Neurocutaneous

Question 1

Neurofibromatosis

Answer 1

Type 1 and 2
Both are autosomal dominant
NF1: chromosome 17 - as neurofibromatosis has 17 characters
NF2: chromosome 22 - all the 2’s

Type 1:
- NF1 gene on chromosome 17
- Cafe au lait spots
- Axillary/inguinal freckling
- Multiple neurofibromas
- Pheochromocytoma
- Lisch nodules (iris) 
CAFE SPOTS:
- Cafe au lait spots
- Axillary freckling
 - Neurofibromas
- Nodules in the Eye
- Skeletal abnormalities - scoliosis
- High blood Pressure 
- Optic Tumour
- Stature (usually short) 
Associated with pheochromocytoma 

Type 2:
- NF2 gene on chromosome 22
- Bilateral vestibular schwannoma (acoustic neuromas) - tinnitus, hearing loss, vertigo
- Meningioma
- Bilateral cataracts
- Can have cafe au lait spots but not specific for type 2
In NF type 2, the mutation is in chromosome 22 and the clinical findings (schwannoma and cataracts) manifests on 2 sides.

Tx
Can use MTOR inhibitors, eg: sirolimus to reduce growth

Question 2

Tuberous Sclerosis

Answer 2

Tuberous sclerosis (TS) is a genetic condition of autosomal dominant inheritance. Like neurofibromatosis, the majority of features seen in TS are neurocutaneous.
Mutation of chromosome 16

Cutaneous features
- depigmented ‘ash-leaf’ spots which fluoresce under UV light
- roughened patches of skin over lumbar spine (Shagreen patches)
- adenoma sebaceum (angiofibromas): butterfly distribution over nose
fibromata beneath nails (subungual fibromata)
- café-au-lait spots* may be seen

Neurological features

• developmental delay
• epilepsy (infantile spasms or partial)
• intellectual impairment

Also

• retinal hamartomas: dense white areas on retina (phakomata)
• rhabdomyomas of the heart
• gliomatous changes can occur in the brain lesions
• polycystic kidneys, renal angiomyolipomata
• lymphangioleiomyomatosis: multiple lung cysts

Angiomyolipomas are the most common benign tumour of the kidney. Although regarded as benign, angiomyolipomas may grow such that kidney function is impaired or the blood vessels may dilate and burst, leading to bleeding.

Tuberous sclerosis results from mutations of the TSC1 or TSC2 gene
- Encode for proteins that have a tumour suppressing effect and disruption of these gene products allows for abnormal cell proliferation in different tissues
- Kidney Manifestations: renal angiomyolipoma, renal cyst
-Renal angiomyolipoma occur in 75% of patients
RCC is less common occurring in 1-2% of adults with TSC

Tx:
Everolimus (mTOR inhibitor) can be used for the management of TSC-associated brain tumours and AMLS
Surgery or embolization may be required for large AMLS or haemorrhage AMLS

Question 3

Von Hippel Lindau

Answer 3

Von Hippel-Lindau (VHL) disease is an inherited disorder characterized by the abnormal growth of both benign and cancerous tumors and cysts in many parts of the body. Tumors usually first appear in young adulthood.

Von Hippel-Lindau (VHL) syndrome is an autosomal dominant condition predisposing to neoplasia. It is due to an abnormality in the VHL gene located on short arm of chromosome 3

HIPPEL

• Hemangioblastomas: benign, highly vascular tumor that can occur in the brain, spinal cord, and retina (the light-sensitive tissue that lines the back of the eye).
• Increase risk of RCC
• Pheochromocytoma
• Pancreatic lesions - cysts, cystadenoma, neuroendocrine tumours
• Eye lesions - retinal angiomas, hemangioblastomas - present as a vitreous haemorrhage and patient can have floaters

Question 4

Ataxia Telangiectasia

Answer 4

5As of Ataxia Telangiectasia

• Autosomal recessive
• ATM gene
• Ataxia
• IgA deficiency
• Angiomas - telangiectasia that mainly involve conjunctiva and face

Increased risk of malignacy

• Leukemia
• Lymphoma
• Gastric carcinoma

Question 5

What are the reasons for hypertension in neurofibromatosis?

Answer 5

Patients with neurofibromatosis may develop hypertension for three main reasons:

• coexistant essential hypertension
• phaechromocytoma
• renal vascular stenosis secondary to fibromuscular dysplasia

Question 6

Which chromosome are affected in the following conditions

• Von hippel lindau
• Tuberous ssclerosis

Answer 6

• von-Hippel Lindau is inherited via chromosome 3

- tuberous sclerosis is often associated with a mutation in chromosome 16 (as is polycystic kidney disease type 1).

Question 7

What are the following mutations associated with?

• NOD2/CARD15
• FXN
• GLA
• SCN5a

Answer 7

NOD2/CARD15 mutations are associated with Crohn’s

FXN mutations are associated with Friedreich’s ataxia

GLA mutations with Fabry disease.

SCN5a mutations are associated with Brugada Syndrome.

Question 8

What are the following trinucleotide repeats associated with?

• CAG
• GAA
• CTG
• CGG

Answer 8

- CAG: Huntington chorea 
We don't hunt in the cages 
-  GAA: Friedrich ataxia - GAA can't walk! 
- CTG: myotonic dystrophy
CTG rhymes with muscular dystrophy  
- CGG: fragile X syndrome
X gon CGGive it to ya

Question 9

Fabry Disease

Answer 9

• X-linked recessive inherited disease
• Lysosomal storage disease
• Typical onset is during childhood but may also appear in 60–80-year-old adults
  Mainly affects boys
  Pathophysiology: α-Galactosidase A deficiency → accumulation of ceramide trihexoside(also known as globotriaosylceramide) in the endothelium of vessels, in the epithelium of many organs, and in smooth muscle cells → disorder affecting many organ systems

FABRYC:

• Foamy urine (Fabry nephropathy)
• α-galactosidase A deficiency/Angiokeratomas
• Burning pain in hands and feet,
• Really sweaty/dry
• YX genotype (male)
• Cardio-Cerebrovascular disease/Ceramide trihexoside accumulation.