Abstract

In this chapter, common genetic syndromes and associations in patients with congenital heart disease including the genetic defect and inheritance, cardiac and noncardiac manifestations, along with some anesthetic considerations and risk mitigation, and the effect of the syndrome on surgical morbidity and mortality are explored. Detailed approaches to anesthetic and surgical management of the specific cardiac lesions are contained in the corresponding Chapters in this textbook. Patients with congenital heart disease and genetic and dysmorphic associations present complex diagnostic and management decisions because of multiorgan disease, and many of these patients have neurodevelopmental disabilities and some have limited life expectancy. Because of these issues, approaches to genetic testing, ethical considerations, and palliative care are also discussed.

Introduction

Approximately 20–30% of patients with congenital heart disease (CHD) also have a genetic syndrome or association comprised of cardiac and extracardiac features [1]. Therefore, patients with genetic syndromes or associations are seen disproportionately in locations where care is provided to patients with CHD. The presence of a syndrome or genetic abnormality is a risk factor for perioperative morbidity/mortality for congenital heart surgery [2], and noncardiac and genetic abnormalities can be associated with additional risk factors such as prematurity and weight <2.5 kg [1]. Patel et al. analyzed the Society of Thoracic Surgeons Congenital Heart Surgery Database and reported on the overall prevalence of noncardiac congenital anatomic abnormalities, genetic abnormalities, and syndromes in neonates undergoing congenital heart surgery of 18.8%. The congenital heart lesions with the highest incidence of a noncardiac anomaly, genetic abnormality, or syndrome were an atrioventricular septal defect, interrupted aortic arch, truncus arteriosus, and tetralogy of Fallot. The most common genetic abnormalities were heterotaxy syndrome, 22q11 deletion, trisomy 21, and Turner syndrome [3]. The presence of a genetic syndrome or abnormality clearly makes a difference in in‐hospital mortality in hypoplastic left heart syndrome (HLHS) and in conotruncal anomalies. The reported in‐hospital mortality for HLHS in patients with a genetic abnormality is 26.7% compared with 19.8% in patients without a genetic abnormality [4]. Michielon et al. report that 22q11 deletion and Trisomy 21 are not risk factors for mortality after repair of conotruncal anomalies, but VACTERL association was associated with a higher risk of mortality [5]. In addition to the well‐known chromosomal disorders and genetic syndromic associations in CHD, newer genetic analysis tools such as whole‐exome sequencing (see below under Genetic Testing) are discovering many new, complex gene variants that are associated with CHD, and so the knowledge of the genetic basis of CHD is expanding and it is likely that an even higher percentage of CHD patients have variants that can explain both the cardiac disease and extracardiac manifestations [6]. Certain genetic syndromes are known to carry an increased anesthetic risk. An understanding of the genetic basis, manifestations, and impact of perioperative management in patients with these syndromes and associations is important for risk stratification, counseling, decision‐making, and mitigation of anesthetic and perioperative risk [1].

Historically, cardiac repair was not offered for patients with some genetic syndromes, including Trisomy 21. In the present day, cardiac repair is often expected, and cardiac transplantation has been performed in patients with Trisomy 21. This change in the pattern of care has increased the life expectancy of patients with Trisomy 21, and patients with Eisenmenger syndrome and other sequelae of longstanding unrepaired cardiac disease rarely present for anesthetic care in the modern era in developed countries. This same evolution is now being seen with other syndromes with Trisomy 21 being the model for nonbiased treatment of CHD [7]. As operative management becomes more common, it is important to tailor perioperative management to optimize outcomes. Genetic‐specific treatment and management protocols have been suggested to reduce perioperative morbidity and mortality [7].

In this chapter, common genetic syndromes and associations in patients with CHD are explored including the genetic defect and inheritance, cardiac and noncardiac manifestations, along with some anesthetic considerations and risk mitigation, and the effect of the syndrome on surgical morbidity and mortality. Detailed approaches to anesthetic and surgical management of the specific cardiac lesions are contained in the corresponding chapters in this textbook. Patients with congenital heart disease and genetic and dysmorphic associations present complex diagnostic and management decisions because of multiorgan disease, and many of these patients have neurodevelopmental disabilities, and some have limited life expectancy. Because of these issues, approaches to genetic testing, ethical considerations, and palliative care are also discussed.

Chromosome 22q11 deletion syndrome

Velocardiofacial syndrome (VCFS), which is also termed DiGeorge syndrome or sequence, 22Q11 deletion syndrome, CATCH 22, and conotruncal anomalies face syndrome, has a broad spectrum of phenotypic variation with more than 180 clinical features. VCFS is one of the most common multiple anomaly syndromes, estimated to occur in approximately 1 : 2,000 live births. VCFS is inherited as an autosomal dominant disorder caused by a microdeletion at chromosome 22q11.2 [8]. The phenotype is extremely heterogeneous, and there is no single clinical feature present in all cases, therefore the diagnosis is established by the chromosome defect itself. Congenital heart disease is present in 70% of cases and comprises a high proportion of all conotruncal anomalies, including more than 50% of cases of interrupted aortic arch, over 15% of patients with tetralogy of Fallot, about 50% of truncus arteriosus patients, and about one third of posteriorly malaligned ventricular septal defects. Hemizygosity of the gene TBX1 is responsible for cardiac defects. Other defects commonly present are cleft palate, usually submucous clefts. Facial anomalies are often associated and include high arched palate, low set ears, and occasionally, varying degrees of micrognathia (Figure 8.1) [8]. Other important features present in a variable percentage of patients are partial hypoparathyroidism causing neonatal hypocalcemia, and relative immunodeficiency from abnormal lymphocyte function. Neurodevelopmental disability is common in VCFS, although in some patients intelligence is normal. The average mean full‐scale IQ is 70–75, with about 55% having an IQ range of 70–100; 45% having an IQ range of 55–70, and a few patients have moderate to severe disability [9]. Individuals with VCFS are at an increased risk for developing a number of neuropsychiatric disorders which include attention deficit with hyperactivity disorder, anxiety and mood disorders, autism spectrum disorder, psychotic disorders, and schizophrenia. Patients with the cardiac diseases noted above should be tested for the 22q11.2 deletion syndrome using fluorescence‐in‐situ hybridization (FISH) or chromosomal microarray (CMA), and other multisystem involvement should be assessed as well, especially hypocalcemia and immune dysfunction leading to increased infection risk, as these may affect anesthetic management. In patients with simpler forms of CHD and VCFS, i.e. tetralogy of Fallot, VSD, and simple truncus arteriosus, surgical outcomes are the same as patients without a chromosome defect. However, in the interrupted aortic arch, surgical outcomes are poorer with the 22q11.2 deletion. Finally, the later neurodevelopmental outcomes at one year or more after cardiac surgery are worse overall with 22q11.2 deletion [10]. In spite of the known mild craniofacial anomalies in this syndrome, airway management and tracheal intubation is most often not problematic.

Trisomy 21

The most common genetic syndrome, Down syndrome (DS) affects about 1/700 live births [11]. Resulting from an additional 21st chromosome, diagnosis often occurs in utero with abnormal levels of maternal serum markers (alpha‐fetoprotein, human chorionic gonadotropin, pregnancy‐associated plasma protein‐A, and inhibin A), as well as increased nuchal translucency and a shortened nasal bone on ultrasound in the first trimester [12, 13]. Postnatal diagnosis is based on a physical exam and FISH to confirm the presence of an extra chromosome 21 (3). Children with DS are typically hypotonic with highly mobile joints and distinctive physical features, including a small head with a short neck, macroglossia, palpebral fissures, broad short hands with a single palmar crease, and Brushfield’s spots on the iris (3) (Figure 8.2) [14, 15]. They typically have short stature and obesity is prevalent with increasing age. Prematurity and low birth weight (<2,500 g) occur more frequently compared to the general population [11, 14]. The presence of a flat nasal bridge, macroglossia, and a smaller hypopharynx with decreased muscle tone, and increased tonsillar and adenoid hypertrophy lead to airway obstruction and obstructive sleep apnea (OSA). In addition, children with DS may have smaller airways with an increased incidence of subglottic stenosis, as well as lower airway disease from reduced airway branching units due to a reduced number of alveolar acini [14]. As many as 8% of children with DS have hypothyroidism which should be screened for annually. Hematologic disturbances including neutrophilia, polycythemia, and thrombocytopenia are common in the newborn period and, in addition, 10% of neonates with DS will have a transient myeloproliferative disorder, also known as transient megakaryoblastic leukemia. Cervical spine abnormalities such as atlantoaxial instability are estimated to occur in 15% of children with DS.

Greater than 40% of children with DS are born with congenital heart disease with atrioventricular septal defect (AVSD), ventricular septal defect (particularly a canal type VSD), tetralogy of Fallot, and patent ductus arteriosus being most common. Racial differences exist in which black children with DS have a much higher incidence of AVSD. Despite a higher prevalence of prematurity and comorbidities than children without DS, no significant difference has been found in survival after congenital cardiac surgery in children with DS [16–18]. Children with DS who undergo mask induction with sevoflurane are known to have an increased risk of bradycardia. In a study of 209 children with DS, 57% experienced significant bradycardia unrelated to the presence of congenital heart disease [11, 19]. While the bradycardia is typically self‐limited, cases of cardiovascular collapse have been documented [20].

Down syndrome patients are known to be at higher risk of developing pulmonary hypertension (PH), especially in the neonatal period. While the lifetime incidence of PH in children with DS remains unknown, one large, retrospective study of children with DS reported an incidence of PH as high as 28% [21]. Prematurity and LBW increase the risk of the development of bronchopulmonary dysplasia‐related PH. Chronic airway obstruction and hypoxia result in increased arteriolar hypertrophy of the pulmonary vasculature which can develop into pulmonary hypertension. Cardiac defects such as AVSD and VSD with a large left to right shunt lead to increased pulmonary blood flow which can further increase the pulmonary vascular resistance. These factors in addition to pulmonary hypoplasia and intrinsic endothelial dysfunction lead to an increased risk of developing pulmonary hypertension.

All patients with DS who require anesthesia should have a preoperative evaluation to screen for the presence of multisystem disease. Patients should be examined for the presence of atlantoaxial instability with radiographic images such as MRI reserved for those with worsening muscle tone or increasing weakness. While the likelihood of a spinal injury under anesthesia in a child with DS is very low, efforts to limit extreme motions of the cervical spine are warranted in all patients with DS [11]. Patients with DS who require anesthesia should at some point have an ECG and echocardiogram to rule out the presence of congenital heart disease and pulmonary hypertension. Thyroid tests to detect hypothyroidism should be performed. Screening for snoring and obstructive sleep apnea should also be performed in all patients with DS who require anesthesia. Blood tests to evaluate for thrombocytopenia are warranted before procedures at high risk for blood loss.

Even with adequate preparation, patients with DS can be challenging for anesthesiologists. Difficult vascular access due to xeroderma and obesity is common. Patients may have increased procedural anxiety which can be worsened by hearing difficulty and language delays. DS patients may have difficulty expressing pain, yet they may be more sensitive to the effects of opioids due to OSA. While it has long been rumored that patients with DS require higher doses of anesthesia, there is no evidence supporting this, and recent studies have all but disproven this hypothesis [22]. Anesthetic risk in patients with DS is dependent on the severity and presence of comorbidities with younger, lower‐weight children with cardiac disease and pulmonary hypertension at the highest risk of complications. In a review of 930 non‐cardiac anesthetics in patients with DS, the cohort of patients with trisomy 21 had an increased incidence of perioperative respiratory adverse events mostly due to an increased incidence of obstructed ventilation [23].

Trisomy 18 and 13

Trisomy 13 (Patau syndrome) and Trisomy 18 (Edwards syndrome), result from having three copies of chromosomes 13 and 18, respectively. Trisomy 18 is the second most common autosomal trisomy occurring in about 1/6,000 live births, while Trisomy 13 occurs in 1/10,000 live births [24, 25]. Antenatal diagnosis occurs in most cases due to maternal age, maternal serum markers (significantly lower human chorionic gonadotropin, unconjugated estriol, and alpha‐fetoprotein), and sonographic changes of the nasal bone and nuchal translucency [23]. Later sonographic findings identify up to 90% of cases. While preterm loss, stillbirth, and elective termination occur in a large majority of cases, survival to term increases with increasing gestational age. Among those who survive to term, the risk of early death is very high, with recent studies showing a survival to 1 year in only 5–10% of children with both Trisomy 13 and 18 [24–26].

Multiple congenital anomalies are often present in children with Trisomy 13 and 18, and invasive procedures are likely needed for survival in most children with the syndrome. Low birthweight occurs in most children with each syndrome. Central nervous system abnormalities are likely to present leading to central apnea, severe developmental delay, and seizures. Feeding difficulties, gastroesophageal reflux, and growth retardation occur in most patients, and a permanent feeding tube is required in many patients. Respiratory insufficiency is multifactorial. Central apnea is common, and hypotonia, micrognathia, laryngo‐tracheomalacia, and a high frequency of cleft lip and palate can lead to obstructive apnea. Because of this, many patients with Trisomy 18 and 13 require lifelong invasive ventilatory support.

Cardiac disease occurs in up to 80% of patients with Trisomy 18 and Trisomy 13, with ASD, VSD, patent ductus arteriosus (PDA), and valvular abnormalities being most common. Until recently, few centers chose to operate on patients with Trisomy 18. Today, most centers offer cardiac surgery for patients with Trisomy 18. A 2019 study of the Society of Thoracic Surgeons Congenital Heart Surgery Database of children with T13 and T18 who underwent cardiac surgery (2010–2017) demonstrated that while 70% of centers offered surgery on these patients, mortality remained high at 15% with a high rate of complications [27]. Those who required preoperative mechanical ventilation had an 8‐fold increased risk of mortality.

Preoperative evaluation of the airway, severity of cardiac disease, and consequences of prematurity is necessary for all children with Trisomy 18 and 13. Difficult intubation and ventilation should be anticipated in patients with Trisomy 18 and 13 because of micrognathia, high prevalence of cleft lip and palate, and a narrow palate [28] (Figure 8.3). Most patients with these chromosomal disorders will require prolonged postoperative mechanical ventilation due to prematurity, central apnea and airway obstruction.

Williams‐Beuren syndrome and Elastin arteriopathies

Williams syndrome (WS) is caused by a deletion on the long arm of chromosome 7q11.22 which most notably codes for the protein elastin, important in the elasticity of blood vessels. Nonsyndromic elastin arteriopathies have similar cardiovascular presentations of WS without the extravascular abnormalities. Diagnosis of WS is typically by FISH (see below under Genetic Testing), demonstrating a segment loss on chromosome 7. Patients with WS are known for their characteristic elfin facies, with a broad forehead, wide mouth, a short‐upturned nose, and epicanthal folds [29] (Figure 8.4). Many have a gregarious, friendly personality; however, periprocedural anxiety is common (14). Feeding difficulties and reflux are common and up to 50% of WS patients have hypercalcemia, especially in infancy. Up to 70% of patients with WS have cardiovascular diseases, most notably supravalvular aortic stenosis (SVAS), supravalvular pulmonary stenosis and ostial stenosis of coronary arteries. Patients with severe outflow tract obstructions and/or coronary disease are at high risk for myocardial ischemia with induction of anesthesia [30, 31]. In addition to a 25% lifetime risk of sudden death in patients with WS, there were several cases of cardiac arrest under anesthesia documented in the literature with an estimated incidence of 5%. Several methods of risk stratification have been proposed in the literature, though prospective studies evaluating their accuracy have not been performed. All patients with WS who present for anesthesia should undergo risk stratification and perioperative planning, and it has been demonstrated that with such planning, the incidence of cardiac arrest may be minimized. Echocardiograms to evaluate the severity of supravalvar aortic and pulmonary stenosis, ECGs screening for latent ischemia should be performed on all patients with WS before anesthetic care. Evaluation of the coronaries should be performed in those with stenosis of the thoracic aorta, moderate to severe SVAS and those with signs of symptoms of ischemia. Both cardiac CT angiography and cardiac catheterization can be used to image the patency of the coronary arteries, with CT angiography having the advantage of being done without general anesthesia and avoiding the temporary interruption of coronary blood flow during catheter‐based angiography which has been the cause of cardiac arrest in several patients with WS [32]. Younger patients (<3 years) with moderate to severe outflow tract gradients or those with biventricular outflow tract obstruction should be considered at high risk for myocardial ischemia during anesthesia (16). Such patients may benefit from preoperative hydration, the use of anesthesia drugs that maintain SVR and minimize myocardial oxygen consumption, and judicious use of vasopressors such as phenylephrine to maintain coronary perfusion pressure. All patients considered high risk should be cared for in centers with the capability for full resuscitation and the availability of extracorporeal membrane oxygenation (ECMO), as standard resuscitation measures may fail in patients with severe coronary stenosis or severe outflow tract obstruction. ECMO standby is used at several centers when caring for moderate to high‐risk WS patients. Chapter 35 presents an extensive discussion of anesthetic risk stratification and approach in WS.

Noonan syndrome

Noonan syndrome (NS), occurring in 1/2,500 live births is the second most common genetic cause of congenital heart disease. Noonan syndrome typically occurs via autosomal dominant inheritance and is a heterogenous disease with a wide range of clinical characteristics. NS is considered a RASopathy, which results from germline mutations in the intracellular RAS/mitogen‐activated protein kinase (MAPK) pathway [33, 34]. Diagnosis is suspected from fetal ultrasound and fetal echocardiography and can be confirmed by DNA sequencing. Distinctive facial features in patients with NS include a tall forehead, hypertelorism with prominent eyes and down‐slanting palpebral fissures, a small jaw and short, webbed neck, and low‐set and posteriorly rotated ears and wide‐spaced nipples with pectus excavatum [35] (Figure 8.5). Hearing and intellectual difficulties are common. Children with NS have short stature, feeding difficulties, and cryptorchidism in up to 80% of males (17, 18). Congenital heart disease occurs in over 80% of children with NS. Pulmonary valve stenosis is the most common congenital heart defect, occurring in over 50% of patients. These dysplastic thickened pulmonary valve leaflets are often resistant to valvuloplasty. Atrial septal defect (ASD) is the second most common cardiac defect. Twenty percent of children with NS have hypertrophic cardiomyopathy often presenting as early as 6 months of age, far earlier than other forms of hypertrophic obstructive cardiomyopathy (HOCM) [33, 34, 36]. Among those NS patients with HOCM, obstruction of the left ventricular outflow tract and congestive heart failure are more common than typical HOCM patients. Earlier diagnosis and the presence of congestive heart failure symptoms are associated with worse long‐term survival in patients with NS‐associated HOCM [36].

Patients with NS who require anesthesia should have recent echocardiograms to screen for cardiac defects and to assess the severity of outflow tract obstruction. Patients with HOCM with moderate to severe left ventricular outflow tract (LVOT) obstruction should have preoperative IV placed for prehydration. Careful titration of induction agents with preservation of systematic vascular resistance while avoiding hypovolemia and tachycardia should be performed to minimize myocardial ischemia during anesthesia. Older patients with NS can have limited mouth opening and more severe micrognathia than infants due to joint immobility with advancing age, and difficult laryngoscopy should be anticipated.

Turner syndrome

Turner syndrome (TS), an X‐linked chromosomal syndrome occurs due to loss of one sex chromosome (45XO). Prenatal diagnosis is often from chorionic villous sampling or amniocentesis. Affected females typically have short stature, a webbed neck, a broad chest with wide‐spaced nipples, and gonadal dysgenesis [37, 38] (Figure 8.6). Airway anomalies include micrognathia, a narrow maxilla, and a high arched palate [39]. Swelling of the hands and feet due to lymphedema can occur and scoliosis is prevalent in up to 10% of children with Turner syndrome. Renal defects such as horseshoe kidney and renal agenesis can occur, and autoimmune diseases such as hypothyroidism and celiac disease occur with high prevalence [37].

The most common congenital heart defects in TS include a bicuspid aortic valve and coarctation of the aorta (CoA). Hypertension is common even in patients without CoA. These patients are at risk of aortic dissection and require lifelong evaluation of blood pressure and aortic dimensions [37].

A careful preoperative workup evaluating the presence and severity of cardiac disease, renal and thyroid function, and the airway is necessary before anesthetic care in patients with Turner syndrome. Difficult laryngoscopy and intubation should be anticipated due to limited neck mobility and retrognathia. Blood pressure lability as well as difficult vascular access may be encountered during anesthetic care [39].

Goldenhar syndrome

Interruption of the blood supply to the first and second brachial arches during the first trimester leads to oculo‐auriculo‐vertebral syndrome, also known as Goldenhar syndrome. Diagnosis typically occurs after birth after noting unilateral facial hypoplasia. Facial asymmetry, mandibular hypoplasia, eye abnormalities, microtia or absent ear on the affected side, and dental abnormalities of varying degrees are typically present [40]. Vertebral abnormalities including cervical vertebral fusion and vertebral hypoplasia are present in up to 60% of patients [40, 41] (Figure 8.7). Various degrees of hearing loss and intellectual disability can occur. Congenital heart defects, commonly ventricular septal defects as well as conotruncal defects have been noted in anywhere from 5 to 58% of patients with Goldenhar syndrome, but the actual prevalence of CHD in Goldenhar syndrome is likely closer to 20% [42].

Anesthetic concerns typically focus on airway management, noting that these patients are among some of the most difficult patients to intubate due to severe micrognathia, a hypoplastic, arched palate, airway deviation towards the affected side, limited neck mobility, and mouth opening. Preparation for difficult mask ventilation and laryngoscopy is mandatory when anesthetizing all patients with Goldenhar syndrome. While various techniques such as intubation through a laryngeal mask airway and video laryngoscopy have been employed successfully, preservation of spontaneous ventilation and having a plan should intubation attempts fail is necessary to avoid harm [43]. These patients often undergo several airway reconstructive surgeries to advance the mandible, though the success of these procedures in patients with Goldenhar syndrome is reported to be less than with other syndromes [44].

Mucopolysaccharidoses and glycogen storage diseases

Mucopolysaccharidoses (MPSs) are a collection of lysosomal storage diseases, caused by the functional deficiency of lysosomal enzymes from a genetic mutation in the pathways of the breakdown of glycosaminoglycans (GAG), which were previously termed mucopolysaccharides. These are rare metabolic disorders characterized by the accumulation of incompletely degraded GAGs in virtually all tissues of the body. Classic phenotypes result, including dwarfism, bone and joint deformities, dysmorphic facial characteristics, developmental delay in some patients, ocular and hearing abnormalities, hepatosplenomegaly, and inguinal or umbilical hernias. Cardiac findings are frequent, but much more common in MPS I (Hurler, Hurler‐Scheie Syndrome), MPS II (Hunter Syndrome), and MPS VI (Maroteaux‐Lamy Syndrome) [45]. Table 8.1 presents the genetic inheritance, involved chromosomes, frequency, and cardiac and non‐cardiac manifestations of these diseases [46–48]. In addition to the six major categories, each has several subtypes with a variable clinical phenotype that depends on the precise enzyme defect; thus presentation, including cardiac disease, is variable. The overall prevalence of these rare diseases together is 1 : 20,000 live births.

Cardiac valvular pathology is the most common manifestation, and leaflet thickening with dysfunction has been reported in more than 80% of patients with MPS I, 50–60% of patients with MPS II, and in essentially all patients with MPS VI [45]. Valvular regurgitation, not stenosis, is more common, and the mitral valve is most commonly affected rather than the aortic. Right‐sided valvular disease is less severe. Markedly thickened mitral valve leaflets, and shortened cordae tendinae result in dysmorphic and poorly mobile leaflets. Coronary artery narrowing and occlusion by GAG deposition in proximal coronary arteries is most common in MPS I and II and can occur early, especially in rapidly progressing forms of the disease. Conduction abnormalities, consisting of bundle branch block or complete heart block are seen up to 40% of these patients, presumably from infiltration of the conduction system with GAGs. Valve repair or replacement is the most common cardiac surgery in patients with mucopolysaccharidoses.

In addition to the cardiac pathology, difficult intubation is the most common anesthetic challenge, and MPS I, II, and, VI have in common mucopolysaccharide deposits in the lips, tongue, epiglottis, tonsils, adenoids, and lower airway making them at high risk for airway obstruction and difficult laryngoscopy. In addition, many have a short, stiff neck, and cervical spine abnormalities including atlantoaxial instability and foraminal stenosis[49] (Figure 8.8). A complete pre‐anesthetic evaluation including these and other involved organ systems and a plan to manage them is crucially important for these diseases [46]. Of particular concern if regional anesthesia is contemplated are case reports of paralysis after combined general/epidural anesthesia in Hurler and Morquio Syndromes (MPS IV); avoiding neuraxial anesthesia is recommended in these patients [50].

Pompe Disease is a glycogen storage disease, which is a group of diseases that share defects in the enzymes that break down glycogen. Pompe Disease has an infantile, juvenile, and adult form, depending on the degree of alpha‐glucosidase deficiency [51]. Glycogen deposits within the cardiac myocytes result in hypertrophic cardiomyopathy, which varies with the enzyme deficiency and can be severe, resulting in biventricular outflow tract obstruction. Alternately, some patients demonstrate dilated cardiomyopathy. Danon Disease is an even more rare X‐linked disorder that can also result in hypertrophic or dilated cardiomyopathy. Imaging studies, non‐cardiac surgery, and cardiac surgery for resection of hypertrophied myocardium to relieve outflow tract obstruction are common anesthetics in this population.

Enzyme replacement therapy (ERT) has been available for the last decade or more for MPS I, II, IV, VI, and VII; which consists of weekly intravenous infusions of the defective enzyme, produced using recombinant DNA methods [52] (Table 8.2). The uniform drawback of the current formulations is that they do not cross the blood‐brain barrier or effectively penetrate many tissues, and thus do not affect central nervous system pathology and have variable effects on other organ systems. Improvements in organ systems pathology are mixed; for the cardiac pathologies, it is generally acknowledged that long‐term ERT reduces or at least stabilizes LV mass index, septal hypertrophy, and ejection fraction in MPS I, II, IV, and VI in most studies. The valvular abnormalities are not improved [53]. Coronary artery pathology improvement has not been specifically addressed, but there are case reports of sudden unexpected death from coronary artery stenosis in ERT‐treated patients. For other pertinent systems, although there have been a few reports of improved obstructive sleep apnea, coarseness of facial features, and respiratory infections with ERT, studies have not yet demonstrated a reduction in adenoidal or tonsillar hypertrophy. Another therapy for MPS disorders has been hematopoietic stem cell transplant, which has shown promise in MPS I, but with mixed results in MPS II, III, IV, and VI. The overall message for the anesthesiologist caring for MPS patients is that each patient requires very careful multisystem evaluation, and because of variable outcomes, patients receiving ERT or who have had stem cell transplants should not be assumed to have significant improvement because these therapies do not appear to be consistently effective in reversing already established pathology even though they may prevent progression of the disease.

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May 17, 2023 | Posted by admin in ANESTHESIA | Comments Off on 8: Genetic Syndromes and Associations in Congenital Heart Disease

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Syndrome: Name, Eponyms, Inheritance,Incidence,Gene Locus, Gene Product	HEENT/Airway	Central nervous system	Cardiovascular	Pulmonary/Thoracic	Other	Additional anesthetic considerations
Alagille syndrome		Intracranial hemorrage/stroke; Developmental delay	90% with cardiovascular anomalies; most commonly branch pulmonary artery stenosis		Spontaneous bleeding of unknown etiology	Airway: unusual facies, possible cervical spine abnormalities with no reports of difficult intubation
Alagille‐Watson syndrome, cholestasis with peripheral pulmonary stenosis, arteriohepatic dysplasia, syndromatic hepatic ductular hypoplasia			Other cardiac lesions: tetralogy of Fallot, tricuspid atesia, patent ductus arteriosus, ventricular septal defect		Biliary excretion abnormalities more than synthetic/metabolic hepatic abnormalities,	Abdominal distension may predispose to gastroesophageal reflux
Autosomal dominant					Butterfly Vertebrae; Possible shortened interpedicular distance,	Neurologic assessment, avoid succinylcholine with myopathies
1 : 70,000					exocrine pancreatic insufficiency	Cardiac work‐up
Chromosome 20p12 microdeletion					Renal disease	Assess coagulation profile – caution with neuraxial analgesia/anesthesia
JAG 1 signaling gene, encodes a ligand for the NOTCH1 receptor, critical for the determination of cell fates in early development					Vitamin K malabsorption – coagulopathies	Caution with positioning – rickets/hepatic osteodystrophy
					Vitamin D malabsorption – rickets/pathologic fractures
					Vitamin E malabsorption – peripheral myopathy/neuropathy
					Liver transplant frequent in severe Alagille’s
CHARGE association	Swallowing/sucking difficulties	Colobomata: typical iris coloboma to anophthalmos	Right‐sided congenital heart disease: tetralogy of Fallot, pulmonic stenosis, double outlet right ventricle	Atresia Choanae	Hypogenitalism	Possible difficult/impossible endotracheal intubation with micrognathia
Parental gonadal mosaicism in some cases; spontaneous mutation	Cleft palate associated with congenital heart disease, mostly tetralogy of Fallot	Cranial nerve dysfunction: CNI – anosmia, CN‐VII – facial palsy, CN‐VIII – hearing loss, CN‐IX/CN‐X – velopharyngeal incordination	atrioventricular septal congenital heart disease: ventricular/atrial septal defect associated with tetralogy of Fallot	tracheoesophageal fistula associated with congenital heart disease, mostly tetralogy of Fallot	Renal anomalies (malrotation, hydronephrosis, reflux) associated with congenital heart disease, mostly atrioventricular septal defect	May require continuous positive airway pressure to maintain airway patency with laryngomalacia/velopalatal insufficiency
1 : 10,000	Hypoplastic mandible (micrognathia) associated with congenital heart disease, mostly tetralogy of Fallot	Delayed motor development, may involve truncal hypotonia	Aberrant subclavian artery and/or right aortic arch		Vertebral anomalies (hemivertebrae, scoliosis) associated with congenital heart disease	May require smaller than expected endotracheal tube for subglottic stenosis
Heterozygous mutation in the CHD7 on chromosome 8q12.	Semicircular canal agenesis, sensorineural or conductive hearing loss	Developmental delay
Chromodomain helicase DNA binding protein 7 (CHD7) gene–neural crest epigenetic chromatin remodeling	Three major issues: micrognathia, laryngomalacia, subglottic stenosis					Aspiration risk with swallowing dysfunction,
						cardiac work‐up for congenital heart defects,
						Thyroid/Parathyroid functional studies for similarities between CHARGE and DiGeorge syndromes
						High incidence of post‐operative airway events
						Successful airway management with laryngeal mask airway has been reported
DiGeorge (22q11‐) syndrome	Craniofacial anomalies: Cleft palate, micrognathia, small mouth	Learning difficulties, other pyschiatric disorders	Cardiac defects: tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, pulmonic stenosis, tricuspid atresia		Hypo‐ or aplasia of parathyroid gland resulting in hypocalcemia	Reports of vasomotor instability
(Velocardiofacial Syndrome, CATCH‐22, conotruncal anomalies face syndrome)	Small thyroid cartiledge with increased anterior angle				Hypo‐ or aplasia of thymus gland resulting in immune deficiencies	Cardiac work‐up for congenital heart disease
sporadic or autosomal dominant
One in two thousand	Short trachea with a reduced number of cartilage rings				Renal & Skeletal anomalies	Possible difficult airway with dysmorphic faces
1.5‐ to 3.0‐Mb hemizygous deletion of chromosome 22q11.2	Laryngobronchialmalacia				DiGeorge anomaly is likely a feature of Velocardiofacial Syndrome	Possible difficult extubation with velopharyngeal insufficiency
TXB1 deletion causes most cardiac defects and other phenotypic features; T‐box genes are transcription factors involved in the regulation of developmental processes	Tracheal bronchi					Recurrent infection risk with thymic dysfunction,
						Persistent hypocalcemia with parathyroid dysfunction leading to seizures,
						report of tachycardia from epinephrine injected with local anesthetics
Down syndrome	High arched narrow palate, macroglossia, subglottic stenosis	Variable intellectual disablity	50% with congenital heart disease: Endocardial cushion defects (50%), ventricular septal defect, patent ductus arteriosus,tetralogy of Fallot	Upper airway obstruction/sleep apnea	Dental abnormalities	Radiologic cervical spine abnormalities do not correlate to neurologic symptoms
Trisomy 21	Obstructive sleep apnea				Higher risk for leukemia
Errors in meiosis that lead to trisomy 21 are overwhelmingly of maternal origin; only about 5% occur during spermatogenesis.	Atlanto‐axial subluxation	Possible altered response to opioids	Predisposed to pulmonary hypertension		Duodenal atresia, Hirschsprung’s disease with gastroesophageal reflux	Atlantoaxial instabilitity may increase with loss of muscle tone under anesthesia
1 in 650–1,000	Smaller tracheal lumen diameter	Hypotonia	Predisposed to bradycardia with inhaled induction; halothane, sevoflurane		Immunosuppression and hypothyroidism	Smaller enotracheal tube (0.5–1 mm)) to avert tracheal trauma
Transient myeloproliferative disorder and megakaryoblastic leukemia of Down syndrome are associated with mutations in the GATA1 gene. Somatic mutations in the JAK2 gene are associated with acute lymphoblastic leukemia			Possible difficult arterial/venous access		Hypotonia, hyperextensibility, dysplastic pelvis	Possible difficult vascular access,
						Possible bradycardic response to high concentration volatile anesthetic agents
Ehler‐Danlos Syndrome (EDS)	Dysphonia ‐ hemi‐laryngeal weakness	Mild/mod weakness, myalgia, and easy fatigability in the majority of patients	Bleeding symptoms for all EDS types			Bleeding symptoms are responsive to desmopressin
EDS – Classical type			Mitral valve prolapse, aortic root/sinus of Valsalva dilatation, septal defects		Classic: I and II – Skin hyperextensibility, widened atrophic scars, joint hypermobility	Report of scoliosis correction using spinal fusion complicated by bleeding and wound dehiscence (D‐29.11)
autosomal dominant disorder type V collagen; chromosome 9q34.3; 1 : 20–50,000
EDS – Hypermobility type		Decreased/absent analgesic effect from lidocaine given subcutaneously, or local anesthetic cream	Mitral valve prolapse, aortic root/sinus of Valsalva dilatation, septal defects		Hypermobility: III – Hyperextensibility ± smooth, velvety skin, generalized joint hypermobility
autosmal dominant or recessive mutation in tenascin X gene
EDS – Vascular type			Medium and large‐size vessel fragility leading to rupture		Vascular: IV – Translucent skin, arterial/intestinal/uterine fragility, extensive brusing, characteristic faces	Premature death from organ rupture (arterial, bowel, uterus)
Autosmal dominant mutation in type III collagen gene: 1 : 100–250,000						Report of success using Recombinant Factor VIIa
EDS – Kyphoscoliosis type	Atlantoaxial subluxation may occur in Type IV				Kyphoscoliosis: VI – Joint laxity, muscle hypotonia, progressive scoliosis, scleral fragility	Report of scoliosis correction using spinal fusion complicated by arterial avulsion/rupture
autosomal recessive mutation in gene for lysyl hydroxylase: fewer than 60 cases
EDS – Arthrochalasia type					Arthrochalasia: VIIA/B – Joint laxity with recurrent subluxations, congenital B/L hip dislocation
Mutation in type I collagen gene; fewer than 30 cases						Careful positioning and skin protection
EDS – Dermatosparaxis type					Dermatosparaxis: VIIC – Severe skin fragility, sagging, redundant skin	Gentle intubation with minimal inspiratory pressures to avoid airway hematomas
10 cases reported						Consider possible cervical instability
13 subtypes recognized in 2017 reclassification						Cardiac work‐up to assess valves and great vessels
						Avoid central vascular access or place under U/S visualization
						Prepare for significant blood loss
						Caution with neuraxial anesthesia/analgesia
Pompe disease: glycogen storage disease type II	Infantile onset: macroglossia	Infantile onset: rapidly progressive muscle weakness – axial hypotonia, areflexia	Infantile onset: cardiomegaly/cardiomyopathy leading to cardiac failure	Infantile onset: respiratory insufficiency with frequent infections	Infantile onset: hepatomegly, elevated creatine kinase