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CONGENITAL HEART DEFECTS AND ASSOCIATED GENETIC DISORDERS - The complexity of cardiac embryology suggests that multiple genes are involved in directing development of the heart. Mutations in control and structural genes appear to result in the great variety of congenital malformations of the heart. ANEUPLOIDY (abnormal number of chromosomes) ****Down Syndrome: Trisomy 21 Atrial/ventricular septal defects (AVSD) 40% of Down Syndrome patients have heart defect Half of these are AVSD Edwards Syndrome Trisomy 18 Ventricular septal defects (VSDs), AVSDs, double outlet right ventricles, and hypoplastic hearts Patau Syndrome Trisomy 13 Atrial and septal defects; Disturbance of the cardiac position has also been reported and includes detrocardia; these findings support the role of chromosome 13 genes in laterality of development. Turner Syndrome 45,X hypoplastic left heart; aortic coarctation; bicusupid aortic valves and mitral valve prolapse. Atrioventricular septal defect (AVSD) characterized by a deficiency of the atrioventricular septum of the heart which is a septum of the heart between the right atrium (RA) and the left ventricle (LV) - results in formation of a hole in the center of the heart and a large single valve between the upper and lower heart chambers. holes allow blood from the heart's left side to enter the heart's right side heart has to work much harder than normal to pump enough blood out to the body Genes associated with AVSD: CRELD1 CRELD2 Gene family thought to be involved in cell adhesion Not related to trisomy GATA4 essential for cardiac development Bone Morphogenic protein-4 Deficiency results in abnormal development of cardiomyocytes Type VI Collagen Chromosome 21 associated Genes fall within the heart defect critical region on chromosome 21 CHROMOSOME DELETION SYNDROMES William’s Syndrome - characteristic appearance with mild short stature, a full lower lip and sloping shoulders characterized as a “cocktail party manner” Supravalvular aortic stenosis (SVAS) – instead of having 3 leaflets on heart valves, you only have 2 – valves did not form properly due to lack of elastin Haploinsufficiency of 7q11 leads to loss of one copy of elastin gene key causative factor for SVAS DiGeorge Syndrome one of the most common congenital defects Catch 22 • Cardiac outflow tract anomalies • Abnormal faces • Thymic hypoplasia • Cleft palate • Hypocalcemia • Microdeletion of chromosome 22 defective cranial neural crest function, especially that associated with those neural crest cells populating aortic arches 3 and 4 multigene, heterozygous, interstitial chromosomal deletion (approximately 30 genes are deleted) DiGeorge Critical Region TBX1 mutations are associated with heart defects (involved with a growth factor) CARDIAC HYPERTROPHY disproportionate hypertrophy of the left ventricle and occasionally also of the right ventricle Major Myopathies: (are others but not listed) Hypertrophic cardiomyopathy (HCM) - - two types of cardiac hypertrophy: pathological and physiological Pathological Occurs under conditions such as hypertension or genetic conditions affecting myofibril proteins. • hypertension, mutations – will get fibrosis!! Can get heart failure Genetically mediated: broader and often subtle phenotype which may be a consequence of incomplete gene penetrance and variable disease expression • - most common inheritance pattern is autosomal dominant with variable penetrance and expression. • Mutations in four contractile protein gene: • b-cardiac myosin • troponin T • a-tropomyosin • myosin binding protein. • Mutations that produce a change in charge are considered to have a major impact on protein stability Clinical Features • Patients may be entirely asymptomatic or affected by varying degrees of dyspnea, chest pain, palpitation, or syncope. • Rhythm disturbances include atrial fibrillation, supraventricular tachycardia, and ventricular tachycardia. • Clinical Risk Stratification: In adults, a family history of sudden death and a personal history of syncope or documented non-sustained ventricular tachycardia are predictors of adverse prognosis. In children, there are few reliable markers of poor prognosis Long QT interval - Long QT syndrome (LQTS) is an abnormality of cardiac rhythm, characterized by delayed ventricular repolarization which is seen as a prolonged QT interval The arrhythmia results in recurrent spontaneous syncope (loss of consciousness), seizures and sometimes, sudden cardiac death. LTQ syndrome is caused by repolarization defects in cardiac cells LTQ syndromes are heterogeneous group of disorders known as channelopathies because they are caused by defects in cardiac ion channels The most common is autosomal dominant (AD) Romano-Ward Syndrome • syncope due to cardiac arrhythmia is the most frequent symptom LTQ triggers are typically adrenergic and include exercise and sudden emotions Ehlers Danlos Syndrome - group of generalized connective tissue disorders result from deficiency of collagen-processing enzymes (collagen 1,3, 5 affected) most clinically important mutations are found in the gene for type III collagen Collagen III is an important component of the arteries potentially lethal vascular problems can occur Vascular Ecchymotic (Type IV) • Only type associated with reduced life expectancy • ****Medium-sized artery spontaneous rupture – can lead to early death • Defect in Type III collagen – it is not as strong • Chromosome 2q31 location • • Diagnosis in Ehlers Danlos IV • Major Criteria • Thin, translucent skin • Arterial/intestinal fragility or rupture; • Extensive bruising • Characteristic facial appearance • Thin lips & philtrum, thin nose, small chin, large eyes ****Weakness of Type III Collagen leads to aneurysm and dissection commonly in visceral arteries and iliaofemoral arteries. Marfan Syndrome - - - Fibrillin is defective leads to poor anchoring of collagen Signs: disproportionately long limbs (arachnodactyly); Joint hypermobility Cardiovascular Sequelae in Marfan’s Syndrome • Tissues don’t adhere well • Normal forces across arterial wall result in shear Leads to Aortic dissection • Collagen sheets are not anchored well and do not undergo effective repair • Results in degeneration of heart valves (particularly aorta and mitral) that lead to murmurs & insufficiency Major criteria • Dilatation of the ascending aorta w/ or w/o aortic regurgitation & involving at least the sinuses of Valsalva; or • Dissection of the ascending aorta Minor criteria • Mitral valve prolapse w/ or w/o mitral valve regurgitation • Mitral Valve Prolapse – Leaflets are stretched and flop back into the left atrium with each heart beat – blood does not move out effectively • Dilatation of the main pulmonary artery in a patient 40 years old in the absence of valvular, peripheral pulmonic stenosis or other obvious cause • Calcification of the mitral annulus 40 years • Dilatation or dissection of the descending thoracic or abdominal aorta 50 years • For cardiovascular system involvement: (1) major criterion or only (1) one of the minor criteria must be present.