Syndromic congenital heart disease

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Cardiac malformations are among the most prevalent malformations in congenital syndromes. A large list of syndromes with congenital heart disease as a common manifestation has known genetic defects. CHD syndromes can be either due chromosome dosage disorders, large chromosomal deletions, small micro-deletions, or single gene defects. Table 2 shows a list of CHD syndromes within each of these categories with the corresponding genetic defect. This section will discuss the most common syndromes that include congenital heart disease as a primary manifestation. Within each syndrome, the phenotypic diversity as well as the spectrum of mutations and chromosomal defects that have been reported will be discussed.

4.1. Down Syndrome (trisomy 21)

Down Syndrome is the most common disorder of chromosome dosage with an incidence of 1 in 700 to 1 in 800 live births. The incidence is known to increase tremendously with increased maternal age, particularly above the age of 35. The main clinical manifestations of Down Syndrome are characteristic dysmorphic facies, mental retardation, premature ageing, congenital heart disease, hearing loss, and increased risk of hematologic malignancies.(Pueschel 1990)

Syndrome with CHD

Genetic Cause for CHD

Disorders of Chromosome Dosage

Trisomy 21 (Down Syndrome)




Chromosomal Microdeletions

Di Georges Syndrome

22q11.2 deletion resulting in absent TBX1 gene

Williams-Beuren Syndrome

Microdeletion of ELN gene; Mutations in ELN gene

Single Gene Defects

Holt-Oram Syndrome

TBX5 mutations

Alagille Syndome

JAG1 or Notch1 mutations; Microdeletion or rearrangement at 20p12 resulting in absent JAG1 gene

Noonan Syndrome

Mutations in PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, and HRAS

CHARGE Association

Mutations in CHD7 and SEMA3E; Microdeletion at 22q11.2

Char Syndrome

Mutations in TFAP2B

Ellis-can Creveld Syndrome

Mutations in EVC or EVC2

Cardiofaciocutaneous Syndrome

Mutations in KRAS, BRAK, MEK1, or MEK2; Microdeletion at 12q21.2-q22

Costello Syndrome

Mutations in HRAS (overlap with Noonan and Cardiofaciocutaneous Syndrome)

Marfan Syndrome

Mutations in Fibrillin-1

Table 2. Syndromes Manifesting Congenital Heart Disease and their Genetic Cause

Table 2. Syndromes Manifesting Congenital Heart Disease and their Genetic Cause

Congenital Heart Disease occurs in 40 to 50% of Down Syndrome patients. The most common abnormality is Atrioventricular Septal Defect (AVSD).(Marino 1993) Other malformations include VSD and TOF among others. Some CHD phenotypes are not seen in Down Syndrome patients such as Transposition of the Great Arteries (TGA) and Situs Inversus.(Marino 1993) Adult patients with Down Syndrome are also predisposed to Mitral Valve Prolapse (MVP) and fenestrations in the cusps of the aortic and pulmonary valves. (Hamada and others 1998)

Given the complexity of the phenotype in Down Syndrome, there has been tremendous effort to build a phenotype map and identify the genetic cause behind each phenotype.(Delabar and others 1993; Korenberg and others 1994) Although successful for other features of Down Syndrome, the cause of the cardiac malformations in Down Syndrome are still unclear. Knowing that CRELD1 gene mutations have been associated with AVSD, one screening of 39 Down Syndrome patients identified two missense CRELD1

mutations and suggested that CRELD1 mutations might cause AVSD in Down Syndrome.(Maslen and others 2006) However other complex hypotheses have been suggested such as epigenetic mechanisms. Despite considerable process for molecular genetic analysis of Down Syndrome has been achieved using mouse models, to date no clear cause for CHD is known.

4.2. Turner Syndrome

Turner syndrome is a condition in females where all or part of one sex chromosome is absent. It is estimated to occur in 1 of 2500 females.(Bondy 2009) It manifests most commonly with characteristic physical features such as short stature, webbed necks, broad chest, low hairline, and low set ears, gonadal dysfunction, and cognitive deficits.(Bondy 2009) Clinical features are highly variable and can sometimes be very mild. Congenital heart disease is found in 20% to 50% of Turner Syndrome patients. The most common malformation is a Coarctation of the Aorta (COA) of the postductal type, which comprises 50% to 70% of CHD in Turner Syndrome.(Doswell and others 2006) Other cardiac malformations seen in Turner Syndrome include Bicuspid Aortic Valve (BAV), Partial Anomalous Pulmonary Venous Connection (PAPVC), and Hypoplastic Left Heart (HLH). In addition, a higher frequency of cardiac conduction abnormalities, hypertension, and aortic dilation has been reported in Turner Syndrome patients.(Doswell and others 2006; Lopez and others 2008) The molecular mechanisms leading to the cardiac malformations in Turner Syndrome are not clear.

4.3. Di George Syndrome

Di George Syndrome (DGS) is also known as Velocardiofacial Syndrome (VCFS) or Chromosome 22q11.2 Deletion Syndrome. It is caused by a 1.5 to 3.0-Mb hemizygous deletion on chromosome 22 q11, which can be inherited in an autosomal dominant fashion, but most commonly arises de novo.(Emanuel 2008) The clinical manifestations are highly variable owing to incomplete penetrance. When the disease is fully penetrant, clinical manifestations include cardiac outflow tract defects, parathyroid gland hypoplasia resulting in hypocalcaemia, thymus gland aplasia resulting in immunodeficiency, and neurologic and facial abnormalities.(Emanuel 2008) Cardiac outflow tact defects in DGS include TOF, type B Interrupted Aortic Arch (IAA), Truncus Arteriosus, Right Aortic Arch, and aberrant right subclavian artery.(Momma 2010) (Yagi and others 2003) The molecular mechanisms leading to the phenotype in DGS are more known than for Down and Turner Syndromes. The microdeletion results in haploinsufficiency of the TBX1 gene, which is responsible for neural crest migration into the derivatives of the pharyngeal arches and pouches in the developing embryo.(Emanuel 2008) Target genes downstream of TBX1 are not yet elucidated, however they are most likely to explain the different phenotypes in DGS.

4.4. Williams-Beuren Syndrome

Williams-Beuren Syndrome (WBS) results from a hemizygous deletion of 1.5 to 1.8 Mb on chromosome 7q11.23, an area that encompasses 28 genes. Its prevalence is estimated to be 1

in 7500.(Stromme and others 2002) Clinically, patients have Supravalvular Aortic Stenosis (SVAS), mental retardation, characteristic facial features, distinctive dental anomalies, infantile hypercalcemia, and peripheral pulmonary artery stenosis.(Beuren and others 1962; Grimm and Wesselhoeft 1980; Williams and others 1961) The cardiac phenotype of vascular stenosis is caused by haploinsufficiency of the Elastin (ELN) gene and is found in at least 70% of the patients.(Pober 2010) Mutations of the ELN gene also result in familial cases of SVAS without the syndromic features of Williams-Beuren.(Curran and others 1993; Metcalfe and others 2000) Although SVAS is the most common lesion in WBS patients, vascular stenoses can occur in any medium or large artery due to the thick media layer. Lesions have been described in aortic arch, descending aorta, pulmonary, coronary, renal artery, mesenteric arteries, and intracranial arteries.(Pober 2010) Half of Williams-Beuren patients also suffer form hypertension, and cardiovascular disease is the most common cause of death in these patients.(Pober 2010; Pober and others 2008)

4.5. Holt-Oram Syndrome

Holt-Oram Syndrome (HOS) is also known as Heart-Hand Syndrome, and it manifests as congenital heart disease and upper limb dysplasia. The heart manifestations are mostly septal malformations and include secundum ASD, VSD, patent ductus arteriosus, and conduction system abnormalities. The upper limb malformations are widely variable but are typically bilateral and asymmetric in severity. They can range from a small abnormality such as a distally-placed thumb to phocomelia or hypoplasia of the shoulders and clavicles. Sometimes the upper limb dysplasia can go unnoticed and will be seen only after radiological imaging. Congenital heart malformations occur in 85% of HOS patients.(Basson and others 1994; Boehme and Shotar 1989)

Genetically, HOS is an autosomal dominant disease caused by mutations in the TBX5 gene, a member of the T-box family of transcription factors. (Basson and others 1997; Li and others 1997b) Haploinsufficiency of TBX5 was shown to be at the origin of the HOS. TBX5 interacts with other cardiac-specific transcription factors GATA4 and NKX2-5 to regulate the expression of downstream genes such as ID2, which are essential in septation of the cardiac chambers as well as development of the conduction system. The functional mechanisms through which the three transcription factors TBX5, GATA-4, and Nkx2-5 interact to mediate processes in heart development have been heavily studied, and there is a very complex network of interactions among these and other transcription factors and downstream genes that exists but that is still partially understood (Figure 1).

Genotype-phenotype correlations were also performed in HOS, and it has been shown that TBX5 mutations that create null alleles result in more severe abnormalities in both upper limbs and the heart as compared to missense mutations.(Basson and others 1999) Some mutations caused very severe cardiac malformations but only subtle upper limb deformities. From a clinical perspective, it is important to look for subtle upper limb malformations in patients with septal deformities, because a diagnosis of HOS can increase the recurrence risk in a sibling from 3% to 50% given that this is an autosomal dominant disease. Clinical genetic testing for TBX5 has also become available in some laboratories across the world.

Genetic Disorders List )"/>
Figure 1. Complex Genetic Interactions of TBX5, GATA4, and Nkx2-5 (Network created using )

4.6. Alagille Syndrome

Alagille Syndrome is inherited in an autosomal dominant fashion and is defined in the presence of intrahepatic bile duct paucity that usually manifests as cholestasis, congenital heart disease, distinctive facies, skeletal, ocular, renal, and neurological abnormalities. (Kamath and others 2011; Li and others 1997a) CHD is found in more than 90% of patients with Alagille Syndrome and the most common lesion is Pulmonary Atery Stenosis (PAS) or hypoplasia. Other common lesions include TOF, pulmonary valve stenosis (PS), and ASD.(McElhinney and others 2002) The prevalence of the disease is estimated at around one in 700,000 neonates when presence of jaundice is used to ascertain cases (Danks and others 1977), but in fact the disease has a tremendous variability in the phenotype and variable penetrance in families so that the actual prevalence is expected to be much higher.

Alagille Syndrome is caused by mutations in the JAG1 gene.(Li and others 1997a; Oda and others 1997) The gene encodes a ligand to the Notch1 receptor. Jagged-Notch cell-cell interactions are crucial in determining cell fates during early developmental processes. The mutations spectrum of JAG1 in Alagille Syndrome encompasses frameshift mutations, nonsense mutations, splice site mutations, or deletion of the whole gene.(Yuan and others

1998) Mutations have also been identified in patients with a predominantly cardiac phenotype.(Li and others 1997a) Some families do have variable penetrance of the mutation as well as variant expressivity of the disease within the same family, such as facial dysmorphism only, or subtle liver disease only within members of the family carrying the same mutation.(El-Rassy and others 2008) JAG-1 mutations are present in 94% of patients that are clinically diagnosed with Alagille Syndrome. A small number of cases are also explained by mutations in the Notch1 gene, the JAG-1 receptor.(McDaniell and others 2006).

Clinical testing for JAG-1 mutations is available. If patients are clinically diagnosed, a JAG-1 mutation could confirm the diagnosis, and indicate the need for multisystem assessment to look for other subclinical abnormalities and possibly prevent them. It would also allow for similar assessment of family members. Due to the high variability of the disease, patients with suspicious right-sided heart lesions such as PAS, TOF, and PS who do not necessarily fulfill the criteria for Alagille Syndrome could also be tested for JAG-1 mutations.

4.7. Noonan Syndrome

Noonan Syndrome (NS) is a dysmorphic cardiofacial syndrome inherited mostly in an autosomal dominant fashion, with some cases occurring sporadically. Its incidence ranges between 1 in 1000 to 1 in 2500 live births.(Tartaglia and others 2010) The characteristic physical features are downward eyeslanting of the eyes, hypertelorism, low-set ears, short stature, short and webbed neck, and epicanthic folds.(Tartaglia and others 2010) Congenital Heart Disease is found in 80 to 90% of patients with Noonan Syndrome and valvar pulmonary stenosis (PS) and Hypertrophic Cardiomyopathy (HCM) are the two most common cardiac manifestations. A large set of cardiac malformations can also occur including secundum ASD, AVSD, TOF, COA, VSD, PDA, and mitral valve disease.(Marino and others 1999; Noonan 1994) Patients might also have deafness, cryptorchidism, motor delay, and bleeding diathesis.(Tartaglia and others 2010)

NS is a genetically heterogeneous syndrome with at least 8 genes that have been associated with the disease so far: PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, and HRAS.(Tidyman and Rauen 2009) Mutations in PTPN11 are most common and explain 50% of the Noonan Syndrome cases, the other 7 genes explain roughly 25% of the cases, and in about 25% of the cases no mutation is found.(Tartaglia and others 2010) All the genes implicated in NS encode proteins that are part of the Ras/Raf/MEK/ERK signaling pathway, an important regulator of cell proliferation, differentiation, and survival. PTPN11 encodes SHP-2, a protein tyrosine phosphatase that plays an important role in the signal transduction to medial the biological processes described above.

Disease penetrance is almost complete with PTPN11 mutations, but there is a wide variability in the phenotype. Clinical testing for some of the genes involved in NS such as PTPN11, SOS1, and KRAS is available. Clinical diagnosis might be helpful might be helpful in borderline cases given the variability in the phenotype.

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  • Demet
    What is Ellis van creveld syndrome?
    2 years ago

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