Cardiovascular Syndromes

Front 1

22q11 DELETION SYNDROME

a) Responsible gene and locus?
b) Protein?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 1

a) ?UFDIL, TBX1, deletion at 22q11.2
b) involved proteins are unknown
c) AD, 93% de novo
d) congenital heart disease (74%) (Tetralogy of fallot, interrupted aortic arch, conotruncal defects), immune dysfunction, palate abnormalities (69%), feeding problems, DD, learning problems (70-90%), hypocalcemia (50%), renal anomalies (37%), psychiatric disorders, medial deviation of the internal carotids
e) serum Ca, PTH, T/B cell subsets, Ig's, post vaccine Ab's, renal US, video laryngoscopy
f) FISH of MLPA for DiGeorge Critical Region delation (95%), 3-Mb or 20kb deletion, no clear genotype-phenotype relationship to deletion size.
g) Abnormal development of the pharyngeal arches somehow related to TBX1 dosage
h) Standard treatment for congen heart disease, palate repair, pharyngeal flap, Ca replacement, no live vaccines if immunodeficient

Front 2

ALAGILLE SYNDROME

a) Responsible genes and loci?
b) Proteins?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 2

a) JAG1 at 20p12, NOTCH2 at 1p11-p13
b) Jagged 1, Neurogenic locus notch homolog protein 2
c) AD, 50-70% de novo
d) Dx: Bile duct paucity on liver bx + any three of: cardiac defects (most often PA disease, TOF, cholestasis, skeletal abnormalities (butterfly vertebrae), eye (posterior embryotoxin, or characeristic facial features. Also developmental delay, growth faliure
e) Bile duct paucity on liver bx
f) seq JAG1 (88%), JAG1 20p12 del FISH (~7%) NOTCH2 seq (<1%)
g) JAG1: truncated protein product rendering it unable to bind to the cell membrane resulting in functional haploinsufficiency
h) Liver transplant, cardiac and renal anomalies treated with standard care, evaluate head injuries and CNS symptoms and vascular accidents, fat soluble vitamins, monitor growth and development.

Front 3

BRUGADA SYNDROME

a) Responsible gene and locus?
b) Protein?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 3

a) SCN5A at 3p21
b) Sodium channel protien type 5 subunit alpha
c) AD
d) Syncope or nocturnal agonal respiration, ST-segment abnormalities in leads V1-V3 on the ECG and a high risk of ventricular arrhythmias and sudden death. Manifests primarily during adulthood (range 2 days to 85 years). Mean age of sudden death: 40 years. May present as SIDS or the sudden unexpected nocturnal death syndrome (a typical presentation in individuals from Southeast Asia). May have fam hx of sudden death.
e) ECG
f) SCN5A scanning/seq (20-25%)
g) Gene mutations cause lack of expression of or acceleration in the inactivation of cardiac sodium channels
h) implantable defibrillators, isoproterenol, avoid indicuing medication (vafotonic agents, alpha adrenergic antagonists, beta adrenergic antagonists, TCA, first generation antihistamines, cocaine, class 1C antiarrhythmic drugs, class 1A agents (procainamide, disopyramide)

Front 4

HEREDITARY HEMORRHAGIC TELANGEICTASIA

a) Responsible gene and locus?
b) Protein?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 4

a) ACVRL1 at 12q11-q14, ENG at 9q34.1
b) serine/threonine-protein kinase receptor R3
c) AD
d) nosebleeds, mucocutaneous telangerctases (lips, oral cavity, fingers, and nose), visceral AV malformation (pulmonary, cerebral, hepatic, spinal, gastrointestinal). Hemorrhage is often the presenting sypmtom of cerebral AVM. Most visceral SVM's present as a result of blood shunting thourgh abnormal vessel and bypassing the capillary beds.
e) Stool for occult blood, CBC (anemia or polycythemia), contrast echo to find pulmonary AVM, head MRI for cerebral AVM, US for hepatic AVM
f) Sequence analysis ACVRL1, ENG (60-80%), duplication/deletion analysis (10%)
g) HHT is assumed to be the result of haploinsufficiency
h) Transcatherter embolization of pulmonary AVM >3.0mm. OCP can decrease/eliminate bleeding. Liver transplant if hepatic AVM is causing heart faliure.

Front 5

HOLT-ORAM SYNDROME

a) Responsible gene and locus?
b) Protein?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 5

a) TBX5
b) T-box transcription factor TBX5
c) AD (85% de novo)
d) Malformation of the carpal bones and varably, the radial and/or thenar bones (left often more severe than right). 100% have carpal bone abnormality. 75% have CHD, most often multiple ASD or VSD, arrhythmia including AV block (even if no CHD).
e) hand x-ray
f) TBX5 sequencing (>70%), del/dup analysis (<1%)
g) The TBX5 protein product is a transcription factor with an imporant role in both cardiogenesis and limb development. TBX5 mutations lead to mutant TBX5 mRNAs that are rapidly degraded or to transcripts with diminished DNA binding- both of rapidly degraded or to transcripts with diminished DNA binding - both of which result in decreased gene dosage
h) Pacemaker if severe heart block, standard cardiac surgery, pollicization may be indicated if thumb aplasia/hypoplasia; annual ECG, annual Holter if hx of abnormal ECG

Front 6

LEOPARD SYNDROME

a) Responsible gene and locus?
b) Protein?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 6

a) PTPN11 at 12q24
b) SHP2
c) AD
d) Lentiginues, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of the genitalia, Retardation of growth, senserineural Deafness. Hypertrophic cardiomyopathy.
e) Audiogram, ECG, echocardiogram
f) PTPN11 sequencing (80%)
g) Loss of function PTPN11 mutations (Noonan syndrome mutations are gain of function).
h) Treatment of cardiac defects, deafness

Front 7

NOONAN SYNDROME

a) Responsible genes and loci?
b) Proteins?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 7

a) PTPN11 at 12q24, SOS1 at 2p21-p22, KRAS at 12p12.1
b) SHP2, Son of sevenless homolog 1, GTPase KRas
c) AD
d) Characteristic facial features, short stature, feeding problems, pulmonary valvue stenosis, hypertrophic cardiomyopathy, cryptorchidism, renal malformation, lymphedema, scoliosis, bleeding disorders, myeloproliferative disorder, increased risk of leukemia and learning disabilities
e) echocardiogram, renal ultrasound, bleeding studies
f) PTPN11 sequencing (50%), SOS1 sequencing (10%), KRAS (<5%)
g) Gain of function mutations that lead to constitutive activation of the Ras MAP Kinase pathway (LEOPARD syndrome is loss of function).
h) Standard cardiac care, orchiopexy, early intervention, GH replacement.

Front 8

WILLIAMS SYNDROME

a) Responsible gene and locus?
b) Protein?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 8

a) ELN in the critical region, at 7q11.23 (Contiguous gene deletion syndrome)
b) Elastin
c) AD, majority de novo
d) CV at any artery may be narrowed, supravalvar aortic stenosis (SAVS) most common (75%). Distinctive facial features. CT: hoarse voice, hernia, rectal prolapse, joint limitation or laxity. MR. Overfriendly, anciety d/o, ADD. Endo: hypercalcemia, hypercalciuria, hypothyroidism, FTT infancy
e) Serum and urine calcium and creatinine, TFTs, hearing and vision evaluation, renal US, echocardiogram
f) FISH or MLPA for 7q11.23 critical region (~99%), point mutation in ELN cause AD isolated SVAS
g) Elastin deletion causes the CV and CT problems, LIMK1 has been linked to the visuospatial construction cognitive deficit
h) PT, OT, ST. Monitor adults who are at risk for MVP, AI, arterial stenosis, SNHL, hypothyroidism, DM. Monitor for hypercalciuria. Aggressive management of constipation.