Syndromes, Genetics, and Heritable Heart Disease

75 

Syndromes, Genetics, and Heritable Heart Disease BENJAMIN J. LANDIS, MD; MATTHEW T. LISI, MD

T

he association between congenital cardiovascular malformations (CVMs) and genetic syndromes is well established.1 Traditionally, a characteristic constellation of clinical features has defined a genetic syndrome. The list of syndromes associated with CVMs is expansive and includes disorders caused by different classes of genetic abnormalities. These include abnormality of chromosome number or large structural chromosomal defects. Down syndrome, which is caused by the presence of three copies of chromosome 21, is the most common aneuploidy syndrome among patients born with CVMs. Alternatively, syndromic CVMs may be caused by microdeletions or microduplications, which encompass smaller chromosomal regions. DiGeorge syndrome, which is caused by the presence of a deleted segment on the long arm of one of the copies of chromosome 22 (22q11.2 deletion), is a common example. A third mechanism known to cause syndromic CVMs is the alteration of DNA sequence at the nucleotide level, which includes single nucleotide variants (SNVs) and small insertions or deletions. Noonan syndrome, which is typically caused by pathogenic SNVs within genes involved in the RAS-MAP kinase signaling pathway (e.g., PTPN11), is an example. In addition to the genetic syndromes associated with CVMs, it is increasingly clear that many cases of isolated, or nonsyndromic, CVMs also have a primary genetic basis. For example, there are many reports of multigenerational families with isolated CVMs showing Mendelian inheritance patterns or complex inheritance patterns.2,3 Furthermore, large epidemiologic studies confirm increased rates of familial recurrence of CVMs across the general population of patients with CVMs.4 The field of human genetics has grown expansively since the publication of the second edition of this textbook. Novel genetic testing technologies coupled with clinical insight have fundamentally changed the way clinicians approach the diagnosis of many diseases. The basic categorization of disease, including syndromic disease, continues to improve by combining the established constellations of clinical signs and symptoms with specific molecular diagnosis. As an example of one major shift in the genetic evaluation of patients with CVMs, chromosomal microarray analysis (CMA) is increasingly used in many pediatric cardiac intensive care units (ICUs) to identify small deletions and duplications of chromosomal material, termed copy number variants (CNVs), across the genome. In addition, next-generation sequencing (NGS) technology now facilitates interrogation of the genome for nucleotide sequence variants across multiple genes in parallel. “NGS panels” apply this 892

technology to test a defined set of genes that are known to be associated with the patient’s clinical presentation (e.g., Noonan syndrome panels test for all the genes known to cause Noonan syndrome simultaneously). Alternatively, NGS technology can be leveraged to sequence all of the coding regions of the genome (exome) or the entire genome in an increasingly time- and costefficient manner. This rapid expansion of genetic testing technology and clinical implementation not only has led to the discovery of new genetic diseases, but has significantly advanced our understanding of the molecular basis of previously described clinical syndromes. The availability and increasing affordability of CMA, NGS panels, and exome sequencing tests have accelerated advancements made in the research setting and are being integrated into routine clinical management of CVMs and other forms of pediatric cardiovascular disease. The clinical practitioner who cares for critically ill patients with CVMs will encounter many patients with genetic syndromes. The syndromic diagnosis may already be established either by prenatal or postnatal evaluations before arriving at the operating room or ICU, or, especially in neonates, the patient may not have a diagnosis yet established at the initial encounter. In either case, it is important not only to understand the genetic cause of these syndromes, but also to be familiar with the clinical features that are typically encountered. This allows providers to predict certain risks and preemptively intervene and may offer the patient and/or family information regarding prognosis, risk of familial recurrence, and identification of occult disease in relatives. This chapter begins with an overview of the interaction between the most common genetic syndromes associated with CVMs and the management of cardiac disease in the ICU, including the important considerations of noncardiac factors. This will include some discussion of clinical outcomes data. A comprehensive review of the impact of genetic syndromes on perioperative outcomes is available to the interested reader.5 Next, we explore our current understanding of the clinical utility of genetic testing in newborns with critical CVMs and highlight recent discoveries related to the genetic basis of syndromic and nonsyndromic CVMs using NGS technology. The chapter includes advisement for the routine involvement of genetics services within the pediatric cardiac ICU and surgical programs. The chapter focuses specifically on the genetic considerations for patients with CVMs, so readers should seek other resources for discussions of the genetics of other forms of pediatric cardiovascular disease, including cardiomyopathy,



CHAPTER 75  Syndromes, Genetics, and Heritable Heart Disease

aortopathy, and channelopathy, for which the availability of comprehensive and affordable multigene panels using NGS techniques, has been a cornerstone of staggering growth in pediatric cardiology.

Syndromic Congenital Cardiovascular Malformations and the Factors Influencing Intensive Care Large studies of pediatric patients with CVMs who require ICU care and/or cardiac surgery find that 10% to 30% of cases have a genetic diagnosis or noncardiac abnormalities.6-10 The true burden of syndromic disease is not completely known due to differences in genetic testing and evaluation practices among studies. Other factors, such as selection of certain age ranges or type of CVMs, may differ between studies and lead to differences in the reported prevalence of disease. These factors notwithstanding, given the high burden of syndromic disease, an important question is whether having a syndromic diagnosis in general influences perioperative outcomes of pediatric patients undergoing cardiac surgery. This question has been assessed by several studies using large cohorts of patients treated over the past two to three decades. The most consistent conclusion among these studies is that a genetic diagnosis significantly increases the risk for postoperative morbidities such as increased risk for respiratory, infectious, and renal complications, resulting in prolonged hospitalization.6,7,11,12 These complications may have long-standing, deleterious effects upon the child’s health in addition to causing increased burden on the family and health care system. Increased hospital mortality following a cardiac operation has been observed in some, but not all, studies. As one may expect, there is strong evidence to support that the risk for mortality is increased for syndromic patients requiring more complex operations. For example, data from the Society of Thoracic Surgeons (STS; years 2002 to 2006) and the Congenital Heart Surgeons’ Society (years 1994 to 2001) showed increased postoperative mortality among patients with a genetic or noncardiac congenital anomaly following stage I palliation for left ventricular outflow tract lesions such as hypoplastic left heart syndrome (HLHS).8 The design of this study highlights a common approach to batch groups of patients with a genetic syndrome together with those having a noncardiac congenital anomaly into one “syndromic” group.9 Although this approach may increase the power to detect differences via study of larger groups of patients, understanding the risk for specific syndromes is more practically useful. Ideally outcomes data pertaining to specific syndromes will become increasingly available as the use of genetic evaluations for patients with CVMs expands, facilitating the study of larger syndrome-specific cohorts and more detailed classification of patients. Fortunately, modern outcomes data have become available for several of the most common syndromes associated with CVMs. We explore these syndromes in the remainder of this section.

Down Syndrome Down syndrome, or trisomy 21, is the most frequent genetic syndrome among children born with a congenital CVM.10 It is estimated to affect between 200,000 and 300,000 individuals in the United States and occurs in at least 1 in 1000 live births.13 Congenital CVMs are present in 40% to 50% of affected children. Atrioventricular septal defect (AVSD) is the most common class

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of CVM identified (50% to 60%), followed by ventricular septal defect (VSD), atrial septal defect (ASD), and tetralogy of Fallot.10 Because of the high incidence of CVMs, all infants with known or suspected Down syndrome should have a comprehensive cardiac evaluation, including echocardiography, within the first few days to weeks of life. Many other organ systems are affected in Down syndrome (Fig. 75.1),14 but the prominent characteristics include impaired cognition, delayed growth, and facial dysmorphism. Other problems of significant importance in the intensive care/surgical setting include upper airway obstruction, atlantoaxial instability, hypothyroidism, and immune deficiency. Congenital anomalies of the gastrointestinal system, including duodenal atresia, Hirschsprung disease, or tracheoesophageal fistula, occur at increased frequency.15 In spite of these factors, the average life expectancy for individuals with Down syndrome now exceeds 50 years. However, these patients also face risks for the development of leukemia and early-onset Alzheimer’s disease.16,17 The cytogenetic abnormality responsible for Down syndrome is the trisomy of chromosome 21 (47, +21) in 93% to 96% of cases or a translocation involving chromosome 21 in 2% to 5% of cases.18 The diagnosis is typically established using the traditional karyotype. Approximately 2% to 4% of cases are associated with mosaicism due to postzygotic nondisjunction, in which case the clinical findings are usually milder. Although advanced maternal age is a risk factor, the majority of mothers bearing children with Down syndrome are between 18 and 35 years of age. If a balanced translocation is identified in a parent, genetic counseling should be performed to discuss that there is increased risk of recurrence in future offspring compared with the more typical cases caused by sporadic nondisjunction. At this time the precise pathogenetic mechanism by which trisomy of chromosome 21 leads to the Down syndrome phenotype remains incompletely understood. A significant risk for patients with Down syndrome is the development of pulmonary vascular disease (PVD). This risk is particularly high among those with nonrestrictive interventricular communication such as complete AVSD or large VSD.19 For example, some studies suggest that more than one-third of patients with trisomy 21 and a CVM have concomitant pulmonary artery hypertension.20 Chronic hypoventilation secondary to upper airway obstruction and sleep apnea may significantly contribute to the development of pulmonary hypertension. This must be dutifully managed to avoid exacerbating what is likely an intrinsic predisposition to develop PVD (see Fig. 75.1).21 The risk for early development of PVD has led to the practice of early repair of large left-to-right interventricular shunts, including complete AVSDs, usually by age 6 months. Airway and craniofacial anomalies may further complicate preoperative and postoperative management by creating difficulty with intubation, secretion clearance, atelectasis, and chylothorax, leading to risk for prolonged mechanical ventilation.22 The palliation of single-ventricle lesions may be particularly precarious for patients with Down syndrome and PVD. Pulmonary hypertension and PVD may be major contributors to the increased mortality observed in patients with Down syndrome after stage I, II, and III palliations.23,24 Preoperative evaluations and postoperative protocols may be useful for the management of patients with Down syndrome and pulmonary hypertension. Other important noncardiac problems that may complicate intensive care include atlantoaxial instability, immune deficiency, and hypothyroidism. Atlantoaxial instability may pose a risk of neurologic injury during intubation, particularly for older children and young adults.25 Dysfunction of the humoral or innate immune

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Down Syndrome Trisomy 21

Airway/Craniofacial Mid-face hypoplasia Small nares Prominent tongue Adenotonsillar hypertrophy Recurrent URI, sleep apnea Heart

Lungs

Congenital defect (50%) AV canal ASD VSD TOF other

Hypoplasia Early onset of pulmonary vascular disease

Other Atlanto-occipital instability Mental retardation Hypotonia GI and renal anomalies e.g., duodenal atresia Multiple/minor anomalies Simian crease Brushfield spots

Evaluation Echocardiogram Karyotyping

• Figure 75.1  Associated defects of Down syndrome. AV, Atrioventricular; ASD, atrial septal defect; VSD, ventricular septal defect; TOF, tetralogy of Fallot. systems may predispose to postoperative infections,24,26 but whether this risk warrants alterations of typical postoperative antibiotic prophylaxis is not established. Hypothyroidism often develops in the first year of life. Because thyroid hormone contributes significantly to cardiovascular stability, it is good practice for all patients with Down syndrome to be screened for hypothyroidism in the time leading up to cardiac surgery and, if diagnosed, to receive adequate outpatient treatment before the operation. Despite the various health challenges associated with Down syndrome and established risk for postoperative complications, recent series including large numbers of patients indicate that hospital mortality after biventricular repairs, including complete AVSD, may be unchanged or even decreased compared with patients without Down syndrome. 23,24,27 For all patients with Down syndrome a planned approach to timing and coordination

of the health care team members involved is crucial for the child and family.

22q11.2 Deletion Syndrome 22q11.2 deletion syndrome occurs in approximately 1 in 4000 individuals and is the most common microdeletion syndrome associated with congenital CVMs. Nearly 75% of patients with 22q11.2 deletion syndrome have a CVM, which most commonly include conotruncal defects, abnormal patterning of the aortic arch and brachiocephalic arteries, and perimembranous VSD (Table 75.1).28,29 The systemic features include facial dysmorphism (Box 75.1; Fig. 75.2) and cleft palate. Additional features likely to impact intensive care include hypoparathyroidism, immunodeficiency, congenital renal anomalies, and airway anomalies (Box 75.2). The

CHAPTER 75  Syndromes, Genetics, and Heritable Heart Disease



• BOX 75.1  Dysmorphic Features Associated With

TABLE 75.1  Cardiac Defects Associated With

22q11.2 Deletion Syndrome

22q11.2 Deletion

Defect

Percentage

No defect or clinically insignificant

22-25

Tetralogy of Fallot

17-20

Interrupted aortic arch

14-17

Ventricular septal defect (VSD)

14-16

Pulmonary atresia with VSD

10

Truncus arteriosus

9

Aortic arch anomaly

5

Vascular ring

3

Pulmonary valve stenosis

2

Other significant defect

4-5

Data from McDonald-McGinn DM, LaRossa D, Goldmuntz E, et al. The 22q11.2 deletion: screening, diagnostic workup, and outcome of results; report on 181 patients. Genet Test. 1997;1:99-108; and Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997;34:798-804.

Narrow palpebral fissures Hooded eyelids Hypertelorism Small, rounded protuberant ears Broad nasal bridge Bulbous nose tip Hypoplastic alae nasi Small mouth Retrognathia/micrognathia Palatal abnormalities Long thin digits

• BOX 75.2  Critical Care Considerations in 22q11.2

Deletion Syndrome

Difficult intubation Laryngeal/tracheal abnormalities Hypocalcemia Seizures Increased risk of infections Possibility of transfusion-related graft-versus-host disease Feeding difficulties

Deletion of Chromosome 22q11.2 Sndrome Airway/Craniofacial Palate abnormalities Facial dysmorphism Retrognathia

Immune/Endocrine T-cell defects Hypocalcemia

Heart Tetralogy of Fallot Interrupted aortic arch Conoventricular VSD Truncus arteriosus

Other Speech defect Variable retardation Learning disability

Evaluation FISH Metabolic Immune System Renal Ultrasound

• Figure 75.2

 

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Associated defects of 22q11.2 deletion syndrome.

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long-term challenges associated with 22q11.2 deletion include developmental delay and neuropsychiatric disorders such as attention-deficit/hyperactivity disorder, autism spectrum disorders, and psychosis.30-32 The 22q11.2 deletion syndrome is caused by hemizygous deletion of a small region of variable length on the short arm of chromosome 22 and is associated with a range of clinical phenotypes. The deletion was initially discovered in patients with the clinical characteristics of DiGeorge syndrome, but it is now understood that the deletion also causes other clinically established syndromes, including velocardiofacial syndrome and conotruncal anomaly face syndrome.33,34 The shift to combining these syndromes nominally into a single 22q11.2 deletion syndrome exemplifies the ongoing integration between syndromic diagnoses and their underlying genetic causes. The genetic test traditionally used to detect 22q11.2 deletion was fluorescence in situ hybridization (FISH), which uses a probe designed to target this chromosomal segment specifically. Practices are now turning toward use of CMA, which has higher diagnostic sensitivity because it is able to detect smaller deletions that may not be identified with FISH. When 22q11.2 deletion is not deleted, the CMA will potentially identify alternative pathogenic CNVs and therefore reach a diagnosis more efficiently. The length of the segment affected by this microdeletion is variable but typically contains between 30 and 40 individual genes. Hemizygous loss of the TBX1 gene may play a major role in causing some features of this syndrome, including CVMs.35 Hypoplasia of the thymus is often present in patients with 22q11.2 deletion syndrome, typically leading to mild to moderate immunodeficiency. Rarely, the thymus is completely aplastic, resulting in severe immunodeficiency. Thymic hypoplasia leading to low T-lymphocyte counts and B-lymphocyte dysfunction may explain reports of increased infectious complications following cardiac surgery.36,37 This may justify the use of broadened postoperative antibiotic regimens, including antifungal therapy,38 although this approach has not been conclusively tested. Further, the immunocompromised status of the patients justifies use of cytomegalovirus-negative, irradiated blood products when transfusions are required to avoid the risk of iatrogenic infection and graft-versus-host disease. Airway management may be challenging due to retrognathia or a congenital airway anomaly, including laryngeal web.39 Depending on the severity of the anomaly, the equipment and personnel necessary to establish an alternative airway should be readily available before the administration of hypnotics and neuromuscular blocking agents.40 Postoperative vocal cord paralysis, particularly after operations involving the aortic arch, or diaphragmatic paralysis can have dramatic clinical consequences and should be investigated and treated. Overt cleft palate, submucous clefts, and velopharyngeal insufficiency may significantly impair swallow function. Hypocalcemia due to developmental hypoplasia of the parathyroid glands may be present, particularly in young infants, and tends to resolve or respond to calcium supplementation. Calcium level should be monitored preoperatively and postoperatively, especially given that patients with 22q11.2 deletion have increased seizure risk independent of the presence of hypocalcemia. Renal abnormalities detectable on ultrasonography, including absent, dysplastic, or multicystic kidneys, are another common finding. The multiple noncardiac abnormalities associated with 22q11.2 deletion often complicate the postoperative course, leading to longer duration of postoperative intensive care.41,42 Although few studies are sufficiently powered to examine patients with 22q11.2 deletion syndrome in terms of mortality, most data support that there is a

• BOX 75.3  Evaluation for Patients With 22q11.2

Deletions

Typical Subspecialty Evaluation Genetics Cardiology Immunology Otolaryngology Plastic surgery Speech and audiology Neurodevelopmental Oral motor and swallowing

Additional Subspecialties as Necessary Endocrinology Gastroenterology Orthopedics Urology Pediatric surgery Psychiatry

Laboratory Evaluation Chromosomal microarray analysis Serum calcium level Complete blood count, T-cell studies, immunoglobulin concentrations Echocardiography Renal ultrasonography Data from McDonald-McGinn DM, LaRossa D, Goldmuntz E, et al. The 22q11.2 deletion: screening, diagnostic workup, and outcome of results; report on 181 patients. Genet Test. 1997;1:99-108; and Ryan AK, Goodship JA, Wilson DI, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997;34:798-804.

slightly increased risk of death following a cardiac operation.7,37,41,43 Mortality risk may be most significant for patients with pulmonary atresia, in which cases excessive bleeding may be a significant risk.36,44 This bleeding risk may be secondary to increased anatomic complexity, but dysfunction of hemostatic pathways, including platelet function, may be contributory.45 Altogether, the broad spectrum of noncardiac systemic anomalies in patients with 22q11.2 deletion syndrome highlights the importance of a multidisciplinary approach involving multiple pediatric specialists in the newborn, perioperative, and ambulatory setting. Box 75.3 lists the recommended specialties for the care team. These are ultimately tailored to match the spectrum of problems in an individual, once appropriate screening evaluations and testing have been completed.

Turner Syndrome Approximately 1 in 2000 females is born with Turner syndrome, which is due to complete or partial absence of one of the two X chromosomes. Turner syndrome predisposes to left-sided CVMs such as bicuspid aortic valve and coarctation of the aorta. Many patients also manifest signs of arteriopathy, including thoracic aortic aneurysm and dissection (TAAD) and systemic hypertension. Venous anomalies, including partial anomalous pulmonary venous return and persistent left-sided superior vena cava, are also frequently encountered.46 The noncardiac features providing clues to the diagnosis are short stature, ovarian dysgenesis, neck webbing, and widely spaced nipples. There is general consensus that patients with Turner syndrome have intrinsic dysfunction of lymphatics.47 This may be one explanation for the high frequency of hydrops

CHAPTER 75  Syndromes, Genetics, and Heritable Heart Disease



fetalis and spontaneous fetal loss. Peripheral lymphedema, which is typically present at birth and self-resolving by early childhood, may be another clue to early diagnosis. Most pertinent to intensive care is the risk for dysfunction of pulmonary lymphatics predisposing to chylothorax and pleural effusions. Congenital pulmonary lymphangiectasia may be the most drastic form of lymphatic dysfunction in Turner syndrome,48 but there is likely a spectrum of lymphatic abnormality that may manifest clinically only when confronted with stressors such as mechanical injury and/or inflammation associated with cardiopulmonary bypass surgery. Congenital renal anomalies occur frequently enough to mandate screening with ultrasonography. There is a long-term risk for development of autoimmune hypothyroidism, so patients with Turner syndrome should undergo routine screening and be tested before cardiac surgery if over 4 years of age.49 Patients with Turner syndrome undergoing surgical repair of coarctation of the aorta have displayed good postoperative outcomes since the adoption of modern surgical techniques, which include careful manipulation of diseased aortic tissues to avoid postoperative hemorrhage.50 In contrast, consistent with arteriopathy, there is evidence that treatment of coarctation with implanted stents may introduce a risk for development of aneurysm or dissection.51-53 The most concerning outcomes data in Turner syndrome concern HLHS. For unknown reasons, patients with HLHS and Turner syndrome display very poor outcomes with mortality between

stage I and stage II palliations reported to be as high as 80% and only 25% survival to stage III palliation.50,54 These poor outcomes may be related to underlying lymphatic disease, but there is a clear need for further study to understand the responsible mechanism. To improve rates of early diagnosis, it is reasonable to perform a karyotype as a routine component of care for every female infant with coarctation. Recent data show testing yields approximately 5% to 12% in girls with coarctation,55,56 and external features may be subtle in the neonatal period or in cases of mosaicism. All patients with Turner syndrome require long-term cardiac surveillance for development of hypertension and TAAD, even in the absence of bicuspid aortic valve. Routine screening with cardiac magnetic resonance imaging in late childhood may identify clinically silent features, including aortic dilation and anomalous pulmonary veins.46 Thus an early diagnosis likely improves short- and long-term outcomes.

Noonan Syndrome Noonan syndrome has a prevalence of 1 in 1000 to 2500 live births. Noonan syndrome is characterized by both cardiac and extracardiac defects (Fig. 75.3).57-59 Noonan syndrome is genetically heterogeneous, but the currently known genes cluster within the RAS-MAP kinase signaling pathway, leading some to classify

Noonan Syndrome Autosomal Dominant Inheritance

Heart/Vascular

Craniofacial/Skin

Dysplatic stenotic pulmonary valve ASD Hypertrophic cardiomyopathy Lymphedema

Hypertelorism Ptosis low-set cupped ears Low hair line Neck webbing Keloid scar Thorax

Genitourinary

wide-set nipples Shield sternum

Cryptorchidism Male hypogonadism Renal anomalies

Other Short stature Variable retardation Cubitus valgus Faxtor XI deficiency Hepatosplenomegaly

Evaluation Echocardiogram Scoring system Family history

• Figure 75.3

 

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Associated defects of Noonan syndrome.

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Noonan syndrome as a “RASopathy.” The most commonly mutated gene in this syndrome is PTPN11.60 Other causative genes in the pathway are SOS1, RAF1, KRAS, NRAS, BRAF, SHOC2, and CBL. Indeed, there are now several disorders related to Noonan syndrome with overlapping but clinically distinct phenotypes that are caused by mutations in the RAS-MAP kinase pathway. These include cardiofaciocutaneous syndrome (BRAF, KRAS), Costello syndrome (HRAS), and Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome; PTPN11, RAF1). There are important clinical considerations for each of these syndromes. The focus of this chapter will be the typical Noonan syndrome. In Noonan syndrome CVMs are observed in at least 80% of cases.61 Pulmonary valve stenosis, often with pulmonary valve dysplasia, is the most frequent cardiac anomaly, followed by hypertrophic cardiomyopathy (HCM). Secundum ASD is often associated with pulmonic stenosis, and a variety of other CVMs are reported.61 The noncardiac features of this syndrome include facial dysmorphism, short stature, kyphoscoliosis, vertebral anomalies, winged scapula, pectus sternal deformity, neck webbing, and cryptorchidism in males. Most cases represent de novo (i.e., not inherited) mutations. However, autosomal dominant familial presentations are also frequently encountered. Currently patients suspected to have Noonan syndrome are tested using an NGS panel designed to sequence all of the genes known to be associated with the clinical phenotype. When a molecular diagnosis of Noonan syndrome is established, screening of parents for the mutation should be strongly considered to identify previously unrecognized carriers who may lack obvious physical features. Whether involved in the perioperative management of cardiac or extracardiac anomalies, intensive care and surgical providers should be cognizant of several features of Noonan syndrome. Abnormalities in coagulation or platelet function are common and may predispose to bleeding complications. Some of the initial descriptions of platelet function deficit and neonatal amegakaryocytic thrombocytopenia have been corroborated by subsequent reports.62,63 Although congenital thrombocytopenia is a rare occurrence,64 comprehensive testing of platelet function has identified abnormalities in greater than 80% of patients.65 In pioneering work Sharland and colleagues,66 studied 72 affected individuals with a mean age of 11.4 years and found that 47 (65%) had a history of abnormal bruising or bleeding and 29 (40%) had a prolonged activated partial thromboplastin time with deficiencies of factors VIII, XI, and XII. These findings were recently replicated in an independent cohort of 39 patients.65 Together these data suggest that preoperative assessment for coagulation-factor deficits and platelet dysfunction may be warranted. Providers should be alert to bleeding complications and exercise caution toward the use of antiplatelet medications. Similar to Turner syndrome, Noonan syndrome may be complicated by disorders of the lymphatic system. Peripheral lymphedema is a common finding in neonates with Noonan syndrome that typically resolves early in life. However, lymphatic dysfunction may assume more severe forms, including lymphatic dysplasia or pulmonary lymphangiectasia.67,68 Recurrent pleural effusion is a rare but troublesome postoperative complication. This appears to be due to a nonspecific effect of thoracotomy in exacerbating previously mild chronic low-grade pulmonary lymphangiectasia. Good response is generally obtained with a combination of thoracentesis, restriction from dietary long-chain fatty acids, fluid restriction, and/or diuretics. Prenatal evidence of lymphedema or fluid accumulation, including fetal hydrops, may be another clue to the diagnosis.69

In terms of the cardiovascular features of Noonan syndrome, the pulmonary valve is usually thickened and dysplastic. The short-term outcomes after balloon valvuloplasty do not appear significantly different from pulmonary valve stenosis in patients without Noonan syndrome, but long-term outcomes are unknown. HCM was originally described as developing late in childhood but has now been recognized in infancy and even prenatally.70,71 The presence of HCM, which is particularly high among patients with mutations in RAF1, increases anesthetic and intraoperative risk. A recent echocardiogram should be available before anesthesia for cardiac or noncardiac surgery in infants or children with Noonan syndrome. There is evidence that some patients with HCM and Noonan syndrome experience worse outcomes compared to non–Noonan syndrome HCM.72 A baseline preoperative electrocardiogram (ECG) is also recommended before surgery. ECG abnormalities, including negative forces in left precordial leads, left axis deviation, and abnormal Q waves, are often present and unrelated to the cardiovascular anatomic phenotype.73 Characterizing the ECG appearance at baseline may help to discern whether abnormalities observed on cardiac monitors during or after surgery represent acute pathology. Although Noonan syndrome does not predispose to cardiac arrhythmia, patients with the related Costello syndrome (HRAS mutation) do have a significant risk for developing supraventricular tachycardia and multifocal atrial tachycardia in particular. Most individuals with Noonan syndrome develop normal cognitive function. Indeed, most children are able to attend regular school. However, increased risk for long-term intellectual disability warrants close monitoring for early signs of developmental delay. In early reports there was concern for a possible association between Noonan syndrome and malignant hyperthermia, as postulated by Hunter and Pinsky.74 Fortunately, this connection has not been supported over time, and risk for malignant hyperthermia is considered to be no different from the general population.75 With increased awareness and advances in genetic testing practices, including family screening, diagnoses are established earlier than in past series.76 Nonetheless the phenotypic variability, including subtlety of features and the changes in facial pattern with growth, still contributes to missed diagnoses.77 In the context of these diagnostic challenges, the pediatric intensivist confronted by a child with growth delay, pulmonary stenosis, and/or cardiomyopathy may be the first to recognize the syndrome in the child and in a parent.

Trisomy 18 (Edwards Syndrome) Trisomy 18 is a severe genetic syndrome characterized by the presence of three copies of chromosome 18. Rarely this additional chromosome is present in only some cell lines, leading to a variable clinical presentation, referred to as mosaic trisomy 18. Trisomy 18 occurs in approximately 1 in 6000 live births and is the second most common trisomy syndrome after trisomy 21. Overall the clinical features of this syndrome are quite dramatic with a very high mortality (90% to 95% in the first year of life) coupled with severe cognitive impairment and diffuse multisystem anomalies among the approximately 50% who survive beyond the first week.78 Congenital CVMs are very common with a prevalence between 80% and 100%. Common cardiac lesions include VSD, ASD, and patent ductus arteriosus (PDA). More complex lesions such as tetralogy of Fallot, double-outlet right ventricle, polyvalvular dysplasia, and AVSDs are also encountered.79,80 Due to the severe

CHAPTER 75  Syndromes, Genetics, and Heritable Heart Disease



899

Ivemark Syndrome R. atrial isomerism

L. atrial isomerism

Heart

Heart

Atrioventricular septal defect Transposition Pulmonary stenosis/atresia Total anomalous pulmonary venous return

Ventricular septal defect Pulmonary stenosis Partial anomalous pulmonary venous return Dextrocardia Airway

Airway Bilateral trilobed lung Short eparterial bronchi

Bilateral bilobed lung Long hypoparterial bronchi

PA PA

Immune system

Immune system

Asplenia/immune deficiency

Polysplenia

GI System Midline liver Malrotation Extra-hepatic biliary atresia (polysplenia only) Splenic abnormality

• Figure 75.4

 

Evaluation Blood smear Howell-Jolly bodies High KV film bronchi Liver spleen scan/MRI

Associated defects of heterotaxy/Ivemark syndrome.

impact of this syndrome on expected outcomes, rapid testing may be considered when the diagnosis is suspected postnatally. Given the grim overall prognosis, including profound neurodevelopmental impairment, the role of cardiac intervention for patients with trisomy 18 has been a significant topic of discussion, and there is little consensus among congenital heart programs at present. There is significant debate surrounding the role of cardiac intervention in modifying mortality and morbidity for these patients. Recent studies have stirred significant debate surrounding this issue by showing optimistic short-term survival rates (80% to 90%) among the few trisomy 18 patients who undergo cardiac surgery.81,82 Others suggest that cardiac surgery and aggressive perioperative care may improve life expectancy and increase the likelihood of hospital discharge.83 Despite these observations it is clear that patient selection was a key aspect of the improvements seen in those who received cardiac surgery. Patients with low birth weight, unstable initial hospital course, very early mortality, and a high burden of noncardiac congenital anomalies and medical complications were significantly less likely to be offered surgical intervention. The appropriateness and utility of cardiac intervention for patients with trisomy 18 remain unclear. Individualized approaches to clinical decision making with the family in partnership with specialists in palliative care are most likely to achieve the best possible outcome for patients with this severe disease.

Heterotaxy Syndrome Heterotaxy syndrome is characterized by disruption of normal thoracoabdominal situs and includes a spectrum of CVMs and noncardiac organ problems (Fig. 75.4).84 This condition is discussed in detail in Chapter 67 of this textbook. Relevant to this chapter, the understanding of the genetic basis of heterotaxy is rapidly advancing. Genes in the Nodal signaling pathway, including DNAH5, ZIC3, CFC1, NODAL, ACVR2B, DNAI1, and LEFTY2, are known to harbor mutations that cause heterotaxy. NGS panels testing for these genes and others are now available clinically. Overall, the risk of familial recurrence of heterotaxy is increased compared with other classes of CVMs.4 Postoperative outcomes for patients with heterotaxy are relatively poor. For example, the diagnosis of heterotaxy was associated with increased postoperative mortality among more than 70,000 total cases in the STS database from 1998 to 2009.85 Mortality risk may be especially elevated in patients with heterotaxy and singleventricle lesions, but these outcomes may be improving over time.86,87 The presence of complex cardiac anatomy may explain some of these observations, including an increased risk for arrhythmia due to anatomic abnormalities of the cardiac conduction system. Frequent findings of asplenia and polysplenia, which are associated with decreased splenic function, increase the risk for postoperative bacterial infections and sepsis (Table 75.2).88,160 Long-term antibiotic

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TABLE 75.2  Anomalies in Heterotaxy Syndrome

Asplenia

Polysplenia

Common atrioventricular canal (85%) with DORV, transposed great arteries, and pulmonic outflow atresia or extreme stenosis

Ventricular septal defect with pulmonic stenosis, normal great arteries or DORV without subaortic conus

IVC intact: frequent anomalous drainage of hepatic vein

IVC interruption with azygos drainage

SVC bilateral, unroofed coronary sinus

SVC may be bilateral

Pulmonary veins often drain into systemic vein, obstructed

Pulmonary venous drainage divided (RPV to RA, LPV to LA)

Lungs: bilateral trilobed

Lungs: bilateral bilobed

Liver: symmetric

Liver: symmetric or normally lobulated, risk of extrahepatic biliary atresia

Viscera: heterotaxy with risk of obstruction due to malrotation

Viscera: heterotaxy with risk obstruction due to malrotation

This table summarizes the most frequently encountered anomalies, recognizing that a frequent overlap occurs in the cardiosplenic variants. DORV, Double-outlet right ventricle; IVC, inferior vena cava; LA, left atrium; LPV, left pulmonary vein; RA, right atrium; RPV, right pulmonary vein; SVC, superior vena cava. Data from Applegate KE, Goske MJ, Pierce G, et al. Situs revisited: imaging of the heterotaxy syndrome. Radiographics. 1999;19:837-852.

prophylaxis is indicated in the presence of splenic dysfunction. Recent data indicate that ciliary dysfunction is frequent in heterotaxy89 and may be a significant contributor to postoperative complications, including prolonged mechanical ventilation and increased need for tracheostomy.90 Screening for ciliary dysfunction may be useful in patients with single-ventricle lesions or unexpectedly prolonged duration of respiratory support.

1p36 Deletion Syndrome 1p36 deletion syndrome is the most common terminal deletion syndrome, affecting nearly 1 in 5000 live births.91 The syndrome is caused by deletion within a large 30-Mb region constituting the terminal portion of the short arm of chromosome 1. An important aspect of this syndrome is significant variation in the length and position of the deleted segment between affected individuals,92 which likely contributes to phenotypic variability observed among cases. The significant majority of patients have de novo mutations. Less commonly, inheritance may occur via balanced translocation or germline mosaicism in an unaffected parent. Adequate genetic counseling and parental genetic testing is essential to delineating the inheritance pattern and providing information about recurrence risk of future pregnancies. The cardiovascular features of this syndrome are diverse, occur in over 70% of patients, and can be divided into two general categories: congenital heart disease and cardiomyopathy. Congenital CVMs include ASD and VSD, each occurring in approximately

25% of patients. Approximately 20% of patients have valvar abnormalities, including stenosis and dysplasia of semilunar or atrioventricular valves. Coarctation of the aorta and conotruncal defects such as tetralogy of Fallot are also reported. Cardiomyopathy is diagnosed in over 25% of patients, manifesting as noncompaction cardiomyopathy and/or dilated cardiomypathy.93,94 Interestingly, detailed molecular analysis has mapped the clinical phenotype of CVM presentation to five critical regions within 1p36. Meanwhile, cardiomyopathy, particularly the noncompaction phenotype, has been mapped to two nonoverlapping critical regions.95,96 This is an important consideration for the management of these patients and an excellent example of using genotype-phenotype relationships to individualize clinical management, risk stratification, and anticipatory guidance for patients and their families. The systemic features of this syndrome vary widely. Neurologic abnormalities are among the most prominent features of this syndrome. These include seizures, infantile spasms, structural brain anomalies, hypotonia, developmental delay, behavioral abnormalities, and moderate to severe intellectual disability. Almost all patients exhibit craniofacial abnormalities, including midface hypoplasia, deeply set eyes, long philtrum, posteriorly rotated low-set ears, and a pointed chin. Limb and genitourinary anomalies are also common.93 Careful evaluation and vigilant monitoring is important to identify these features in a timely manner. The extensive and severe features of this syndrome highlight the importance of identifying this microdeletion in the neonatal period. Many of these features can significantly impact perioperative management of cardiac disease. Furthermore, careful analysis of the genotype may guide clinical decisions targeting specific cardiac and noncardiac risks. Akin to other rare genetic syndromes, risk prediction will become more accurate as greater numbers of these patients are diagnosed and followed over time.

Diagnostic Considerations in Cardiovascular Genetics Genetic testing adds an important dimension to the diagnosis and management of congenital CVMs. Establishing a genetic diagnosis often enhances the accuracy of information about prognosis available for patients and families. Genetic testing may facilitate individualized treatment decisions directed toward mitigating both short- and long-term risk factors and, in some cases, may determine the optimal timing and type of cardiac intervention or indication thereof. A genetic diagnosis enhances the accuracy of predicting recurrence risk, which, for example, may be as high as 50% for individuals with autosomal dominant disorders such as Noonan syndrome. Many cardiac ICUs have begun to use genetic evaluation and testing in a systematic way for patients with congenital CVMs. In general, genetic testing decisions may be guided by the patient’s specific type of CVM or may involve the combined consideration of CVM with the presence of specific noncardiac congenital anomalies. Initial testing may target a specific syndromic diagnosis, such as a karyotype when Down syndrome is suspected. In cases in which a specific syndrome is not suspected, broad testing with CMA may be the first consideration. Some congenital heart centers have developed algorithms to streamline the processes for genetic evaluation and testing in the ICU,97 but at this time there is no standardized approach. There is strengthening evidence to support using the CMA as a first-line test for all infants with clinically significant CVMs admitted to the ICU. A systematic approach to testing, assisted by institutional protocols, can significantly enhance



CHAPTER 75  Syndromes, Genetics, and Heritable Heart Disease

the accuracy and cost-effectiveness of genetic testing for cardiac patients.98 The overall yield for CMA testing varies between studies and partially depends on lesion type. Recent publications together estimate that approximately 10% of patients with significant CVMs harbor a CNV that is clinically actionable,99-104 even when excluding known syndromic causes such as 22q11.2 deletion syndrome. This high yield of testing supports its routine use, recognizing that yields may vary between different classes of CVMs. Future studies are necessary to begin to define whether testing may be stratified clinically according to class of CVM. The CNVs that have been most frequently identified in large studies using CMA include 1q21.1 duplication or deletion, 8p23.1 deletion or duplication, and 15q11.2 deletion or duplication. Early screening with CMA can identify patients with rare syndromic conditions that would be challenging to diagnose by clinical assessment alone. Testing with CMA may drastically accelerate the timing of diagnosis for infants with subtle dysmorphic features or subclinical noncardiac congenital anomalies and before the onset of symptoms manifesting later in life such as developmental delay. Interestingly, recent studies have consistently identified CNVs that are typically associated with syndromic CVMs in patients lacking the typical noncardiac features, highlighting the variable expression of many genetic syndromes. Importantly, CMA has greater resolution than FISH to detect small duplications and deletions in patients with microdeletion or microduplication syndromes such as 22q11.2 deletion syndrome or Williams syndrome (7q23.11 deletion) and therefore may be considered a first-line test even when these specific diagnoses are suspected. 1q21.1 deletion syndrome is a rare condition associated with a spectrum of congenital CVMs, including left-sided obstructive lesions, ASD, VSD, and conotruncal defects. 105 Craniofacial anomalies such as frontal bossing, epicanthal folds, long philtrum, and/or highly arched palate occur in over 75% of individuals. Other risks include developmental delay, behavioral abnormalities, microcephaly, hypotonia, and seizures.106-108 An early diagnosis of this rare condition facilitates the opportunity to screen for neurodevelopmental abnormalities and intervene early. 1q21.1 deletion is also characterized by reduced penetrance and variable phenotypic expression. For example, CVM is present in 10% to 25%, and inheritance of the deletion from an undiagnosed parent who apparently lacks CVM and has an overall mild phenotype may equal the rate of de novo occurrences.106,107 This possibility highlights the importance of routinely testing the parents of genotype-positive children, independent of parental signs or symptoms for certain syndromes, including 22q11.2 deletion and Noonan syndrome. This enables counseling about recurrence risk for future pregnancies and identification of other family members who are at risk. Clearly, adequate genetic counseling and family testing are an essential part of the care plan.

Applying Genomic Testing to Cardiovascular Malformations The advent of NGS technology and exome sequence analysis has facilitated major advances in the understanding of the genetic basis of CVMs.109 Most strikingly, exome data from the Pediatric Cardiac Genomics Consortium (PCGC) support that de novo mutations at the nucleotide level may account for up to 10% of congenital CVMs.110 At the same time, it is becoming clear that inherited variants with reduced penetrance also contribute

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to a significant proportion of CVMs, particularly among those patients with apparently isolated CVMs. 111,112 Another major finding that has emerged from the PCGC data is the significant overlap between genes that cause CVMs and the genes that cause neurodevelopmental disorders in patients without CVMs.110 Thus early diagnosis of a pathogenic mutation in certain genes may indicate the need for closer neurodevelopmental monitoring and early intervention. As we better understand the effect of these genotypes on neurodevelopmental outcomes in patients with CVMs, genetic testing may increasingly guide surgical decisions, including the optimal timing for operation. There remains much to be learned in terms of the analysis and interpretation of the voluminous data generated by exome and whole genome sequencing. It is likely that expanded clinical use of these technologies, coupled with improved understanding of underlying mechanisms, will advance the care of pediatric cardiovascular disease in completely new directions.

Cardiovascular Genetics in a Multidisciplinary Team Given the advantages and continual improvements of genetic testing, it may be tempting for programs to implement widespread use of testing without an adequate consideration of the risks and necessary counseling involved. The results of any genetic test can be confusing, equivocal, and difficult to explain to a patient or family. Tests may identify a previously documented genetic change that has a known association with the cardiac and noncardiac anomalies present in the patient. Conversely, tests may identify genetic changes that are novel, poorly understood, or difficult to associate with the patient’s clinical finding. Results of this nature, frequently called variants of unknown/uncertain significance, are common and frustrating to both families and providers.113 Adequate family counseling before genetic testing can make a significant difference in a family’s ability to cope with unexpected or confusing results. For this reason, genetic counseling services must be a central part of any team considering a comprehensive genetic testing program. Providers trained in genetic medicine, including genetic counselors and medical geneticists, should function as part of the planning, development, and ongoing use of any genetic testing protocol. The involvement of genetic counseling services dramatically improves the efficacy, efficiency, and patient satisfaction of genetic testing, and a genetic counselor should be available for consultation to discuss testing options and results with patients and their families. Dedicated cardiovascular genetics services are optimally positioned to work collaboratively as part of multidisciplinary teams consisting of cardiothoracic surgeons, cardiologists, intensivists, medical geneticists, and genetic counselors. Constant changes in genetic testing technology, coupled with the variable availability of medical genetics professionals across centers, make this an ongoing challenge for congenital heart programs. An important step toward developing strong clinical programs will be to improve training in cardiovascular genetics.114

Additional Cardiac Syndromes Alagille: Intrahepatic biliary cirrhosis due to bile duct paucity, dysmorphic facies, ocular anomalies, vertebral anomalies. Frequent cardiac defects are branch pulmonary artery stenosis, tetralogy of Fallot, pulmonary valve stenosis. Genetics: heterozygous mutation in JAG1 (majority) or NOTCH2 gene.115,116

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CHARGE: Eye anomaly (Coloboma), Heart defect usually conotruncal defects including tetralogy of Fallot and VSD, (choanal Atresia), Retardation of growth and/or development, Genitourinary abnormality, and Ear anomalies/deafness, including cochlear dysplasia. Genetics: heterozygous mutation in CHD7 (majority) or SEMA3E gene.117,118 Cornelia de Lange: Craniofacial anomalies, including cleft palate, intellectual disability, seizure, renal anomalies. Frequent cardiac defects include pulmonary valve stenosis, peripheral pulmonary stenosis, septal defects, tetralogy of Fallot, and risk for progressive dysplasia of the atrioventricular valves. Genetics: heterozygous mutation in genes important for cohesin complex (NIPBL, SMC1A, or SMC3 gene).119 Cri du chat: Craniofacial anomalies, severe neurologic impairment, laryngeal anomalies likely contributing to characteristic highpitched cry. Frequent cardiac defects are septal defects, PDA, and TOF. Genetics: hemizygous 5p15 deletion.120 Ellis–van Creveld: Short stature with polydactyly; dysplasia of nails, hair, and teeth; risk for thoracic dystrophy; normal cognitive development. Frequent cardiac defects are common atrium, AVSD, and systemic or pulmonary venous anomalies. Genetics: mutation of EVC or EVC2 gene. Usually autosomal recessive: clusters noted among Amish communities.121 Fetal alcohol: Facial dysmorphism, intellectual disability, short fingers. A variety of heart defects with VSD and ASD as the most common.122 Goldenhar: Unilateral facial microsomia, microtia, preotic skin tag, coloboma of the eye, renal anomalies. Frequent heart defects include tetralogy of Fallot and septal defects. Also referred to as oculoauricular vertebral syndrome. Genetic cause unknown.123,124 Holt-Oram: Although originally described as an autosomal dominant syndrome with absent thumb and an ASD, considerable phenotypic heterogeneity exists, with “digitalized” (finger-like) thumb or rarely phocomelia. Cardiac defects are variable and usually involve septation defects with ASD as the most frequent.125 Genetics: heterozygous mutation of the TBX5 gene at chromosome 12q24.126 Jacobsen: Craniofacial anomalies including trigonocephaly, syndactyly, intellectual disability, platelet dysfunction, including Paris-Trousseau syndrome. Cardiac defects include VSD and left-sided obstructive lesions including HLHS. Genetics: hemizygous deletion on long arm of chromosome 11 (breakpoint at 11q23).127 Kabuki: Characteristic facial appearance, fetal finger pads, intellectual disability, cleft lip/palate, renal anomaly. Cardiac defects include septal defects, coarctation of the aorta, and tetralogy of Fallot. Genetics: heterozygous mutation in KMT2D (also known as MLL2).128,129 Marfan: see Chapter 53. Duchenne muscular dystrophy: Progressive muscular weakness often complicated by cardiomyopathy.130 Genetics: mutation in the dystrophin gene located at chromosome Xq22. X-linked recessive. PHACE: Posterior fossa malformation, Hemangioma, Arterial anomalies consisting of stenosis/aneurysm of cervicocranial arteries increasing risk for stroke, Cardiac defects, and Eye anomalies. Frequent cardiac defects are coarctation of the aorta, VSD, and aberrant subclavian artery. Genetics: unknown.131 Pompe: Most severe of the many forms of glycogen storage disease due to an inherited deficiency in α-1,4-glucosidase (acid maltase). Cardiomyopathy with short PR interval. Genetics: autosomal recessive.132

Rubella: Congenital deafness, cataracts, and sometimes intellectual disability and microcephaly may follow maternal rubella in early pregnancy. Cardiac sequelae usually PDA and pulmonary arterial stenosis.133 An example of a preventable “environmental” syndrome.134 Smith-Lemli-Opitz: Intellectual disability, microcephaly, skeletal anomalies. Cardiac defects include septal defects and tetralogy of Fallot. Genetics: mutation in the DHCR7 gene with autosomal recessive inheritance.135,136 Smith-Magenis: Craniofacial abnormalities, ocular abnormalities, developmental delay, sleep disturbance, seizures, hypercholesterolemia. Frequent cardiac defects are septal defects, tetralogy of Fallot, and total anomalous pulmonary venous return. Genetics: hemizygous deletion of 17p11.2.137 Trisomy 13 (Patau): Severe psychomotor delay, polydactyly, cleft lip/palate, holoprosencephaly. Frequent cardiac defects are ASD, VSD, cardiac positional anomalies.138,139 VACTERL association: Vertebral defects, Anal atresia, Cardiac defects, Tracheo-esophageal fistula, Renal anomalies, and Limb defects. Frequent cardiac defects are VSD (most cases) and tetralogy of Fallot. Genetics: unknown.140 Williams: Characteristic facial features, intellectual disability, neonatal hypercalcemia (usually transient), hypothyroidism. Frequent cardiac defects are supravalvar aortic and pulmonary stenosis, branch pulmonary stenosis, peripheral pulmonary stenosis, stenosis of thoracic aorta, bicuspid aortic valve. Genetics: a contiguous gene deletion syndrome with hemizygosity at chromosome 7q11.23, including the locus for ELN (elastin). Nonsyndromic familial supravalvar aortic stenosis involves heterozygous mutation of ELN.141-143 Wolf-Hirschhorn: Characteristic facial features (“Greek warrior helmet”), cleft lip/palate, seizures, renal anomalies. Frequent cardiac defects are septal defects, pulmonary stenosis, and patent ductus arteriosus. Genetics: hemizygous deletion of 4p16.3.144

Ethical Considerations Child-Parent–Health Care Team Triad Ethics and cardiology are inseparable. When an infant or child with a heart problem needs intensive care, decisions involving life and death or possible long-term morbidity are made on a daily, even hourly basis. By necessity these decisions are being made by surrogates, the family (or legal guardian) and the health care team, not by the child. This triangular relationship of child, family, and health care team has been referred to as the triangle of understanding.145 It is an error to infer that ethical issues arise for discussion only when a disorder is in its terminal stages or when a genetic syndrome associated with a poor prognosis is diagnosed. Ethical considerations are always with us, as in Fost’s memorable phrase “Ethics, ethics everywhere.”146 In this brief section we revisit an infant described in a previous edition who was treated in the pediatric ICU setting and review some of the ethical considerations. These considerations are affected not only by the rapid advances in technology, making previously lethal conditions treatable, but also by new genetic information and by rapid societal change.147-150 Illustrative Case.  A young married woman, Mrs. M., had routine obstetric ultrasound imaging at 18 weeks. Previous obstetric history was significant for two previous uncomplicated pregnancies. The prenatal sonogram documented multiple congenital anomalies, including microcephaly and hydrocephalus, bilateral shortened



CHAPTER 75  Syndromes, Genetics, and Heritable Heart Disease

arms, and congenital heart disease. The couple declined amniocentesis. Despite the high potential for in utero fetal death, they wished to maintain the pregnancy. The next several sonograms showed poor fetal growth. Mrs. M. arrived at the labor and delivery suite at 39 weeks for elective induction and delivery. A viable baby girl weighing 1.6 kg was delivered without difficulty: The Apgar scores were 6 and 8. The infant was transferred to the neonatal intensive care unit for further evaluation. After multiple consultations it was confirmed that she had complex congenital heart disease with microcephaly, hydrocephalus, imperforate anus, limb and vertebral anomalies, diffuse tracheomalacia, and renal anomalies. Chromosomes were 46 XX. A diagnosis of VACTERL association was made. On the first day of life, the infant required intubation and mechanical ventilation. Family meetings were arranged to review and discuss the infant’s status. Based on examination and magnetic resonance imaging scans, pediatric neurology anticipated that Baby M would be severely impaired, cognitively and physically, and partially blind and deaf. Bronchoscopic findings of severe diffuse tracheomalacia led pediatric pulmonologists to conclude that long-term mechanical ventilation would most likely be needed. Pediatric cardiologists predicted that surgery to repair the infant’s complex heart defect was possible, but the current weight of 1.6 kg was a complicating factor. Pediatric orthopedic specialists, after reviewing the arm anomalies, concluded that future surgical intervention might be able to make the arms functional. Despite the poor overall prognosis and recommendations of the medical team not to intervene, the family wished to proceed with the multiple palliative and corrective surgeries.

Current Concepts This infant presented a dilemma, which allows a chance to review some of the concepts that are brought to bear on pediatric ethical dilemmas in general. Landwirth,151 in discussing pediatric and neonatal resuscitation, emphasized the unique nature of pediatrics, including the standing of the parents as surrogate decision makers. Others have stressed that in caring for the critically ill infant, three long-term issues must be considered: benefit to the child, the parents, and society as a whole. Some of the concepts currently under active discussion are those of beneficence, societal good, quality of life years, and patient autonomy. How can these concepts be applied to the difficult problem of Baby M? If the family and health care team disagree, what help is available to bring about consensus? Although each of us tries to bring both reason and moral thinking to these discussions, we are each influenced by our prior experiences, whether of an infant once deemed unsalvageable who grew to give happiness to all his family, or of some child who, after many years of care and support, died tragically after prolonged suffering. Beneficence.  Beneficence, and its corollary, lack of maleficence, is clearly a paramount concept. In simple terms, the infant should receive treatment focused on ensuring or restoring an active happy life, with the minimum of pain and distress involved in the treatment.152,153 The pediatrician, in considering beneficence, has to imagine how he or she would wish to be treated if in the infant’s place.154 Achieving such a goal is very difficult in an infant like Baby M with a complex cardiac problem and many extracardiac anomalies. For example, often lack of knowledge of the true prognosis exists; less often, controversy occurs over the certainty and accuracy of the various diagnoses.

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Most physicians would not find it beneficent to submit an infant to several cardiac operations, multiple invasive procedures, and 6 months in intensive care on ventilator support, if the outcome for that particular condition were known to be uniformly fatal by age 1 year. However, in the real world, the knowledge database is very rarely that conclusive. For example, although most infants with trisomy 18 and heart disease die very early, between 5% and 10% live for more than a year, and no certain way is known at present of identifying the potential survivors.155 Some parents of such an infant, even when informed of the poor prognosis for intellectual development, do not feel justified in withholding cardiac or other surgical care. Room exists for much honest disagreement on the optimal course to pursue, but it is essential that the parents and health care team have the best available facts and be able to participate knowledgeably in the decision. Societal Good.  Societal good is clearly achieved by the restoration to health of a child with coarctation of the aorta or tetralogy of Fallot, who can be expected to reach adult life and become a full member of society; indeed, although this is often not mentioned, society benefits in uncounted ways from the joy and activity of a healthy growing child. However, when an infant such as Baby M has severe multisystem involvement with anticipated developmental disability of uncertain degree, the picture is intuitively less clear. A wide philosophic gulf stretches between those who think societal good means raising a child who will be a wage earner and those who think society benefits from seeing and helping the handicapped. Sometimes, as may have happened with Baby M, the family’s religious or ethical beliefs hold that the sanctity of individual life transcends all other considerations. The health care team always must consider societal good, but in a broad context. Quality-adjusted life-years.  Quality-adjusted life-years (QALYs) is a concept discussed in medical ethics and also in medical economics. For the critically ill infant with successfully repaired coarctation of the aorta and no other anomalies, it is reasonable to estimate a future normal life expectancy of more than 70 years with an excellent quality of life. Any calculations of this kind are precarious in Baby M because of uncertainties surrounding the duration of time on ventilator support and the ultimate neurologic and cognitive outcome. Again, individual philosophic variations exist as to the definition of quality of life. Individual lives vary in intensity, duration, and beauty, and each can have its own essential value. Some authors use the term slippery slope to express the dangers of being judgmental and derogatory about the quality of life of others. Autonomy.  Autonomy implies the importance of the individual in making his or her own life decisions. Respect for individual autonomy, implying the need for truly informed consent, is a concept accepted for both adults and children. Vicarious decisions must necessarily be made for infants such as Baby M, who are not yet autonomous but are completely dependent on others for care, love, and decisions. In intensive care settings the triangle of understanding may become complex, particularly if care is prolonged. Instead of one physician, a health care team is present, whose chief may change on a weekly or other timed basis; the ICU nurse and cardiac nurse specialist often provide most of the vital sense of continuity. Instead of two involved parents, there may be a single teenage mother, often accompanied by varying family members with differing philosophies, or the parents may already be separated or divorced, each accompanied by a new partner. When confronted with the question of whose autonomy should be most considered, that of the health care team or the family, it can be helpful to remember that the family will be the long-term caregivers.

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Informed Consent.  Informed consent is integral to respect for the patient’s or family’s autonomy: in the absence of good knowledge of the medical facts and the probable prognosis, they cannot act autonomously. Some of the most public discussions of informed consent have involved gene therapy and other major advances involving the revolutionary upsurge in genetic knowledge.156,157 Other concepts discussed in the literature on medical ethics concern futility and wrongful life. The concept of futility implies that treatment may be discontinued or withheld if efforts to prolong life will be futile or result in a meaningless existence. Decisions involving this concept are made almost daily in active intensive care settings in the presence of irreversible brain damage from various causes. Like most ethical concepts, this one is easier in the more extreme situations. Now generally accepted objective criteria are known for a diagnosis of brain death. The presence of profound irreversible brain injury may be more difficult to determine with certainty. When doubt exists as to how long life may be prolonged or the implications of a cardiac syndrome for a “meaningful” life, unanimity may be hard to achieve.

Bringing Ethical Concepts to the Bedside, or How Can These Concepts Be Applied to Baby M and Others With Severe Syndromes? First, the health care team, in helping the child and family, must avoid being overly directive. Although the team has an obligation to share with the family their medical and scientific knowledge of the child’s status and prognosis, they must separate the facts from their own individual feelings and beliefs. Some of us believe that it also is important to share at least some of one’s uncertainties: For example, with Baby M the degree of sight and hearing loss can probably be established with accuracy, but the cognitive function and need for ventilator support are less predictable. The forceful projection of medical beliefs on others is often described as “paternalism.” Conversely, it is almost impossible, if even supposing it to be desirable, to counsel without conveying some sense of one’s own stance. Each member of the health care team must know and examine his or her own ethical and moral viewpoint. This helps in the control of bias and provides assurance in the decision-making process. The increasing use of formal teaching on ethics and moral reasoning in medical and nursing schools is a major advance, one that will help future generations caring for the critically ill child with cardiac disease.158 Every physician, nurse, and health care team member involved in critical care knows how difficult the concept of beneficence can be in practice. Second, if possible, the health care team should develop a consensus so that the family’s great and overwhelming sense of grief, loss, and uncertainty should not be further exacerbated by conflicting opinions and prognoses. Divisions among the health care team tend to arise most often in three critical situations: (1) the medical facts are unknown or in dispute; a consensus can be built only on what all know to be the truth; (2) the concept of meaningful life cannot be agreed on for the individual child; and

(3) the moral, ethical, and philosophic viewpoints of the team and family either are unknown, at variance, or have not yet been properly discussed. After the medical facts are known with clarity, a consensus must be established. This involves much time and empathy. Discussion with an ethics committee may clarify the facts and cool some of the heated dialogue.159 All the team members may be helped to realize that pediatrics, usually such a joyful field, may sometimes present severe ethical dilemmas. It is very helpful to have seen older children and even adults who have survived long and arduous times in intensive care and are now leading healthy lives. The perspective of future possibilities is daily involved in the ethics of critical care. The child is and must remain the focus, the apex of the triangle of understanding. Some of the ethical dilemmas faced today arise from technologic advances; some have always existed. The ethical challenge in an intensive care setting lies in providing skilled, compassionate, thoughtful, and well-informed care and information to the critically ill child and family. In most infants with heart defects and syndromes, societal good and many excellent individual QALYs can be achieved if the concepts of beneficence and autonomy accompany skilled and loving care. Even on the rare occasions when the goal of treatment and the assurance of a normal life fail, skilled care accompanied by compassion, love, and grace still avails much. The suffering of the child, the family, and the caregivers is, to some degree, allayed by ethical treatment. Each person reading this chapter should consider how he or she would have advised the family of Baby M or how an ethics committee consultation could bring light and consensus. Caring for the heart of a child remains forever inseparable from ethics.

Conclusion The role of genetics in the evaluation and treatment of patients with congenital CVMs continues to grow. Cumulative experience in the intensive care of patients with syndromic disorders has led to improved perioperative outcomes for certain syndromes. Nonetheless, there is a need for collaboration between centers to delineate the perioperative risks and outcomes for patients with the less common syndromes. This includes the need to understand long-term outcomes. At the same time, technologic advances in genetic testing expand our ability to establish an early genetic diagnosis in patients with syndromic and nonsyndromic CVMs. These technologies are opening new avenues to investigate the etiology of CVMs. It will be important to define the clinical implications of newly discovered classes of genetic diagnoses. Genetics services interfacing directly with the cardiac ICU team will help to counsel families, guide testing choices, interpret results of testing, and supply insight about the implications of negative or positive testing results. We can safely project that genetics will have an increasingly prominent role in the care of patients with CVMs.

References A complete list of references is available at ExpertConsult.com.



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