Cardiovascular system Flashcards
22q11 DELETION SYNDROME
(DiGeorge, Velocardiofacialsyndrome, Shprintzensyndrome)
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46,XY.ish 22q11.2(D22S75×2)
Responsible genes: TBX1
Proteins: T box 1 transcription factor C
Cytogenetic locus: 22q11.2
Inheritance: AD; 93% de novo
Clinical Features and Diagnostic Criteria: congenital heart disease (74%) , immune dysfunction, palate abnormalities (69%), feeding problems, developmental delay, learning problems (70-90%), hypocalcemia (50%), renal anomalies (37%), psychiatric disorders, medial deviation of the internal carotids
Molecular Tests:FISH, microarray, or MLPA for DGCR deletion (95%). 3-Mb deletion most common; no clear genotype-phenotype relationship to del size. (A small % with S/Sx22q11 del without a DGCR deletion have 10p13-p14 deletion)
Disease Mechanism: Abnormal development of the pharyngeal arches (in embryo developes to the palate) related to TBX1 dosage
Treatment/Prognosis: Standard Txfor CHD, palate repair, pharyngeal flap, Ca replacement, no live vaccines if immunodeficient
ALAGILLE SYNDROME
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Responsible genes: JAG1, NOTCH2
Proteins: Jagged 1, Neurogenic locus notch homolog protein 2
Cytogenetic locus (loci): 20p12, 1p13-p11
Inheritance: AD, 50-70% de novo
Clinical Features and Diagnostic Criteria: Dx: Bile duct paucity (less of) on liver bx+ any three of: cardiac defects (most often PA disease, TOF), cholestasis, skeletal abnormalities (butterfly vertebrae), eye (posterior embryotoxin), or characteristic facial features. Also developmental delay, growth failure
Clinical Tests: Bile duct paucity on liver bx,
Molecular Tests:seq JAG1(>89%), JAG120p12 del FISH (~7%), NOTCH2 seq(1-2%)
Disease Mechanism: JAG1:Truncated protein product rendering it unable to bind to the cell membrane resulting in functional haploinsufficiency
Treatment/Prognosis: Liver transplant, cardiac and renal anomalies treated in standard manner, evaluate head injuries and CNS symptoms for vascular accidents, fat soluble vitamins, monitor growth and development
BRUGADA SYNDROME
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Responsible gene: SCN5A (Pathogenic variants in 22 other genes : ABCC9, CACNA1C, CACNA2D1, CACNB2, FGF12, GPD1L, HCN4, KCND2, KCND3, KCNE5, KCNE3, KCNH2, KCNJ8, PKP2, RANGRF, SCN1B, SCN2B, SCN3B, SCN10A, SEMA3A, SLMAP, and TRPM4, each <1%)
Protein: Sodium channel protein type 5 subunit alpha
Cytogenetic locus: 3p21 (SCN5A)Inheritance: AD (except KCNE5XLR)
Clinical Features and Diagnostic Criteria: Syncope or nocturnal agonalrespiration. 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 yrs). Mean age of sudden death: 40 yrs. May present as SIDS or the sudden unexpected nocturnal death syndrome (a typical presentation in individuals from Southeast Asia). May have FH sudden cardiac death.
Clinical Tests: ECG
Molecular Tests:SCN5A scanning/seq(15-30% of cases)
Disease Mechanism: Gene mutations cause lack of expression of or acceleration in the inactivation of cardiac sodium channels.
Treatment/Prognosis: Implantable defibrillators, isoproterenol, avoid inducing medication (vagotonicagents, alpha adrenergic antagonists, beta adrenergic antagonists, TCA, first generation antihistamines, cocaine, class 1C antiarrhythmic drugs, class 1A agents (procainamide, disopyramide)
CARDIO-FACIO-CUTANEOUS SYNDROME
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Responsible genes: BRAF,MAP2K1, MAP2K2, KRAS
Proteins: B-Rafproto-oncogene serine/threonine-protein-kinase, Dual specificity mitogen-activated protein kinase 1 and 2, GTPaseKRas
Cytogenetic loci: 7q34, 15q22.31,19p13.3, 12p12.1
Inheritance: AD (majority de novo)
Clinical Features and Diagnostic Criteria: Cardiac abnormalities (pulmonic stenosis, septal defects, hypertrophic cardiomyopathy, arrhythmia), distinctive facial features, and cutaneous abnormalities (xerosis, hyperkeratosis, ichthyosis, eczema, ulerythema ophyrogenes), mild-moderate intellectual disability, neoplasia in some, most often ALL
Clinical Tests: echocardiogram, renal ultrasound, cognitive testing
Molecular Tests:gene sequencing
Disease Mechanism: sustained activation of the Ras MAPK pathway downstream effectors: MEK and/or ERK
Treatment/Prognosis: Standard cardiac care, dermatology consultation, early intervention and individualized education plans
COSTELLO SYNDROME
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Responsible genes: HRAS
Proteins: GTPaseHRas
Cytogenetic loci: 11p15.5
Inheritance: AD (majority de novo)
Clinical Features and Diagnostic Criteria: feeding issues, developmental delay, intellectual disability, coarse facial features, loose, soft skin, hypertrophic cardiomyopathy, pulmonary stenosis, arrhythmia
Clinical Tests: echocardiogram, neurocognitive testing
Molecular Tests:gene sequencing
Disease Mechanism: Missense mutations lead to constitutive activation of the abnormal protein product resulting in increased signaling through the Ras MAP Kinase pathway
Treatment/Prognosis: Standard cardiac care, dermatology consultation, early intervention and individualized education plans, may require assisted feeding (nasogastric or gastric tube)
HEREDITARY HEMORRHAGIC TELANGIECTASIA
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Responsible genes: ACVRL1, ENG, GDF2, SMAD4
Proteins: Serine/threonine-protein kinase receptor R3, Endoglin, Growth/differentiation factor 2, Mothers against decapentaplegic homolog 4
Cytogenetic loci: 12q11-q14, 9q34.1, 10q11.22,18q21.2
Inheritance: AD
Clinical Features and Diagnostic Criteria: nosebleeds, mucocutaneoustelangiectases(lips, oral cavity, fingers, and nose), visceral AV malformation (pulmonary, cerebral, hepatic, spinal, gastrointestinal). Hemorrhage is often the presenting symptom of cerebral AVM. Most visceral AVM’s present as a result of blood shunting through the abnormal vessel and bypassing the capillary beds.
Clinical Tests: Stool for occult blood, CBC (anemia or polycythemia), contrast echo to find pulmonary AVM, Head MRI for cerebral AVM, US for hepatic AVM,
Molecular Tests:Sequence analysis ACVRL1, ENG(60-80%), duplication/deletion analysis (10%)
Disease Mechanism: HHT is assumed to be the result of haploinsifficiency
Treatment/Prognosis: Transcatherterembolization of pulmonary AVM >3.0mm. OCP can decrease/eliminate bleeding. Liver transplant if hepatic AVM is causing heart failure.
HOLT-ORAM SYNDROME
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Inheritance: AD (85% de novo)
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Responsible gene: TBX5, SALL4 (related disorder)
Protein: T-box transcription factor TBX5, Sal-like protein 4
Cytogenetic loci: 12q24.1, 20q13.2
Inheritance: AD (85% de novo)
Clinical Features and Diagnostic Criteria: Malformation of the carpal bone(s) and, variably, the radial and/or thenarbones (left often more severe than right). 100% have carpal bone abnormality. 75% have CHD, most often multiple ASD or VSD, arrhythmia (even if no CHD)
Clinical Tests: hand xray
Molecular Tests:TBX5sequencing (>70%), Del/Duplanalysis (<1%). Rarely due to SALL4 mutations resulting in similar syndrome
Disease Mechanism: The TBX5protein product is a transcription factor with an important role in both cardiogenesisand limb development. TBX5mutations lead to mutant TBX5mRNAs that are rapidly degraded or to transcripts with diminished DNA binding-both of which result in decreased gene dosage.
Treatment/Prognosis: Pacemaker if severe heart block, standard cardiac surgery, pollicizationmay be indicated if thumb aplasia/hypoplasia. Annual ECG, annual Holter if h/o abnormal ECG
Noonan syndrome with Multiple Lentigines (NSML) formerly known as LEOPARD Syndrome
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Responsible gene: PTPN11, RAF1, BRAF, MAP2K1Protein: SHP2, RAF proto-oncogene serine/threonine-protein kinase, B-Raf, mitogen-activated protein kinase 1
Cytogenetic locus: 12q24, 3p25
Inheritance: AD
Clinical Features and Diagnostic Criteria: Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of the genitalia, Retardation of growth, sensorineural Deafness. Hypertrophic cardiomyopathy in majority
Clinical Tests: Audiogram, ECG, echocardiogram
Molecular Tests:PTPN11 sequencing (90%), RAF1 (<5%), others rare rare
Disease Mechanism: Loss of function PTPN11mutations (versus Noonan syndrome PTPN11 mutations which are gain of function)
Treatment/Prognosis: Treat cardiac defects, deafness
NOONAN SYNDROME
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Responsible genes: PTPN11, SOS1, KRAS, RAF1, NRAS, CBL, SHOC2, BRAF, RIT1, SOS2, MAP2K1
Proteins: SHP2, Son of sevenlesshomolog 1, GTPaseKRAS, RAF proto-oncogene serine/threonine-protein kinase, NRAS, CBL, SHOC2, B-rafproto-oncogene serine/threonine-protein kinase, Ric-like protein w/o CAAX Motif 1, Son of sevenlesshomolog 2
Cytogenetic loci: 12q24.1, 2p22-p21, 12p12.1, 3p25, 1p13.2, 11q23.3, 10q25, 7q35, 1q22, 14q21.3 Inheritance: AD
Clinical Features and Diagnostic Criteria: Characteristic facial features, short stature, feeding problems, pulmonary valve stenosis, HCM (RAF1,RIT1 most enriched), cryptorchidism, renal malformation, lymphedema, bleeding disorders, myeloproliferative disorder, incl. risk of leukemia and learning disabilities
Clinical Tests: Echocardiogram, renal ultrasound, bleeding studies
Molecular Tests:PTPN11sequencing (50%), SOS1 sequencing (10%), RAF1, RIT1 (10% each), SHOC2 (2%), KRAS, SOS2(1% each), NRAS/CBL/BRAF/MAP2K1 (<1%)
Disease Mechanism: Gain of function mutations that lead to constitutive activation of the Ras MAP Kinase pathway
Treatment/Prognosis: Standard cardiac care, orchiopexy, early intervention, GH replacement
WILLIAMS SYNDROME
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Responsible gene: Contiguous gene deletion syndrome, ELN in the critical region Protein: ElastinCytogenetic locus: 7q11.23
Inheritance: AD, majority of cases de novo
Clinical Features and Diagnostic Criteria: CVany artery may be narrowed, supravalvaraortic stenosis (SVAS) most common (75%). Distinctive facial features. CT: hoarse voice, hernia, rectal prolapse, joint limitation or laxity. ID. Overfriendly, anxiety d/o, ADD. Endo:hypercalcemia, hypercalciuria, hypothyroidism, FTT infancy
Clinical Tests: Serum and urine calcium and creatinine, TFTs, hearing and vision evaluation, renal US, echocardiogram
Molecular Tests: FISH, microarray, or MLPA for 7q11.23 critical region (~99%). Point mutations in ELNcause AD isolated SVAS
Disease Mechanism: Elastin deletion causes the CV and CT problems, LIMK1 has been linked to the visuospatial construction cognitive deficit
Treatment/Prognosis: PT, OT, ST. Monitor adults who are at risk for MVP, AI, arterial stenosis, SNHL, hypothyroidism, DM. Monitor for hypercalciuria. Aggressive management of constipation
