23 Syndromic Diseases with Cardiac Involvement
23.1 Overview of Syndromic Diseases with Cardiac Involvement
An overview of the most common syndromic diseases associated with congenital heart defects is presented in Table 23.1. Marfan and Marfanlike syndromes are discussed separately in Chapter 23.2.
Syndrome | Characteristics | Associated heart defects | Remark |
Trisomy 21 (Down syndrome) | Short stature, generalized muscle hypotonia, simian crease, sandal gap (large distance between the 1st and 2nd toes), clinodactyly of the 5th finger, brachycephalus with mongoloid eye slant, epicanthus, macroglossia, Brushfield spots, psychomotor retardation, average IQ of 50 (considerable variation), pancreas annulare, Hirschsprung disease | AVSD, VSD, Fallot tetralogy, PDA, rarely coarctation of the aorta, aortic stenosis | Most common chromosomal abnormality with an incidence of 1:650 of all live births; the incidence increases with maternal age. Approximately 40–50% of children have a heart defect, approximately half of these have AVSD |
Trisomy 18 (Edwards syndrome) | Intrauterine growth retardation, short trunk, small nipples, microcephaly, craniofacial anomalies (prominent occiput, low-set ears, small mouth, micrognathia), renal anomalies. Typical hand position: flexion of the fingers where the index finger and little finger are bent over the middle and ring fingers | VSD (almost always present, often as malalignment VSD), cardiac valvulopathy (“polyvalvular disease,” such as thickened leaflets, long chordae, hypoplastic or absent papillary muscles), DORV, Fallot tetralogy | Second most common chromosomal abnormality with an incidence of 1:3,500 of all live births. The prognosis is poor. Most children die within the first weeks of life, only 10% survive the first year. Survival into adulthood has been described in some cases, but severe mental retardation is always present |
Trisomy 13 (Patau syndrome) | Microcephaly, scalp defects, microphthalmia, coloboma, cleft lip and palate, flexion contractures of the fingers, rocker bottom feet, polydactyly, renal anomalies, mental retardation | PDA, VSD, ASD, valvular anomalies, coarctation of the aorta | Incidence 1:4000–10,000 of all live births. Cardiac defects occur in 80%, the majority of those affected have complex cardiac defects. The prognosis is as poor as that of trisomy 18, the mortality rate in the first year of life is 80–90% |
Trisomy/tetrasomy 22p (“cat-eye” syndrome) | Mild mental retardation, hypertelorism, iris coloboma, ear tags, kidney dysplasia (large variability of the phenotype) | Anomalous pulmonary venous connections, Fallot tetralogy, VSD, left persistent superior vena cava, interrupted inferior vena cava, tricuspid atresia | Cardiac defects occur in 40% of patients |
Turner syndrome (45, X0) | Congenital lymphedema (almost pathognomonic), short stature, pterygium colli, short fingers, widely spaced nipples, ovarian dysgenesis, renal anomalies | Coarctation of the aorta, bicuspid aortic valve, aortic stenosis, hypoplastic left heart syndrome, aortic dilation, aortic dissection | Incidence 1:2,500 of all female newborns. Cardiac defects occur in 20–40% of patients, usually obstruction or hypoplasia of the left heart. The spectrum ranges from asymptomatic bicuspid aortic valve up to hypoplastic left heart syndrome. The most common is coarctation of the aorta |
Noonan syndrome | Short stature, pterygium colli, chest deformities, congenital lymphedema, cryptorchismus, mental retardation (usually mild) | Myxomatous valvular pulmonary stenosis, hypertrophic cardiomyopathy, ASD, VSD | Affected genes: mostly PTPN11 mutation, rarely KRAS, SOS1, autosomal dominant inheritance. The phenotype is similar to Turner syndrome |
Microdeletion 22q11 (DiGeorge syndrome, velo-cardio-facial syndrome, Shprintzen syndrome, “conotruncal anomaly face” CATCH 22) | Cardiac anomalies, abnormal facies, thymus hypoplasia, cleft palate, hypocalcemia, mental retardation of varying degrees. Pronounced genotype-phenotype variability | Interrupted aortic arch, truncus arteriosus communis, Fallot tetralogy, pulmonary atresia with VSD, VSD, aortic arch anomalies | Incidence 1:5,000 of all live births. Malformation of the 3rd/4th pharyngeal pouch. The great variability of expression is reflected in the different names of the syndrome, all of which are now summarized as microdeletion 22q11. Cardiac defects occur in approximately 80% of patients. Typical defects are conotruncal anomalies, i.e., heart defects affecting mainly the great vessels. Patients with 22q11 microdeletion should always be examined for immune defects |
Holt–Oram syndrome | Malformations of the upper extremities | ASD, VSD, anomalous pulmonary venous connection, conduction disturbances | Affected gene: TBX5, autosomal dominant inheritance, cardiac anomalies occur in about 75% of patients, an ASD is typical |
Alagille syndrome | Intrahepatic cholestasis (biliary atresia), typical face (prominent forehead and chin, deep-set eyes, and anomalies of the anterior chamber [posterior embryotoxon]), butterfly vertebrae | Peripheral pulmonary stenosis, Fallot tetralogy, valvular pulmonary stenosis, ASD, VSD | Affected genes: JAG1, NOTCH2, autosomal dominant inheritance, cardiac defects occur in approximately 90% of patients, peripheral pulmonary stenosis is typical |
Ellis–van Creveld syndrome (chondroectodermal dysplasia) | Short stature, short limbs, ectodermal dysplasia (hypoplastic nails, dental abnormalities), polydactyly, narrow thorax, usually normal intelligence | Common atrium, ASD I, AVSD | Affected gene: EVC, autosomal recessive inheritance. Cardiac defects occur in approximately 50% of cases, anomalies that affect the embryonic AV channel are typical |
Williams–Beuren syndrome (“elfin face” syndrome) | Short stature, mental retardation, elflike facies with midface hypoplasia, hypodontia, very good verbal skills, friendly behavior, sometimes social disinhibition, hoarse voice, hypercalcemia, hypogenitalism, early tendency to arterial hypertension | Supravalvular aortic stenosis, (peripheral) pulmonary stenosis, coarctation of the aorta, coronary artery stenosis, renal artery stenosis | Incidence 1:10,000–20,000 of all live births. Affected gene: elastin gene (ELN1), microdeletion 7q11.2. Cardiac defects occur in approximately 75% of cases. Supravalvular aortic stenosis is typical, less often peripheral pulmonary stenosis, coarctation of the aorta, and stenosis of the peripheral arteries |
VATER association (VACTERL association) | Combination of vertebral, anorectal, cardiac, tracheo-esophageal (tracheal fistulas), esophageal (esophageal atresia), renal, and limb anomalies, intrauterine growth retardation | Broad range of cardiac anomalies, most common are VSD, single umbilical artery | Incidence 1:6,000 of all live births, mostly sporadic occurrence, cardiac defects are present in approximately 50% of the cases |
CHARGE association | Coloboma, cardiac anomalies, choanal atresia, retarded development, genital hypoplasia, ear anomalies | Conotruncal anomalies (Fallot tetralogy, DORV, truncus arteriosus communis), aortic arch anomalies (vascular rings, arteria lusoria, interrupted aortic arch) | Affected genes: CHD7, SEMA3E. Cardiac defects are present in approximately 70% of cases, conotruncal and aortic arch anomalies are typical |
LEOPARD Syndrome | Lentiginosis (pigmentation of the skin), ECG changes, ocular anomalies, pulmonary stenosis, genital anomalies, retardation, deafness | Valvular pulmonary stenosis, hypertrophic cardiomyopathy, conduction disorders | Affected gene: PTPN11. Cardiac defects are present in more than 70% of cases, valvular pulmonary stenosis is typical |
Smith–Lemli–Opitz syndrome | Syndactyly of the 2nd and 3rd toes, short stature, microcephaly, genital anomalies | ASD, VSD, AVSD, anomalous pulmonary venous connection | Incidence 1:20,000 of all live births, affected gene DHCR7, autosomal recessive inheritance |
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