Multi organ disorder of non-malignant growths abundantly in the: heart, kidneys, eyes, skin, brain.

Associated brain tumor: Giant Cell Astrocytoma

Hamartia: malformed tissues

Hamartoma: benign growths

Mutation: TSCI and TSC2 genes codingfor Hamartin and Tuberin proteins (tumor supressor genes)

Ash Leaf spots: areas of hypomelanin

Renal angiomyolipoma: made up of smooth muscle, fat, BV's.

If found bilaterally: 80-90% chance that the person has T.S.

FBN1 on Chromosome 15

Encodes for the Fibrillin-1 protein (glycoprotein), this is a component of the ECM.

Homocystinuria (lens dislocates downward)

Congenital Contractural Arachnodactyly

Ehlers Danlos syndrom

Stickler Syndrome

MEN 2B

Above average height

Arachnodactyly

Spinal abnormalities

Lens dislocation (upper portions: pt can't see up)

Aortic Aneurysm or (more LIkely) Dilated Aorta

Dural ectasia

Spontaneous pneumothorax

Von Recklinghausen diz

Mutation of NFT1 gene, found on Chrom 17

Tumor supressor gene neurofibromin (inhibits p21 RAS oncoprotein)

Diagnostic/Clinical: Cafe au lait spots, neurofibromas (schwann cell tumours), Lisch nodules (hamartomas of iris, optic Nerve tumor)

Central NFT

Mutated MERLIN protein, 22q12 chromosome

Clinically: Bilateral acoustic Schwannoma's are pathognomic of NFT2

Tumors cause: HA, balance problems, Facial weakness/paralysis (CNVII)

increases risk of Meningioma and Epindymoma

MC found around cerebellopontine angle

If cochlear part of CNVIII is involved: sensorineural hearing loss,tinnitus

If vestibular part of CNVIII is involved: nystagmus, imbalance, and vertigo.

If CN VII is implicated: paralysis of mm of facial expression, no taste in anterior 2/3 of the tongue, hyperacusi due to paralysis of stapedius.

CN V: no corneal reflex, no sensation around mouth and nose, paralysis of muscles of mastication.

Trinucleotide repeat CAG
Anticipation

CAG encodes for the AA glutamine

Affected gebe is Huntingtin and is located on chrom 4

Genetic mutation causes atrophy of the caudate nucleus, causing a loss of GABAergin neurons.

Huntington's disease findings:

Personality changes

CHorea

Muscle rigidity

Writhing

Psychomotor function worsens: abnormal facial expression, decreased motor control, chewing problems, swallowing and speaking problems.

Impaired executive planning: exp abstract reasoning and cognition.

Short and longterm deficits

Anxiety

Depression

Blunted Affect

Aggression

Compulsive behaviours

Retinal cancer caused by mutation of RB1 gene on chrom 13.

Hyperphosphorylated RB is inactive and allows E2F to activate G1-->S phase

Hypophosphorylated RB is active and doesn't allow E2F to allow progression of G1 to S phase.

Leukocoria

Deteriorating vision

Irritation of the eye

Concurrent glaucoma

Enlargement of the eye

Part of Well Baby Screening, looking for:

Red reflex: red/orange retinal reflection

Corneal light reflex: symmetrical reflection of light

2 types: Type 1 (Steinert's diz) and Type 2 (PROMM)

Chronic, slowly progressing multisystemic disease characterized by:

1. Muscle wasting

2. Cardiac disturbances

3. Endocrine Disorders

4. Visual Disturbances

Type 1: DMPK gene, longarm of chromosome 19

Encodes for myotonic dystrophy protein kinase

Is a trinucleotide repeat disorder (CTG)

Type 2: PROMM, ZNF9 gene, chromosome 3

Tetranucleotide repeat disorder (CCTG)

Mutation of LDLR gene that encodes the LDL receptor protein

Gene on chromosome 19, SHORT arm

Main findings: Xanthelasma, tendon xanthomas.

HIgh risk of atherosclerosis which may lead to CAD.

MCC is AD version but there's also an AR version

AD version: 3 mutations in PKD1, 2, 3

MCC is PKD1 whose gene is on Chromosome 16 and codes for a protein that regulates the cell cycle and intracellular transport of Calcium in epithelial cells

In kidneys: multiple cysts

Extrarenal findings include:

1. Cerebral aneurysms

2. Pancreatic and hepatic cysts

3. MVP

4. Aortic root dilatation****

5. Colonic Diverticula

VHL tumor suppressor gene located on chromosome 3

Benign and malignant tumors (MC in CNS)

Capillary Hemangioblastomas in retina

***Clear cell renal carcinoma (almost pathognomic): renal mass with hematuria on clinical vignettes

Pheochromocytoma (what is this patient likely to develop?)***

Pancreatic neuroendocrine tumors****

Family hx and symptoms

Management: no cure, routine screening, and early recognition and symptomatic tx to improve quality of life.

MCC of dwarfism, no MR

Mutation of FGFR3 at epiphyseal growth plate

This leads to abnormal cartilage formation at epiphysis, but doesn't affect skull.

Short stature

Large head to body size difference

Prominent forehead

Decreased mm tone

Bowed legs

Spinal stenosis

Kyphosis and lordosis (no scoliosis)

Porphobilinogen deaminase deficiency that disturbs heme production

2nd MC porphyria (after cutanea tarda)

Findings:

Severe Abd pain

Peripheral Neuropathy

CNS signs

NO RASH********

Type 1 and 2: AD, Type 3: AR

vWF deficiency

vWF required for platelet adhesion

gene located on Chromosome 12

Presents with:

Easy Bruising

Heavy menses

Bleeding Gums

Nosebleeds

Type 1: quantitative defect of vWF (most cases)

Type 2a: qualitative defect (normal quantity)

Type2b: HYPERBINDING of vWF to Glycoprotein 1 (GP1)

Type 3: complete absence of vWF.

Dx: measure vWF quantity in a vWF Ag assay

or

Measure vWF functionality with an of these: GP1 binding assay, Collagen binding assay, Ristotectin Cofactor activity...If no clumping then vWF not working.

Mgmt: Desmopressin (Type I and IIa only)

MOA: stimulates vWF release from Weibel Palade bodies of endothelial cells and increases vWF levels.

Osteogenesis Imperfecta: mutation

Qualitative or quantitative deficiency of type 1 collagen (decreased structural quality of collagen)

Glycine is replaced with bulky amino acids

Type 1: mild, COL1A1gene

Type 2: LETHAL, COL1A1 and A2 gene

Type 3: progressive, deforming ""

Type 4: deforming, normal sclera ""

Type 5: similar to 4 (histo: mesh-like)

Type 6: "" Histo- fish scale

Type 7: CRTAP gene, cartilage associated protein

Type 8: severe/lethal, Leprecan protein (LEPRE1 gene)

Defect in CNA4A gene

Defective voltage gated calcium channels (blood K+ levels fall rapidly)

Manage: avoid strenuous exercise, high carb meals, others.

Give K+ sparing diuretic like SPIRONOLACTONE to keep K+ levels up.

Defect in RBCs cytoskeleton due to Spectrin and Ankyrin abnormalities.

Manifests with: Jaundice, Hemolytic Anemia, Splenomegaly

Findings: Elliptocytosis (oval RBCs)

Small/red rbc's with no central pallor

***Reticulocytosis/increased RDW/ increased MCHC

Confirm with osmotic fragility test

Ankyrin: mediates attachment of membrane proteins to cytoskeleton.

Spectrin: cytoskeletalprotein, lines intracellular side of Plasma Membrane creating a scaffold, maintains PM's integrity.

Li-Fraumeni syndrome: everything

Early cancer due t p53mutation and a somatic mutation of a 2nd allele.

Look for MULTIPLE cancers in someone under 45 y/o

MC tumors: breast, adrenals, brain, blood, and sarcomas

Hereditary hemorrhagic telangiectasia.

Findings: telengiactasias in skin+ mucus membranes of lips/oronasopharynx/respi tract/GI/GU tract

Rupture leads to epistaxis,GI bleeding, hematuria.