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Block 4 - Emergency Medicine > A+P: Common Genetic D/o in Primary > Flashcards

A+P: Common Genetic D/o in Primary Flashcards

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Royal College: Emergency Medicine 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
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2
Q

Inheritance pattern of CF

A

autosomal recessive

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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
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4
Q

Frequency of CF

A

White > Hispanics > AA

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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

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6
Q

NOTE

A

if they have a (+) sweat Cl- test, you still need to do further testing

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7
Q

CF Common Findings

A
  • Salty sweat
  • Poor growth & weight gain
  • Chronic coughing & wheezing (more sickly child)
  • Thick mucus & phlegm
  • Greasy, smelly stools
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8
Q

CF & the lungs

A
  • small airways obstruction
  • recurrent resp exacerbations
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9
Q

CF & skin

A

excessively salty sweat

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10
Q

CF & the liver

A
  • biliary cirrhosis
  • gallstones
  • hepatic steatosis
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11
Q

CF & the pancreas

A
  • exocrine pancreatic insuff
  • fat-soluble Vit malabsorption
  • CF related DM
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12
Q

CF & the colon

A
  • meconium ileus
  • distal intestinal obstruction synd
  • fibrosing colonopathy
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13
Q

CF & the Reproductive system

A
  • congenital bilateral absence of vas deferens
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14
Q

CF & Msk system

A
  • osteoporosis
  • arthritis
  • hypertrophic pulm osteoarthropathy
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15
Q

CF: referrals

A
  • endocrinology
  • gastroenterology
  • genetics
  • pulmonology
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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
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17
Q

Describe Ivacaftor (Kalydeco)

A

a small molecule drug that acts as a potentiator & enhances the gaiting activity of CFTR channel

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18
Q

Ivacaftor (Kalydeco) can be used for how many specific pathogenic variants in the CFTR gene?

A

10

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19
Q

Ivacaftor (Kalydeco) is not indicated for which pts?

A

pts w/ homozygous F508del, which is the MC mutation (abt 45% white)

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20
Q

Describe Lumacaftor/Ivavaftor (Orkambi)

A

a corrector that has been demonstrated to improve folding & trafficking of F508del CFTR to cell surface

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21
Q

Lumacaftor/Ivavaftor (Orkambi) is used in which type of CF pts?

A

pts w/ 2 copies of F508del

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22
Q

What does CAVD stand for?

A

congenital absence of the Vas Deferens

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23
Q

How is CAVD found?

A
  • ID’d during eval of infertility
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24
Q

What is seen w/ CAVD?

A
  • Azoospermia
  • Severe oligospermia
  • Low volume of ejaculated semen w/ a specific chemical profile
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25
Q

What is the chemical profile of CAVD ejaculated semen?

A
  • low pH
  • elev [citric acid]
  • elev acid [phosphatase]
  • low [fructose]
  • failure to coagulate
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26
Q

NOTE

A

Hypoplasia or aplasia of vas deferens & seminal vesicles may occur either bilaterally or unilaterally

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27
Q

NOTE CAVD

A

Testicular development & function & spermatogenesis are usually normal–> IVF for having a child

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28
Q

CAVD: PE

A

Absence of vas deferens on palpation

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29
Q

CAVD Inheritance pattern

A

autosomal recessive

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30
Q

CAVD cause:

A

pathogenic variants in CFTR gene

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31
Q

CAVD: freq

A

1-2% of all male infertility

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32
Q

CAVD: Dx

A

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)

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33
Q

NOTE

A

A pt w/ CAVD will have CF, but CF patient won’t have CAVD

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34
Q

What does FH stand for?

A

Familial Hypercholesterolemia

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35
Q

What is a FH patient at risk for?

A

Premature atherosclerotic CVD due to lifelong exposure to elev LDL-C

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36
Q

What % of incr significant risk of fatal or nonfatal coronary event in those w/ FH?

A
  • Males: 50% risk by 50yrs
  • Females: 30% risk by 60yrs
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37
Q

FH: Common Findings

A
  • 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
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38
Q

Common areas of Xanthomas in FH

A
  • around the eyelids
  • w/n tendons of the elbows
  • hands
  • knees
  • feet (Achilles tendon)
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39
Q

What condition has a corneal arc? & describe?

A
  • FH
  • Halo around the eye
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40
Q

FH: inheritance pattern

A

mostly autosomal dominant
1 is autosomal recessive

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41
Q

FH: Cause

A

pathogenic variants in genes
- LDLR
- APOB
- LDLRAP1
- PCSK9

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42
Q

FH: freq

A

1:200-250 (~220)

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43
Q

What is the most common genetic cause of CVD?

A

FH

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44
Q

FH: Dx

A
  • genetic sequencing
  • multigene panel + clinical support
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45
Q

Which 4 genes are assoc. w/ FH?

A
  • LDLR
  • APOB
  • LDLRAP1
  • PCSK9
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46
Q

Which FH genes are autosomal dominant

A
  • LDLR
  • APOB
  • PCSK9
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47
Q

Which FH genes are autosomal recessive

A

LALRAP1

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48
Q

Which FH genes are loss of function?

A
  • LDLR
  • APOB
  • LALRAP1
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49
Q

Which FH genes are gain of function?

A

PCSK9

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50
Q

Molecular Mechanism of FH (4 steps)

A
  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
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51
Q

FH: referrals

A

cardiology/lipid specialist, if needed

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52
Q

FH: reduction of CAD RFs

A
  • 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
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53
Q

Kids w/ FH management:

A
  • referral to a lipid specialist
  • diet & lifestyle mods
  • statins in kids starting ~8yo
54
Q

Kids & adults homozygous for FH: management

A
  • referral to a lipid specialist or specialized center for management of multi drug therapy
  • LDL apheresis is often required
  • liver transplant (rare)
55
Q

FH: diagnostic criteria

A
  • extreme hypercholesterolemia
  • Hx of premature CAD or other CVD
  • Xanthomas
  • Corneal arcus
  • FHx of features suggestive of FH
  • Genetic testing
56
Q

NOTE

A

if they have pathogenic variant for FH (with or w/o Sx) they NEED to be on statin

57
Q

Qualifications for extreme hypercholesterolemia

A
  • 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
Q

Rationale for Genetic Testing

A
  • 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
Q

Marfan Syndrome inheritance pattern

A

autosomal dominant

60
Q

Is Marfan synd compatible w/ life?

A

2 abnl copies is incompatible w/ life

61
Q

Marfan Synd: Cause

A
  • pathogenic variants in the FBN1 gene
  • Codes for fibrillin, PRO that ultimately provides strength & flexibility to CT
62
Q

Marfan Synd: freq

A

1:5,000

63
Q

Marfan Synd: Dx

A
  • genetic sequencing of the single gene
  • multigene panel + clinical support
64
Q

Marfan Synd: common findings

A
  • 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
Q

Marfan Synd: Classical facial features

A
  • dolichocephaly
  • downslanting palpebral fissures
  • malar hypoplasia
  • retrognathia
66
Q

Marfan Synd: Other PE Findings (think pictures)

A
  • arachnodactyly
  • thumb sign (Steinburg)
  • wrist sign (Walker)
67
Q

Marfan Synd: referrals

A
  • cardiology
  • genetics
  • ophthalmology
68
Q

Marfan Synd: referrals to consider

A
  • cardiothoracic surg
  • orthopedics
  • PT
69
Q

Marfan synd: Management

A
  • Yearly cardiac exam w/ echo
  • ARBs > BBs –>reduce hemodynamic stress on the aortic wall
  • Yearly eye exam
70
Q

What does PKD stand for?

A

Polycystic kidney Dz

71
Q

PCK inheritance pattern

A

autosomal dominant or autosomal recessive

72
Q

Most common inheritance pattern for PCK? & %?

A

autosomal dominant (95%)

73
Q

PKD: Cause

A

pathogenic variants in PKD1& PKD2 genes (AD) & PKDH1 gene (AR)

74
Q

PKD: freq

A

AD 1:500-1,000 ppl WW
AR 1:20,000-40,000 ppl WW

75
Q

PKD: Dx

A

genetic sequencing + clinical support

76
Q

PKD: Common Findings

A
  • Multiple cysts on the kidneys
  • HTN
  • Hematuria (blood in urine)
  • Kidney stones
  • Pain in back or sides
  • Recurrent UTIs
  • Heart valve abnormalities
77
Q

ADPKD dx is established in proband w/ any of the following:

A
  • 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
Q

PKD: referrals

A
  • genetics
  • nephrology
79
Q

PKD: referrals to consider

A

cardiology

80
Q

PKD: Management

A
  • 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
Q

What should be avoided in PKD?

A
  • long-term nephrotoxic agents
  • high levels of caffeine
  • use of estrogens & poss. progestogens by ppl w/ severe polycystic liver dz;
  • smoking
  • obesity
82
Q

Neurofibromatosis 1: Inheritance pattern

A
  • autosomal dominant but many cases result from new mutations (de novo; ~50%)
83
Q

Neurofibromatosis 1: Cause

A

pathogenic variants in the NF1 gene
- Codes for neurofibromin, a PRO that acts as a tumor suppressor.

84
Q

Neurofibromatosis 1: Freq

A

1:3,000 ppl

85
Q

Neurofibromatosis 1: Dx

A
  • gene sequencing
86
Q

Neurofibromatosis 1: Common Findings

A
  • Café-au-laitmacules
  • NFs (look hard but soft like tissue paper)
  • Short stature
  • Macrocephaly (large head)
  • Axillary or groin freckling
  • Scoliosis
  • Learning difficulties
    a spectrum
87
Q

What are the freckling in the eyes found in NF called?

A

Lisch nodules

88
Q

Diagnostic Criteria for Neurofibromatosis 1

A

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
Q

Neurofibromatosis 1: referrals

A
  • genetics
  • ophthalmology
90
Q

Neurofibromatosis 1: referrals to consider

A
  • developmental peds
  • neurology
  • oncology
  • PT
91
Q

Neurofibromatosis 1 Management

A
  • 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
Q

Neurofibromatosis 1 NOTE

A

what you see on top of the skin is
2-3x larger under the skin

93
Q

Neurofibromatosis 2 will having hearing loss by 30 b/c

A

bilateral vestibular (acoustic) schwannomas
- speech therapy early b/c they will become deaf

94
Q

Neurofibromatosis 2: Inheritance pattern

A

autosomal dominant but many cases result from new mutations (de novo; ~50%)

95
Q

Neurofibromatosis 2: Cause

A

pathogenic variants in the NF2 gene
- Codes for merlin (aka schwannomin), a PRO that acts as a tumor suppressor

96
Q

Neurofibromatosis 2: Freq

A

1:33,000

97
Q

Neurofibromatosis 2: Dx

A

genetic sequencing + clinical support

98
Q

Neurofibromatosis 2: Common findings

A
  • 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
Q

Diagnostic Criteria for Neurofibromatosis 2

A
  • 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
Q

Neurofibromatosis 2: referrals

A
  • audiology/ENT
  • genetics
  • ophthalmology
101
Q

Neurofibromatosis 2: referrals to consider

A
  • neurology
  • oncology
102
Q

Neurofibromatosis 2: Management

A
  • 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
Q

Neurofibromatosis 2: Tx of vestibular schwannoma

A
  • primarily surg
  • stereotactic radiosurg,
    most commonly w/ gamma knife, may be an alternative to surg
104
Q

What is Huntington’s Dz?

A

A progressive disorder of motor, cognitive & psych disturbances

105
Q

Mean age of onset for Huntington Dz?

A

35 - 44yo

106
Q

Median survival time of Huntington Dz?

A

15 - 18yrs after onset

107
Q

Huntington Dz: inheritance pattern

A

autosomal dominant

108
Q

Huntington Dz: Cause

A

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
Q

Huntington Dz: Freq

A

3-7:100,000 (European ancestry)

110
Q

Huntington Dz: Dx

A

trinucleotide analysis of single gene

111
Q

Huntington dz: early S/Sx

A
  • Irritability, depression, small involuntary movements, poor coordination & trouble learning new info or making decisions
  • chorea
112
Q

What happens to movements as dz progresses?

A

become more pronounced
- trouble walking, speaking & swallowing
- changes in personality & decline in thinking & reasoning abilities

113
Q

Huntington Dz: referrals

A
  • genetics
  • neuro
  • movement specialist
  • HD support group
114
Q

Huntington Dz: Management

A
  • 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
Q

Huntington Dz: Pharm tx includes

A
  • 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
Q

What should be avoided in Huntington Dz?

A
  • Avoid L-dopa-containing compounds (may incr chorea)
  • alcohol & smoking
117
Q

Describe dementia

A

typically begins w/ subtle & poorly recognized failure of memory
- (often called mild cognitive impairment) & slowly becomes more severe & eventually, incapacitating

118
Q

Alz Dz: common findings

A
  • confusion
  • poor judgment
  • language disturbance
  • visual complaints
  • agitation
  • withdrawal
  • hallucinations
119
Q

Occasional sx seen in Alz Dz

A
  • seizures
  • Parkinsonian features, incr muscle tone, myoclonus, incontinence & mutism occur
120
Q

Alz Dz inheritance pattern

A

autosomal dominant

121
Q

Alz Dz: Cause

A

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
Q

Pathogenic variants are found in about how many genes that incr risk of Alz Dz?

A

~20

123
Q

Which gene is controversial in Alz Dz?

A

APOE gene

124
Q

Alz Dz: Freq

A

unknown but affects > 5 million Americans
–> 95% of all AD is late onset (>60-65yrs)
–> 5% is early onset (<60-65yrs)

125
Q

Alz Dz: Dx

A

usually clinical/based on Sxs
–> 25% of all AD is familial & 75% is nonfamilial
–> Sequencing analysis of the genes, if indicated

126
Q

Alz Dz: referrals

A
  • neurology
  • Psych?
127
Q

Alz Dz: Management

A
  • Appropriate pharm therapy
  • Supportive care w/ attention to nursing needs, dietary intake & special equipment
128
Q

What is the pharm therapy for Alz Dz

A
  • Donepezil (Aricept)
  • Galantamine (Razadyne)
  • Rivastigmine (Exelon)
129
Q

Those affected w/ Alz usually survive ____ years after appearance of Sx

A

8 to 10yrs

130
Q

The course of Alz Dz can last how many years?

A

1 - 25yrs

131
Q

Survival of Alz is shorter in which pts?

A

ppl dx after age 80 vs those dx at a younger age

132
Q

In Alz, Death usually results from____

A
  • general inanition (body wasting)
  • malnutrition
  • Pneumonia

Block 4 - Emergency Medicine (4 decks)

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