Exam #3: Genetic Disorders Flashcards
What is the definition of an autosomal dominant disorder?
- Person has one good gene, where most have two
- Makes 50% as much of the normal protein
What are the four categories of autosomal dominant disorders?
1) Quantity or arrangement of large structural proteins
2) Regulator proteins & receptors
3) Deficiency in proteins that are normally in low supply
4) Anti-oncogene deletion syndromes
What are the chances of an affected parent passing on an autosomal dominant disorder?
50% chance of either sex being affected
**Does NOT skip generations
What is reduced penetrance?
Condition in which the individual has the genetic mutation but does not have outward symptoms of disease
What is variable expressivity?
Different severity of disease with same genetic mutation
*****Note that this is different b/c here, ALL patient exhibit outward symptoms of disease
What is Marfan Syndrome?
This is a disorder of connective tissues, manifested with changes in the:
1) Skeletal
2) Ocular
3) Cardiovascular systems
What is the mutation associated with Marfan Syndrome?
- Inherited defect in Fibrillin-1 gene (FBN1)
- Located on Chromosome 15
**Note that Fibrillin-1 is also important in sequestering TGF-B, a cytokine that increases periosteal growth & has deleterious effects on vascular smooth muscle
Where is fibrillin found?
Fibrillin-1 is the glycoprotein constituent of microfibrils, a component of ELASTIC fiber in connective tissue that are especially prominent in:
1) Aorta
2) Suspensory ligament of lens
3) Periosteum
**Fibirillin is found in the elastin part of these structures
What is the specific mutation that is seen in Marfan?
Missense mutation causes glycine to replaced for cysteine leading to:
1) Progressive loss of microfibirls
2) Elastin defects
What are the symptoms of Marfan’s Syndrome? What are the three major systems that are effected in Marfan’s Syndrome?
Ocular
- Ectopia lentis
- Myopia (nearsighted)
Skeletal
- Pectus carnatum
- Pectus excavatum
- Arachnodactyly (long-slender fingers)
Cardiovascular
- Mitral valve prolapse
- Aortic bulging
- Aortic dissection
What are the major criteria for the diagnosis of Marfan’s Syndrome?
1) Pectus carinatum
2) Pectus excavatum requiring surgery
3) Lens disolcation i.e. “ectopia lentis”
4) Dissection of ascending aorta
*****Genetic findings i.e. Fibrillin-1 mutation
What is the difference between pectus excavatum & carinatum?
Pectus carinatum= “pigeon chest”
Pectus excavatum= “hollow chest”
What cytokine is most affected by Fibrillin-1 mutations?
TGF-B
What is cystic medial degeneration?
Elastic fibers, instead of running in parallel arryas are disrupted by pools of blue mucinous ground substance
What is Ectopia Lentis?
Detachment of the lens due to lax suspensory ligaments that leads to corneal flattening & near-sightedness
How does Marfan’s Syndrome affect the heart? What are the consequences?
Mitral Valve Prolapse
- Floppy/ parachute mitral valve that bulges up into the atrium
What is an aortic dissection? What are the symptoms of an aortic dissection?
Stabbing or shearing pain that radiates to the back
What is an aortic root dilation?
This is a dilation of the base of the aorta that can lead to recurgitation of the aortic leaflets into the ventricles
What is Ehlers-Danlos Syndrome?
Family of autosomal dominant disorders that primarily effect collagen leading to:
- Hypermobility
How many types of Elher’s Danlos Syndrome are there?
Six
What are Type I & II Ehler’s Danlos Syndrome?
Classic
What type of collagen is affected in Type I & II EDS?
Type V–specifically, alpha chains
What type of collagen is affected in Type IV EDS?
Type III
What collagen defects are Type V & VI EDS associated with?
Deficiency in enzymes that modify collagen, lysyl hydroxylase & lysyl oxidase
What collagen defects is associated with Type VII EDS?
Procollagen peptidase deficiency–> cannot turn procollagen into collagen
What is the most deadly form of EDS?
Type III–b/c this is the one that most affects the collagen of the vasculature
What are the two classes of EDS that are autosomal recessive?
Type VI & Type VII
Describe the microscopic appearance of collagen in Type I EDS. What is the appearance that is pathognonomic for Type I?
“Bear paw” or clumped collagen fibers
What are the symptoms seen in EDS?
- Hyperelasticitiy
- Hypermobility
- Skin & joint fragility (small injuries can cause serious trauma)
- Sutures don’t hold well
- Bleeding tendency
Where is the defect in collagen synthesis that occurs in Type III EDS?
Collagen IV cannot escape the RER
What type of EDS is associated with congenital hip dislocation?
Type VII
What are the significant complications associated with Type IV EDS?
- Excessive bruising
- Uterine rupture
- Posterior tibial artery rupture
*****Note that this is the most serious form of EDS
Describe the microscopic appearance of collagen in EDS.
Discombobulated elastic fibers
What Type of EDS is associated with kyphoscoliosis?
Type VI
What is Neurofibromatosis?
This is one of the most common autosomal dominant disorders that is characterized by:
1) Neurofibromas
2) Cafe-au-lait macules
3) Lisch nodules
4) Axillary and/or inguinal freckling
What is the inheritance pattern fro Neurofibromatosis?
Autosomal Dominant
What mutations is associated with NF1?
- NF1 gene mutation
- Located on chromosome 17
- Encodes the tumor suppressor “neurofibromin” that downregulates the function of p21 ras oncoprotein i.e. conversion of ras-GTP to ras-GDP
What are the characteristics of Type 1 Neurofibromatosis?
100% penetrance but VARIABLE expressivity
Outline the function of Neurofibromin (NF1) in the Ras signaling pathway.
NF1 is a GTPase that catalyzes the conversion of ras-GTP to ras-GDP
What malignancy is associated with NF1?
- Malignant peripheral nerve sheath tumors
- Pheochromocytoma
- Wilms tumor
- Rhabdomyosarcoma
- Leukemia
What are the diagnostic criteria for NF1?
1) 6+ cafe au lait macules
2) Freckling in the armpits or groin
3) > 2 neurofibromas or 1 plexiform neurofibroma
4) >2 Lish nodules
5) Optic glioma
6) Bone lesions
- Abnormally shaped sphenoid
- Tibial bowing
7) A first degree relative diagnosed with NF
What is an optic glioma?
Tumor arising from glial cells surrounding the optic nerve
What is a plexiform neurofibroma?
Single large tumor
What are the major symptoms of NF1?
- Axillary or inguinal freckling
- Cafe au lait macules
- Lisch nodules i.e. benign growth on the iris
- Neurofibromas
What is the neurofibroma?
Benign peripheral nerve tumors
What are spindle cells associated with on microscopic examination?
NF1
What are Lisch Nodules?
Pigmented hamartomas that occur in the eyes
Where do neurofibromas grow in the body?
Along nerve sheaths
What is the difference between a neurofibrom & a Schwannoma?
Schwannaoma=
- Schwann cells only
- Enucleated (pushed to the side)
Neurofibromas=
- combination of tissues that grows within the actual nerve
- Cannot spare the nerve to remove
What are the characteristics of Neurofibromatosis Type 2?
Much less prevalence compared to NF1
- Commonly presents with hearing loss
What is the genetic basis for NF2?
- NF2 gene
- Located on chromosome 22
- Encodes for Merlin/ Schwannomin
Outline the function of Merlin in Ras signaling.
Merlin/ Schwannomin is a tumor suppressor that inhibits the Ras signaling pathway
What is the most common presentation of NF2?
Bilateral vestibular schwannomas that affects the vestibular of the 8th cranial nerve
What diagnosis of NF2 based on?
Vestibular Schwannomas
What is the most common presenting diagnositc symptom of NF2?
Hearing loss followed by:
- Tinnitus
- Headache
- Balance disturbance
What is the gross appearance of a vestibular schwannoma?
“A bunch of grapes”
What is the difference between Antoni A & B in regards to a Vestibular Schwannoma?
A=
B=
What is a Verocay body?
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What is a Verocay body?
Alternating nuclear palasade & anuclear zone
What is the second most common tumor associated with NF2?
Meningioma
