A+P: Common Genetic D/o in Primary Flashcards
1
Q
Clinical Responsibilities
A
- Medical & FHx
- Perform PE (+ a dysmorphology exam)
- Order genetic testing
- Interpret genetic results
- FU w/ pts & families regarding results
- Collaborate w/ geneticists, genetic counselors, dieticians & psychologists as needed
2
Q
Inheritance pattern of CF
A
autosomal recessive
3
Q
Cause of CF
A
- pathogenic variant in CFTR gene
- a PRO that provides instruction to making a channel that transports negatively charged particles (Cl-) into & out of cell
4
Q
Frequency of CF
A
White > Hispanics > AA
5
Q
Dx for CF
A
GS is sweat Cl- test (abnl ≥60 mEq/L)
- Newborn screening (elev trypsinogen)
- Sequencing analysis of the single gene
6
Q
NOTE
A
if they have a (+) sweat Cl- test, you still need to do further testing
7
Q
CF Common Findings
A
- Salty sweat
- Poor growth & weight gain
- Chronic coughing & wheezing (more sickly child)
- Thick mucus & phlegm
- Greasy, smelly stools
8
Q
CF & the lungs
A
- small airways obstruction
- recurrent resp exacerbations
9
Q
CF & skin
A
excessively salty sweat
10
Q
CF & the liver
A
- biliary cirrhosis
- gallstones
- hepatic steatosis
11
Q
CF & the pancreas
A
- exocrine pancreatic insuff
- fat-soluble Vit malabsorption
- CF related DM
12
Q
CF & the colon
A
- meconium ileus
- distal intestinal obstruction synd
- fibrosing colonopathy
13
Q
CF & the Reproductive system
A
- congenital bilateral absence of vas deferens
14
Q
CF & Msk system
A
- osteoporosis
- arthritis
- hypertrophic pulm osteoarthropathy
15
Q
CF: referrals
A
- endocrinology
- gastroenterology
- genetics
- pulmonology
16
Q
CF: Management
A
- freq visits to monitor changes in Sx
- resp tract cultures 4x/year
- annual PFTs, CXR, electrolytes, fat-soluble vit levels, IgE levels
-Bronchoscopy & chest CT exam when indicated - Monitor weight gain & caloric intake in infants until 6mos
- Annual oral glucose tolerance test in ppl >10yo
- Eval BMD (adolescence)
- Annual LFTs & liver US
17
Q
Describe Ivacaftor (Kalydeco)
A
a small molecule drug that acts as a potentiator & enhances the gaiting activity of CFTR channel
18
Q
Ivacaftor (Kalydeco) can be used for how many specific pathogenic variants in the CFTR gene?
A
10
19
Q
Ivacaftor (Kalydeco) is not indicated for which pts?
A
pts w/ homozygous F508del, which is the MC mutation (abt 45% white)
20
Q
Describe Lumacaftor/Ivavaftor (Orkambi)
A
a corrector that has been demonstrated to improve folding & trafficking of F508del CFTR to cell surface
21
Q
Lumacaftor/Ivavaftor (Orkambi) is used in which type of CF pts?
A
pts w/ 2 copies of F508del
22
Q
What does CAVD stand for?
A
congenital absence of the Vas Deferens
23
Q
How is CAVD found?
A
- ID’d during eval of infertility
24
Q
What is seen w/ CAVD?
A
- Azoospermia
- Severe oligospermia
- Low volume of ejaculated semen w/ a specific chemical profile
25
What is the chemical profile of CAVD ejaculated semen?
- low pH
- elev [citric acid]
- elev acid [phosphatase]
- low [fructose]
- failure to coagulate
26
NOTE
Hypoplasia or aplasia of vas deferens & seminal vesicles may occur either bilaterally or unilaterally
27
NOTE CAVD
Testicular development & function & spermatogenesis are usually normal--> IVF for having a child
28
CAVD: PE
Absence of vas deferens on palpation
29
CAVD Inheritance pattern
autosomal recessive
30
CAVD cause:
pathogenic variants in **CFTR gene**
31
CAVD: freq
1-2% of all male infertility
32
CAVD: Dx
Azoospermia AND
- Absence of vas deferens on palpation (rarely, small vas def)
OR
- ID of biallelic CAVD-causing CFTR pathogenic variants (establishes dx if clinical features are inconclusive)
33
NOTE
A pt w/ CAVD will have CF, but CF patient won't have CAVD
34
What does FH stand for?
Familial Hypercholesterolemia
35
What is a FH patient at risk for?
Premature atherosclerotic CVD due to lifelong exposure to elev LDL-C
36
What % of incr significant risk of fatal or nonfatal coronary event in those w/ FH?
- Males: 50% risk by 50yrs
- Females: 30% risk by 60yrs
37
FH: Common Findings
- Severely elev LDL (LDL-C) levels--> atherosclerotic plaque deposition in coronary arteries & proximal aorta at an early age
- Xanthomas – patches of cholesterol buildup (worsen w/ age b/c extremely high cholesterol)
- CAD which may manifest as angina & MI; stroke occurs more rarely
38
Common areas of Xanthomas in FH
- around the eyelids
- w/n tendons of the elbows
- hands
- knees
- feet (Achilles tendon)
39
What condition has a corneal arc? & describe?
- FH
- Halo around the eye
40
FH: inheritance pattern
mostly autosomal dominant
1 is autosomal recessive
41
FH: Cause
pathogenic variants in genes
- LDLR
- APOB
- LDLRAP1
- **PCSK9**
42
FH: freq
1:200-250 (~220)
43
What is the most common genetic cause of CVD?
FH
44
FH: Dx
- genetic sequencing
- multigene panel + clinical support
45
Which 4 genes are assoc. w/ FH?
- LDLR
- APOB
- LDLRAP1
- PCSK9
46
Which FH genes are autosomal dominant
- LDLR
- APOB
- PCSK9
47
Which FH genes are autosomal recessive
LALRAP1
48
Which FH genes are loss of function?
- LDLR
- APOB
- LALRAP1
49
Which FH genes are gain of function?
PCSK9
50
Molecular Mechanism of FH (4 steps)
1. Mature LDLR receptor sits in membrane in clathrin coated pits
2. It is able to bind to LDL-C through its interaction w/ APOB PRO
3. ARH adaptor PRO is req for clustering LDLR receptor in pit & once receptor binds LDL it is endocytosed
4. Endocytosed pits eventually become lysosomes where cholesterol is released & LDLR is targeted for degradation by PCSK9
51
FH: referrals
cardiology/lipid specialist, if needed
52
FH: reduction of CAD RFs
- stop smoking
- regular exercise
- healthy diet
- weight control
- tx HTN
- low-dose aspirin (high-risk ppl)
- pharmacotherapy (statins w/ additional meds) to reduce lipid levels
53
Kids w/ FH management:
- referral to a lipid specialist
- diet & lifestyle mods
- statins in kids starting ~8yo
54
Kids & adults homozygous for FH: management
- referral to a lipid specialist or specialized center for management of multi drug therapy
- LDL apheresis is often required
- liver transplant (rare)
55
FH: diagnostic criteria
- extreme hypercholesterolemia
- Hx of premature CAD or other CVD
- Xanthomas
- Corneal arcus
- FHx of features suggestive of FH
- Genetic testing
56
NOTE
if they have pathogenic variant for FH (with or w/o Sx) they NEED to be on statin
57
Qualifications for extreme hypercholesterolemia
- Untx adults w/ **LDL-C >190** or **total cholesterol >310**
- Untx children/adolescents w/ LDL-C levels >160 mg/dL or total cholesterol levels >230 mg/dL)
58
Rationale for Genetic Testing
- Presence of incr risk in ppl w/ pathogenic variants
- Availability of effective tx to lower LDL-C levels
- Current yields published in literature
- Enhancement of cascade testing w/ genetic testing
- Likelihood of improved med compliance
59
Marfan Syndrome inheritance pattern
autosomal dominant
60
Is Marfan synd compatible w/ life?
2 abnl copies is incompatible w/ life
61
Marfan Synd: Cause
- **pathogenic variants in the FBN1 gene**
- Codes for fibrillin, PRO that ultimately provides strength & flexibility to CT
62
Marfan Synd: freq
1:5,000
63
Marfan Synd: Dx
- genetic sequencing of the single gene
- multigene panel + clinical support
64
Marfan Synd: common findings
- Tall & slender build
- long arms, legs & fingers
- Pectus carinatum/excavatum
- Spontaneous pneumothorax
- High, arched palate & crowded teeth
- Heart murmurs (aortic root dilatation, MVP)
- Extreme nearsightedness or lens dislocation (ectopia lentis)
- scoliosis
- flat feet
65
Marfan Synd: Classical facial features
- dolichocephaly
- downslanting palpebral fissures
- malar hypoplasia
- retrognathia
66
Marfan Synd: Other PE Findings (think pictures)
- arachnodactyly
- thumb sign (Steinburg)
- wrist sign (Walker)
67
Marfan Synd: referrals
- cardiology
- genetics
- ophthalmology
68
Marfan Synd: referrals to consider
- cardiothoracic surg
- orthopedics
- PT
69
Marfan synd: Management
- Yearly cardiac exam w/ echo
- ARBs > BBs -->reduce hemodynamic stress on the aortic wall
- Yearly eye exam
70
What does PKD stand for?
Polycystic kidney Dz
71
PCK inheritance pattern
autosomal dominant or autosomal recessive
72
Most common inheritance pattern for PCK? & %?
autosomal dominant (95%)
73
PKD: Cause
pathogenic variants in **PKD1& PKD2 genes (AD)** & **PKDH1 gene (AR)**
74
PKD: freq
AD 1:500-1,000 ppl WW
AR 1:20,000-40,000 ppl WW
75
PKD: Dx
genetic sequencing + clinical support
76
PKD: Common Findings
- Multiple cysts on the kidneys
- HTN
- Hematuria (blood in urine)
- Kidney stones
- Pain in back or sides
- Recurrent UTIs
- Heart valve abnormalities
77
ADPKD dx is established in proband w/ any of the following:
- Age-specific US criteria and an affected 1st-degree relative w/ ADPKD
- Age-specific MRI criteria & an affected 1st-degree relative w/ ADPKD
- ID of a heterozygous pathogenic variant in one of the genes
78
PKD: referrals
- genetics
- nephrology
79
PKD: referrals to consider
cardiology
80
PKD: Management
- Monitor BP closely (ACE/ARB); early BP monitoring starting in childhood (2yo)
- Vasopressin V2 receptor antagonists to slow disease progression
- Brain MRI screening for intracranial aneurysms in those at high risk
- Screening echo if heart murmur & FHx of a 1st-degree
81
What should be avoided in PKD?
- long-term nephrotoxic agents
- high levels of caffeine
- use of estrogens & poss. progestogens by ppl w/ severe polycystic liver dz;
- smoking
- obesity
82
Neurofibromatosis 1: Inheritance pattern
- autosomal dominant but many cases result from new mutations (de novo; ~50%)
83
Neurofibromatosis 1: Cause
pathogenic variants in the **NF1 gene**
- Codes for neurofibromin, a PRO that acts as a tumor suppressor.
84
Neurofibromatosis 1: Freq
1:3,000 ppl
85
Neurofibromatosis 1: Dx
- gene sequencing
86
Neurofibromatosis 1: Common Findings
- Café-au-lait macules
- NFs (look hard but soft like tissue paper)
- Short stature
- Macrocephaly (large head)
- Axillary or groin freckling
- Scoliosis
- Learning difficulties
**a spectrum**
87
What are the freckling in the eyes found in NF called?
Lisch nodules
88
Diagnostic Criteria for Neurofibromatosis 1
2 or more of the following:
- >/= 6 café-au-lait spots in kids
- >/= 2 cutaneous/subcutaneous NFs or 1 plexiform neurofibroma
- Axillary or groin freckling
- Optic pathway glioma
- >/=2 Lisch nodules
- Body dysplasia (sphenoid wing dysplasia, +/- pseudarthrosis)
- 1st degree relative w/ NF1
89
Neurofibromatosis 1: referrals
- genetics
- ophthalmology
90
Neurofibromatosis 1: referrals to consider
- developmental peds
- neurology
- oncology
- PT
91
Neurofibromatosis 1 Management
- Yearly eye exam until age 8yrs, then every 2yrs after
- Yearly blood pressure screening
- Yearly PE (skin & neuro)
- Asses speech & motor skills for deficits that may req further assessment
- Evaluate for precocious puberty
- **Begin annual mammo in women at age 30yrs** incr risk of breast CA b/t 30 - 50yo)
92
Neurofibromatosis 1 NOTE
what you see on top of the skin is
2-3x larger under the skin
93
Neurofibromatosis 2 will having hearing loss by 30 b/c
bilateral vestibular (acoustic) schwannomas
- speech therapy early b/c they will become deaf
94
Neurofibromatosis 2: Inheritance pattern
autosomal dominant but many cases result from new mutations (de novo; ~50%)
95
Neurofibromatosis 2: Cause
pathogenic variants in the **NF2 gene**
- Codes for merlin (aka schwannomin), a PRO that acts as a tumor suppressor
96
Neurofibromatosis 2: Freq
1:33,000
97
Neurofibromatosis 2: Dx
genetic sequencing + clinical support
98
Neurofibromatosis 2: Common findings
- Vestibular schwannomas (acoustic neuroma)
- Hearing loss
- Tinnitus (ringing in the ears)
- Problems w/ balance
- Cataracts
- Other intracranial, cranial nerve, or spinal nerve tumors
- Focal weakness (b/c spinal tumors, mononeuropathy, or polyneuropathy)
99
Diagnostic Criteria for Neurofibromatosis 2
- Bilateral vestibular schwannomas
- 1st degree relative w/ NF2 + unilateral vestibular schwannoma OR any TWO of the following: tumors
- unilateral vestibular schwannoma + TWO of the following: tumors
-Multiple meningiomas & Unilateral vestibular schwannoma OR any 2 tumors
100
Neurofibromatosis 2: referrals
- audiology/ENT
- genetics
- ophthalmology
101
Neurofibromatosis 2: referrals to consider
- neurology
- oncology
102
Neurofibromatosis 2: Management
- Annual head MRI start at ~10-12yo & cont. until 40s
- Hearing evaluation
- Poss. hearing aids &/or cochlear or brain stem implants
- Annual complete eye exam
- Tx vestibular schwannoma
- Lip-reading & ASL
103
Neurofibromatosis 2: Tx of vestibular schwannoma
- primarily surg
- stereotactic radiosurg,
most commonly w/ gamma knife, may be an alternative to surg
104
What is Huntington's Dz?
A progressive disorder of motor, cognitive & psych disturbances
105
Mean age of onset for Huntington Dz?
35 - 44yo
106
Median survival time of Huntington Dz?
15 - 18yrs after onset
107
Huntington Dz: inheritance pattern
autosomal dominant
108
Huntington Dz: Cause
pathogenic variants (trinucleotide repeat of ‘CAG’) in the **HTT gene** - Codes for huntingtin, a PRO that appears to play an important role in (neurons) in brain.
109
Huntington Dz: Freq
3-7:100,000 (European ancestry)
110
Huntington Dz: Dx
trinucleotide analysis of single gene
111
Huntington dz: early S/Sx
- Irritability, depression, small involuntary movements, poor coordination & trouble learning new info or making decisions
- chorea
112
What happens to movements as dz progresses?
become more pronounced
- trouble walking, speaking & swallowing
- changes in personality & decline in thinking & reasoning abilities
113
Huntington Dz: referrals
- genetics
- neuro
- movement specialist
- HD support group
114
Huntington Dz: Management
- Appropriate pharm therapy:
- Regular evals of appearance & severity of chorea, rigidity, gait problems, depression, behavioral changes & cognitive decline
- Routine assessment of functional abilities using BOSH scale & UHDR scale
- Supportive care w/ attention to nursing needs, dietary intake, special equipment & eligibility for state & federal benefits
115
Huntington Dz: Pharm tx includes
- Typical neuroleptics (haloperidol), atypical neuroleptics (olanzapine), benzos, or monoamine-depleting agent tetrabenazine for choreic movements
- Anti-parkinsonian agents for hypokinesia & rigidity
- Psychotropic drugs or some types of antiepileptic drugs for psych disturbances (depression, psychotic Sxs, outbursts of aggression)
- Valproic acid for myoclonic hyperkinesia
116
What should be avoided in Huntington Dz?
- Avoid L-dopa-containing compounds (may incr chorea)
- alcohol & smoking
117
Describe dementia
typically begins w/ subtle & poorly recognized failure of memory
- (often called mild cognitive impairment) & slowly becomes more severe & eventually, incapacitating
118
Alz Dz: common findings
- confusion
- poor judgment
- language disturbance
- visual complaints
- agitation
- withdrawal
- hallucinations
119
Occasional sx seen in Alz Dz
- seizures
- Parkinsonian features, incr muscle tone, myoclonus, incontinence & mutism occur
120
Alz Dz inheritance pattern
autosomal dominant
121
Alz Dz: Cause
**APP, PSEN1, or PSEN2 genes**
When mutations are present, large amts of a toxic PRO fragment called amyloid B-peptide are produced in the brain, leading to amyloid plaques.
122
Pathogenic variants are found in about how many genes that incr risk of Alz Dz?
~20
123
Which gene is controversial in Alz Dz?
APOE gene
124
Alz Dz: Freq
unknown but affects > 5 million Americans
--> 95% of all AD is late onset (>60-65yrs)
--> 5% is early onset (<60-65yrs)
125
Alz Dz: Dx
usually clinical/based on Sxs
--> 25% of all AD is familial & 75% is nonfamilial
--> Sequencing analysis of the genes, if indicated
126
Alz Dz: referrals
- neurology
- Psych?
127
Alz Dz: Management
- Appropriate pharm therapy
- Supportive care w/ attention to nursing needs, dietary intake & special equipment
128
What is the pharm therapy for Alz Dz
- Donepezil (Aricept)
- Galantamine (Razadyne)
- Rivastigmine (Exelon)
129
Those affected w/ Alz usually survive ____ years after appearance of Sx
8 to 10yrs
130
The course of Alz Dz can last how many years?
1 - 25yrs
131
Survival of Alz is shorter in which pts?
ppl dx after age 80 vs those dx at a younger age
132
In Alz, Death usually results from____
- general inanition (body wasting)
- malnutrition
- Pneumonia
