Genetics

Génétique

Genetic conditions and associations

Trisomy 21 (Down syndrome)

Common cardiac anatomic lesion: atrio-ventricular septal defect, Atrial septal defect, Ventricular septal defect, coarctation, tetralogy of Fallot.

1 in 800 lives births. Physical: up-slanted palpebral fissures with epicanthal folds, small low set ears with overfolded upper helices, short neck with excess skinfolds, prominent tongue, flattened occiput, exaggerated gap between 1st and 2nd toe ("sandal sign"), hypotonia. Brushfield spots are not pathognomonic, 75% have it (7% of normal newborns): speckled areas in periphery of iris. Simian crease (single transverse palmar crease) is present in 5% of normal newborns when single and 1% when bilateral with boys 2x more. 45% of Down infants have a single simian crease. A baby with a single simian crease has 1 in 60 chances of having Down (cause 45% down have it and incidence is 1/800). Need extensive cardiac evaluation cause 40-50% have congenital heart defects (60% being canal AV - AVSD), also VSD, PDA. Congenital hypothyroidism in 2% (0.025% in normal = 1/4000). Other conditions = GI malformation (duodenal atresia, Hirschsprung, T-E fistula), cryptorchidism, lens opacities and cataracts, strabismus, hearing loss (sensorineural and conductive). Risk of leukemia: 50x in 0 to 4 years; 10x in 5 to 29 years, 20x lifetime risk. Transient myeloproliferative disease (marked leukocytosis, blast cells, thrombocytopenia, HSM = spontaneously resolve) and leukemoid reaction (increased WBC with myeloblasts without splenomegaly = resolve spontaneously). Full trisomy in 94%, mosaic in 2.4% and translocation in 3.3%. Nondisjunction at Meiosis I cause lengthy stage of meiotic arrest; 10% of all T21 derive from an extra chrom 21 from father.

Health Supervision for Children with Down Syndrome Updated AAP July 2011.pdf

Noonan

Common cardiac anatomic lesion: Dysplastic / thickened pulmonary valve, Pulmonary stenosis, ventricular septal defect, atrial septal defect, patent ductus arteriosus, branch stenosis of pulmonary artery, interrupted aortic arch, hypertrophic cardiomyopathy, neonatal cardiomyopathy (hydrops), aortic valvular stenosis, tetralogy of Fallot. Similar features to Turner (can present as hydrops, cardiomyopathy). Rasopathy (same family as Costello Syndrome). Dorsal hand and pedal edema, low posterior hairline, web neck (pterygium colli), congenital elbow flexion (cubitus valgus), broad chest with wide spaced nipples, narrow, hyperconvex nails, prominent ears, short fourth metacarpal and or metatarsal. Differences with Turner = Turner only women with chromosome disorder, near normal intelligence, Coarctation, amenorrhea and ovarian dysgenesis / Noonan will affect both sex, normal chromosome, AD, cognitive challenges, pulmonary stenosis, normal menstrual cycle.

Trisomy 18 (Edward syndrome)

Common cardiac anatomic lesion: Bicuspid aortic valve, pulmonary stenosis, Atrial septal defect, patent ductus arteriosus, Ventricular septal defect, atrio-ventricular septal defect, coarctation, interrupted aortic arch, coarctation, tetralogy of Fallot, polyvalvular disease, double outlet right ventricle.

Most common autosomal trisomy after T21 in live born. 1 in 6000. IUGR, microcephaly, overlapping fingers (2nd over 3rd; or 5th over 4th), hypoplastic nails, small pelvis, rocker bottom feet, clenched hands, prominent occiput, micrognathia, Pierre-Robin sequence, small mouth, small palpebral fissures, malformed low-set ears, umbilical / inguinal hernia, cryptorchidism, short sternum. 90% mortality by 1 year. Majority with complete trisomy (maternal origin mostly). More females (3:1).

Trisomy 13 (Patau syndrome)

Common cardiac anatomic lesion: Atrial septal defect, Ventricular septal defect, patent ductus arteriosus, hypoplastic left heart syndrome, atrio-ventricular septal defect, tetralogy of Fallot, coarctation, interrupted aortic arch.

80% with complete trisomy (chromosome extra from maternal origin) and reminder due to translocation. Midline abnormalities - cardiac, cutis aplasia, polydactyly, transverse palmar crease, narrow hyperconvex fingernails, cleft lip/palate, colobomas, retinal dysplasia, umbilical/inguinal hernia, cryptorchidism, bicornate uterus, microcephaly, holoprosencephaly, persistence of fetal hemoglobin. 90% mortality reported by 1 year.

Turner

Common cardiac anatomic lesion: Coarctation of the aorta, Bicuspid aortic valve, Aortic Stenosis, Ventricular septal defect, mitral valve prolapse, aortic dissection, atrial septal defect, atrio-ventricular septal defect, pulmonary stenosis, interrupted aortic arch, total anomalous pulmonary venous return.

45 X. May be mosaic. The chromosome missing usually from paternal origin (risk does not increase with maternal age). Lymphedema of feet and or hands (can present as hydrops). Cubitus valgus, cystic hygroma. Short stature. Primary amenorrhea due to ovarian dysplasia. Short stature often prompts initial workup. Most with normal mental development. Webbed neck with low hairline, broad chest with wide-spaced nipples. Risk of Coarctation: 1 in 8000. Shield chest. Spatial-perceptual difficulties. Streak ovaries with deficient follicles. Most common aneuploidy anomaly = 1.4%. Only monosomy to survive, 99% will be lost pregnancy.

DiGeorge/velocardiofacial syndrome

Common cardiac anatomic lesion: Ventricular septal defect, coarctation of the aorta, interrupted aortic arch, right-sided aortic arch, truncus arteriosus, pulmonary atresia, d-TGA, tetralogy of Fallot, double outlet right ventricle, tricuspid atresia. Any cardiac defect may be a sign of underlying Di George.

CATCH22 (congenital heart, abnormal face, thymus hypophlasia or aplasia, cleft palate / cerebral – developmental delay, hypocalcaemia (hypoparathyroidism), deletion of 22q11. Heart = conotruncal (TOF, truncus arteriosus, interrupted aortic arch, right sided Aortic arch, DORV).

Marfan

Common cardiac anatomic lesion: Dilated aortic root, aortic aneurysm, tricuspid valve and mitral valve prolapse. Mutation of fibrillin – 15q21.1. Autosomal dominant. Abnormal crosslinking between collagen and elastin. Degeneration of elastic elements in aortic root leading to dilation, and eventually risk of acute dissection or rupture. Tall, thin habitus, hypermobile joints, pectus excavatum/carinatum, kyphscoliosis, lens dislocation, scoliosis, etc. Revised Ghent nosology for diagnosis and molecular testing.

peds_2013-2063.pdf

Ehlers Danlos syndrome

Common cardiac anatomic lesion: Dilated aortic root and mitral valve prolapse.

William Syndrome

Common cardiac anatomic lesion: supravalvular aortic stenosis, peripheral pulmonary artery stenosis, pulmonary stenosis. Elfin facies; small and abnormally shaped primary teeth, low muscle tone, joint laxity, hypoplastic nails, hoarse voice, blue eyes, stellate iris pattern, enamel hypoplasia, increased calcium, frequent ear infections, hyperacusis (sensitivity to loud noises), failure to thrive, strong social orientation and music capacities (cocktail party syndrome), anxiety problems. Cause by elastin deletion on chromosome 7 (microdeletions) - 7q11.23.

Leopard syndrome

Multiple Lentiggines syndrome = Lentigines, ECG abnormalities, Ocular hypertelorism (wideset eyes; other facial anomalies include broad nasal root, prognathism, low set ears), pulmonary stenosis, Abnormal genitalia (crypto or monorchidism, missing ovaries), Retarded growth (initial normal BW and length), Deafness (sensorineural). Lentigines = freckling reminiscent of large cat in large numbers 10000+ also inside mouth and sclera (small pigmented spot on skin with clear defined edge). AD (PTPN11 gene mutation). ECG = mostly bundle branch block. Dx if lentigines and 2 other criteria. If no lentigines need 3 other criteria and a 1st degree relative with disease.

Alagille syndrome

Common cardiac anatomic lesion: Tetralogy of Fallot, peripheral pulmonary stenosis, ventricular septal defect, atrial septal defect.

Klinefelter syndrome

Common cardiac anatomic lesion: Tetralogy of Fallot and mitral valve prolapse.

47, XXY. Disproportional long arms, clinodactyly, hypogonadism, hypogenitalia, gynecomastia, infertility, behavioral challenges.

CHARGE

Common cardiac anatomic lesion: Coarctation, Endocardial cushion defect (AVSD), tricuspid atresia, ventricular septal defect, atrial septal defect, patent ductus arteriosus, double outlet right ventricle, tetralogy of Fallot, right-sided aortic arch, truncus arteriosus. Coloboma, Heart anomalies, Choanal Atresia, retardation (mental developmental delay and growth), Genital anomalies (genito-renal-urinary), Ear anomalies (semi-circular canal classically). Defect in 4th brachial arch and derivates of the 3rd and 4th pharyngeal pouches. At risk of severe combined immunodeficiency due to thymus dysfunction or absence. AD due to CHD7 gene in 70%. Most de novo mutations. Chromodomain helicase DNA binding protein 7. May have also congenital diaphragmatic hernia, imperforate anus, esophageal atresia, microcephaly, significant neurodevelopmental challenges.

VACTERL

Common cardiac anatomic lesion: Hypoplastic left heart syndrome, ventricular septal defect. VATER: Vertebral, anal imperforation, Tracheo-Esophageal fisutal with usually esophageal atresia, Renal or radial anomalies VACTERL: VATER and cardiac + limb anomalies (radial)

Apert syndrome (Acrocephalosyndactyly)

Common cardiac anatomic lesion: Ventricular septal defect, coarctation of the aorta, pulmonary stenosis, tetralogy of Fallot.

Autosomal dominant - mutation in fibroblast growth factor receptor 2 gene. Hypertelorism, midface hypoplasia, abnormal skull, large fontanels, broad distal phalanx of thumb / big toe, syndactyly, cranyosynostosis (coronal).

Rubenstein-Taybi Syndrome

Common cardiac anatomic lesion: Ventricular septal defect, atrial septal defect, patent ductus arteriosus.

16p13.3 - cAMP-regulated enhancer binding protein (CREB) mutation or deletion - mostly sporadic. Broad thumbs, radial angulation, broad toes, clinodactyly, flat feet, downward slanting of palpebra fissures, hypoplastic maxilla, prominent nose, long eyelashes, heavy eyebrows (synophrys), nasolacrimal duct obstruction, ptosis, glaucoma, hirsuitism, hypotonia, cryptorchidism, growth deficiency, increased risk of tumours (leukemia, brain).

Beckwith Wiedemann

Cardiac association: Atrial septal defect, ventricular septal defect and cardiomegaly. Facial appearance round in childhood with prominent cheeks and narrowing of forehead with trend to normalization in adolescence. 7.5% risk of embryonal cell tumors. Overgrowth disorder usually present at birth. A minority (<15%) cases of BWS are familial. Hypoglycemia. Macrosomia, Macroglossia, Hemihyperplasia (asymmetric overgrowth of one or more regions of the body), Omphalocele or umbilical hernia, Embryonal tumor (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma) in childhood, Visceromegaly involving one or more intra-abdominal organs including liver, spleen, kidneys, adrenal glands, and/or pancreas, Cytomegaly of the fetal adrenal cortex (pathognomonic), renal abnormalities including structural abnormalities, nephromegaly, nephrocalcinosis, and/or later development of medullary sponge kidney, Anterior linear ear lobe creases and/or posterior helical ear pits. Placental mesenchymal dysplasia. Autosomal dominant with variable expression / incomplete penetrance - gene located at 11p15.5. Polyhydramnios.

Ellis-van Creveld Syndrome

Common cardiac anatomic lesion: Atrial septal defect, single/common atrium.

Autosomal recessive (chondroectodermal dysplasia). Short distal extremities, polydactyly (more hands than feet), narrow thorax, nail hypoplasia.

Holt-Oram Syndrome

Common cardiac anatomic lesion: Atrial septal defect, ventricular septal defect.

Autosomal dominant with variable expression. Some association with 12q2 locus. Upper limb defects, absent/hypoplastic/abnormal thumbs, narrow shoulders.

Neurofibromatosis

Common cardiac anatomic lesion: Atrial septal defect, coarctation of the aorta, complete heart block, hypertrophic cardiomyopathy, interrupted aortic arch, pulmonic stenosis, ventricular septal defect.

Treacher Collins Syndrome

Common cardiac anatomic lesion: Atrial septal defect, ventricular septal defect.

Autosomal dominant. Mandibulofacial dysostosis. Mutation in TCOF1 gene (chromosome 5). Lower eyelid coloboma, mandibular hypoplasia, malformed ears, malar hypoplasia, conductive hearing loss, dysmorphic ears, down-slanting papebral fissures, normal intelligence, airway anomalies.

Thrombocytopenia absent radius syndrome

Common cardiac anatomic lesion: Atrial septal defect, tetralogy of Fallot, dextrocardia.

Autosomal recessive. Thrombocytopenia in infancy, absent bilateral radii with present thumbs, ulnar anomalies, hip dysplasia.

Pentalogy of Cantrell

Common cardiac anatomic lesion: Atrial septal defect, coarctation of the aorta, total anomalous pulmonary venous return, ectopia cordis, tetralogy of Fallot.

Tuberous Sclerosis

Common cardiac anatomic lesion: Rhabdomyoma (cardiac tumour), coarctation of the aorta, interrupted aortic arch.

Carpenter syndrome

Common cardiac anatomic lesion: patent ductus arteriosus, ventricular septal defect, atrial septal defect, pulmonary stenosis, transposition of great arteries.

Autosomal recessive. Polydactyly, syndactyly, clinodactyly, lateral displacement of inner canthus, brachycephaly.

Cat eye syndrome

Common cardiac anatomic lesion: total anomalous pulmonary venous return and persistent left superior vena cava.

Chromosome 22 quadruplicated or triplicated at the 22q11 area. Down-slanting palpebral fissures, anal atresia with fistula, coloboma of iris, renal agenesis.

Cornelia de Lange

Occasionally associated with ventricular septal defect.

Micromelia (small feet/hands), clinodactyly, syndactyly, synophrys, thin upper lip, long eyelashes, long philtrum, micrognathia, hypertonicity, hirsutism, low posterior hairline.

Pompe disease (glycogen storage IIa)

Common cardiac anatomic lesion: hypertrophic cardiomyopathy (secondary to glycogen deposition).

Cri du chat syndrome (5p-)

Occasionally associated with ventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, pulmonary valve atresia with ventricular septal defect, pulmonary valve stenosis, and double-outlet right ventricle (Reference).

Partial deletion of the short arm of 5th chromosome (deletion of paternal origin in 80%). Hypertelorism, downward slant palpebral fissures, epicanthal folds, low-set ears, cat-like cry (abnormal laryngeal development), microcephaly, hypotonia, failure to thrive.

Goldenhar syndrome

Occasionally associated with ventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, coarctation.

1st / 2nd brachial arch anomalies. Maxiallary / mandibular hypoplasia, malformed ears, hemivertebrae, abnormal vertebra (hypoplasia), renal abnormalities, tongue anomalies.

Hurler syndrome

Common cardiac anatomic lesion: thickening of valves (mitral), coronary artery disease, hypertrophic cardiomyopathy.

Teratogens

Alcohol

Fetal alcohol syndrome is associated with ventricular septal defect, atrial septal defect, tetralogy of Fallot and coarctation.

Phenytoin / Dilantin / Hydantoin syndrome

Associated with ventricular septal defect, atrial septal defect, tetralogy of Fallot, pulmonary stenosis, patent ductus arteriosus and coarctation.

Carbamaepine

Associated with ventricular septal defect, and tetralogy of Fallot.

Valproic acid

Associated with ventricular septal defect, aortic stenosis, hypoplastic left heart syndrome, atrial septal defect, tetralogy of Fallot, pulmonary atresia, patent ductus arteriosus, coarctation, interrupted aortic arch.

Retinoic acid

Associated with Conotruncal malformations (tetralogy of Fallot, pulmonary atresia with ventricular septal defect, double-outlet right ventricle, double-outlet left ventricle, truncus arteriosus and transposition of the great arteries), truncus arteriosus, aortic arch abnormalities, hypoplastic left heart syndrome.

Thalidomide

Associated with Conotruncal anomalies (tetralogy of Fallot, pulmonary atresia with ventricular septal defect, double-outlet right ventricle, double-outlet left ventricle, truncus arteriosus and transposition of the great arteries)

Phenylketonuria in the mother

Associated with tetralogy of Fallot, ventricular septal defect, coarctation.

Lithium

Associated with Ebstein's anomaly, tricuspid atresia.

Maternal diabetes

Associated with hypertrophic cardiomyopathy (specifically septal hypertrophy) and conotruncal anomalies (tetralogy of Fallot, pulmonary atresia with ventricular septal defect, double-outlet right ventricle, double-outlet left ventricle, truncus arteriosus and transposition of the great arteries)

Congenital Rubella Syndrome

Associated with ventricular septal defect, atrial septal defect, peripheral pulmonary artery stenosis, patent ductus arteriosus.

tp-10-09-2366.pdf

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