Genetic Diseases & Syndromes Flashcards
1
Q
Down syndrome
A
- Most common chromosomal abnormality in live births
- Increased incidence w/ advancing maternal age
- Age 35 1:400
- Age 45 1:35
2
Q
Down syndrome prenatal testing
A
- Quad screen
- Nuchal translucency
3
Q
Cause of Down syndrome
A
- Gamete has 2 copies of chromosome 21
- Trisomy 21 is cause of 95%
- Roberstonian translocation = 4%
4
Q
Down syndrome prevalance
A
1:500 pregnancies
5
Q
Down syndrome characteristics
A
- Intellectual disability
- Characteristic facial appearance
- 40% cardiac defects
- 75% hearing loss
- > 50% visual problems
- 7% have GI defects
- Increased social skills
- 1/2 develop Alzheimer disease
6
Q
Edwards Syndrome
A
- Trisomy 18
- 2nd most common autosomal trisomy
- IUGR
- Many die before birth or in first month
- Increased risk w/ advanced maternal age
7
Q
Edwards syndrome characteristics
A
- Kidney, heart, GI defects
- Developmental delay
- Club foot (Rocker bottom feet)
- Low set ears, small jaw
8
Q
Edwards syndrome prevalence
A
1: 5000 live born infants
- Highly lethal in-utero (85% lost btwn 10 wks gestation & term)
- 50% die in 1st week of life
- 2% have 1 year survival
9
Q
Patau syndrome
A
- Trisomy 13
- Increased risk w/ advanced maternal age
10
Q
Patau syndrome prevalence
A
1: 16000 live births
- Many die within 1st days or weeks of life
11
Q
Patau syndrome characteristics
A
- Severe intellectual disability
- Cleft lip or palate
- Seizures
- Small jaw
- Polydactyly
- Heart, brain/spinal defects
12
Q
Patau syndrome etiology
A
- Most cases = 3 copies of chromosome 13
- Some due to Robertsonian translocation involving chromosome 13 & 14
13
Q
Cri-du-chat syndrome
A
- Deletion of part of short arm of chromosome 5
- Partial monosomy (only a portion of a chromosome has 1 copy instead of 2)
14
Q
Cri-du-chat etiology
A
- Most cases = spontaneously
15
Q
Cri-du-chat characteristics
A
- Cat like cry due to abnormal larynx
- Intellectual disability
- Wide set eyes, low ears
16
Q
Cri-du-chat prevalence & how is it detected?
A
1: 50,000 births
- Detected in utero w/ CVS
17
Q
Klinefelter’s syndrome
A
- Extra X chromosome, 47XXY
- Occurs during gametogenesis
- Accounts for 1st trimester losses
- Most common sex chromosome aneuploidy in males
18
Q
Klinefelter’s characteristics
A
- Affects male physical & cognitive development
- Physical traits become more apparent after puberty
- Hypogonadism, infertility
- Gynecomastia, reduced hair
19
Q
Turner syndrome
A
- 45X
- Affects development in females
- Monosomy
20
Q
Turner syndrome characteristics
A
- Gonadal dysgenesis (non-functional ovaries)
- Short stature
- Broad chest
- Webbed neck
- Amenorrhea
- Infertility
- Cardiovascular defects
21
Q
Huntington’s disease
A
- Neurodegenerative disease (progressive brain disorder)
- Adult onset: latent for 3-5 decades, then manifests as progressive neuronal dysfunction
22
Q
Huntington’s disease characteristics
A
- Uncontrolled movements
- Emotional problems
- Loss of thinking ability
- Changes in personality
- Involuntary jerking movements: chorea
23
Q
Early signs of Huntington’s
A
- Depression
- Irritability
- Poor coordination
- Trouble learning
24
Q
Huntington’s etiology
A
- HD gene on chromosome 4 that encodes for huntington
- Autosomal dominant
- Average time from sx onset to death = 15 yrs
25
Alzheimers syndrome
- Neurodegenerative disease
- Most common form of dementia in elderly
- Death usually occurs within 10 yrs of dx
26
Causes of dementia
- 65% Alzheimers
| - 35% vascular
27
Alzheimers population
Begins after age 60 (risk increases w/ age)
28
Alzheimers pathophysiology
- Loss of cholinergic neurons in brain
- Formation of plaques/tangles
- Atrophy of brain
- Resultant effect - blocked communication
29
Alzheimers mode of inheritance
Several gene mutations cause predisposition
| - 2 forms of genes have been identified: familial (early onset); sporadic (late onset)
30
Alzheimers clinical manifestations
- Progressive mental deterioration (memory loss, confusion, disorientation)
31
Familial Alzheimers
- Many members of multiple generations affected
- Sx start before age 65
- Mutations on chromosomes 1, 14, or 21 (forms "sticky" protein that forms clumps in brain)
- Rare, <5%
- Autosomal dominant
32
Sporadic Alzheimers
- Develops after 65
- Accounts for most cases of AD
- One gene increases risk: Chromosome 19 apolipoprotein E (APOE)
33
Definitive dx of sporadic Alzheimers
Autopsy- plaques, tangles
34
Risk factors of breast/ovarian cancer
- Gender
- Age
- Family hx
35
Mode of inheritance of breast/ovarian cancer
Up to 10% are caused by predisposing genetic factors
36
Clinical manifestations of breast/ovarian cancer
- Early age of breast cancer onset (<50)
- Family hx of both breast and ovarian cancer
- Increased bilateral cancers
- Increased development of both cancers in the same person
- Increased incidence of prostate cancer in family
- Male breast cancer
37
2 major cancer susceptibility genes
BRCA1, BRCA2
| - Tumor suppressor genes
38
BRCA1
- On chromosome 17
| - Autosomal dominant
39
BRCA2
- On chromosome 13
| - Autosomal dominant
40
Genetic testing
- Test individual who is affected first
41
Colorectal cancer
- May occur sporadically (most) or familial
| - Results from interaction of both genetic and environmental factors (diet, lack of exercise, smoking, obesity)
42
What is considered a positive family hx?
1 of more people in family w/ colorectal cancer or premalignant polyps
- May be due to: chance, shared exposure to a carcinogen or diet/lifestyle factors, combination of gene mutations and environmental risk factors)
43
Familial adenomatous polyposis (FAP)
- < 1% of colorectal cancers
| - Autosomal dominant (50% chance of passing to offspring)
44
FAP genetic mutation
Mutation in APC gene
- Tumor suppressor on chromosome 5
- 100s/1000s of polyps developing in adolescents
- Cancer develops in 20s
- Risk of cancer = 100% (before 50yo)
- Polyp --> cancer = 10+ years
45
Once FAP is dx, what is recommended?
Total colectomy before age 20
46
Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
- aka. Lynch Syndrome
- 2-3% of colorectal cancers
- Autosomal dominant
- More rapid transition from adenoma to cancer than FAP
- Cancer occurs in 30s & 40s
47
HNPCC genetic mutation
In one of many genes that code for DNA repair
48
Nonpolyposis refers to what?
Colorectal cancer that can occur when a small # or no polyps are present
- 50% chance of cancer in women
- 70% in men
- Associated w/ other cancers
49
If genetic testing reveals HNPCC
- Regular colonoscopy starting at age 25 in relatives (or 5 yrs younger than age of dx of family member)
- Upper endoscopy every 2 yrs to screen for gastric cancer
- Screening for endometrial & ovarian cancer in women 25-35
50
Chronic myelogenous leukemia
- Myloproliferative disorder
- Translocation btwn chromosome 9 & 22
- Philadelphia chromosome (22)
51
Chronic myelogeneous leukemia population
- More common in men
| - Median age = 55
52
Philadelphia chromosome (22)
Produces a protein that codes for an enzyme that causes too many stem cells to develop into WBCs
53
Pathophysiology of CML
- Increased production of abnormal/nonfunctional WBCs
| - WBCs take up bone marrow space
54
Clinical presentation of CML
- Insidious onset
- Slow progression over months to years
- Anemia, bleeding
- Fever, night sweats, fatigue
55
CML Dx
Bone marrow aspiration for karyotype
56
Hemophilia
- Bleeding disorder caused by mutations in genes that code for coagulation
- Mutation on F8 & F9 genes on X chromosome
- X-linked recessive
- Males are most affected
57
Mutation on F8
- Causes factor VIII deficiency
- Results in hemophilia A (classic form)
- More common
58
Mutation on F9
- Causes factor IX deficiency
| - Results in hemophilia B (Christmas Disease)
59
Clinical manifestations of hemophilia
- *Hemarthrosis
- Bleeding into muscles/tissues
- Prolonged bleeding/oozing after injury or surgery
60
Sickle cell disease
- Atypical hemoglobin molecules (hemoglobin S)
- Distorts RBC into crescent shape
- Abnormally shaped RBCs break down prematurely
- Mutation on HBB gene
61
Sickle cell clinical manifestations
- Anemia
- Infections
- Episodic pain
- SOB
- Fatigue
- Delayed growth
62
Sickle cell inheritance
Autosomal recessive
63
Sickle cell population
Greece, Africa, Turkey, Italy, Arabian Peninsula, India, South America, Central America, Caribbean
64
Cystic fibrosis pattern of inheritance
Autosomal recessive
| - 2 copies of mutated gene are needed for disease to be expressed
65
Cystic fibrosis genetic mutation
Mutation in the CFTR gene
- CFTR codes for a protein that regulates chloride channels
- When mutated, a defective protein is made --> disruption of chloride & H2O transport
66
Clinical manifestations of cystic fibrosis
- Thick, sticky mucous obstructing airways in lungs & ducts in pancreas
- Can affect pancreas, intestines, exocrine glands, hepatobiliary system
67
Cystic fibrosis sx
- Difficulty breathing, infections in lungs
- Problems w/ nutrient digestion
- Buildup of mucous prevents pancreatic enzymes from reaching intestine
- Failure to thrive, poor growth rate
- *Meconium ileus: newborn intestinal obstruction due to thick fecal waste products
68
What is the most common cause of morbidity associated with CF?
Pulmonary disease
- Pulmonary system can’t defend against pathogens --> sinusitis & bronchitis
- S. aureus, P. aeruginosa, Aspergillus
- Nasal polyps, nosebleeds, chronic sinus infections
69
Population & incidence of CF
- White population in US
- 1 in 3500 white newborns
- Carrier incidence: 1 in 25
70
CF Dx
- Most dx by age 1
- Sweat chloride test:
Chloride channel doesn’t allow chloride to be reabsorbed
- [chloride] in sweat is elevated
71
Marfan syndrome mode of inheritance
- Autosomal dominant
- An inherited mutation or a new mutation of fibrillin-1 gene (FBN1)
- Causes defects in CT affecting:
Bones
Ligaments
Muscles
Blood vessels
Heart valves
72
Marfan clinical manifestations
```
Tall stature
Long, thin arms & legs
Arm span wider than body height
Long, narrow face
High arched palate
Overcrowded teeth
Scoliosis
Hyperflexible joints
Chest deformities
```
73
Marfan primary features
* Dislocated lens of the eye – vision problems
| * Aortic aneurysm/dissection
74
Major cause of morbidity/mortality in Marfan syndrome?
Heart defects
- Mitral valve prolapse, aortic valve regurg
- SOB, fatigue, palpitations
75
Marfan syndrome recommendations
Avoid contact sports, caffeine, & decongestants due to increased stress placed on CV system
76
Neurofibromatosis Type 1
- aka. von Recklinghausen
- Most common type
- Subcutaneous tumors
77
Neruofibromatosis Type 1 pattern of inheritance
- Autosomal dominant
- Mutation on NF1 gene on chromosome 17
(tumor suppressor gene)
- Results in:
Growth of neurofibromas
Changes in skin pigmentation
78
NF - Type 1 manifestations
- Hyperpigmented skin lesions (café-au-lait spots)
- Lisch nodules in iris
- Freckles in axillae & groin
79
NF Type 1 dx features
- 1.5 cm or larger café-au-lait spot post puberty OR 6 or more café-au-lait spots 0.5 cm or larger before puberty
- 2 or more neurofibromas
- Axillary or inguinal freckling (Crowe sign*)
- Optic glioma
- 2 or more Lisch nodules
- 1st degree relative w/ NF1
80
Pathophysiology of PKD
- Clusters of fluid filled sacs develop in kidneys
- Affects ability to filter blood
- Kidneys become enlarged & can fail
81
PKD clinical manifestations
- HTN
- Back pain
- Hematuria
- UTIs, kidney stones
82
PKD other associations
- Liver cysts
- Heart valve abnormalities
- Increased risk of aortic & brain aneurysms
83
What are the 2 forms of PKD?
Autosomal dominant: sx start in adulthood
- 1 in 1000
- PKD1 & PKD2 genes
- Usually inherited (90%)
Autosomal recessive: rare, lethal early in life
- 1 in 30,000
- PKHD1 gene
84
What % of newborns have a congenital defect?
10%
| - Unknown etiology*
85
Teratology
Study of abnormal development
- Teratogens: anything capable of disrupting embryonic or fetal development & producing malformations
- Critical period for teratogenic effects is 3-16 weeks gestation
- Timing of exposure determines which systems are affected
86
Newborn screening
- Biochemical analysis
- Determines whether certain proteins are present or absent
- Typically autosomal recessive conditions
- “Inborn errors of metabolism”: Inherited defect in 1 or more enzymes
87
When is the 1st & 2nd test performed in newborn screening?
1st test: 24-36 hrs (heal stick)
| 2nd test: @ 1st office visit, 5-10 days
