Congenital Cardiac Malformations in the Neonate: Isolated or Syndromic? Anita E. Beck and Louanne Hudgins NeoReviews 2003;4;105 DOI: 10.1542/neo.4-4-e105

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Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010 Article genetics Congenital Cardiac Malformations in the Neonate: Isolated or Syndromic? Anita E. Beck, MD, PhD*, Objectives After completing this article, readers should be able to: Louanne Hudgins, MD* 1. Delineate the approximate percentage of children born with a structural cardiac malformation. 2. Determine when to consider the diagnosis of a possible genetic condition in a neonate who has a structural cardiac lesion. 3. List the most common genetic conditions associated with some specific cardiac malformations. 4. Characterize the genetic tests required in diagnosing specific syndromes. 5. Describe the role of a genetics consultation for the neonate who has a congenital cardiac malformation.

Introduction Congenital heart disease is a significant source of neonatal morbidity and mortality. In liveborn infants, approximately 1/170 is diagnosed as having a structural malformation of the cardiac system. With the increased availability of good-quality prenatal ultrasonogra- phy, many of these babies are being diagnosed prior to birth, allowing for improved management and treatment. When a congenital cardiac lesion is suspected in a newborn, physicians in multiple specialties must converge to diagnose and treat this possibly life-threatening condition. General pediatricians, neonatologists, and cardiologists are key to the immediate stabili- zation and care of affected children. The prognosis for a child who has a congenital cardiac malformation depends not only on the severity of the heart defect, but on whether there is an underlying syndrome present that would have implications for other medical issues or cognitive development. A careful search must be undertaken to exclude other major malformations or minor anomalies (dysmorphic features) that might lead to the diagnosis of a syndrome. Cardiac malformations have many causes. Isolated cardiac malformations are believed to result from the interaction among multiple genes and environmental factors, known as multifactorial inheritance. In contrast, when a cardiac malformation is associated with other major malformations or minor anomalies, it is considered syndromic and can be caused by a teratogen, chromosome abnormality, or single gene disorder. Teratogenic causes include infectious etiologies (eg, rubella), chemical exposures (eg, ethanol, anti- convulsants), and maternal conditions (eg, diabetes). Syndromes in which the neonate carries an entire extra chromosome (trisomies 13, 18, or 21) or a missing chromosome (eg, Turner syndrome) are well known to be associated with cardiac defects. Other chromo- somal problems, such as cytogenetically visible deletions (eg, 11p-) or small deletions visible only by fluorescence in situ hybridization (FISH) analysis (eg, Williams syndrome, Abbreviations 22q11 deletion syndrome), also include cardiac malforma- ASD: atrial septal defect tions. In other syndromes, congenital heart malformations AV: atrioventricular can be caused by mutations in single genes, such as TBX5 FISH: fluorescence in situ hybridization (Holt-Oram syndrome), JAG1 (Alagille syndrome), or ZIC3 VSD: ventricular septal defect (X-linked situs inversus). For the purposes of this review, we concentrate on relatively common disorders that have a

*Lucile Salter Packard Children’s Hospital and Stanford University Medical Center, Stanford, CA.

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Table 1. Genetic Syndromes Associated With Specific Cardiac Malformations

Other Conditions Most Specific That Can Have Associated Genetic Same Cardiac Cardiac Malformation Syndrome Test Malformation Atrial septal defect Holt-Oram Research only (TBX5 gene mutations) Turner Syndrome Trisomy 21 Kabuki None Noonan syndrome Atrioventricular canal Trisomy 21 (Down) Routine chromosome study Situs ambiguous 22q11 deletion Coarctation of the aorta Turner Routine chromosome study Kabuki syndrome Conotruncal defects 22q11 deletion Fluorescence in situ hybridization Interrupted aortic arch (FISH) to detect microdeletion of Truncus arteriosus the 22q11 region Tetralogy of Fallot Perimembranous ventricular septal defect Dextrocardia Kartagener Ciliary biopsy Situs ambiguous Research Hypoplastic left heart Turner Routine chromosome study Jacobsen (11q-) Routine chromosome study Peripheral pulmonary artery Alagille FISH (clinical) to detect Williams stenosis microdeletion of the 20p12 region Turner JAG1 gene mutation analysis (research) Noonan Sequence PTPN11 gene Supravalvular aortic stenosis Williams FISH with 7q11 region probe Ventricular septal defect Trisomy 21 Routine chromosome study Kabuki Holt-Oram 22q11 deletion FISH with 22q11 region probe Trisomy 13 Trisomy 18 genetic (chromosomal or single gene) basis and are asso- prompt a search for additional undiagnosed malforma- ciated with characteristic congenital cardiac malforma- tions. Second, an understanding of the general prognosis tions. for children who have the specific condition can help Although no individual cardiac malformation is pa- direct the decision to proceed with surgical repair of the thognomonic for a particular syndrome, specific cardiac cardiac lesion. Third, with a specific diagnosis in hand, anomalies often are seen in specific syndromes (Table 1). the family can be counseled more accurately about With the assistance of a medical geneticist, the clinician whether this same condition is expected to recur in future who understands which cardiac malformations are asso- children. ciated with which syndromes and who conducts a careful The purpose of this report is to review specific cardiac dysmorphologic examination of the newborn often can malformations and the conditions that are most likely make the appropriate diagnosis. and, therefore, should be considered. Associated features It also is important to obtain a complete family his- for each condition are outlined, and available testing is tory, searching for similar or related medical issues in reviewed (Table 1). Other less specific cardiac lesions, extended family members. A positive family history may when present, also are discussed (Table 2). be a clue to the diagnosis, but the absence of a family history does not exclude a genetic condition. Atrioventricular Septal Defect (AV Canal) The identification of a syndrome that includes a car- The atrioventricular (AV) septal defects are a group of diac malformation can have many implications. First, cardiac malformations whose incidence is approximately knowledge of other noncardiac manifestations that can 1/6,500 and which share defects of the AV septum and occur in children who have the specific diagnosis can the AV valves (mitral and tricuspid). AV septal defects e106 NeoReviews Vol.4 No.4 April 2003 Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010 genetics cardiac malformations

Table 2. Cardiac Malformations Seen in Selected Genetic Syndromes

% with Cardiac Syndrome Incidence Defects Most Common Cardiac Findings Trisomy 21 (Down) 1/700 40 Atrioventricular (AV) canal, ventricular septal defect (VSD) Turner 1/2,500 35 Aortic coarctation, aortic stenosis, bicuspid aortic valve, hypoplastic left heart 22q11 deletion (velocardiofacial, 1/2,000 to 1/4,000 75 Conotruncal (interrupted aortic arch, truncus DiGeorge) arteriosus, tetralogy of Fallot, perimembranous VSD) Alagille 1/70,000 90 Peripheral pulmonic artery stenosis, tetralogy of Fallot, VSD, atrial septal defect (ASD), aortic stenosis, aortic coarctation Holt-Oram 85 ASD, VSD, mitral valve prolapse Jacobsen (11q-) Rare Hypoplastic left heart Kabuki 1/32,000 50 Aortic coarctation, ASD, VSD Kartagener 50 Dextrocardia with situs inversus Noonan 1/2,000 65 Pulmonic stenosis Situs ambiguous 95 Dextrocardia, congenitally corrected transposition of the great arteries, patent ductus arteriosus, VSD, peripheral pulmonic stenosis Williams 1/10,000 to 50,000 80 to 100 Supravalvular aortic stenosis, peripheral pulmonic stenosis, ASD

can be partial or complete. The complete defect is char- translocation involving chromosome 21, which can be acterized by an abnormal communication between both inherited from a parent. atria and both ventricles as well as one common AV valve, The complete AV septal defect also can be seen in reflecting incomplete separation of the AV valves. cases of situs ambiguous, and partial AV defects are The association with which most practitioners are found in the 22q11 deletion syndrome. familiar is that of the complete AV septal defect in trisomy 21 (Down syndrome). In fact, approximately 75% of newborns who have a complete AV septal defect Atrial Septal Defect (ASD) have Down syndrome. The clinician should look for the An ASD is an abnormal communication between the characteristic features of up-slanting palpebral fissures, atria that results in shunting of blood between the two small ears with overfolded superior helices, in-curving of chambers. The incidence of the most common type, the the fifth fingers (clinodactyly), single transverse or secundum type atrial septal defect, is 1/2,300. bridged palmar creases, and an increased space between The Holt-Oram syndrome (also known as the “hand- the first and second toes, often with an accompanying heart” syndrome) should be considered in a newborn plantar crease. Approximately 40% of newborns who who has an ASD and defects of the upper limbs, specifi- have trisomy 21 have cardiac malformations, and of those cally of the radial ray. The limb defects can include an who have a heart defect, about 40% have a complete AV absent radius or thumb, a triphalangeal thumb, or more septal defect. A ventricular septal defect (VSD) is seen in dramatic reduction defects of the upper limb. The car- 30%, atrial septal defect (ASD) in 9%, tetralogy of Fallot diac defects associated with Holt-Oram syndrome also in 6%, and patent ductus arteriosus in 9%. It always is can include VSDs. TBX5, the gene that causes this syn- important to obtain routine chromosome study (karyo- drome, is found at chromosome 12q24, but clinical type) for a child who has Down syndrome because it is testing is not available at this time. critical for accurate recurrence risk counseling to separate Other genetic syndromes in which an ASD can be the 95% of children who have trisomy 21 due to nondis- seen include Kabuki syndrome, Turner syndrome, tri- junction from the 2% to 3% who have a Robertsonian somy 13, trisomy 21, and Noonan syndrome.

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Interrupted Aortic Arch Coarctation of the Aorta In this condition, there is congenital absence of a portion Coarctation of the aorta results in a narrowing of the of the aortic arch. Type B is the most common and aortic arch (often near the level of the ductus arteriosus) involves an interruption between the left carotid and the and leads to increased resistance to blood flow from the left subclavian arteries. proximal to distal aorta. Aortic coarctation is seen in One study found that 52% of children who had inter- 1/2,500 neonates. rupted aortic arch had a microdeletion in the 22q11 If the child who has aortic coarctation is a female, region, which leads to the 22q11 deletion syndrome Turner syndrome should be considered. Congenital car- (also known as velocardiofacial, DiGeorge, CATCH 22, diac malformations occur in 35% of newborns (and 75% Shprintzen, or conotruncal anomalies face syndromes). of fetuses) who have Turner syndrome. The most com- mon types of cardiac lesions are obstructive left-sided, This deletion syndrome is found in 1/2,000 to 4,000 such as aortic coarctation, aortic stenosis, bicuspid aortic live births. Affected neonates characteristically have long valve, and hypoplastic left heart. Approximately 75% of fingers and toes, a laterally built-up nose or bulbous nasal newborns who have Turner syndrome and a cardiac tip, and less commonly, cleft palate or bifid uvula (Fig. defect have coarctation of the aorta. Associated features 1). In addition, they can have aplasia or hypoplasia of the that may present in the affected neonate include a broad thymus or the parathyroid glands, leading to a specific chest with wide-spaced nipples, puffiness of the hands T-cell immunodeficiency or hypocalcemia and subse- and feet (Fig. 3), and a webbed posterior neck. Routine quent seizures, respectively. chromosome analysis likely would show a 45,X karyotype The cardiac defects found in 75% of the children who (50%) or a 46,XX karyotype in which one of the two X have the 22q11 deletion syndrome characteristically in- chromosomes is abnormal (eg, ring, deletion) or a mo- volve malformations of the conotruncal structures. These saic karyotype. cardiac defects include tetralogy of Fallot, interrupted Kabuki syndrome is another condition in which aortic aortic arch, truncus arteriosus, and perimembranous coarctation is a common feature. Approximately 50% of VSDs. those who have Kabuki syndrome are estimated to have Because the clinical features of this syndrome can be cardiac malformations, and 50% of those have aortic quite subtle, a routine karyotype and FISH study for the coarctation. In addition, ASDs, VSDs, partial anoma- 22q11 deletion or a consultation with a medical geneti- lous pulmonary venous return, or valvular pulmonic cist should be obtained. In at least 90% of cases, the stenosis can be seen. Clinically, affected children ex- microdeletion appears as a new mutation; fewer than 10% hibit long palpebral fissures with eversion of the lower are inherited from one of the parents. third of the eyelid, arched eyebrows, prominent ears (often with ear pits), and persistence of the fetal fin- gertip pads. Renal ultrasonography can reveal kidney Supravalvular Aortic Stenosis anomalies. At this time, the genetic cause of Kabuki syndrome is unknown. Aortic stenosis is a left-sided outflow tract obstruction that occurs in 1/3,000 newborns. The obstruction can Peripheral Pulmonary Artery Stenosis lead to left ventricular hypertrophy or aortic insuffi- Peripheral pulmonary artery stenosis is a narrowing that ciency. The supravalvular form of this condition results obstructs blood flow from the right ventricle at the level when the fibromembranous narrowing occurs above the of the pulmonary arteries. This increases resistance to aortic valve and coronary arteries. flow from the right ventricle, causing right ventricular If a newborn presents with supravalvular aortic steno- hypertrophy. sis, the diagnosis of Williams syndrome should be con- Peripheral pulmonary artery stenosis can be associated sidered strongly. Associated features that can be seen in with Alagille syndrome, Noonan syndrome, Williams the neonate (Fig. 2) include periorbital fullness of sub- syndrome, or Turner syndrome. If peripheral pulmonary cutaneous tissues, prominent lips, long philtrum, and artery stenosis is associated with hepatic cholestasis (bile evidence of hypercalcemia (found in 10%). duct hypoplasia/increased direct bilirubin), Alagille syn- A FISH study for a microdeletion of the 7q11 region drome should be considered. Other features of Alagille should be ordered. Most cases of Williams syndrome are syndrome include characteristic eye findings (posterior sporadic, but autosomal dominant inheritance has been embryotoxon), spine defects (eg, butterfly vertebrae), reported. and characteristic facial features (eg, a broad forehead e108 NeoReviews Vol.4 No.4 April 2003 Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010 genetics cardiac malformations

and a pointed chin). Alagille syndrome has been found to pulmonary infections, chronic sinusitis, and male infer- be caused by mutations in the JAG1 gene. FISH testing tility (due to sperm immobility). Because this leads to a that can detect a microdeletion of the 20p12 region mirror-image heart, the incidence of serious cardiac mal- containing the JAG1 gene is available clinically, but it is formations is low. Kartagener syndrome is caused by a only positive in approximately 7% of cases of Alagille defect in one component of the dynein arm. Mutations in syndrome. Additional testing is available on a research the gene encoding axonemal dynein intermediate chain basis only. (DNAI1) at chromosome position 9p21-p13 can cause Noonan syndrome, which occurs in 1/2,000 new- this autosomal recessive phenotype. It likely will be dis- borns, presents with similar clinical features to Turner covered that mutations in other similar genes also can syndrome, including webbed neck, a broad shield- cause the Kartagener syndrome phenotype. Currently, shaped chest, and short stature. This diagnosis should be the diagnosis is established with a biopsy of nasal mucosa considered in a male or a female who has a normal 46,XX to assess ciliary function. karyotype but a “Turner syndrome-like” phenotype. The other types of laterality defects present with situs Noonan syndrome has been found to be due to autoso- ambiguous (left/right anatomic structures are discor- mal dominant mutations in the PTPN11 gene (chromo- dant in their positioning), bilateral “right-sidedness” some 12q24.1). Clinical testing to sequence the PTPN11 gene recently has become available and can leading to asplenia, or bilateral “left-sidedness” leading detect mutations in approximately 50% of patients. to polysplenia. Affected children have a high incidence of serious complex cardiac defects. An X-linked form of this Hypoplastic Left Heart condition has been described, with mutations found in In hypoplastic left heart syndrome, the left ventricle of the ZIC3 gene at Xq25. Mutations have been found in the heart becomes so hypoplastic that it has great diffi- other autosomal genes as well, including lefty and nodal. culty maintaining systemic blood flow. The right ventri- Clinical testing is not yet available. cle is dilated and hypertrophied, and an ASD is present. The entire systemic output is dependent on flow through the large ductus arteriosus. Often aortic or mitral valve Conclusions atresia or stenosis is present, with hypoplasia of the Although congenital cardiac malformations typically are ascending aorta. sporadic, it is important to identify those cases in which This devastating condition can be seen in female the cardiac finding is part of a syndrome. Without know- infants who have Turner syndrome, which should ing the specific cause of the cardiac lesion, a general prompt the clinician to look for the previously men- recurrence risk of 3% to 4% is quoted if healthy parents tioned features of this syndrome. Another chromosomal have one affected child, and fetal echocardiography is abnormality that can be seen with this cardiac malforma- recommended in subsequent pregnancies. A more accu- tion is 11q- (Jacobsen syndrome). Accordingly, routine rate assessment of risk can be determined if a specific chromosome analysis should be undertaken in infants diagnosis is made. who present with hypoplastic left heart syndrome. Clin- A genetics evaluation is most appropriate in neonates ical findings in the neonate may include intrauterine who have congenital cardiac malformations associated growth retardation, widely spaced eyes, a triangular skull with dysmorphic features. A chromosomal analysis may shape with a prowlike forehead, and a large mouth held be indicated, and for certain cardiac lesions, more specific in an open position. testing is required. A FISH test to rule out the 22q11 Dextrocardia deletion is particularly important for conotruncal heart Dextrocardia indicates that the heart is located in the lesions. In the newborn who has supravalvular aortic right chest, and this finding can be seen in syndromes in stenosis, a FISH test to exclude a deletion of the 7q11.23 which there are defects of normal body right-left symme- region responsible for Williams syndrome may be try. The finding also may be associated with situs abnor- needed. As more scientific information is gained, the malities of the visceral organs. Approximately 20% to causes of additional genetic disorders involving cardiac 25% of individuals who have complete situs inversus (all defects will be discovered. When these tests become left/right anatomic structures in a mirror-image reversal) clinically available, clinicians will have an increased ability have Kartagener syndrome (immotile cilia syndrome). to diagnose infants who have various cardiac malforma- Later in life, affected children show evidence of recurrent tion syndromes.

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Suggested Reading Gene Clinics/Gene Tests. http://www.genetests.org/ Aylsworth, AS. Clinical aspects of defects in the determination of Neilson DE, Robin NH. Advances in the genetics of pediatric heart laterality. Am J Med Gen. 2001;101:345–355 disease. Contemp Pediatr. 2002;19:85–100 Emanuel BS, McDonald-McGinn D, Saitta SC, Zackai EH. The Online Mendalian Inheritance in Man. http://www.ncbi.nlm. 22q11.2 deletion syndrome. Adv Pediatr. 2001;48:39–73 nih.gov/omim/ Emmanouilides GC, Riemenschneider TA, Allen HD, Gutgesell Riopel DA.The heart. In: Stevenson RE, Hall JG, Goodman RM, HP, eds. Moss and Adams Heart Disease in Infants, Children eds. Human Malformations and Related Anomalies. Vol II. and Adolescents: Including the Fetus and Young Adult. 5th ed. New York, NY: Oxford University Press; 1993: 237–253 Baltimore, Md: Williams and Williams; 1995

NeoReviews Quiz

9. Cardiac malformations have many causes, including congenital infections, chemical exposures, maternal conditions, and genetic syndromes. Of the following, a single gene mutation resulting in a cardiac malformation is most characteristic of: A. Down syndrome. B. Holt-Oram syndrome. C. Prader-Willi syndrome. D. Turner syndrome. E. Velocardiofacial syndrome.

10. Alagille syndrome, caused by a single gene mutation (JAG1), is characterized by hepatic cholestasis, spinal defects, and cardiac malformations. Of the following, the most common cardiac malformation in Alagille syndrome is: A. Atrioventricular septal defect. B. Dextrocardia. C. Interrupted aortic arch. D. Peripheral pulmonary artery stenosis. E. Supravalvular aortic stenosis.

e110 NeoReviews Vol.4 No.4 April 2003 Downloaded from http://neoreviews.aappublications.org by J Michael Coleman on August 12, 2010 Congenital Cardiac Malformations in the Neonate: Isolated or Syndromic? Anita E. Beck and Louanne Hudgins NeoReviews 2003;4;105 DOI: 10.1542/neo.4-4-e105

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