Cardiogenetics

Question 1

How is the molecular dx of Noonan syndrome established

Answer 1

established in a proband w suggestive findings and a heterozygous pathogenic variant in most genes or biallelic PVs in LZTR1

molecular genetic testing including the use of a multigene panel
top 3 PVs are PTPN11 (50%); SOS1 (10-13%); LZTR1 (~8%)

Question 2

What prenatal features can be seen in Noonan syndrome

Answer 2

APA has been observed in cohorts w simplex NS
polyhydramnios, increased distended jugular lymphatic sacs, NT, cystic hygroma, pleural effusion, and ascites
relative macrocephaly
cardiac and renal anomalies
in chromosomally normal fetuses w increased NT, it is estimated that 3-15% have PTPN11 associated NS

Question 3

What are the clinical features associated w Noonan syndrome

Answer 3

feeding difficulties, postnatal growth failure, delayed bone maturity, more than 50% of females and nearly 40% of males have an adult height below the 3rd centile; impaired growth hormone release
cardiovascular: frequency of congenital heart dz between 50-80%; pulmonary valve stenosis most common, found in 25-71%; HCM in 10-29% in which 50% are dx by 6mo; electrocardiographic abnormality in ~90% of individuals w NS
Psychomotor development: early developmental milestones may be delayed, joint hyperextensibility, hypotonia, 50% of school age children meet dx criteria for a developmental coordination disorder; 25% have learning difficulties, 10-15% require special ED; hearing loss in 40%, language impairments, impairment in attention and executive functioning, heightened risk for ASD
Genitourinary: mild renal abnormalities in 11%, dilatation of the renal pelvis is common; cryptorchidism in 60-80%, hypogonadotropic hypogonadism; puberty may be delayed in females, normal fertility is the rule
skeletal: thoracic scoliosis in 13-30%, pectus carinatum w broad chest and increased inter-nipple distance in 28-95%; upper limb anomalies, radioulnar synostosis, brachydactyly, and fifth finger clinodactyly; micrognathia, high arched palate, dental crowding, osteopenia in adults; multiple giant cell lesions of the jaw, joints, and/or soft tissue
bleeding diathesis: 1/3 w NS have one or more coagulation defects may manifest as severe sx hemorrhage, clinically mild bruising, or lab abnormalities with no clinical consequences
lymphatic: varied abnormalities including lymphedema
ocular: ptosis, strabismus, refractive errors, amblyopia, nystagmus in 95%
OTHER: follicular keratosis, cafe au lait spots and lentigines, Arnold I Chiari malformation, hepatosplenomegaly, malignancies

Question 4

What are the evolving facial features seen in Noonan syndrome

Answer 4

neonate: tall forehead, widely spaced eyes, low set posteriorly rotated ears w a thickened helix; short neck w excess nuchal skin and low posterior hairline
infancy: prominent eyes, depressed nasal bridge, wide base, bulbous tip
childhood: facial appearance is often lacking in affect or expression
adolescence: inverted triangle, eyes are less prominent and features are sharper, skin webbing
older adult: skin appears transparent and wrinkled

Question 5

What malignancies are individuals w Noonan syndrome at increased risk for

Answer 5

Juvenile myelomonocytic leukemia: transient myeloproliferative disorder in neonatal/early infancy; 10% progress to JMML
PTPN11 has a predisposition to this unusual childhood leukemia but runs a more benign course; also 3X risk for ALL and AML
rhabdomyosarcoma, neuroblastoma, low grade gliomas, glioneuronal tumors

overall cancer risk is 4% by 20yo; bc it does not exceed 5% risk, no screening recommendations

Question 6

What is the incidence of Noonan syndrome

Answer 6

1 in 1,000-2500

Question 7

What are the tx recommendations for Noonan syndrome

Answer 7

short stature: GH therapy
feeding difficulties: consider tube feedings especially those with CHDs/cardiomyopathy
standard txs for: behavioral manifestations, CHDs, HCM, cryptorchidism, renal anomalies/hydronephrosis, bleeding diathesis, abnormal vision and/or strabismus, hearing loss, Chiari malformation, and JMML w other malignancies

Question 8

What should be avoided in pts w Noonan syndrome

Answer 8

Aspirin since it can exacerbate a bleeding diathesis

Question 9

What is the de novo rate for AD Noonan syndrome

Answer 9

30-75% have an affected parent (25-70% de novo rate)
in simplex cases, pat origin of the de novo pathogenic variant has been found universally to date; significant sex ratio bias favoring transmission to males

Question 10

How is the dx of CHARGE syndrome established

Answer 10

established in a proband w suggestive clinical and imaging findings and a heterozygous PV in CHD7 identified by molecular testing

Question 11

How is the molecular dx of CHARGE syndrome established

Answer 11

sequence of CHD7 then del dup and/or CMA

Bc CHD7 disorder typically includes multiple congenital anomalies, it is also reasonable to pursue CMA testing first, unless classic features of CHD7 disorder (ex: the CHARGE syndrome phenotype) are apparent

a distinctive epigenetic signature in blood leukocytes has been identified in individuals w CHD7 disorder; can therefore be considered to clarify the dx in individuals with (1) suggestive findings of CHD7 disorder for which no PV has been identified OR (2) a VUS has been identified

Question 12

What does CHARGE stand for

Answer 12

Coloboma
Heart defect
Atresia of the choanal (choanal atresia)
Restricted growth and development (delayed growth)
Genital hypoplasia
Ear anomalies

Question 13

What are the clinical features associated w CHARGE syndrome

Answer 13

CHD7 disorder exhibits a high degree of clinical variability even among individuals in the same family and those in different families
DEVELOPMENT: motor delays due to vestibular anomalies, poor head control, delayed motor milestones, reduced fine motor skills; language delay, hearing loss, vision loss, cognitive impairment; multiple sensory deficits (vision, hearing, balance and smell), intellectual outcome is within the normal range in 50% of the individuals w clinical features; ADHD, repetitive behavior, OCD; self-abuse is occasionally seen, increased pain threshold; many adults are able to live independently
GASTRO: frequently seen, GERD, constipation, abdominal pain, malrotation of the intestines, intussusception, choking due to mouth stuffing
IMMUNODEFICIENCY: decreased # or function of T cells, rarely absent thymus
SKELETAL: craniosynostosis, vertebral anomalies, scoliosis, extra/missing ribs, ectrodactyly (absence of toes/fingers), polydactyly, finger-like thumb, brachydactyly; hypermobility and contractures
NEUROMUSCULAR: hypotonia, abnormal shoulder girdle muscles
DENTAL: overbite, hypodontia, poor mineralization of the teeth

Question 14

What is the life expectancy of someone w CHARGE syndrome

Answer 14

highly depends on the severity of manifestations, since the phenotypic spectrum of CHD7 disorder is substantial

in childhood, adolescence, and adulthood, increased mortality is likely related to a combination of residual heart defects, infections, aspiration, or choking, respiratory issues including obstructive and central apnea, and possibly seizures
life span for many individuals can be normal

Question 15

What are the tx recommendations for pts w CHD7 disorder

Answer 15

growth failure: nutrition optimization
obesity: exercises and dietary intervention
poor visual acuity/blindness: corrective lenses
photophobia: tinted glasses or sun hat
hearing impairment/deafness: cochlear implant, tx of SNHL and conductive hearing loss depend on degree of hearing loss
poor balance: adjustments for truncal support while sitting, consideration of myofascial release (can improve posture and flexibility)
choanal atresia/stenosis: airway bypass by tracheostomy or endotracheal intubation, sx correction
esophageal atresia: standard sx repair
cleft palate: sx correction
CHDs, arrhythmias, PTS: tx per cardiologist
standard tx for constipation, cryptorchidism, severe scoliosis, seizure disorder, behavioral issues, hypogonadotropic hypogonadism, hypothyroidism, renal malformation, HTN, recurrent infections

Question 16

What % of PVs are de novo in CHARGE syndrome

Answer 16

almost 100%
decreased function or LOF of CHD7 leads to the clinical manifestations of the disorder

Question 17

How is the dx of Char syndrome established

Answer 17

in a proband w suggestive clinical findings and/or a heterozygous PV in TFAP2B on molecular genetic testing

sequence analysis only

Question 18

What are the clinical features associated w Char syndrome

Answer 18

1. typical facial features (86%): depressed nasal bridge and broad flat nasal tip, widely spaced eyes, downslanted palpebral fissures, mild ptosis, short philtrum, triangular mouth, thickened everted lips
2. patent ductus arteriosus (68%): results in primary HTN if not corrected
3. stereotypic hand anomalies (57%): aplasia or hypoplasia of the middle phalanges of the fifth finger

Question 19

What is the mechanism of dz for Char syndrome

Answer 19

evidence for dominant negative (missense) AND loss of function; loss of function alleles are likely to act through haploinsufficiency

Question 20

What does VACTERL stand for

Answer 20

Vertebral defects
Anal atresia
Cardiac Defects
Tracheo-
Esophageal fistula
Renal anomalies
Limb abnormalities

Question 21

What are the clinical features associated w VACTERL? how is dx established?

Answer 21

dx is established when at least three component features are present:
vertebral defects (60-80%) commonly accompanied by rib anomalies
imperforate anus/anal atresia (55-90%)
cardiac defects (40-80%)
tracheo-esophageal fistula (50-80%) with or without esophageal atresia
renal anomalies (50-80%) including renal agenesis, horseshoe kidney, cystic and/or dysplastic kidneys
limb abnormalities (40-50%) including radial anomalies like thumb aplasia/hypoplasia

Question 22

What is the etiology for VACTERL

Answer 22

sporadic

Question 23

What is the management/tx for VACTERL? What is the prognosis

Answer 23

management @ centers around sx correction of the specific congenital anomalies (typically anal atresia, certain cardiac manifestations, and/or tracheo-esophageal fistula)

prognosis can be relatively good, though some pts will continue to be affected by their congenital malformations throughout life; do NOT tend to have neurocognitive impairment

Question 24

What is hypertrophic cardiomyopathy

Answer 24

typically defined by the presence of unexplained left ventricular hypertrophy (LVH) w a max wall thickness of 15mm in adults or a z score >3 in children
if there is a FH of HCM, or if genetic testing confirms that a relative has inherited the family’s pathogenic sarcomere variant, a max LV wall thickness >13mm supports dx

Question 25

How is the dx of HCM established

Answer 25

most often established w noninvasive cardiac imaging, including echo and/or cardiac MRI
asymmetric septal hypertrophy is the most common pattern, but can also be concentric, or confined to other walls or the LV apex
findings on transthoracic echo: systolic anterior motion of the mitral valve, mid-ventricular obstruction, diastolic dysfunction (LV relaxation, is an early phenotype of HCM rather than a secondary consequence of LVH)

Question 26

When is the onset of HCM? What are the associated clinical features?

Answer 26

LVH and the clinical dx of HCM often become apparent during adolescence around the onset of puberty or during young adulthood but can be earlier (infancy/childhood) or later in life
clinical features are highly variable; can be asymptomatic LVH to arrhythmias (atrial fibrillation, malignant ventricular arrhythmias) to refractory heart failure; manifestations differ even in same family
shortness of breath (w exertion), chest pain, palpitations, orthostasis (BP drops when you stand up), presyncope, and syncope

Question 27

What is the progression of HCM (despite the high variability)

Answer 27

1/3 have detectable intracavitary obstruction at rest, 1/3 can develop outflow tract obstruction w provocation; may be at higher risk for symptom progression and death than those w/out outflow tract obstruction
increased atrial fibrillation (AF) can have significant morbidity due to increased risk of thromboembolism and symptomatic deterioration; prevalence increases w age and duration of dz; overall prevalence is ~20% but is ~60% by 60yo for those dx w HCM by 40yo; individuals w HCM and AF the prevalence of thromboembolic complications has been ~27%
~5-10% of individuals w HCM progress to end-stage dx w impaired systolic function and sometimes left ventricular dilatation and regression of LVH; annual mortality rate is ~11% and cardiac transplant may be required
sudden cardiac death is a relatively rare complication of HCM but may be the first manifestation
whereas death occurs most often in adolescents or young adults, it may occur at any age and the risk persists throughout life

Question 28

What is the lifespan of someone with HCM

Answer 28

mortality rate is ~3x higher, but the mortality rate in younger individuals with HCM, ages 20-29, is as much as 4x higher than expected; sudden death accounts for ~16% of deaths

Question 29

What syndromic conditions have HCM as a feature

Answer 29

Danon dz, Fabry, Friedreich ataxia, hereditary transthyretin amyloidosis, Pompe dz, RASopathies (Noonan, Cardiofasciocutaneous syndrome, Costello, Noon w multiple lentigines)

Question 30

What are the genes involved w nonsyndromic HCM? What are the molecular features

Answer 30

genes w the strongest clinical validity encode different components of the sarcomere
PVs in one of the genes encoding a component of the sarcomere are found in ~50-60% of probands w a FH of HCM and ~20-30% of probands w/out a FH
3-5% of affected individuals have more than one sarcomere gene variant; <1% will have more than 1 PV

MYBPC3 (50%), MYH7 (33%), TNNI3 (5%), TNNT2 (3%)

Question 31

When is genetic testing recommended for HCM

Answer 31

In individuals fulfilling dx criteria for HCM to enable cascade screening of relatives
confirm the dx in individuals w clinical evidence that is suggestive of HCM

purpose is to identify syndromic HCM that could have different tx and/or management and inform risk assessment of relatives of a proband

genetic testing for HCM is best viewed as a family test rather than an individuals since results are most accurately interpreted after integrating genetic and medical test (echo, EKG) results from multiple FMs

Question 32

What testing should be ordered for HCM

Answer 32

comprehensive, multigene panels that also includes del/dup analysis
exome (or genome) sequencing is another possible testing method, though the anticipated incremental yield is low

Question 33

What cascade testing is appropriate for a family w suspected HCM

Answer 33

at-risk FMs should seek clinical eval and be offered genetic testing if a PV has been identified in the family
if the pathogenicity is uncertain, testing other affected FMs as part of a segregation analysis can help in variant interpretation
if there is a VUS, testing of UNAFFECTED family members is not helpful

Question 34

What surveillance is recommended for asymptomatic FMs of a proband w a known HCM PV

Answer 34

those identified as heterozygous should undergo clinical cardiovascular screening by physical exam, EKG, and echo q1-2yrs
those who are not heterozygous are not at increased risk and don’t need surveillance

Question 35

What surveillance is recommended for asymptomatic FMs of a proband w an unknown HCM PV

Answer 35

if onset in affected individual is in childhood, family members should start screening immediately q1-2yrs
if onset in affected individual is in adolescence, family members should start NO LATER THAN PUBERTY q2-3yrs
if onset in affected individual is in adulthood, start screening immediately q3-5yrs

bc penetrance of dx features is age dependent, a single unremarkable eval does not exclude the possibility of future development of HCM

Question 36

How is the clinical dx of DCM established

Answer 36

Both of the following must be present:
1. Left ventricular enlargement: most commonly assessed in adults by either echo or cardiac MRI
2. Systolic dysfunction, a reduction in the myocardial force of contraction: an ejection fraction of <50% is considered systolic dysfunction; can be estimated from a left ventricular angiogram, echo, or MRI

Question 37

What are the clinical features associated w DCM

Answer 37

initially manifests in adults in the 4th-6th decade but can present earlier
Manifestations usually occur late in the dz course w one or more of the following findings:
heart failure: congestion (edema, orthopnea, paroxysmal nocturnal dyspnea) and/or reduced cardiac output (fatigue, dyspnea on exertion)
arrhythmias and/or conduction system dz
thromboembolic dz: stroke or systematic embolus secondary to left ventricular mural thrombus
pregnancy: peripartum or pregnancy-associated cardiomyopathy that occurs during or soon after pregnancy

Question 38

What syndromic conditions have DCM

Answer 38

Barth syndrome, DMD/BMD, Emery-Dreifuss muscular dystrophy, HFE hemochromatosis, Kearns-Sayre syndrome

Question 39

How is the molecular cause of DCM established

Answer 39

should be offered to every individual of any age w nonischemic DCM including those w peripartum or pregnancy associated cardiomyopathy
variants in >30genes have been identified in up to 30-35% of individuals w familial DCM or in simplex cases

cardiomyopathy multigene panel is ordered w ~27% detection rate

Question 40

What is the recommended cardiac surveillance for FMs when a proband has a known PV

Answer 40

molecular genetic testing is recommended
asymptomatic at-risk relatives who do not meet criteria for DCM may represent early DCM when echo results are ambiguous (LV enlargement w normal systolic function, decreased ejection fraction but normal sized left ventricle) and/or echo results are normal but EKG results are abnormal. Screening q1-3yrs

in general, FMs without the DCM related PV identified in the proband are no longer considered to be at increased risk for DCM and thus may be discharged from cardiac surveillance

Question 41

What is the recommended cardiac surveillance for FMs when a proband does not have a known PV

Answer 41

perform cardiac screening on asymptomatic at-risk FMs at intervals based on the individual’s age
if a first degree at-risk relative shows evidence of DCM, a dx of familial DCM is made and the surveillance recommendations should extend to that person’s first degree relatives. Screening via echo, physical exam, and ECG q3-5yrs

Question 42

How is CPVT dx established

Answer 42

In the presence of a structurally normal heart, normal resting EKG, and exercise or emotion induced bidirectional or polymorphic ventricular tachycardia
OR
individuals who have a heterozygous PV in RYR2, CALM1, CALM2, CALM3, CASQ2, or KCNJ1 OR biallelic PVs in CASQ2, TECTRL, TRDN

Question 43

What molecular testing should be ordered for dx of CPVT

Answer 43

multigene panel; RYR2 accounts for 60-70% of PVs

Question 44

What are the clinical features associated with CPVT

Answer 44

Inherited arrhythmogenic dz characterized by cardiac electrical instability exacerbated by acute activation of the adrenergic nervous system
~30% experience at least one cardiac arrest and up to 80% have one or more syncopal spells

main clinical manifestation is episodic syncope occurring during exercise or acute emotion
sudden death may be the first clinical manifestation of the disorder in previously asymptomatic individuals who die suddenly during exercise or while experiencing acute emotions

mean onset (usually first syncopal episode) is between 7-12yo
instances of SIDS have been associated with PVs in RYR2
FH is present in ~30% of probands

Question 45

What are phenotype-genotype correlations seen in CPVT? Penetrance?

Answer 45

Typical phenotype is caused by the presence of PVs in RYR2 (GOF variants), CASQ2
mean penetrance of RYR2 PVs is 83% (Asymptomatic individuals are in the minority)
biallelic CASQ2 PVs have been 100% penetrant

Question 46

What are the recommended txs for CPVT

Answer 46

Adrenergic-dependent triggered activity w beta blockers (nadolol is most effective)
arrhythmia control w flecainide
cardiac arrest, recurrent syncope, or polymorphic/bidirectional VT despite optimal therapy

avoid digitalis since it can favor the onset of cardiac arrhythmias

Question 47

What is the recommended surveillance for those w CPVT

Answer 47

q6-12mo resting EKG, stress test, Holter monitoring, echo and MRI at least q2yrs
limitation of physical activity

Question 48

What is the recommended surveillance for FMs of a proband w CPVT but no PV identified

Answer 48

all first degree relatives of an affected individual should be evaluated w resting EKG, Holter monitoring, echo, and most important, stress testing

Question 49

What is the de novo rate for RYR2-related CPVT

Answer 49

30-40%

Question 50

What is the molecular pathogenesis for CPVT

Answer 50

CALM1, CALM2, CALM3, CASQ2, RYR2, TECRL, and TRDN are all involved in control of intracellular calcium fluxes, sarcoplasmic reticulum calcium release, and the cystolic free Ca concentration

Question 51

What are the clinical features associated w ARVC

Answer 51

heart palpitations, syncope, or even sudden death in adults (although it may less commonly be seen in children, most often are affected in second decade)
Progression:
1. concealed phase: minimal scar formation that goes undetected by cardiac MRI; might experience sustained ventricular arrhythmias, potential risk of sudden cardiac death
2. symptomatic arrhythmias including palpitations, syncope, and presyncope
3. right ventricular failure
4. biventricular pump failure (resembling DCM)

Question 52

What is the pathophysiology of ARVC

Answer 52

affects the right ventricular apex, the base of the right ventricle, and the right ventricle outflow tract
arrythmias in ARVC most frequently arise from the right ventricle and have left bundle branch block morphology; characterized by fibrofatty replacement of the myocardium

evidence that the left ventricle can often become involved as well

Question 53

What is the prognosis of ARVC

Answer 53

survival >72% at 6yrs following dx
cardiac mortality and need for transplant are <5%

prognosis is worse for those w >1 ARVC-related PV, w an increased propensity to arrhythmias and progression to cardiomyopathy

Question 54

What is the prevalence of ARVC

Answer 54

1 in 1,000-1,250

Question 55

How is the clinical dx of ARVC established

Answer 55

rely on a combination of EKG and signal averaged EKGs, imaging studies that include 2D echo, cardiac MRI or right ventricular angiography, presence of arrhythmia documented by telemetric monitoring, genetic testing, and FH

Question 56

How is the molecular dx of ARVC established

Answer 56

PV identified in up to 66% of probands w ARVC; 2-4% have more than 1 PV identified
all are AD w the exception of DSC2 and DSG2 which are associated w AD and AR inheritance

Order a multigene panel that should minimally include the definitive genes and moderate genes

Question 57

Which genes are most commonly associated w ARVC

Answer 57

PKP2 (34-74%)
DSG2 (5-26%)
DSP (2-39%)
DSC2 (1-2%)

Question 58

What is the de novo rate in ARVC

Answer 58

1.4%

Question 59

What screening should family members of an individual w a clinical dx of ARVC whom the genetic cause has not been identified undergo

Answer 59

screening for cardiac involvement is recommended:
medical hx
EKG w consideration for signal-averaged EKG
Holter monitoring
Cardiac MRI
Echo

children under 10 are NOT usually screened, since manifestations of ARVC are not usually seen in children prior to 10yo

Question 60

What screening should a proband w ARVC undergo

Answer 60

EKG annually or more frequently depending on symptoms
Holter monitoring, event monitoring, implantable loop recorder
Exercise stress testing
Cardiac MRI w frequency dependent on symptoms and findings
Echo w frequency depending on symptoms and findings and degree of left ventricular involvement

Question 61

What are the general management recommendations for probands w ARVC

Answer 61

focused on prevention of syncope, cardiac arrest, and sudden death
beta blockers as first line therapy
decrease of ventricular tachycardia burden has been observed after successful catheter ablation
primary tx for ventricular tachycardia is implantable cardioverter-defibrillator placement
heart transplantation is considered when ARVC has progressed to right or left ventricular heart failure

Question 62

What is the pregnancy management for ppl w ARVC

Answer 62

majority tolerate pregnancy well with no additional complications

Question 63

What are the cardiac features associated w LQTS

Answer 63

characterized by QT prolongation and T wave abnormalities on EKG; predisposes individuals to a significant risk of life-threatening arrhythmic events, especially in young individuals

T wave abnormalities (tachyarrhythmias, typically ventricular tachycardia torsade de points) –> usually self-terminating and can result in palpitations, syncope, or dizziness
In some instances, TdP degenerates to ventricular fibrillation and aborted cardiac arrest or sudden death (in 10-15%, is the first sign of the condition)

Question 64

How is the clinical dx of LQTS established

Answer 64

LQTS >3.0 in the absence of a secondary cause for QT prolongation is sufficient for a dx of LQTS (based on how prolonged the QT signal is, Torsade de pointes, heart rate, T wave patterns, clinical hx, family hx, PV identified)

identified a genetic cause in 80% of individuals

Question 65

What are the clinical features associated with LQTS? Age of onset? What are the differences between type 1, type 2, and type 3?

Answer 65

cardiac events can occur from infancy through middle age but are most common from the preteen yrs-20s, with the risk generally diminishing throughout that time period

cardiac events in individuals >40yo are more likely associated w SCN5A-related LQTS

T1 (KCNH2, 30-35%): cardiac trigger is auditory stimuli, emotion, sleep, and exercise
T2 (KCNQ1, 25-30%): cardiac trigger is exercise and emotion
T3 (SCN5A, 5-10%, GOF variants): cardiac trigger is sleep
combined, they account for 90% of PVs that cause LQTS

Question 66

Genotype/phenotype correlations in LQTS

Answer 66

incidence of syncopal events is highest in KCNQ1 and lowest in SCN5A
incidence of sudden cardiac arrest or death is highest in SCN5A
KCNH2 has increased mortality in women >12-13yo, particularly up to 9mo postpartum; common trigger is sudden arousal
KCNQ1 has severely increased mortality in boys 5-15yo, although risk for girls 13-20yo can also be high; most sudden cardiac deaths occur during exercise (swimming) and emotion
SCN5A has increased mortality from childhood throughout adulthood for both genders; QT prolongation is more pronounced during slow heart rate and events usually occur during sleep or rest

Question 67

What puts pts at increased risk for sudden death in LQTS

Answer 67

dependent on hx of syncopal episodes, proband status (being first in the family w a genetic cause established), QTc interval, tx, age, and gender
boys are relatively high risk before adolescence and girls after the onset of adolescence (13-14yo)

Question 68

What is the prevalence of LQTS

Answer 68

1 in 2500

Question 69

What molecular testing should be ordered for suspected LQTS

Answer 69

multigene panel
exon or multiexon dels or dups in KCNH2 or KCNQ1 have been identified in ~3% of individuals w LQTS

Question 70

What tx should be offered for asymptomatic individuals w LQTS

Answer 70

Beta blockers are clinically indicated in all asymptomatic individuals, including those who have a PV on molecular testing w a normal QTc interval
ICD NOT recommended; prophylactic placement can be considered for asymptomatic individuals suspected to be at very high risk (>2PVs); LQTS-related sudden death in a close relative is NOT an indication for ICD in an asymptomatic individual

Question 71

What txs should be offered for symptomatic individuals w LQTS

Answer 71

Beta blockers are the mainstay of therapy for LQTS; daily administration using long-acting agents (nadolol) to increase compliance
ICD recommended in individuals w LQTS resuscitated from a cardiac arrest bc of high recurrence
Left cardiac sympathetic denervation (LCSD) is recommended for high risk individuals w LQTS in whom ICD therapy is refused or contraindicated and/or in whom beta blockers are either not effective, not tolerated, not accepted, or contraindicated
sodium channel blockers for individuals w selected PVs in SCN5A and a QTc interval >500ms

Question 72

What is the pregnancy management for someone w LQTS

Answer 72

Postpartum period is associated w increased risk for a cardiac event, especially in individuals w KCNH2 related LQTS
beta blocker tx was associated w a reduction of events in the nine mo after delivery

Question 73

What surveillance is recommended for FMs of a proband w LQTS

Answer 73

Undergo QTc analysis on resting EKG and, in those w normal QTc on resting EKG, QTc analysis on exercise EKG

absence of LQTS related findings on EKG eval cannot be used to assess genetic status

Question 74

How is the clinical dx of Brugada syndrome established

Answer 74

proband w Type 1 EKG findings AND at least one of the following:
documented ventricular fibrillation
self-terminating polymorphic ventricular tachycardia
FH of sudden cardiac death
coved-type EKGs in FMs
electrophysiologic inducibility
syncope or nocturnal agonal respiration

in ~75% dx is established based on clinical hx and EKG results

Question 75

What testing is ordered for the dx of Brugada syndrome

Answer 75

serial single gene testing starting w SCN5A (sequence then del dup)
or a multigene panel

Question 76

What are the clinical features associated w Brugada syndrome

Answer 76

manifests primarily during adulthood, w a mean age of sudden death of ~40yo
prevalent among males although both sexes are at a high risk for ventricular arrhythmias and sudden death
most common presentation is that of a person in the 5th decade w malignant arrhythmias and a previous hx of syncopal episodes
can occur in conjunction w conduction dz
may also include sudden infant death and sudden unexpected nocturnal death syndrome

Question 77

What are the precipitating factors of Brugada syndrome

Answer 77

fever, cocaine use, electrolyte disturbances, and use of class I antiarrhythmic medications and a number of other noncardiac meds

Question 78

What is the pathophysiology of Brugada syndrome

Answer 78

caused by a sodium channelopathy, associated w age-related progressive conduction abnormalities

Question 79

What is the penetrance of SCN5A in Brugada syndrome

Answer 79

among individuals w an SCN5A PV ~20-30% have an EKG dx of Brugada syndrome
~80% manifest the characteristic EKG changes when challenged w a sodium channel blocker

Brugada syndrome is responsible for 4-12% of unexpected sudden deaths and for up to 20% of all sudden death in individuals w an apparently normal heart

Question 80

What are the tx recommendations of Brugada syndrome

Answer 80

implantable cardioverter defibrillators (ICDs) are the only therapy currently known to be effective
electrical storms respond well to infusion of isoproterenol, the first line of therapy before other antiarrhythmics

Question 81

What is the surveillance for someone w a FH of Brugada syndrome

Answer 81

undergo EKG monitoring q1-2yrs beginning at birth
EKG changes have low sensitivity in establishing the diagnoses

Question 82

What is the pregnancy management for pts w Brugada syndrome

Answer 82

hormonal changes during pregnancy can precipitate arrhythmic events in women w Brugada syndrome; low dose isoproterenol followed by oral quinidine

Question 83

What is the de novo rate for Brugada syndrome

Answer 83

~1%

Question 84

What is the molecular pathogenesis for Brugada syndrome

Answer 84

SCN5A encodes the alpha subunit of the cardiac sodium channel and is responsible for the initial upstroke of the action potential in the EKG

Question 85

How is the dx of Jervell and Lange-Nielsen syndrome established

Answer 85

Established in a proband w suggestive findings (profound congenital SNHL and long QTc interval most often elicited by emotion or exercise) and identification of biallelic PVs in either KCNQ1 or KCNE1

Question 86

What testing should be ordered for dx of Jervell and Lange-Nielsen

Answer 86

serial single gene testing starting w sequence analysis of KCNQ1(~90%) w del/dup; KCNE1 (~10%) next if only 1 found or no PVs found
there is also Norwegian founder variants that need to be included in order to be picked up
multigene panel can also be ordered

Question 87

What are the clinical features associated w Jervell and Lange-Nielsen

Answer 87

classic presentation: deaf child who experiences syncopal episodes during periods of stress, exercise, or fright

all individuals have profound bilateral congenital sensorineural deafness
have a QTc interval >500ms indicating increased time for ventricular depolarization and repolarization; may culminate in syncope or sudden death
QTc appears to be associated w increased risk for death in infancy (SIDS); 50% have cardiac events before 3yo, with emotion and exercise being the primary triggers; more than half of untx children w JLNS die before 15yo

individuals w KCNQ1 related JLNS have an increased incidence of iron deficiency anemia and hypergastrinemia

females are at lower risk for cardiac arrest/sudden death; vestibular dysfunction may also present

Question 88

What are the recommended txs for Jervell and Lange-Nielsen

Answer 88

Hearing loss tx w cochlear implant (Although it is safe, special precautions are necessary during anesthesia bc of the increased risk for cardiac arrhythmia
cardiac issues: main goal is to prevent syncope, cardiac arrest, and sudden death; efficacy of beta blocker tx is partial: 51% have cardiac events and 27% have sudden death or cardiac arrest

cardiac events occur frequently despite beta blockade. 86% tx exclusively w beta blockers experienced a cardiac event

ICD should be considered for individuals w a hx of cardiac arrest or failure to respond to other treatments: QTc interval >550ms, syncope before 5yo, or male sex age >20yo w KCNQ1 PV

tx of iron deficiency anemia should follow standard guidelines

Question 89

How should relatives be evaluated if the PVs in the family are not known for Jervell and Lange-Nielsen

Answer 89

EKG testing to evaluate for QTc prolongation
standard NBS programs are sufficient to identify hearing loss in children
For sibs of a proband:
audiology exam
electrophysiologic eval for evidence of LQTS
molecular genetic testing if PVs are known
comprehensive electrocardiographic testing for evidence of QTc prolongation

Question 90

What % of PVs in Jervell and Lange-Nielsen are also associated w LQTS

Answer 90

67%

Question 91

What is the molecular pathogenesis seen in Jervell and Lange-Nielsen

Answer 91

caused by an aberration in a potassium channel found in the inner ear and the heart
for KNCQ1: Both del and dup of one or more exons are known to cause LQTS; Recessive variants may exhibit a dominant negative effect
for KCNE1: consists of 3 exons; four PVs have been associated w JLNS, all of which are missense. Majority are associated w LQTS

Question 92

How is the dx of Timothy syndrome established

Answer 92

heterozygous PV in CACNA1C via sequence analysis then del dup
can also do a cardiac arrhythmia or epilepsy multigene panel

Question 93

What are the clinical features associated w Timothy syndrome

Answer 93

very high mortality w only few individuals who reached reproductive age
combination of prolonged QT interval, autism, and CHD w syndactyly of the fingers and toes
dx is made within the first few days of life based on the markedly prolonged rate-corrected QT interval in an infant w bradycardia and 2:1 atrioventricular block
cutaneous syndactyly of the fingers/toes which may be unilateral or bilateral
craniofacial features: low set ears, depressed nasal bridge, premaxillary underdevelopment, baldness at birth and for the first 2yrs of life, followed by thin scalp hair; small, widely spaced teeth and poor dental enamel w severe caries

developmental delays, autism, epilepsy, frequent infections, intermittent hypoglycemia

Question 94

What is the pathogenesis of Timothy syndrome

Answer 94

associated w calcium channel function, at risk for cardiac arrhythmia of a specific type; GOF variants are associated w Timothy syndrome (AD)
p.Gly406Arg PV in exon 8A causes the classic phenotype

Question 95

What cardiac manifestations are associated w Timothy syndrome

Answer 95

long QT interval are observed in nearly all w GOF PVs
bradycardia w markedly increased QT prolongation
other electrocardiographic manifestations (2:1 AV block, macroscopic T wave alternans)
Tachyarrhythmias/sudden death: more often polymorphic ventricular tachycardia and torsade de pointes that may degenerate and leading to cardiac arrest
Cardiovascular malformations: PDA, patent foramen ovale, VSD, tetralogy of Fallot, or HCM

Question 96

What is the life span for someone w Timothy syndrome

Answer 96

typical phenotype has high mortality and most individuals w this phenotype do not reach reproductive age despite appropriate use of ICD and other therapies of non-cardiac conditions

Question 97

What tx is recommended for ppl w Timothy syndrome

Answer 97

standard care for cardiovascular malformations, sx release of syndactyly, DD/ID, epilepsy, and hypoglycemia
beta blockers, pacemaker placement for bradycardia, ICD fpr tachyarrhythmias

Question 98

What surveillance is recommended for pts w Timothy syndrome

Answer 98

f/u cardiac eval including EKG/Holter, and echo q6-12mo
evals of ppl w pacemaker/ICD q12mo
neuro eval q6-12mo

Question 99

How is the clinical dx of Andersen Tawil established

Answer 99

presence of two of the following three criteria:
1. Periodic paralysis
2. Symptomatic cardiac arrhythmias or electrocardiographic evidence of enlarged U-waves, ventricular ectopy, or a prolonged QTc or QUc interval
3. Characteristic facies, dental anomalies, small hands and feet, AND at least two of the following:
Low-set ears
Widely spaced eyes
Small mandible
Fifth-digit clinodactyly
Syndactyly of toes 2 and 3

OR one of the above three criteria AND at least one FM who meets 2 of the three criteria

Question 100

What supportive findings are consistent w the dx of Andersen Tawil syndrome

Answer 100

elevated/normal/low serum potassium concentration
normal routine nerve conduction electrophysiology between episodes
ECG w prominent U waves, prolonged QU intervals, premature ventricular contractions, polymorphic ventricular tachycardia, and bidirectional ventricular tachycardia

Question 101

How is the molecular dx of Andersen Tawil syndrome established? Testing to be ordered?

Answer 101

heterozygous PV in KCNJ2
serial single gene testing: sequence analysis of KCNJ2 then del/dup; if nothing identified, sequence analysis of KCNJ5

Question 102

What is the classic triad associated w Andersen Tawil syndrome

Answer 102

1. periodic paralysis (episodic flaccid muscle weakness)
2. cardiac abnormalities
3. characteristic facial appearance
   present in 60-80% of individuals w KCNJ2 PV

Question 103

Describe the clinical features associated w Andersen Tawil syndrome

Answer 103

affected individuals present initially w periodic paralysis or cardiac symptoms in the first or second decade
weakness occurs spontaneously; mild permanent weakness is common
ventricular arrhythmias may manifest (most commonly) as palpitations; less common syncope, cardiac arrest or sudden death; prominent U waves, prolonged QU intervals that sets it apart from LQTS
DCM is a secondary phenotype as a consequence of chronic tachycardia
physical features include: low set ears, widely spaced eyes, small mandible, fifth-finger clinodactyly, second and third toe syndactyly, short stature, broad nasal root, scoliosis, triangular face, persistent primary dentition, multiple missing teeth, dental crowding, joint laxity, mild learning difficulties, afebrile seizures

clinical manifestations tend to be more severe in females

Question 104

What are the tx recommendations for Andersen Tawil syndrome

Answer 104

management of attacks depends on associated potassium level: low–> give oral potassium; high–> usually resolve in an hr but can give carbs and do mild exercise to facilitate the process

Question 105

What surveillance should someone w Andersen Tawil syndrome undergo

Answer 105

for asymptomatic ppl w KCNJ2 PV, annual screening including EKG and 24hr Holter monitor followed by referral to cardiologist if abnormalities are identified

Question 106

What is the de novo rate for Andersen Tawil syndrome? What should parents undergo if there is a suspected de novo case?

Answer 106

50%
detailed neuro and cardio eval, 24hr Holter monitoring, EKG, and molecular testing for KCNJ2

Question 107

What is the clinical dx criteria for Marfan syndrome called? Describe the calculation of the systemic score

Answer 107

Ghent criteria; equal to or >7 is a dx
Scored as follows:
Wrist AND thumb sign 3
Wrist OR thumb sign 1
Pectus carinatum 2
Pectus excavatum 1
Hindfoot deformity 2
Pes planus 1
Pneumothorax 2
Dural ectasia 2
Protrusio acetabulae 2
Reduced upper segment to lower segment AND increased arm span to height ratio 1
scoliosis/kyphosis 1
reduced elbow extension 1
3 of 5 facial features 1
skin striae 1
myopia 1
mitral valve prolapse 1

Question 108

How is the molecular dx of Marfan syndrome established

Answer 108

established in a proband w a PV in FBN1 known to be associated w Marfan syndrome and EITHER of the following:
1. aortic root enlargement
2. ectopia lentis

if ghent score is <7 and/or aortic root measurment is borderline w/out FBN1 PV, use “nonspecific connective tissue disorder” until f/u showing aortic root dilatation

Question 109

What molecular dx methods should be ordered for Marfan syndrome

Answer 109

single gene testing w sequence analysis of FBN1 followed by del/dup
Marfan/Loeys-Dietz, familial thoracic aortic aneurysms and dissections multigene panel

Question 110

What are the body systems affected by Marfan syndrome? Describe the clinical features

Answer 110

ocular, skeletal, cardiovascular systems w a high degree of variability; clinical manifestations run true within families, suggesting that FBN1 PV is the predominant determinant of phenotype

eyes
myopia (50%) often progressing rapidly during childhood
ectopia lentis is a hallmark feature seen in 60%; generally evident in childhood but can present later in life
increased risk for retinal detachment, glaucoma, early cataract formation

skeletal
excessive linear growth of the long bones and joint laxity; tend to progress during periods of rapid growth, not necessarily tall by population standards but are taller than predicted for family
pes cavus, dolichostenomelia, increase in arm span to height ratio and decrease in upper to lower segments; overgrowth of the ribs –> pectus carinatum or pectus excavatum; scoliosis
combination of bone overgrowth and joint laxity leads to thumb and wrist signs
pes planus, hindfoot deformity (inward rotation of the ankle)
protrusio acetabuli

craniofacial features
enophthalmos, long and narrow face, malar hypoplasia, micrognathia, retrognathia, highly arched and narrow palate w tooth crowding

Cardio
dilatation of the aorta w predisposition for aortic tear and rupture
aortic dissection rare in childhood; in adults, significant risk for aortic dissection or rupture when the max dimension reaches ~5/ocm
Mitral valve prolapse w or w/out regurgitation
tricuspid valve prolapse w or w/out regurgitation
enlargement of the proximal pulmonary artery

other
stretching of the Dural sac in the lumbosacral region can lead to bone erosion and nerve entrapment
hernias and skin stretch marks
lung bullae which can predispose to spontaneous pneumothorax

Question 111

What is the leading cause of cardiovascular morbidity and mortality in Marfan syndrome

Answer 111

mitral valve prolapse w congestive heart failure; is also the leading indication for cardiovascular sx in young children w severe Marfan syndrome

Question 112

What is the prognosis for a pt w Marfan syndrome

Answer 112

w proper management, life expectancy is that of the general population

Question 113

What are genotype phenotype correlations in Marfan syndrome

Answer 113

as a general rule, a variant that causes the in frame loss or gain of central coding sequence through dels, insertions, or splicing errors is associated w more severe dz
ectopia lentis is less common in individuals w haploinsufficiency of FBN1

Question 114

What are the tx recommendations for a pt w Marfan syndrome

Answer 114

standard tx for refractive errors (myopia), glaucoma/cataracts/retinal detachment, pectus deformity (generally do not need sx), hernias, and pneumothoraxes

lens dislocation may require sx removal of the lens
bracing/sx stabilization of spine for scoliosis that is severe/progressive
protrusio acetabulae (hip dislocation) may need PT, analgesics, or anti inflammatory meds
pes planus may need arch support although some find them irritating
dental crowding may necessitate a palate expander
sx repair of aortic root dilatation should be considered in infancy when rate of diameter approaches 0.5-1cm per yr or there is progressive and severe aortic regurgitation
severe valve dysfunction, congestive heart failure, arrhythmias require immediate attention of cardiothoracic sx

meds that reduce hemodynamic stress on the aortic wall, like beta blockers and angiotensin receptor blokcers are routinely prescribed

Question 115

What surveillance should pts w Marfan syndrome undergo

Answer 115

measurement of length, height, and weight at each visit
ophthalmologic exam at least annually
musculoskeletal clinical assessment at each visit
dental eval annually
cardio: echo annually, more often if aortic root is >4.5cm and dilatation is >0.3 cm/yr; CT/MRA of the entire aorta at least annually in anyone w a hx or aortic root replacement or dissection

Question 116

What is the pregnancy management for someone w Marfan syndrome? What are they at risk for?

Answer 116

risk of more rapid dilation of the aorta or aortic dissection during pregnancy, delivery, or in the immediate postpartum period; especially impt to those who start pregnancy w an aortic dilatation of >4.0cm

should continue use of beta blockers but discontinue ARBs
cardio imaging w echo q2-3mo during pregnancy, should continue postpartum due to increased risk of aortic dissection

Question 117

What is the de novo rate for Marfan syndrome

Answer 117

25%

Question 118

What is the molecular pathogenesis for Marfan syndrome

Answer 118

fibrillin-1 is an extracellular matrix protein that contributes to large structures called microfibrils that are found in elastic and non-elastic tissues
abnormal forms of fibrillin 1 are believed to have dominant negative activity
haploinsufficiency has also been implicated in its pathogenesis

Question 119

What is the name of the criteria for joint hypermobility

Answer 119

Beighton criteria; > or = 5 meets dx criteria
one point for each of the following:
1. passive dorsiflexion of each fifth finger >90 degrees
2. passive apposition of each thumb to the flexor surface of the forearm
3. hyperextension of each elbow >10 degrees
4. hyperextension of each knee >10 degrees
5. ability to place the palms flat on the floor w the knees fully extended

Question 120

How is the dx of classic EDS established

Answer 120

established in a proband w suggestive findings and a heterozygous PV in one of the genes

no consensus clinical criteria; dx requires molecular testing

Question 121

What molecular testing should be ordered for classic EDS

Answer 121

multigene targeted testing: sequence analysis of COL5A1 and COL5A2 (more severe) performed first then del dup; then targeted testing of COL1A1 PV p.934C>T should be done next if no PV is identified

Question 122

What alternate testing could be ordered if no PV is identified in a pt w classic EDS

Answer 122

COL5A1 null allele test: if a PV cannot be identified on molecular testing, a type V collagen abnormality can sometimes be demonstrated if the proband is heterozygous for a polymorphic marker in COL5A1; Copy DNA is analyzed from fibroblasts to identify the presence of one or both markers; if one marker is not expressed, that allele is assumed to be nonfunctional (not widely available)

Transmission electron microscopy: TEM findings of collagen flowers on skin bx can support the dx, but do not confirm it

Question 123

What are the clinical features seen in classic EDS

Answer 123

characterized by skin hyperextensibility, abnormal wound healing, and generalized joint hypermobility

skin
hyperextensible, can easily extend and snap back after release; soft, velvety, or doughy to the touch; fragile, manifested by splitting of the dermis following relatively minor trauma; poor wound healing (cigarette paper like, also referred to as atrophic and/or hemosiderotic scars)
molluscoid psuedotumors; subcutaneous spheroids; piezogenic papules; acrocyanosis (painless constriction or narrowing of the small blood vessels in the skin); chilblains
tissue fragility in multiple organs: cervical insufficiency during pregnancy, inguinal and umbilical hernia, hiatal and incisional hernia, recurrent rectal prolapse in early childhood; dislocations/subluxations of large and small joints, chronic joint and limb pain

other
joint instability, foot deformities (congenital clubfoot, pes planus, temporomandibular joint dysfunction), muscular hypotonia, easy bruising w a tendency toward prolonged bleeding in spite of normal coagulation status; shortened or bulbous roots that lead to loosening of the teeth

cardio
Mitral valve prolapse may occur, tends to be of little clinical consequence; aortic root dilatation in young individuals and rarely progresses; at risk for spontaneous rupture of large arteries

Question 124

What is the recommendation for someone w classic EDS that becomes pregnant? What are the risks that are involved?

Answer 124

ascorbic acid (vitamin C) may reduce easy bruising; physiotherapist referral should be made to address instability and pain; monitoring for IUGR and cervical insufficiency through cervical length screening; monitor for preterm labor during the third trimester; prophylactic desmopressin and tranexamic acid along w postpartum oxytocin should be considered due to increased risk for postpartum hemorrhage

premature rupture of the membrane and prematurity are 2x as common; breech presentation is more frequent is baby is affected; IUGR may occur; perineal tearing, postpartum hemorrhage, pelvic prolapse, and incontinence following delivery

Question 125

What are the surveillance recommendations for pts w classic EDS

Answer 125

assess for skin fragility, joint instability at each visit or as needed
neuro eval for hypotonia and motor development at each visit for infants and children
assess for easy bruising and clotting factors at each visit
echo only for those w abnormal results annually

Question 126

What is the de novo rate for classic EDS

Answer 126

50%
classic EDS is variable and cannot be predicted based on FH or the presence of a PV identified on prenatal testing

Question 127

What is the molecular pathogenesis for classic EDS

Answer 127

type I collagen is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis, and tendon
“functional” haploinsufficiency of type V collagen, caused either by loss of expression of one COL5A1 allele, inefficient trafficking of mutated protein through the endoplasmic reticulum, or impaired incorporation of mutated alpha chains into type V collagen heterotrimers

Can also be dominant negative effect

Question 128

Generally, what are the three criteria that need to be met for a clinical dx of hypermobile EDS

Answer 128

1. Generalized joint hypermobility w a Beighton score of > or = 5 for adults, >= 4 for those >50yo
2. Evidence of 2 of the following: systemic manifestations of a more generalized connective tissue disorder, FH and musculoskeletal complications
3. Exclusion of alternative diagnoses

Question 129

Describe the second piece of criterion needed to make a dx of hypermobile EDS

Answer 129

AT LEAST 2 OF FEATURES A, B, and C MUST BE PRESENT
Feature A: 5 or >
unusually soft or velvety skin, mild skin hyperextensibility, unexplained striae on the back, groin, thighs, breast, and/or abdomen; bilateral piezogenic papules of the heel, recurrent or multiple abdominal hernias (hiatal hernia does not count toward this feature), atrophic scarring, pelvic floor, rectal, and/or uterine prolapse; dental crowding and high or narrow arched palate, arachnodactyly, arm span to height ratio of >1.05, mitral valve prolapse
Feature B:
+ FH w at least one first degree relative independently meeting the current dx criteria
Feature C: at least 1
musculoskeletal pain in 2 or > limbs, recurring daily for at least 3mo; chronic widespread pain for at least 3mo; recurrent joint dislocations or frank joint instability in the absence of trauma

Question 130

Describe the third piece of criterion needed to make a dx of hypermobile EDS

Answer 130

ALL must be met:
absence of unusual skin, ocular, periodontal, vascular, or visceral organ tissue fragility or skeletal dysplasia

exclusion of alternative dx associated w joint hypermobility

features must be due to hypermobile EDS and NOT a co-existing rheumatologic disorder (if one exists)

Question 131

What are the clinical features associated with hypermobile EDS

Answer 131

generalized joint hypermobility, joint instability, pain, soft hyperextensible skin w atrophic scars and easy bruising, dental crowding, abdominal hernias, pelvic organ prolapse, marfanoid habitus, mitral valve prolapse, aortic root dilatation
subluxations, dislocations, soft tissue injury which may occur spontaneously or with minimal trauma; degenerative joint and chronic soft tissue disorders
chronic pain and fatigue, swallow and phonation disorders, functional bowel disorders, cardiovascular autonomic dysfunction, migraine, entrapment and peripheral neuropathies and dystonia, urogynecologic disorders, anxiety disorders, and inflammation from mast cell activation disorders
mitral valve prolapse, aortic root dilatation typically of a mild degree w no increased risk of cardiac complications

joint hypermobility/laxity: females tend to have more joint laxity; increases the risk for: acute joint/soft tissue injury, chronic joint/soft tissue injury
pain: chronic pain that can be physically and psychosocially disabling, fatigue, sleep disturbance, headaches, muscular/myofascial pain, neuropathic pain, pain from tissue damage, visceral pain from the GI and urogynecologic tissues, osteoarthritic pain
skin: soft and mildly hyperextensible, piezogenic papules, atypical stretchmarks, atrophic scars, easy bruising, spontaneous bruising
hematologic: mildly prolonged bleeding, epistaxis, bleeding from the gums, menorrhagia, abnormalities of von Willebrand factor and platelet function
GI: functional disorders including GERD, gastritis, IBS, abdominal wall herniation may be present
cardio: autonomic dysfunction (Atypical chest pain, palpitations at rest or on exertion, orthostatic intolerance w syncope or w/out), mitral valve prolapse (7%), aortic root dilatation (15%)
oral/dental: high, narrow palate and dental crowding; variable laryngeal and upper airway inflammation, dysphagia, and dysphonia
ocular: xerophthalmia, high myopia, increased lens curvature, eyelid laxity, minor lens opacities
neuro: headaches, intracranial HTN, intracranial hypotension, Chiari I malformation, craniocervical instability, ASD/ADHD
primary immune deficiencies such as complement and immunoglobulin deficiencies
gynecologic: urinary incontinence, fecal incontinence, pelvic organ prolapse, rectal prolapse, pelvic pain, sexual dysfunction in 25-75%

Question 132

What txs are available for pts w hypermobile EDS

Answer 132

musculoskeletal: improved joint stability w exercises to increase muscle strength and reduce muscle tension, braces and splints, OT/PT
pain: PT/OT, dry needling, behavioral therapies, complimentary therapies best for pain management; NSAIDs, acetaminophen, and opioids are most beneficial for pts
hematologic: platelet disorders may respond to tranexamic or mefenamic acid; for severe bleeding or operative prophylaxis, desmopressin acetate
GI: gastritis/GERD may require intensive therapy w proton pump inhibitor; upper endoscopy for resistant symptoms; tricyclic antidepressants for those w neuropathic pain
cardio: standard for hypotension; significant aortic root dilatation and abdominal and pelvic vascular compression syndromes, require referral to a specialist
oral/ENT: standard tx for periodontal dz; TMJ dysfunction- intraoral devices/retainers
urogynecologic: use of antifibrinolytics for pain and bleeding given their platelet effect

Question 133

What specialists should someone w hypermobile EDS see

Answer 133

musculoskeletal
heme
GI
cardio
dentist
ENT/pulm
ocular
neuro
rheumatologist/autoimmune assessment
neuro
urogynecologic

Question 134

What is the recommended pregnancy management for someone w hypermobile EDS

Answer 134

should include preconception assessment, antenatal eval, intrapartum planning, and postpartum care
musculoskeletal complications: pain and joint instability may arise from the first time or worsen during pregnancy

higher incidence of preeclampsia, eclampsia, preterm rupture of membranes, preterm birth, antepartum hemorrhage, postpartum hemorrhage, hyperemesis gravidarum, shoulder dystocia, caesarian would infection, postpartum psychosis, etc.

those w known aortic root dilatation should have echo in each trimester
echo is NOT needed if aortic root is normal prior to pregnancy

Question 135

How is the dx of vascular EDS established

Answer 135

identification of heterozygous PV in COL3A1 on sequence analysis then del dup
abnormalities in synthesis and mobility of type III collagen chains on biochemical analysis of type III procollagen from cultured fibroblasts when vascular EDS is suspected by molecular genetic testing does not identify a COL3A1 PV; now almost exclusively used to characterize the outcome of splice site alterations identified by DNA sequence analysis

Question 136

What are the clinical features associated w vascular EDS in children

Answer 136

majority are dx before 18 bc of a +FH
four minor dx features- distal joint hypermobility, easy bruising, thin skin, and clubfeet- are most often present in those without major complications
death that occurs in the first 2 decades of life almost always result from spontaneous artery rupture or dissection (artery rupture is responsible for all deaths in young males, death before 20yo was seen in a 3:1 ratio of males to females

Question 137

What are the clinical features associated w vascular EDS in adults

Answer 137

vascular rupture and GI perforation or organ rupture are the presenting signs in 70%; these complications are dramatic and often unexpected, presenting as sudden death, stroke and its neuro sequelae, acute abdomen, retroperitoneal bleeding, uterine rupture at delivery, and/or shock

cardio: rupture, aneurysm, and/or dissection of major and minor arteries; sites of arterial rupture are the thorax and abdomen (66%), head and neck (17%), and extremities (17%); unexplained acute pain warrants immediate medical attention; chest pain or symptoms of “heart attack” were described in 80%, later identified to have experienced a coronary artery dissection; venous varicosities also occur

GI: perforation of the GI tract occurs in ~15% though seldom in individuals w null variants; most GI perforations occur in the sigmoid colon; bowel rupture is rarely lethal; individuals who survive a first complication may experience recurrent rupture; recurrent perforation may lead to colonic resection

pulmonary: spontaneous and/or recurrent pneumothoraxes may be the first significant presenting feature of vascular EDS. hemoptysis can be severe and recurrent, even life threatening
ocular: keratoconus; can have sudden onset ocular symptoms w blurred vision, diplopia, ocular pain, proptosis, almost always requires immediate intervention to save vision

Question 138

What is the molecular cause of hypermobile EDS (type III EDS)

Answer 138

there isn’t one that has been identified

Question 139

What tx recommendations are available for pts w vascular EDS

Answer 139

affected individuals should seek immediate medical attention for sudden, unexplained pain
sx intervention may be lifesaving in the face of bowel rupture, arterial rupture, or organ rupture (some physicians and affected individuals consider total colectomy as prophylactic measure to avoid recurrent bowel complications and the need for repeat sx

Question 140

What surveillance is recommended for pts w vascular EDS

Answer 140

noninvasive imaging such as u/s exam, MRA, or CT angiogram
bc arterial tear/dissection may result at the site of entry of the catheter and at sites of high-pressure injection, conventional angiograms are NOT recommended

screening q18mo

routine colonoscopies and elective sxs are advised againt

Question 141

What pregnancy management is recommended for pts w vascular EDS

Answer 141

pregnancy has been actively discouraged for women w vascular EDS bc of high reported risks of mortality
~1/2 of women have no complications, 1/2 have prematurity, and uterine, cervical, and vaginal tears that can contribute to morbidity

Question 142

What is the de novo rate for vascular EDS

Answer 142

50%

Question 143

What prenatal biochemical testing is available for vascular EDS

Answer 143

analysis of cultured CVS cells can be used as an alternative to molecular testing. Biochemical testing for prenatal dx of vascular EDS should be performed only if the molecular etiology cannot be identified

Question 144

What is the pathogenesis of vascular EDS

Answer 144

PVs in COL3A1 typically result in a structural alteration of type III collagen that leads to intracellular storage and impaired secretion of collagen chains
production of 1/2 the normal amount of type III procollagen occurs in a minority of individuals

Question 145

What features are suggestive of a dx of familial hypercholesterolemia

Answer 145

extreme hypercholesterolemia
hx of premature coronary artery disease (before 55yo)
physical exam findings: xanthomas, xanthelasmas (yellowish, waxy deposits that can occur around the eyelids), corneal arcus (white, gray, or blue opaque ring in the cornea)
FH of: familial hypercholesterolemia, elevated LDL-C, premature CAD, Xanthomas/xanthelasmas

Question 146

How is the molecular dx of familial hypercholesterolemia established

Answer 146

heterozygous PV in LDLR, APOB, GOF in PCSK9
Biallelic LOF PVs in APOB, LDLR, LDLRAP1 and GOF PVs in PCSK9
order a small multigene panel or a broader dyslipidemia panel

Question 147

What are the clinical features associated w familial hypercholesterolemia

Answer 147

elevated LDL-C (unable to be lowered by diet alone), atherosclerotic plaque deposition at an early age and worsening over time starting soon after birth, increased risk for angina
myocardial infarction, peripheral artery dz, potentially have stroke
22 fold increased risk for coronary artery dz
untx men are at 50% risk for a fatal or nonfatal coronary event by 50yo; untx women are at 30% risk by 60yo
1 in 10 w a hx of early onset myocardial infarction have FH
xanthomas on the elbows, hands, feet, and knees in 30-50%; interdigital xanthomas occur in those with biallelic PVs in APOB, LDLR, PCSK9
xanthelasmas; corneal arcus caused by abnormal deposition of lipids in the cornea which does not resolve w tx

those w homozygous PVs present w a more severe phenotype that varies by affected gene and residual enzyme function

Question 148

What tx recommendations have been established for adults w familial hypercholesterolemia

Answer 148

regular physical activity, healthy diet, weight control, statin therapy
additional tx is LDL-C levels are not controlled: eztimibe, bile acid sequestrants, PCSK9 inhibitors
more aggressive tx necessary in those w clinically evident CAD, DM or metabolic syndrome, FH of CAD, current smoking, high lipoprotein
Cardiovascular dz: consider low dose aspirin, smoking cessation, tx for DM, tx of HTN

Question 149

What tx recommendations have been established for children w familial hypercholesterolemia

Answer 149

regular diet and exercise
statin as first line agent
consider additional lipid lowering therapy if target LDL-C is not achieved w lifestyle modification
tx for HTN/DM if present

Question 150

What surveillance is recommended for pts w familial hypercholesterolemia

Answer 150

in those w severe FH: echo, CT, angiogram, and cardiac catheterization
measurement of lipid levels @2yo w varying interval depending on status

Question 151

What pregnancy management is recommended for pts w familial hypercholesterolemia

Answer 151

statins are contraindicated in pregnancy bc of concerns for teratogenicity
bile acid binding resins are generally considered safe
use of other drugs has not been well studied

Question 152

How is the dx of ARPKD established

Answer 152

biallelic PVs in PKHD1
single gene testing followed by del/dup analysis is NOT useful and NOT recommended
PKD or KD multigene panel

Question 153

Describe the perinatal/infantile presentation of ARPKD

Answer 153

pulmonary: pulmonary hypoplasia, oligo or anhydramnios is a major cause of morbidity/mortality, hypoventilation and respiratory distress, persistent pulm HTN

kidney: large bilateral flank masses are typically present on physical exam; polyuria, polydipsia, overt acute kidney injury or kidney failure may be seen in the first weeks of life; function is often impaired; kidney function at the end of the first yr of life is more severely impaired in individuals w the largest kidneys; more than 50% of affected individuals progress to kidney failure requiring KRT in the first two decades of life; UTIs are common

hepatobiliary involvement: hepatic fibrosis invariably present at birth
other: premature birth is common, feeding difficulties may result from mechanical compression of the stomach

Question 154

Describe the childhood/young adulthood presentation of ARPKD

Answer 154

kidney: ranges from enlarged kidneys w multiple macrocysts, increased echogenicity to only mild functional and structural kidney dz in individuals w liver-predominant phenotypes; larger kidneys may be associated w more rapid progression to kidney failure; more than 50% progress to kidney failure requiring KRT in the first two decades of life

hepatobiliary involvement: progressive portal HTN, GI bleeding, splenomegaly, Caroli dz: dilatation of the intrahepatic bile ducts and dilatation of the common bile duct in more than 60%

other: cholangiocarcinoma in adulthood but does not seem to be a major issue during childhood

Question 155

What is the prognosis for pts w ARPKD

Answer 155

~20-30% of affected infants die in the neonatal period or within the first yr of life, primarily of respiratory insufficiency or superimposed pulmonary infections
~50% of affected individuals progress to kidney failure during the first two decades of life
a significant number of individuals w ARPKD who require KTx also have significant hepatobiliary dz and progressive portal HTN; deaths were attributable to cholangitis and/or sepsis

Question 156

What genotype/phenotype correlations exist in pts w ARPKD

Answer 156

biallelic truncating variants: severe phenotypes; associated w poorer kidney and liver outcomes w early/perinatal demise in most persons
biallelic missense variants vs missense/null variants: mild to moderate phenotypes in persons w at least 1 missense variant

Question 157

What are the perinatal/infantile tx recommendations for ARPKD

Answer 157

pulmonary: non-invasive and/or respiratory support; a very cautious approach to bilateral nephrectomies, especially in the first months of life during which maturation process of autonomic cardiovascular control occur, is recommended

kidney: dialysis and kidney transplantation; not the leading cause of neonatal demise; nutritional support and may need to supplement w growth hormone

Question 158

What are the childhood/young adulthood tx recommendations for ARPKD

Answer 158

kidney: KTx is the tx of choice for children with kidney failure; peritoneal dialysis
hepatobiliary dz: in severe instances of intractable portal HTN or severe dual renal and hepatobiliary dz, LTx or simultaneous/combined liver and kidney transplant is a viable option

Question 159

What evals should a parent of a proband w ARPKD undergo

Answer 159

kidney u/s since those who are heterozygous may, in rare cases, have very mild cystic kidney manifestations, or more frequently, liver cysts

Question 160

What testing should be done for a fetus w enlarged cystic kidneys

Answer 160

karyotype or microarray and detailed fetal u/s

molecular testing of PKHD1 may be appropriate. Failure to detect 2 PVs does not exclude the dx
prenatal hyperechogenicity and enlargement of the fetal kidneys alone are not sufficient to definitively dx ARPKD prenatally

Question 161

How is the dx of ADPKD established

Answer 161

in a proband w ANY of the following:
1. age specific u/s criteria and an affected first degree relative w ADPKD (presence of 3 or > unilateral/bilateral kidney cysts in an individual 15-39yo; 2 or > cysts in each kidney in an individual 40-59yo; large echogenic kidneys w/out distinct macrocytic cysts in an infant/child at 50% risk for ADPKD
2. age specific MRI criteria and an affected first degree relative w ADPKD (for individuals 16-40yo who are at 50% risk for ADPKD bc they have an affected first degree relative, the presence of more than 10 cysts is sufficient for a dx of ADPKD)
3. identification of a heterozygous PV

Question 162

How is the dx of ADPKD exluded

Answer 162

absence of kidney cysts by u/s exam virtually excludes a dx of ADPKD caused by truncating PKD1 PV in an at-risk person age 15-30yo or >30yo
dx not excluded when: have a PV that is incompletely penetrant or nontruncating PKD1 PVs in other ADPKD related genes associated w milder dz
MRI or contrast enhanced CT exam provides further assurance for the exclusion of the dx if cysts are absent

FH used as a rough guide to predict the severity of dz in other affected family members, although there is significant intrafamilial variability

Question 163

What molecular testing should be ordered for ADPKD

Answer 163

multigene panel w PKD1 (~78%), PKD2, ALG5, ALG9, DNAJB11, GANAB, IFT140 and other genes

Question 164

What are the clinical features associated w ADPKD

Answer 164

Kidney
all individuals develop cysts within the kidneys, substantial variability in the severity of kidney dz and other manifestations
poor prognostic factors: dx before 30yo, first hematuria before 30yo, onset of HTN before 35yo, hyperlipidemia and high BMI, high urine sodium excretion, lower kidney blood flow, lower serum high density lipoprotein cholesterol, large total kidney volume, presence of a truncating PKD1 PV; more severe in males
kidney function abnormalities, HTN, kidney pain, and kidney insufficiency; kidney size is a strong predictor of subsequent decline in kidney function; PKD1 related ADPKD is more severe bc more cysts develop earlier, not because they grow faster
reduction in urinary concentrating capacity and excretion of ammonia, development of kidney stones (20%), crystal deposition may accelerate the rate of cystogenesis

uncontrolled HTN increases risk for: faster decline of kidney function, valvular heart dz and aneurysms, fetal and maternal complications during pregnancy
pain is a common manifestation resulting from kidney enlargement and distortion by cysts; most often pain resolves in 2-7days
UTIs and cyst infection; kidney cell carcinoma w a higher proportion of sarcomatoid, bilateral, multicentric, and metastatic tumors; ~50% w ESKD by 60yo

extra-kidney manifestations
polycystic kidney dz in 85% by 25-34yo; usually asymptomatic and rarely cause liver failure
dilatation of the biliary ducts w possible episodes of cholangitis
seminal vesicle cysts in 40% of males but rarely cause infertility
vascular/cardiac: intracranial and arterial aneurysms, dilatation of the aortic root, dissection of the thoracic aorta, abnormalities of the cardiac valves and possible coronary artery aneurysms; mitral valve prolapse is the most common valvular abnormality (in 25%)
diverticular dz: colonic diverticulosis and diverticulitis are more common in individuals w ESKD associated w ADPKD than other kidney dzs

Question 165

What is the penetrance in ADPKD

Answer 165

age and genotype dependent; few cysts may be evident during childhood or young adulthood
~1% are mosaic for ADPKD

Question 166

What are the tx recommendations for someone w ADPKD

Answer 166

goal is to slow progression of declining kidney function and reducing morbidity and mortality
vasopressin V2 receptor antagonist can slow increase in kidney volume, delay decline in kidney function, and preserve filtration
antihypertensive agents for HTN
lipid control/statins to prevent hyperlipidemia, control of acidosis w maintenance of serum bicarbonate, moderation of caloric intake and low impact exercise to maintain normal BMI to delay ESKD
therapy for cyst decompression w aspiration; in individuals w many cysts contributing to pain, laparoscopic or sx cyst fenestration through lumbotomy or flank incision, nephrectomy may be indicated
cyst hemorrhage and gross hematuria are usually self limited and respond well to conservative management w bed rest, analgesics, and adequate hydration to prevent development of obstructing clots
most individuals w polycystic liver dz have no symptoms and require no tx; if symptoms occur, avoid estrogens and use of proton pump inhibitors

for ruptured/symptomatic aneurysms: sx clipping of the ruptured aneurysm at its neck
when aortic root diameter reaches 55-60mm, replacement of the aorta is indicated

Question 167

What evals should someone w an asymptomatic at risk adult relative for ADPKD undergo

Answer 167

imaging w abdominal u/s, CT, or MRI exam
molecular genetic testing if familial PV is known

at-risk relatives wanting to undergo kidney donation need to be evaluated as outline above; in potential donors w a small number of cysts, comprehensive genetic analysis w a PKD panel may be helpful to exclude PVs in known PKD related genes

for those under 18, testing is NOT recommended bc this is adult onset condition

Question 168

What pregnancy management is recommended for pts w ADPKD

Answer 168

should be monitored closely for the development of HTN and UTIs, only a slight potential for increased fetal complications
should be monitored closely for development of preeclampsia, IUGR, and oligohydramnios
second tri prenatal sonographic exam if either parent has ADPKD to assess fetal kidney size and echogenicity, presence of fetal kidney cysts and amniotic fluid volume

Question 169

What are the ways ADPKD can be inherited

Answer 169

AD (mostly), rarely can have biallelic PVs in PKD1/PKD2, digenic ADPKD

Question 170

What is the de novo rate for ADPKD

Answer 170

10-20%

Question 171

What is the molecular pathogenesis for ADPKD

Answer 171

is a ciliopathy, with loss of cilia associated w ADPKD
truncating variants through loss of function; increasing evidence that some hypomorphic nontruncating PKD1 PVs have a folding/trafficking defect of PC1

the genomic region encoding PKD1 has undergone a complex segmental dup; six copies of the 5’ three quarters of the gene are present as pseduogenes elsewhere on chromosome 16

Question 172

What % of pts w Williams syndrome have long QT syndrome

Answer 172

13%