenic, and lead to seizures.
- Subependymal ___ - these are areas of abnormal growth of brain tissue that verge on being a frank benign tumor, seen on ____ area. On lower right part of lower left picture. These have a risk of growing into a tumor –> into a subependymal giant cell astrocytoma.
- Subependymal ___ ___ ___ (On the right). Image is done with contrast which lights up the tumors.
Neurologic manifestation of these = seizures!
Brain findings of Tuberous Sclerosis
Brain Tumors
- Cortical tubers - Abnormal growth of brain tissue –> cortical tubers.
Hamaratomas (a mostly benign, focal malformation that resembles a neoplasm in the tissue of its origin) growth of the brain –> seizures often arise from cortical tubers.
(Top left picture - white spots on surface of the brain (most outside) are cortical tubers). These are highly epileptogenic, and lead to seizures.
- Subependymal nodules - these are areas of abnormal growth of brain tissue that verge on being a frank benign tumor, seen on subependymal area. On lower right part of lower left picture. These have a risk of growing into a tumor –> into a subependymal giant cell astrocytoma.
- Subependymal giant cell astrocytomas (On the right). Image is done with contrast which lights up the tumors.
Neurologic manifestation of these = seizures!
What is this?
Hand: Periungal fibromas
Back: Shagreen/Collagenoma
What are these?
1st picture: ash leaf
2nd: angiofibroma
These are skin findings in a person with tuberous sclerosis
Diagnostic Criteria for Tuberous Sclerosis:
Major:
•Need major criteria OR __ major and ___ minor criteria:
- Skin - __ ___, ___fibroma, ___ fibroma (nail beds), shagreen/collagenoma
- Brain - __ __, ___ nodules, subependymal giant cell ____
- kidney, heart or lung issues
- ___ hamartoma
Minor:
- Dental __
- Gingival ___
- Confetti ____
- ___ of spleen, liver
- ___achromic patch
- ___ cysts
Diagnostic Criteria for Tuberous Sclerosis:
Major:
•Need 2 major criteria OR 1 major and 2 minor criteria:
- Skin - ash leaf, angiofibroma, periungal fibroma (nail beds), shagreen/collagenoma
- Brain - cortical tubers, subependymal nodules, subependymal giant cell astrocytomas
- kidney, heart or lung issues
- retinal hamartoma
Minor:
- Dental pits
- Gingival fibromas
- Confetti macules
- hamartoma of spleen, liver
- retinal achromic patch
- renal cysts
What are these?
These are minor findings of Tuberous Sclerosis.
In order to diagnose, you must have two major findings, or 1 major finding and 2 minor findings.
What is the timeline for tuberous sclerosis?
Early signs: ash leaf and seizures
Puberty/early child hood: angiofibromas, collagenomas
Early adult: kidney disease
adult: periungal fibromas, lung and cardiac tumors
Ashley was born with a brain tumor and seizures. She met angie in gradeschool and they made a collage of pictures. as ashley grew up, she only ate kidney beans and rice. during her adult hood, she had self esteem issues and said “i am PERY UGLY!!” and later, started smoking and developed lung and cardiac tumors.
Sturge-Weber syndrome:
- Inheritance is ____
- Activating mutation in __ gene
- ___ ___ activating gene
- Codes for a cell surface___
- When receptor is activated, exchanges__ for ___ and regulates cellular activity
- Mutation during embryonic development leads to anomalies in __ and __ structures
Clinical Findings:
Skin:
- __-___ stain, usually on 1/2 face
- __ (increased intraocular pressure)
- ___
- ___ malformations within the ___ mater
- Causes ____ of meninges and brain tissue
- Tram-track ___ on CT
Sturge-Weber syndrome:
- Inheritance is sporadic
- Activating mutation in GNAQ gene
- Guanine nucleotide activating gene
- Codes for a cell surface receptors
- When receptor is activated, exchanges GDP for GTP and regulates cellular activity
- Mutation during embryonic development leads to anomalies in mesoderm and ectoderm structures
Clinical Findings:
Skin:
•port-wine stain, usually on face
- glaucoma (increased intraocular pressure)
- seizures
- vascular malformations within the pia mater
- Causes calcification of meninges and brain tissue
- Tram-track calcification on CT
We took the tram on the calcified track to meso grill in equador. At the restaurant, the specials were sturgin. So, you sporadically chose your sturgin as your entree. In addition to your meal, you ordered 1/2 glasss of port wine. You we’re really upset because your sturgin was so dry, that you had to GNAw on it. Because of that you gave no TIP (GTP). At the end of your meal, they gave you seez candies. They tastes so bad, that you broke your glass and glass went into you eye. You screamed “GLASS-EYE-OW! *GLACOMA” had peed a vast amount.
What is this?
Sturge-Weber Syndrome
Tuberous Sclerosis
NF2
NF1
What is this?
Cortical Tubers…founds in tuberous sclerosis
