Down syndrome

Down syndrome is present in at least one in 1000 live births and is caused by trisomy of chromosome 21 due to true aneuploidy, unbalanced translocation, or mosaicism.Reference Bull ^{34 ,} Reference Cocchi, Gualdi and Bower ³⁵ Approximately 40–50% of patients with Down syndrome present with CHD, most frequently atrioventricular septal defect, followed by ventricular septal defect, atrial septal defect, patent ductus arteriosus, and tetralogy of Fallot.Reference Bull ^{34 ,} Reference Freeman, Taft and Dooley ³⁶

Survival after cardiac surgery is generally favourable, as summarised in Table 1, with more detailed information in Supplementary Table S2; three large contemporary database reviews – encompassing a spectrum of cardiac operations and cumulatively including nearly 7000 patients with Down syndrome – demonstrated that in-hospital mortality risk decreased (Healthcare Cost and Utilization Project Kids’ Inpatient Database)Reference Evans, Dharmar, Meierhenry, Marcin and Raff ^{37 ,} Reference Seifert, Howard, Silber and Jobes ³⁸ or was not different (Society of Thoracic Surgeons database)Reference Fudge, Li and Jaggers ³⁹ when compared with children without Down syndrome. Cardiac lesions studied specifically in Down syndrome are atrioventricular septal defects, conotruncal defects (primarily tetralogy of Fallot), and single ventricle lesions. Poor outcomes after repair of atrioventricular septal defects were reported in early surgical eras,Reference Morris, Magilke and Reller ^{40 ,} Reference Reller and Morris ⁴¹ but recent evidence indicates that children with Down syndrome undergoing biventricular repair for complete atrioventricular septal defect have betterReference Evans, Dharmar, Meierhenry, Marcin and Raff ^{37 ,} Reference St Louis, Jodhka and Jacobs ⁴² or similar early mortality ratesReference Formigari, Di Donato and Gargiulo ^{43 –} Reference Lange, Guenther, Busch, Hess and Schreiber ⁴⁶ compared with patients without Down syndrome. Re-operation rates may be lower in Down syndrome, likely related to less complex atrioventricular valve and outflow tract anatomy.Reference St Louis, Jodhka and Jacobs ^{42 –} Reference Al-Hay, MacNeill, Yacoub, Shore and Shinebourne ^{44 ,} Reference Lange, Guenther, Busch, Hess and Schreiber ⁴⁶ Increased risk for post-operative complete heart block is reported after ventricular septal defect repairReference Fudge, Li and Jaggers ^{39 ,} Reference Tucker, Pyles, Bass and Moller ⁴⁷ but not after atrioventricular septal defect repair.Reference St Louis, Jodhka and Jacobs ^{42 ,} Reference Desai, Branco and Comitis ⁴⁸

Table 1 Summary of post-operative mortality and hospital length of stay outcomes among four frequently encountered genetic syndromes.

AVSD=atrioventricular septal defect; CoA=coarctation of the aorta; IAA=interrupted aortic arch; LOS=length of stay (in-hospital); PA-VSD=pulmonary atresia with ventricular septal defect; PTA=persistent truncus arteriosus; SV=single ventricle; TAPVR=total anomalous pulmonary venous return; TOF=tetralogy of Fallot; and VSD=ventricular septal defect

Classification of risk for poor early post-operative outcomes relative to patients without the syndromic diagnosis (high: studies reviewed only demonstrating increased mortality or LOS, medium: studies demonstrating increased or no difference in mortality or LOS, low: studies demonstrating no difference in mortality or LOS)

^* Some studies reported decreased mortality

^** Studies reported increased mortality, decreased mortality, and no difference in mortality

Similar to complete atrioventricular septal defect repair, Down syndrome does not significantly impact early mortality after surgery for tetralogy of FallotReference Michielon, Marino and Formigari ^{32 ,} Reference Evans, Dharmar, Meierhenry, Marcin and Raff ^{37 ,} Reference Fudge, Li and Jaggers ^{39 ,} Reference Reller and Morris ^{41 ,} Reference Mulder, Pyles, Stolfi, Pickoff and Moller ⁴⁹ or conotruncal defects collectively (predominantly tetralogy of Fallot).Reference Michielon, Marino and Oricchio ^{31 ,} Reference Anaclerio, Di Ciommo and Michielon ³³ In contrast, Down syndrome may significantly worsen outcomes for single ventricle lesions. Review of the Kids’ Inpatient Database found that early mortality was increased both after systemic-to-pulmonary shunt placement and after stage 2 palliation.Reference Evans, Dharmar, Meierhenry, Marcin and Raff ³⁷ Review of the Society of Thoracic Surgeons database also demonstrated increased hospital mortality for all stages of single ventricle palliation.Reference Fudge, Li and Jaggers ³⁹ Increased mortality (35%) after stage 3 palliation was observed in the Pediatric Cardiac Care Consortium databaseReference Gupta-Malhotra, Larson, Rosengart, Guo and Moller ⁵⁰ but was not corroborated by the Kids’ Inpatient Database or a smaller single-centre series.Reference Evans, Dharmar, Meierhenry, Marcin and Raff ^{37 ,} Reference Furukawa, Park and Yoshikawa ⁵¹ The reasons for poor outcomes after single ventricle palliations in these patients are undefined but likely related to predisposition for pulmonary hypertension, which may also contribute to prolonged hospitalisation after stage 2 and stage 3 palliations.Reference Fudge, Li and Jaggers ^{39 ,} Reference Furukawa, Park and Yoshikawa ⁵¹

Many features of Down syndrome impact peri-operative morbidity. Pulmonary and pulmonary vascular co-morbidities feature prominently (Table 2 and Supplementary Table S3). Congenital respiratory tract anomalies may be present at multiple levels and include macroglossia/glossoptosis, adenotonsillar hypertrophy, sub-glottic stenosis, laryngomalacia, tracheal stenosis, complete tracheal rings, and tracheobronchomalacia. Hypotonia can exacerbate anatomical narrowing. Patients are at risk for pulmonary hypertension due to chronic hypoventilation related to airway obstruction and sleep apnoea as well as intrinsic risk for pulmonary vascular disease.Reference Levine and Simpser ^{52 –} Reference Stebbens, Dennis, Samuels, Croft and Southall ⁵⁴ Craniofacial and upper airway anomalies can complicate peri-operative airway management and/or performance of trans-oesophageal echocardiography.Reference Shott ^{55 –} Reference Hilberath, Oakes and Shernan ⁵⁷ Pulmonary abnormalities include pulmonary hypoplasia, interstitial lung disease secondary to chronic aspiration or infection, tracheal bronchus predisposing to recurrent right upper lobe collapse or pneumonia, sub-pleural cysts predisposing to pneumothorax, and lymphatic abnormalities including pulmonary lymphangiectasia.Reference Cooney and Thurlbeck ^{58 –} Reference Ochiai, Hikino and Nakayama ⁶³ These airway co-morbidities manifest clinically as increased risk for post-operative respiratory complications,Reference Fudge, Li and Jaggers ^{39 ,} Reference Desai, Branco and Comitis ^{48 ,} Reference Ip, Chiu and Cheung ⁶⁴ prolonged mechanical ventilation,Reference Furukawa, Park and Yoshikawa ^{51 ,} Reference Ip, Chiu and Cheung ^{64 ,} Reference Morray, Mac Gillivray and Duker ⁶⁵ pneumothorax,Reference Desai, Branco and Comitis ⁴⁸ chylothorax,Reference Doell, Bernet and Molinari ^{22 ,} Reference Fudge, Li and Jaggers ³⁹ chylopericardium,Reference Campbell, Benson, Williams and Adatia ⁶⁶ and failed extubation.Reference Harrison, Cox and Davis ⁶⁷ These observations mandate vigilant assessment and treatment of the pulmonary status in the post-operative period, which may be optimised by pre-operative consultation and testing, particularly in high-risk patients – for example, single ventricle lesions.

Table 2 Classes of risks and suggested peri-operative precautions/actions for specific syndromes.

AGS=Alagille syndrome; AV=atrioventricular; BP=blood pressure; CPB=cardiopulmonary bypass; DS=Down syndrome; EEG=electroencephalogram; EVC=Ellis–van Creveld; HTX=heterotaxy syndrome; LDS=Loeys–Dietz syndrome; LQT=prolonged QT interval; MFS=Marfan syndrome; NS=Noonan syndrome; PVR=pulmonary vascular resistance; SND=sinus node dysfunction; TS=Turner syndrome; and WS=Williams syndrome

Dysfunction of B- and T-lymphocytes and neutrophils may predispose to infections and exacerbate the inflammatory response to cardiopulmonary bypass.Reference Doell, Bernet and Molinari ^{22 ,} Reference Fudge, Li and Jaggers ^{39 ,} Reference Desai, Branco and Comitis ^{48 ,} Reference Furukawa, Park and Yoshikawa ^{51 ,} Reference Kusters, Verstegen, Gemen and de Vries ^{68 –} Reference Roussot, Lawrenson, Hewitson, Smart and De Decker ⁷¹ Congenital hypothyroidism occurs in ~1%, and thyroid screening at regular intervals, including at ages 6 and 12 months, is indicated because an additional 4–18% develop hypothyroidism.Reference Bull ^{34 ,} Reference Murphy, Philip and Macken ^{72 ,} Reference Gibson, Newton and Selby ⁷³ Pre-operative thyroid screening is indicated so that hypothyroidism can be treated pre-operatively. As thyroid levels decrease with cardiopulmonary bypass surgery and impact myocardial function and cardiovascular stability,Reference Talwar, Khadgawat and Sandeep ^{74 ,} Reference Plumpton, Anderson and Beca ⁷⁵ intra-operative and post-operative parenteral therapy may be indicated. The risk for atlantoaxial instability calls for appropriate peri-operative precautionary measures to avoid neurological injury, especially in mid-to-late childhood.Reference Bull ^{34 ,} Reference Davidson ⁷⁶ Increased risk for seizures – ~8% in the general Down syndrome population – should also be considered.Reference Goldberg-Stern, Strawsburg and Patterson ⁷⁷ Taken together, Down syndrome presents significant co-morbidities that can impact peri-operative outcomes. Fortunately, mortality outcomes have improved over time for the most-frequent lesions, but non-cardiovascular abnormalities continue to contribute to post-operative morbidity outcomes and require clinical vigilance and future research.

22q11 deletion syndrome

Microdeletion of 22q11.2 causes several disorders with overlapping clinical phenotypes including DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome, and is present in approximately one in 5000 live births.Reference Tezenas Du Montcel, Mendizabai, Ayme, Levy and Philip ^{78 ,} Reference Goodship, Cross, LiLing and Wren ⁷⁹ Suggestive features include long narrow face and small protuberant ears with thick and crumpled helices.Reference Bassett, McDonald-McGinn and Devriendt ⁸⁰ CHD is present in at least 75%.Reference Ryan, Goodship and Wilson ⁸¹ The typical cardiac lesions are conotruncal defects and abnormalities of the aortic arch and brachiocephalic arteries, including type B interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, pulmonary atresia with ventricular septal defect, isolated ventricular septal defect, and abnormal aortic arch sidedness and/or branching.Reference Goldmuntz, Clark and Mitchell ^{82 –} Reference McElhinney, Driscoll and Levin ⁸⁴

Peri-operative outcomes are summarised in Table 1 with more detailed information in Supplementary Table S4. Early reports observed very high operative mortality in neonates with DiGeorge syndrome.Reference Marmon, Balsara, Chen and Dunn ⁸⁵ Although increased hospital mortality was also observed in a more contemporary series of patients with conotruncal defects,Reference Anaclerio, Di Ciommo and Michielon ³³ there is strong evidence that 22q11 deletion no longer results in early mortality for the vast majority of cardiac lesions;Reference Michielon, Marino and Oricchio ^{31 ,} Reference Michielon, Marino and Formigari ^{32 ,} Reference Mercer-Rosa, Pinto, Yang, Tanel and Goldmuntz ^{86 –} Reference McDonald, Dodgen and Goyal ⁸⁸ however, substantial post-operative morbidity persists including slow recovery and increased frequency of cardiac events such as the need for re-operation.Reference Michielon, Marino and Oricchio ^{31 ,} Reference Michielon, Marino and Formigari ^{32 ,} Reference Mercer-Rosa, Pinto, Yang, Tanel and Goldmuntz ^{86 ,} Reference O’Byrne, Yang and Mercer-Rosa ⁸⁷ Notably, patients with pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries have consistently demonstrated increased early mortality in the setting of 22q11 deletion.Reference Reddy, McElhinney and Amin ^{89 –} Reference Carotti, Albanese and Filippelli ⁹³ In addition, early operative mortality after Norwood stage 1 operation was observed in two of five patients in the Congenital Heart Surgeons’ Society database from 1994 to 2001, supporting the concept that genetic syndromes continue to impact high-risk operations.Reference Patel, Hickey and Mavroudis ²⁵

Congenital malformations including cleft palate, sub-mucous clefts, retrognathia, Pierre Robin sequence, congenital laryngeal web, and vascular ring may complicate airway management.Reference Ryan, Goodship and Wilson ^{81 ,} Reference Yotsui-Tsuchimochi, Higa, Matsunaga, Nitahara and Shono ^{94 ,} Reference McElhinney, Jacobs, McDonald-McGinn, Zackai and Goldmuntz ⁹⁵ Bronchomalacia and bronchospasm have been observed in patients with 22q11 deletion and pulmonary atresia with ventricular septal defect, which may be related to compression by aortopulmonary collateral vessels.Reference Yamagishi, Maeda and Higuchi ^{96 ,} Reference Ackerman, Wylam and Feldt ⁹⁷ Although prolonged mechanical ventilation was not observed after unifocalisation of the major aortopulmonary collateral arteries,Reference Asija, Hanley and Roth ⁹⁸ increased post-operative respiratory complications including prolonged intubation and post-extubation stridor have been observed.Reference Ziolkowska, Kawalec and Turska-Kmiec ⁹⁹

Thymic aplasia occurs rarely (<1% of cases) and is associated with severe immune deficiency. More commonly, thymic hypoplasia causes mild-to-moderate immune deficiency. Complete pre-operative immunological evaluation and blood product precautions – cytomegalovirus-negative and irradiated blood products – are indicated for all cases to prevent iatrogenic infection and graft versus host disease.Reference Bassett, McDonald-McGinn and Devriendt ^{80 ,} Reference Marmon, Balsara, Chen and Dunn ^{85 ,} Reference Jatana, Gillis, Webster and Ades ¹⁰⁰ Low T-lymphocyte counts are present in 75–80% of patients with 22q11 deletion.Reference Kobrynski and Sullivan ¹⁰¹ B-lymphocyte dysfunction with immunoglobulin deficiency also may have clinical significance.Reference Patel, Akhter and Kobrynski ^{102 ,} Reference Smith, Driscoll and Emanuel ¹⁰³ Frequent infectious complications including fungal infections have been reportedReference Barker, O’Brien and Welke ^{23 ,} Reference Marmon, Balsara, Chen and Dunn ^{85 ,} Reference McDonald, Dodgen and Goyal ^{88 ,} Reference Carotti, Marino and Di Donato ^{91 ,} Reference Ziolkowska, Kawalec and Turska-Kmiec ⁹⁹ but not uniformly.Reference Mercer-Rosa, Pinto, Yang, Tanel and Goldmuntz ^{86 ,} Reference O’Byrne, Yang and Mercer-Rosa ^{87 ,} Reference Mahle, Crisalli and Coleman ⁹⁰ It has been suggested that prophylaxis with broad-spectrum antibiotics including antifungal agents may be indicated.Reference Carotti, Digilio and Piacentini ¹⁰⁴ Developmental hypoplasia of the parathyroid glands results in hypocalcaemia in 40–80% of patients and is often accompanied by hypomagnesaemia.Reference Cheung, George and Costain ¹⁰⁵ Close peri-operative electrolyte monitoring is necessary to preserve cardiac function, avoid dysrhythmia, and prevent secondary seizures. Peri-operative seizures are linked to worse neurodevelopmental outcomes in 22q11 deletion.Reference Cheung, George and Andrade ¹⁰⁶ Annual assessment of thyroid function is recommended because hypothyroidism is present in 20–30% of patients; a routine pre-operative thyroid screening approach similar to Down syndrome may be reasonable.Reference Bassett, McDonald-McGinn and Devriendt ^{80 ,} Reference Cheung, George and Costain ^{105 ,} Reference Stagi, Lapi and Gambineri ¹⁰⁷

Interestingly, the gene encoding glycoprotein Ib (GP1BB), which is responsible for autosomal-recessive Bernard–Soulier disease, is located within the 22q11 region. Patients with 22q11 deletion, and thus hemizygous deletion of GP1BB, may have abnormally large platelets and thrombocytopaenia (macrothrombocytopaenia).Reference Naqvi, Davidson and Wong ^{108 ,} Reference Latger-Cannard, Bensoussan and Gregoire ¹⁰⁹ Platelet dysfunction has been described previously.Reference Liang, Morel-Kopp and Curtin ^{110 ,} Reference Kato, Kosaka and Kimura ¹¹¹ Post-operative bleeding accounted for a significant proportion of post-operative deaths in patients with pulmonary atresia with ventricular septal defect.Reference Mahle, Crisalli and Coleman ^{90 ,} Reference Carotti, Albanese and Filippelli ⁹³ A complete haematological workup may be indicated before operations requiring small vessel anastomoses – for example, unifocalisation – and unexplained severe post-operative bleeding should trigger concern for Bernard–Soulier disease due to mutation of the non-deleted GP1BB allele.Reference Nakagawa, Okuno, Okamoto, Fujino and Kato ¹¹² Renal and urinary tract abnormalities are present in 30–40% of patients, including renal agenesis, multi-cystic dysplastic kidneys, hydronephrosis, and vesicoureteral reflux.Reference Ryan, Goodship and Wilson ^{81 ,} Reference Stewart, Irons, Cowan and Bianchi ¹¹³ Increased need for post-operative dialysis has been observed.Reference McDonald, Dodgen and Goyal ⁸⁸ Autonomic dysfunction may in some cases explain post-operative hypotension refractory to usual therapy.Reference Shashi, Berry and Hines ¹¹⁴ Taken together, the developmental abnormalities associated with 22q11 deletion likely contribute to mortality after complex operations and morbidity across the spectrum of CHD surgery. Improvements in anticipatory management of common abnormalities – for example, immune dysfunction and hypocalcaemia – will continue to improve outcomes. Abnormalities that are less frequently recognised – for example,. haematological dysfunction – should be anticipated and acted upon when deviation from expected recovery is encountered.

Heterotaxy syndrome

Heterotaxy syndrome, a disorder of laterality characterised by abnormal thoracoabdominal situs, is frequently associated with CHD and is present in at least one in 10,000 live births.Reference Lin, Ticho, Houde, Westgate and Holmes ¹¹⁵ Mutations in genes such as DNAH5, ZIC3, CFC1, NODAL, ACVR2B, DNAI1, and LEFTY2, many of which are components of the Nodal signal transduction pathway, have been identified;Reference Sutherland and Ware ¹¹⁶ familial recurrence is more frequently observed compared with other cardiac lesions.Reference Oyen, Poulsen and Boyd ⁹ CHD is often complex, including complete atrioventricular canal defect, anomalous pulmonary and systemic venous return, and pulmonary outflow tract obstruction. Heterotaxy can be sub-classified as right atrial isomerism versus left atrial isomerism as determined by atrial appendage and bronchopulmonary anatomy.Reference Jacobs, Anderson and Weinberg ¹¹⁷ In general terms, right atrial isomerism typically has more severe CHD, often requires single ventricle palliation, and has worse survival in childhood.Reference Lim, McCrindle and Smallhorn ^{118 –} Reference Freedom, Jaeggi, Lim and Anderson ¹²⁰ In right atrial isomerism, abnormal morphology and function of the sinoatrial node and the atrioventricular conduction system predispose to both tachyarrhythmia and bradyarrhythmiaReference Gilljam, McCrindle, Smallhorn, Williams and Freedom ^{121 –} Reference Kim, Kim, Lim and Lee ¹²⁴ – for instance, supra-ventricular tachycardia has been observed in up to 25% of cases, including re-entrant mechanisms mediated by twin atrioventricular nodes.Reference Wren, Macartney and Deanfield ^{125 –} Reference Anagnostopoulos, Pearl and Octave ¹²⁷ Atrioventricular block and sinus node dysfunction are more frequently observed in left atrial isomerism.Reference Wren, Macartney and Deanfield ^{125 ,} Reference Anagnostopoulos, Pearl and Octave ¹²⁷ In addition to arrhythmia concerns, non-compaction cardiomyopathy is described and may contribute to unexpected ventricular dysfunction.Reference Wessels, De Graaf and Cohen-Overbeek ¹²⁸

Peri-operative outcomes in heterotaxy are summarised in Table 1 and Supplementary Table S5. The complexities of both cardiovascular and non-cardiovascular abnormalities likely contribute to poor outcomes.Reference Freedom, Jaeggi, Lim and Anderson ¹²⁰ Increased mortality following any cardiac surgery has been observed in the Society of Thoracic Surgeons’ database.Reference Jacobs, Pasquali and Morales ^{129 ,} Reference Swisher, Jonas and Tian ¹³⁰ Mortality after initial single ventricle palliation is reported to range from 10 to 23%.Reference Gilljam, McCrindle, Smallhorn, Williams and Freedom ^{121 ,} Reference Jacobs, Pasquali and Morales ^{129 ,} Reference Ota, Fujimoto and Murata ^{131 ,} Reference Hashmi, Abu-Sulaiman and McCrindle ¹³² In the setting of total anomalous pulmonary venous return, poor outcomes may be related to hypoplastic pulmonary veins and increased pulmonary vascular reactivity.Reference Ota, Fujimoto and Murata ^{131 –} Reference Jenkins, Sanders and Orav ¹³³ Despite these challenges, there was similar survival between heterotaxy and non-heterotaxy patients undergoing primary repair for total anomalous pulmonary venous return but increased need for pulmonary vein re-operation.Reference Morales, Braud and Booth ¹³⁴ Mortality rates after stage 3 palliation ranged widely from as high as 19–43%Reference Stamm, Friehs and Duebener ^{123 ,} Reference Bartz, Driscoll and Dearani ^{135 ,} Reference Humes, Feldt and Porter ¹³⁶ to as low as 3–4% in recent studies.Reference Stamm, Friehs and Duebener ^{123 ,} Reference Kim, Kim, Lim and Lee ^{124 ,} Reference Jacobs, Pasquali and Morales ¹²⁹ Complex anatomy can potentially complicate cardiac transplantation but did not impact early (or late) graft survival;Reference Larsen, Eguchi and Mulla ¹³⁷ however, early mortality was recently reported in two of five patients undergoing cardiac transplantation.Reference Jacobs, Asante-Korang and O’Brien ¹³⁸ Overall, there is strong evidence that heterotaxy confers significant peri-operative mortality risk.

Post-operative respiratory morbidity was frequently observed.Reference Swisher, Jonas and Tian ¹³⁰ Up to 40% of patients with heterotaxy and CHD have dysfunctional airway cilia similar to primary ciliary dyskinaesia.Reference Nakhleh, Francis and Giese ¹³⁹ Indeed, ciliopathy is a suspected developmental mechanism for cardiovascular and non-cardiovascular malformations.Reference Sutherland and Ware ¹¹⁶ Respiratory ciliary dysfunction, diagnosed by nasal nitric oxide levels or nasal video microscopy, has been associated with post-operative respiratory complications, including failed extubation, respiratory failure, respiratory infection, stridor, pleural effusion, atelectasis, pneumothorax, or pulmonary oedema, as well as with the need for tracheostomy.Reference Harden, Tian and Giese ¹⁴⁰ It has been suggested that beta-agonist therapy may be effective by improving ciliary motility.Reference Harden, Tian and Giese ^{140 ,} Reference Shiima-Kinoshita, Min, Hanafusa, Mori and Nakahari ¹⁴¹

Splenic abnormalities including asplenia (often left atrial isomerism) polysplenia (often right atrial isomerism) or the presence of accessory splenule are frequently observed.Reference Anderson, Devine, Anderson, Debich and Zuberbuhler ¹⁴² Asplenia clearly increases risk of bacterial infections in children.Reference Waldman, Rosenthal, Smith, Shurin and Nadas ¹⁴³ Splenic function in the setting of polysplenia may also be impaired and should be evaluated using scintigraphy.Reference de Porto, Lammers and Bennink ¹⁴⁴ Sepsis was the cause of early post-operative mortality in 13% of deaths in a large heterotaxy population.Reference Serraf, Bensari and Houyel ¹⁴⁵ Oropharyngeal malformations including micrognathia, choanal atresia, and cleft lip/palate can contribute to airway management difficulties.Reference Williams and Feng ^{146 ,} Reference Ticho, Goldstein and Van Praagh ¹⁴⁷ Renal anomalies including renal agenesis, cystic malformation, and horseshoe kidney are also frequently observed.Reference Hashmi, Abu-Sulaiman and McCrindle ^{132 ,} Reference Ticho, Goldstein and Van Praagh ¹⁴⁷

The surgical outcomes in heterotaxy are improving, but persistent challenges include complex anatomy such as abnormal cardiac position, hypoplastic and anomalous pulmonary veins, and single ventricle morphology, predisposition for arrhythmia, and pulmonary and immunological dysfunction.

Turner syndrome

Turner syndrome occurs in approximately one in 2000 female live births and is caused by complete or partial absence of the X chromosome.Reference Nielsen and Wohlert ^{148 ,} Reference Bondy ¹⁴⁹ Features include short stature, ovarian dysgenesis, webbed neck, low posterior hairline, and widely spaced nipples.Reference Frias and Davenport ¹⁵⁰ There is a high rate of foetal mortality, often in the setting of foetal hydrops.Reference Surerus, Huggon and Allan ¹⁵¹ Those surviving to birth often have cardiovascular malformations including bicuspid aortic valve, coarctation of the aorta, partial anomalous pulmonary venous return, persistent left superior caval vein, and hypoplastic left heart syndrome.Reference Ho, Bakalov and Cooley ^{152 –} Reference Gotzsche, Krag-Olsen, Nielsen, Sorensen and Kristensen ¹⁵⁵ Turner syndrome accounts for at least 5% of coarctation of the aorta among girls, which may indicate karyotype screening of all female neonates with coarctation.Reference Wong, Burgess, Cheung and Zacharin ¹⁵⁶ There is also significant long-term risk of aortic dilation and dissection that is likely under-recognised.Reference Matura, Ho, Rosing and Bondy ^{157 ,} Reference Carlson, Airhart, Lopez and Silberbach ¹⁵⁸ Electrocardiographic abnormalities including prolonged QT interval are frequently encountered, but risk of life-threatening arrhythmia has not been established.Reference Bondy, Ceniceros, Van, Bakalov and Rosing ¹⁵⁹

Turner syndrome does not appear to increase mortality risk after repair of coarctation of the aorta but has been associated with longer hospitalisation (Table 1 and Supplementary Table S6).Reference Cramer, Bartz, Simpson and Zangwill ¹⁶⁰ By comparison, mortality appears to be significantly increased in patients with hypoplastic left heart syndrome – for instance, 9 out of 11 infants with Turner syndrome undergoing Norwood stage 1 operation died by 4 months of age as per the Congenital Heart Surgeons’ Society database.Reference Patel, Hickey and Mavroudis ²⁵ In a retrospective single institution study, 8 out of 10 infants with Turner syndrome undergoing stage 1 palliation for hypoplastic left heart syndrome died before stage 2 operation, and both the survivors were mosaic XO.Reference Reis, Punch, Bove and van de Ven ¹⁶¹ In a more recent series, all four patients with Turner syndrome undergoing stage 1 palliation survived to hospital discharge, but three were reported to have died before stage 3 palliation.Reference Cramer, Bartz, Simpson and Zangwill ¹⁶⁰ A precise explanation for these outcomes has not been established thus far, but lymphatic abnormalities may contribute.Reference Reis, Punch, Bove and van de Ven ¹⁶¹ Automatic karyotype screening in girls with hypoplastic left heart syndrome may be indicated because some features develop over time or may be subtle in mosaic cases.

Predisposition to vascular complications were described in earlier case series that reported significant post-operative haemorrhage and risk for aortic rupture, possibly related to increased arterial tissue fragility and peri-operative systemic hypertension.Reference Ravelo, Stephenson and Friedman ^{162 ,} Reference Brandt, Heintz, Rose, Ehrenhaft and Clark ¹⁶³ Fortunately, improvements in surgical technique and intensive care have effectively reduced post-operative bleeding risk. Morphological abnormalities such as elongation of the transverse arch (present in 50% of cases) may impact surgical approach,Reference Ho, Bakalov and Cooley ¹⁵² which may lead to longer cross-clamp time during coarctation repair.Reference Cramer, Bartz, Simpson and Zangwill ¹⁶⁰ Although unlikely to develop in the early post-operative period, there is established risk for dissection after surgical repair or transcatheter stenting of aortic coarctation.Reference Oza, Siegenthaler and Horvath ^{164 –} Reference Fejzic and van Oort ¹⁶⁶ Small case series have provided evidence that balloon angioplasty or stent placement for coarctation is safe and effective in the short term,Reference Kataoka, Ozawa, Inage and Benson ^{167 ,} Reference Zanjani, Thanopoulos, Peirone, Alday and Giannakoulas ¹⁶⁸ but covered stents may be the best approach in the context of intrinsically abnormal arterial tissue.

The non-cardiovascular abnormalities that potentially impact peri-operative risk and outcomes include the lymphatic, renal, and endocrine systems. Lymphatic dysfunction can present as foetal lymphoedema or pulmonary lymphatic anomalies such as congenital pulmonary lymphangiectasia, which may predispose to post-operative chylothorax.Reference Bellini, Boccardo, Campisi and Bonioli ¹⁶⁹ Postnatal peripheral lymphoedema may be a clue to Turner syndrome diagnosis but has no clear clinical impact and usually resolves by 2 years of age without intervention.Reference Bondy ¹⁴⁹ Abnormalities of the renal and urinary system are present in 30–40% of patients, including horseshoe kidney in 10%.Reference Bondy ¹⁴⁹ Hypothyroidism develops in up to 25% of cases, most commonly autoimmune related, and annual thyroid screening is recommended starting at 4 years of age.Reference Bondy ^{149 ,} Reference Gawlik, Gawlik, Januszek-Trzciakowska, Patel and Malecka-Tendera ¹⁷⁰ In summary, Turner syndrome most clearly impacts outcomes for hypoplastic left heart syndrome. Further investigation is needed to explain these poor outcomes and develop novel approaches and interventions. Arteriopathy associated with Turner syndrome predisposes to hypertension and aortic complications, such as dissection, mandating acute peri-operative blood pressure management and longitudinal follow-up.

Williams syndrome

Williams syndrome occurs in approximately one in 10,000 live birthsReference Stromme, Bjornstad and Ramstad ¹⁷¹ and is associated with 7q11.23 microdeletion. Haploinsufficiency of the elastin gene (ELN) is responsible for the cardiovascular manifestations. Facial features during infancy include a short upturned nose with a flat nasal bridge, peri-orbital puffiness, and long philtrum and later develop into full lips, wide smile, and coarse appearance. Relative strengths in verbal skills and social personality may belie intellectual disability that is present in most cases.Reference Pober ¹⁷² Familial supra-valvar aortic stenosis is associated with ELN mutations and presents with similar cardiovascular features but none of the non-cardiovascular features.

The spectrum of vascular manifestations in Williams syndrome is consistent with generalised arteriopathy. The majority of patients with Williams syndrome have supra-valvar aortic stenosis (45–75%), which may be “hourglass” or “diffuse” type.Reference Collins ¹⁷³ Severe supra-valvar aortic stenosis is unlikely to regress and can be progressive,Reference Wren, Oslizlok and Bull ^{174 –} Reference Del Pasqua, Rinelli and Toscano ¹⁷⁶ but mild stenosis is likely to remain stable.Reference Del Pasqua, Rinelli and Toscano ^{176 –} Reference Collins, Kaplan, Somes and Rome ¹⁷⁸ Additional vascular findings include branch pulmonary stenosis, peripheral pulmonary artery stenosis, supra-valvar pulmonary stenosis, and stenosis of the thoracic aorta, as well as bicuspid aortic valve and mitral valve prolapse.Reference Collins ¹⁷³ The pulmonary arterial lesions often spontaneously improve or resolve over time,Reference Wren, Oslizlok and Bull ^{174 –} Reference Del Pasqua, Rinelli and Toscano ^{176 ,} Reference Collins, Kaplan, Somes and Rome ¹⁷⁸ but regression also is less likely when severe stenosis is present.Reference Stamm, Friehs and Moran ¹⁷⁹ Surgical repair of supra-valvar aortic stenosis in patients with Williams syndrome has good mortality outcomes with no significant difference in long-term survival compared with familial or sporadic supra-valvar aortic stenosis.Reference Deo, Burkhart and Schaff ¹⁸⁰ On the other hand, early mortality can be as high as 20% for cases presenting with the combination of severe supra-valvar aortic stenosis and moderate-to-severe pulmonary stenosis.Reference Stamm, Friehs and Moran ^{179 ,} Reference Monge, Mainwaring and Sheikh ¹⁸¹

Balloon angioplasty of supra-valvar aortic stenosis has been dispelled due to lack of success.Reference Del Pasqua, Rinelli and Toscano ¹⁷⁶ After transcutaneous stent placement for native or residual post-operative aortic coarctation, there is significant risk for developing re-stenosis, characterised by fibrosis and vascular smooth muscle cell proliferation.Reference Apostolopoulou, Kelekis, Laskari, Kaklamanis and Rammos ^{182 ,} Reference Mookerjee, Roebuck and Derrick ¹⁸³ Indeed, patients with stenosis of the thoracic aorta have high re-intervention rates.Reference Collins, Kaplan and Rome ¹⁸⁴ The pulmonary arteries are also predisposed to re-stenosis, aneurysm formation, intimal flap formation, dissection, and rupture after catheter-based interventions.Reference Pham, Moller, Hills, Larson and Pyles ^{185 ,} Reference Geggel, Gauvreau and Lock ¹⁸⁶ These outcomes indicate that arteriopathy may limit the effectiveness and increase risk factors when performing catheter-based interventions for arterial stenoses.

It is critical to recognise the risk of sudden cardiac death in patients with Williams syndrome, particularly during procedural sedation or anaesthesia or coronary angiography.Reference Stamm, Friehs and Moran ^{179 ,} Reference Burch, McGowan, Kussman, Powell and DiNardo ^{187 –} Reference Conway, Noonan, Marion and Steeg ¹⁹⁰ This risk is highest in those with coronary ostial stenosis or severe biventricular outflow tract obstruction. Among 242 patients with Williams syndrome undergoing 435 cardiac operations or catheter-based interventions, described in the Pediatric Cardiac Care Consortium database, 12 of 15 deaths occurred in the setting of biventricular outflow tract obstruction.Reference Pham, Moller, Hills, Larson and Pyles ¹⁸⁵ Coronary ostial stenosis is present in at least 5% of cases and is more common in the “diffuse” type of supra-valvar aortic stenosis or when stenosis of the thoracic aorta is present.Reference Collins, Kaplan, Somes and Rome ^{178 ,} Reference Stamm, Li, Ho, Redington and Anderson ¹⁹¹ Potential mechanisms of coronary stenosis include adhesion of aortic valve leaflets, overhanging of the supra-valvar ring, or reactive changes to hypertension. Coronary artery stenosis can develop during childhood in the absence of supra-valvar aortic stenosis,Reference Bonnet, Cormier, Villain, Bonhoeffer and Kachaner ^{192 ,} Reference van Pelt, Wilson and Lear ¹⁹³ and dilation and tortuosity of the coronary arteries are well recognised.Reference Martin and Moseley ¹⁹⁴ These observations suggest primary arteriopathic mechanisms. QT interval prolongation is present in up to 15% of cases, which may predispose to ventricular dysrhythmia and also contribute to sudden death risk.Reference Collins, Aziz, Gleason, Kaplan and Shah ^{195 ,} Reference Collins, Aziz, Swearingen and Kaplan ¹⁹⁶ As coronary stenosis can be sub-clinical, it is critical that patients undergo complete assessment of the coronary arteries when appropriate and that providers be cognizant of the risk factors for sudden death around the time of interventional procedures.

Systemic hypertension develops in up to 50% of individuals, which is secondary to renal artery stenosis in some cases. In most cases, hypertension may rather be due to abnormal vascular function or morphology in the distal arteries, but the precise mechanisms are not well understood.Reference Broder, Reinhardt and Ahern ¹⁹⁷ Cerebral artery stenosis causing ischaemic stroke has been observed in children and should be suspected if neurological changes develop.Reference Kaplan, Levinson and Kaplan ¹⁹⁸ Selecting target blood pressure ranges around the time of procedures can be complicated by the presence of pre-existing hypertension combined with coronary or cerebral artery stenosis, which requires highly attentive pre-operative and post-operative care.

Owing to a 15–30% prevalence of sub-clinical hypothyroidism, often due to thyroid hypoplasia, thyroid function testing is recommended every 4 years, and pre-operative evaluation should include thyroid function tests and clinical evaluation for symptoms.Reference Stagi, Bindi and Neri ^{199 – 202} Congenital hypothyroidism due to severe thyroid hypoplasia has also been reported.Reference Stagi, Manoni, Salti, Cecchi and Chiarelli ²⁰³ Airway management may be challenging due to facial dysmorphism.Reference Medley, Russo and Tobias ²⁰⁰ Based on a concern for mild myopathy in some patients, there have been recommendations to avoid the use of succinylcholine and closely monitor the effects of non-depolarising neuromuscular blockade.Reference Medley, Russo and Tobias ²⁰⁰ Anomalies of the kidneys and urinary tract, such as renal aplasia, kidney duplication, horseshoe kidney, and bladder diverticuli, are present in up to 40% of the cases.Reference Pankau, Partsch, Winter, Gosch and Wessel ^{204 ,} Reference Sforzini, Milani and Fossali ²⁰⁵ Proteinuria was observed in 25% of patients, suggesting that kidney function should be monitored closely.Reference Ingelfinger and Newburger ²⁰⁶ Although there is predisposition for episodic hypercalcaemia and hypercalciuria, particularly as neonates, nephrocalcinosis is uncommon.Reference Pober, Lacro, Rice, Mandell and Teele ²⁰⁷

Taken together, severe vascular stenosis of the systemic and/or pulmonary arteries increase risk, and asymptomatic patients may be at risk for sudden cardiac death in the setting of occult coronary artery stenosis. These risks pertain to cardiac and non-cardiac procedures.

Noonan syndrome and related disorders

Noonan syndrome has a prevalence of one in 1000–2500 live births.Reference Roberts, Allanson, Tartaglia and Gelb ²⁰⁸ Disease-causing mutations in genes associated with the RAS-MAPK signaling pathway, such as PTPN11 (most frequent), SOS1, RAF1, KRAS, NRAS, BRAF, SHOC2, and CBL, are identified in up to 60% of the cases.Reference Romano, Allanson and Dahlgren ²⁰⁹ Cardiofaciocutaneous syndrome (BRAF, KRAS) and Costello syndrome (HRAS) are disorders related to Noonan syndrome with overlapping phenotypic features and genetic aetiologies.Reference Roberts, Allanson and Jadico ²¹⁰ Neonatal features of Noonan syndrome include tall forehead, hypertelorism, arched eyebrows, low-set posteriorly rotated ears with thick helices, low posterior hairline, and excessive nuchal skin.Reference Romano, Allanson and Dahlgren ²⁰⁹ Many of these features become more subtle over time, but short stature, pectus deformity, and neck webbing often remain prominent.Reference Roberts, Allanson, Tartaglia and Gelb ²⁰⁸ Patients with Noonan syndrome often achieve normal intelligence,Reference Cesarini, Alfieri and Pantaleoni ²¹¹ whereas cardiofaciocutaneous and Costello syndromes often have more significant developmental delay.Reference Roberts, Allanson and Jadico ^{210 ,} Reference Axelrad, Glidden, Nicholson and Gripp ²¹²

At least 80% of patients with Noonan syndrome have cardiac lesions including pulmonary valve stenosis (50–60%) and secundum atrial septal defect (6–30%).Reference Roberts, Allanson, Tartaglia and Gelb ^{208 ,} Reference Prendiville, Gauvreau and Tworog-Dube ²¹³ Hypertrophic cardiomyopathy is present in ~20% of patients, especially RAF1 mutations, and portends worse survival than non-syndromic hypertrophic cardiomyopathy;Reference Hickey, Mehta and Elmi ^{214 ,} Reference Pandit, Sarkozy and Pennacchio ²¹⁵ however, spontaneous regression occurred in nearly 20% of patients diagnosed in infancy.Reference Prendiville, Gauvreau and Tworog-Dube ²¹³ Fibromuscular dysplasia with clinically significant narrowing of the coronary arteries has been reported in the setting of Noonan syndrome and hypertrophic cardiomyopathy.Reference Ishikawa, Sekiguchi and Akasaka ²¹⁶ Electrocardiographic abnormalities are frequently observed, including predominantly negative forces in the left pre-cordial leads, left axis deviation, and abnormal Q waves.Reference Croonen, van der Burgt, Kapusta and Draaisma ²¹⁷ Although there are no particular rhythm abnormalities associated with Noonan syndrome, individuals with Costello syndrome (HRAS mutation) develop atrial tachycardia (often multi-focal) in ~50% of cases.Reference Lin, Alexander and Colan ²¹⁸ Early post-operative mortality outcomes have not been frequently reported in Noonan syndrome. Cardiac transplantation in the setting of Noonan syndrome is described, but outcome data are similarly scant.Reference Shaw, Kalidas, Crosby, Jeffery and Patton ²¹⁹ Longitudinal screening for occult hypertrophic cardiomyopathy may be indicated, particularly among those with PTPN11 or RAF1 mutations, in part to mitigate risk during cardiac and non-cardiac procedures.

Systemic features most likely to impact peri-operative outcomes are haematological and lymphatic abnormalities. Haematological abnormalities such as platelet dysfunction and coagulation factor deficiency are present in 30–65% of cases.Reference Romano, Allanson and Dahlgren ^{209 ,} Reference Witt, McGillivray and Allanson ^{220 –} Reference Wiegand, Hofbeck, Zenker, Budde and Rauch ²²³ Severe congenital thrombocytopaenia has been described.Reference Nunes, Aguilar and Prado ²²⁴ A recent study reported frequent easy bruising and post-surgical bleeding (15–25%), platelet dysfunction (80%), and factor VII deficiency (20%).Reference Artoni, Selicorni and Passamonti ²²⁵ Bleeding diathesis may predispose patients to spontaneous gastrointestinal or sub-arachnoid haemorrhage, which may respond to administration of recombinant factor VII.Reference Tofil, Winkler, Watts and Noonan ^{226 ,} Reference Dineen and Lenthall ²²⁷ Owing to the risk of coagulopathy, complete blood count and basic coagulation testing is warranted before operations, haematology consultation should be considered, and aspirin may be avoided.Reference Roberts, Allanson, Tartaglia and Gelb ^{208 ,} Reference Romano, Allanson and Dahlgren ²⁰⁹

Lymphatic abnormalities are observed in ~20% of cases.Reference Romano, Allanson and Dahlgren ²⁰⁹ Peripheral lymphoedema often spontaneously resolves within the first several years but can have late onset.Reference Ho, Wang and Li ²²⁸ Similar to Turner syndrome, pulmonary lymphatic abnormalities including congenital pulmonary lymphangiectasia may predispose to chylothorax.Reference Bellini, Boccardo, Campisi and Bonioli ^{169 ,} Reference Fabretto, Kutsche and Harmsen ^{229 –} Reference Goens, Campbell and Wiggins ²³¹ Post-operative pericardial and pleural effusions were not significantly increased in a series of ~120 operations.Reference Prendiville, Gauvreau and Tworog-Dube ²¹³ Cutaneous leaking of lymphatic fluid from a femoral vascular access site due to lymphangiectasia has been reported during cardiac catheterisation.Reference Tsang, Cheung, Leung and Chau ²³²

Taken together, Noonan syndrome and related disorders are notable for genotype–phenotype relationships such as the associations between RAF1 and hypertrophic cardiomyopathy and HRAS and atrial tachycardia. Bleeding and lymphatic abnormalities may complicate the peri-operative course. Additional peri-operative outcome studies are warranted.

Marfan syndrome and related disorders

Marfan syndrome is present in approximately one in 5000 live births and most commonly caused by mutations in the FBN1 gene, which encodes the extracellular matrix protein fibrillin-1.Reference Dietz, Loeys, Carta and Ramirez ²³³ Skeletal abnormalities – for example, pectus deformity, long arms, short upper body segment, craniofacial dysmorphism, and arachnodactyly – and ocular abnormalities – such as ectopia lentis and myopia – are often present.Reference Loeys, Dietz and Braverman ²³⁴ Cardiovascular involvement consists of aortopathy, characterised by thoracic aortic aneurysm and risk for dissection, and mitral valve prolapse. Development and intellectual ability are typically normal. Although most patients with Marfan syndrome do not require cardiac surgery until adulthood,Reference Gott, Greene and Alejo ²³⁵ excellent operative survival has been demonstrated in children undergoing aortic root replacement.Reference Cattaneo, Bethea and Alejo ^{236 –} Reference Roubertie, Ben Ali and Raisky ²³⁸ Peri-operative providers should recognise risk for pneumothorax and other pulmonary co-morbidities including pulmonary emphysema.Reference Wood, Bellamy, Child and Citron ²³⁹ Pectus deformity or severe scoliosis may also impact surgical approach and recovery. Some patients with particularly severe cardiovascular disease are referred to as having neonatal Marfan syndrome, which is associated with mutations in exons 24–32 of FBN1.Reference Booms, Cisler and Mathews ^{240 ,} Reference Sutherell, Zarate and Tinkle ²⁴¹ Arachnodactyly, congenital contractures, and crumpled ears feature prominently in these neonates, who often present with severe mitral and tricuspid valve regurgitation, leading to cardiac failure and death within the first few months of life. Rare cases of surgical success including quadrivalvar replacement and cardiac transplantation have been reported.Reference Strigl, Quagebeur and Gersony ^{242 ,} Reference Krasemann, Kotthoff and Kehl ²⁴³

Loeys–Dietz syndrome, which is associated with mutations in the TGF-β receptor genes TGFBR1 and TGFBR2, has overlapping but distinct phenotypic features with Marfan syndrome.Reference Drera, Ritelli and Zoppi ²⁴⁴ Systemic features include hypertelorism, bifid uvula, cleft palate, craniosynostosis, and velvety/thin skin. Talipes equinovarus and camptodactyly may also be diagnostic clues in a neonate.Reference Muramatsu, Kosho and Magota ²⁴⁵ The major cardiovascular manifestations are generalised arterial tortuosity and risk for aneurysm and dissection. Additional cardiovascular lesions include bicuspid aortic valve, atrial septal defect, and mitral valve prolapse. Vascular disease in Loeys–Dietz syndrome is typically more severe than Marfan syndrome with risk of rapid progression and aortic dissection. Dissection is described as early as 6 months of age.Reference Williams, Loeys and Nwakanma ²⁴⁶ There is also often more extensive arterial involvement, which may require complete aortic replacement. Tortuosity and aneurysm of the brachiocephalic and intra-cranial arteries may predispose to cerebrovascular events.Reference Maccarrick, Black and Bowdin ^{247 ,} Reference Malhotra and Westesson ²⁴⁸ Despite the aggressive vascular features of the disease, successful aortic root replacement in infancy has been reported.Reference Cleuziou, Eichinger, Schreiber and Lange ²⁴⁹ Furthermore, there were no operative deaths among two series of children with Loeys–Dietz syndrome undergoing aortic root replacement.Reference Williams, Loeys and Nwakanma ^{246 ,} Reference Patel, Arnaoutakis and George ²⁵⁰ Cardiovascular complications in the setting of complex CHD have included progressive pulmonary artery dilation and rupture and post-operative mitral leaflet rupture.Reference Muramatsu, Kosho and Magota ^{245 ,} Reference Kawazu, Inamura, Kayatani, Okamoto and Morisaki ^{251 ,} Reference Nishida, Tamura and Yamazaki ²⁵² Similar to Marfan syndrome, patients with Loeys–Dietz syndrome have increased risk of post-operative pneumothorax.Reference Maccarrick, Black and Bowdin ^{247 ,} Reference Patel, Arnaoutakis and George ²⁵⁰ Careful peri-operative positioning should be utilised due to risk of low bone mineral density and increased fracture risk as well as cervical spine anomalies.Reference Maccarrick, Black and Bowdin ^{247 ,} Reference Kirmani, Tebben and Lteif ^{253 –} Reference Fuhrhop, McElroy, Dietz, MacCarrick and Sponseller ²⁵⁵ Tortuosity or aneurysm of the peripheral arteries also may impact vascular access.Reference Maccarrick, Black and Bowdin ²⁴⁷

Taken together, early post-operative outcomes are generally favourable for these conditions, but the risk of recurrent aneurysm or dissection mandates lifelong surveillance. Loeys–Dietz syndrome has unusual characteristics that may not be well recognised due to the more recent discovery and characterisation of the disorder.

Alagille syndrome

Alagille syndrome has a prevalence of at least one in 70,000 live births and is associated with the Notch signaling pathway genes JAG1 (97% of cases) and NOTCH2 (1% of cases).Reference Turnpenny and Ellard ²⁵⁶ The hallmark systemic manifestations include bile duct paucity, resulting in cholestasis, facial dysmorphism – deep-set eyes, prominent ears, triangular face with broad forehead, and pointed chin – vertebral anomalies, and ocular anomalies, often posterior embryotoxon. CHD is present in at least 90% of the cases. The most common cardiovascular findings are right-sided lesions including proximal branch pulmonary artery stenosis, peripheral pulmonary artery stenosis, tetralogy of Fallot, or pulmonary valve stenosis. Left-sided lesions and septal defects are also observed but are less frequent.Reference McElhinney, Krantz and Bason ²⁵⁷ In addition to the hallmark systemic features, renal anomalies are observed in ~40% of patients, which includes 20% with renal dysplasia and 5% risk of developing chronic renal failure.Reference Kamath, Podkameni and Hutchinson ²⁵⁸ There is evidence that patients with Alagille syndrome have relatively poor longitudinal outcomes in the setting of tetralogy of Fallot or pulmonary atresia with ventricular septal defect;Reference McElhinney, Krantz and Bason ^{257 ,} Reference Blue, Mah and Cole ²⁵⁹ however, positive early outcomes were recently reported among 15 patients with pulmonary atresia and major aortopulmonary collateral arteriesReference Mainwaring, Sheikh, Punn, Reddy and Hanley ²⁶⁰ and six patients undergoing primary surgical reconstruction of peripheral pulmonary artery stenosis.Reference Monge, Mainwaring and Sheikh ¹⁸¹ Owing to congenital biliary anomalies, Alagille syndrome may present the unusual challenge of requiring paediatric cardiac surgery in patients with severe liver disease; two small case series have reported operative mortality in two out of four children with Alagille syndrome and end-stage liver disease undergoing cardiac surgery.Reference Bacha, Hardin and Cronin ^{261 ,} Reference Odim, Wu, Laks, Banerji and Drant ²⁶²

It is increasingly clear that Alagille syndrome is a disorder characterised by diffuse arteriopathy and that arterial anomalies – aneurysm or stenosis – significantly contribute to poor outcomes. In a large cohort of 268 patients with Alagille syndrome, systemic arterial anomalies or intra-cranial vascular events were present in nearly 10% of patients, and vascular accidents were responsible for 34% of the observed mortality.Reference Kamath, Spinner and Emerick ²⁶³ Spontaneous haemorrhage in the gastrointestinal tract, nasal/oral mucosa, and uterine lining are also reported in the absence of liver failure. It is speculated that elevated levels of apolipoprotein E may impair normal haemostasis,Reference Lykavieris, Crosnier, Trichet, Meunier-Rotival and Hadchouel ²⁶⁴ but a primary arterial fragility may be likely. A unique case report of a child with recurrent aortopulmonary shunt dehiscence due to extensive atherosclerosis and plaque at the anastomosis site has prompted some to consider routine screening and treatment for dyslipidaemia to prevent exacerbation of arterial disease in these patients.Reference May, Hanley, Connolly and Reddy ²⁶⁵ Taken together, systemic arteriopathy presents significant challenges to both early and late survival outcomes.

Trisomy 13 and 18

Patients with trisomy 13 – Patau syndrome – or trisomy 18 – Edwards syndrome – have severe co-morbidities and poor prognosis with >90% of the affected infants dying by age 1 year. Given the severe multi-systemic nature of these disorders, the presence of CHD may not impact overall survival.Reference Rasmussen, Wong, Yang, May and Friedman ²⁶⁶ Cardiac lesions are most commonly septal defects, but left ventricular non-compaction associated with progressive heart failure has been described in trisomy 13.Reference McMahon, Chang and Pignatelli ^{267 ,} Reference Yukifumi, Hirohiko, Fukiko and Mariko ²⁶⁸ Despite poor overall survival, cardiac operations including palliative and complete repairs may be beneficial in select groups.Reference Maeda, Yamagishi and Furutani ^{269 ,} Reference Graham, Bradley, Shirali, Hills and Atz ²⁷⁰ The care for these patients and families requires a balanced multi-disciplinary approach including palliative care specialists.

CHARGE syndrome

CHARGE syndrome is present in approximately one in 8500 live births.Reference Issekutz, Graham, Prasad, Smith and Blake ²⁷¹ Most cases (~70%) are associated with mutation in the CHD7 gene, which encodes a chromodomain helicase DNA-binding protein, and are rarely associated with mutation in SEMA3E;Reference Zentner, Layman, Martin and Scacheri ^{272 ,} Reference Lalani, Safiullah and Molinari ²⁷³ 22q11 deletion has also been described in patients clinically diagnosed with CHARGE syndrome.Reference Corsten-Janssen, Saitta and Hoefsloot ²⁷⁴ The major diagnostic criteria (“four C’s”) are coloboma, choanal atresia, cranial nerve dysfunction, and characteristic ear anomalies, external and middle ear anomalies.Reference Blake and Prasad ²⁷⁵ CHD is present in ~75% of patients and includes conotruncal and septal defects, including atrioventricular septal defects.Reference Zentner, Layman, Martin and Scacheri ^{272 ,} Reference Corsten-Janssen, Kerstjens-Frederikse and du Marchie Sarvaas ²⁷⁶ Forebrain central nervous system malformations are frequently observed,Reference Lin, Siebert and Graham ²⁷⁷ yet significant intellectual disability is not guaranteed.Reference Blake and Prasad ²⁷⁵ Immunological dysfunction including severe T-cell deficiency has been reported.Reference Jyonouchi, McDonald-McGinn, Bale, Zackai and Sullivan ²⁷⁸ Renal anomalies are observed in ~30–40% cases and include solitary kidney, hydronephrosis, renal hypoplasia, duplex kidneys, and vesicoureteral reflux.Reference Blake and Prasad ²⁷⁵

Peri-operative outcomes have not been frequently reported, but sub-optimal longitudinal outcomes for patients with conotruncal defects have been suggested.Reference Michielon, Marino and Oricchio ³¹ A major peri-operative risk factor is the high frequency of anatomical and functional abnormalities of the respiratory tract. Upper airway anomalies – choanal atresia, cleft lip/palate, and micrognathia – and laryngotracheal anomalies – tracheoesophageal fistula, laryngomalacia, tracheomalacia, sub-glottic stenosis, laryngeal cleft, and anterior larynx – may complicate airway management.Reference Stack and Wyse ^{279 ,} Reference Morgan, Bailey and Phelps ²⁸⁰ Cranial nerve dysfunction – for example, cranial nerves IX and X – leads to pharyngeal and laryngeal dysfunction and poor airway protection, a problem that may be exacerbated by high frequency of gastroesophageal reflux.Reference Bergman, Blake and Bakker ²⁸¹ Indeed, post-operative airway events are frequently encountered – 35% in a recent series – occurring most frequently after cardiac surgery.Reference Blake, MacCuspie and Hartshorne ²⁸² In an early case series, over half of deaths were attributed to pulmonary aspiration.Reference Blake, Russell-Eggitt, Morgan, Ratcliffe and Wyse ^{283 ,} Reference Wyse, Al-Mahdawi, Burn and Blake ²⁸⁴ Pituitary structural abnormalities may be associated with neonatal hypocortisolism and should be considered in cases of refractory hypotension.Reference James, Aftimos and Hofman ^{285 ,} Reference Gregory, Gevers and Baker ²⁸⁶

Ellis–van Creveld syndrome

Ellis–van Creveld syndrome is a rare autosomal-recessive disorder (EVC or EVC2 mutations) with increased occurrence among the Amish population inhabiting Pennsylvania, United States of America.Reference Baujat and Le Merrer ²⁸⁷ Frequent characteristics include short stature, polydactyly, short ribs, and dysplastic nails, hair, and teeth. Notably, cognitive development is normal. CHD is present in ~60% and includes common atrium, atrioventricular septal defect, and systemic and pulmonary venous abnormalities.Reference O’Connor, Rider and Thomas Collins ^{288 ,} Reference Hills, Kochilas, Schimmenti and Moller ²⁸⁹ Overall, three noteworthy retrospective studies have analysed cardiac surgical outcomes. A case series of nine patients undergoing cardiac surgery at a single centre from 2004 to 2009 observed a preponderance of respiratory morbidity.Reference O’Connor, Rider and Thomas Collins ²⁸⁸ Death occurred within 150 days after surgery in four out of nine patients, primarily due to respiratory failure. Respiratory complications, including three of five survivors requiring tracheostomy, were attributed to a thoracic dystrophy similar to Jeune syndrome. Increased procedure-related respiratory morbidity was also observed in the Pediatric Health Information System database from 2004 to 2011.Reference O’Connor, Tang and Collins ²⁹⁰ In fairly stark contrast with these reports, a review of the Pediatric Cardiac Care Consortium database from 1982 to 2007 identified no operative mortality among 21 children undergoing cardiac surgery.Reference Hills, Kochilas, Schimmenti and Moller ²⁸⁹ The reason for the discrepancy between these reports is unclear. Notably, thoracic dystrophy may improve with somatic growth, suggesting benefit of deferring surgery for as long as possible.Reference O’Connor, Rider and Thomas Collins ²⁸⁸ Together, these observations indicate the need for complete pulmonary evaluation and consideration of invasive haemodynamic assessment before cardiac operations.

VACTERL

VACTERL association likely represents a genetically heterogeneous population consisting of vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula with oesophageal atresia, renal anomalies, and limb defects.Reference Solomon ²⁹¹ The renal anomalies include unilateral agenesis, horseshoe kidney, cystic disease, and dysplasia, and there is risk for chronic kidney disease with progression to end-stage renal disease.Reference Ahn, Mendoza, Kaplan and Reznik ²⁹² In a cohort of 46 patients, 31 had CHD, which was most frequently ventricular septal defect.Reference Cunningham, Hadley and Hannoush ²⁹³ Probably due to the currently imprecise nature of this diagnosis, there are little outcomes data available.

PHACES

PHACES association includes posterior fossa malformations, haemangioma – often large, segmental, and involving the head or neck – arterial anomalies, cardiac defects, eye abnormalities, and sternal defects.Reference Rao, Drolet, Holland and Frommelt ²⁹⁴ A genetic aetiology has not been established. Arterial manifestations include anomalous patterning, stenosis, occlusion, or aneurysm of the cervical and/or cerebral arteries, which are usually ipsilateral to the haemangioma.Reference Hess, Fullerton and Metry ^{295 ,} Reference Heyer, Dowling and Licht ²⁹⁶ Aortic arch sidedness is also often ipsilateral to the haemangioma.Reference Bronzetti, Giardini and Patrizi ²⁹⁷ Cardiovascular malformations are present in ~40% of patients, including aberrant subclavian artery, coarctation of the aorta (~20%), and ventricular septal defect (~15%).Reference Bayer, Frommelt and Blei ²⁹⁸ Coarctation morphology is often complex and is rarely associated with bicuspid aortic valve.Reference Rao, Drolet, Holland and Frommelt ²⁹⁴ Preparation for surgical repair of coarctation should include a complete evaluation of the aortic arch and head and neck arteries by cardiac catheterisation or other imaging modality to optimise surgical approach.Reference Rao, Drolet, Holland and Frommelt ^{294 ,} Reference Giardini, Gholam, Khambadkone and Kostolny ²⁹⁹ Peri-operative providers should also recognise increased risk for sub-glottic haemangioma and risk for ischaemic stroke and seizures during infancy.Reference Hartemink, Chiu, Drolet and Kerschner ^{300 –} Reference Burrows, Robertson and Mulliken ³⁰²

Cri du chat syndrome

Cri du chat syndrome (5p15 deletion) has a prevalence of approximately one in 15,000 live births.Reference Cerruti Mainardi ³⁰³ A distinguishing feature is the characteristic high-pitched cry. Neonatal craniofacial features include microcephaly and round face with large nasal bridge, hypertelorism, and micrognathia. Severe psychomotor and growth delay is observed in most cases. Tracheal intubation may be complicated by the presence of laryngeal abnormalities including small larynx, narrow diamond-shaped larynx, and laryngomalacia, and large, floppy epiglottis.Reference Yamashita, Tanioka, Taniguchi, Matsuki and Oyama ³⁰⁴ CHD is present in ~20% of the patients, including patent ductus arteriosus, ventricular septal defect, atrial septal defect, and right ventricular outflow tract obstructive lesions including tetralogy of Fallot.Reference Hills, Moller, Finkelstein, Lohr and Schimmenti ³⁰⁵ Outcomes data are limited, but a review of the Pediatric Cardiac Care Consortium from 1982 to 2002 identified 18 children undergoing cardiac surgery, including five complete tetralogy of Fallot repairs, who had good overall survival with one operative death.Reference Hills, Moller, Finkelstein, Lohr and Schimmenti ³⁰⁵

Jacobsen syndrome

Jacobsen syndrome has a prevalence of approximately one in 100,000 live births and is associated with a deletion on the long arm of chromosome 11 with break point at 11q23.Reference Grossfeld, Mattina and Lai ³⁰⁶ The pathogenic gene for cardiovascular manifestations may be ETS1.Reference Glessner, Bick and Ito ¹⁶ Dysmorphic features include skull deformity – for example, trigonocephaly – hypertelorism, strabismus, low posteriorly rotated ears, and syndactyly. Intellectual disability and behavioural abnormalities are observed in the majority of cases. CHD occurs in ~50% of cases, primarily consisting of ventricular septal defect or left-sided obstructive lesion, including up to 5% with hypoplastic left heart syndrome.Reference Mattina, Perrotta and Grossfeld ^{307 ,} Reference Favier, Jondeau and Boutard ³⁰⁸ Importantly, there is often increased bleeding risk due to a platelet disorder – Paris–Trousseau syndrome – characterised by neonatal thrombocytopaenia, which can be severe but improves with age, and platelet dysfunction, which often persists.Reference Grossfeld, Mattina and Lai ^{306 ,} Reference Favier, Jondeau and Boutard ³⁰⁸ Pre-operative evaluation of platelet function using thromboelastography may be warranted. Airway management can be complicated by micrognathia and anterior laryngeal opening.Reference Blaine Easley, Sanders, McElrath-Schwartz, Martin and Mark Redmond ³⁰⁹ Central hypothyroidism has been reported.Reference Pivnick, Velagaleti and Wilroy ³¹⁰ Renal and urinary tract malformations, including dysplasia, hydronephrosis, and unilateral agenesis, occur rarely.Reference Grossfeld, Mattina and Lai ^{306 ,} Reference Mattina, Perrotta and Grossfeld ³⁰⁷

Kabuki syndrome

Kabuki syndrome has a prevalence of approximately one in 32,000 live births and in most cases is associated with mutations in the MLL2 gene, which encodes a histone methyltransferase.Reference Ng, Bigham and Buckingham ^{311 ,} Reference Niikawa, Kuroki and Kajii ³¹² Its naming is derived from a characteristic appearance of long palpebral fissures with lower eyelid eversion and arched eyebrows, resembling masks worn in Kabuki theatre. Another characteristic finding is foetal finger pads. Intellectual disability is present in ~90% and seizures in 12–25%.Reference Schrander-Stumpel, Spruyt, Curfs, Defloor and Schrander ^{313 –} Reference Bogershausen and Wollnik ³¹⁵ Cardiac defects are present in ~50% of cases and include ventricular septal defect, atrial septal defect, left-sided obstructive lesions – most commonly coarctation of the aorta – and tetralogy of Fallot.Reference Schrander-Stumpel, Spruyt, Curfs, Defloor and Schrander ^{313 ,} Reference Digilio, Marino, Toscano, Giannotti and Dallapiccola ^{314 ,} Reference Armstrong, Abd El Moneim and Aleck ³¹⁶ Abnormalities in humoral immunity, including low levels of IgA, total IgG, or IgG sub-classes, were observed in ~50%, which may explain the predisposition to upper respiratory infections, and potentially impacts peri-operative risk.Reference Hoffman, Ciprero and Sullivan ³¹⁷ Cleft lip/palate including sub-mucous clefts occurs in ~50%.Reference Schrander-Stumpel, Spruyt, Curfs, Defloor and Schrander ³¹³ Renal abnormalities include renal dysplasia, agenesis, horseshoe kidney, ectopic kidney, and hydronephrosis.Reference Armstrong, Abd El Moneim and Aleck ³¹⁶

Smith–Magenis syndrome

Smith–Magenis syndrome has a prevalence of approximately one in 25,000 live birthsReference Greenberg, Guzzetta and Montes de Oca-Luna ³¹⁸ and is associated with the deletion of 17p11.2.Reference Greenberg, Guzzetta and Montes de Oca-Luna ^{318 ,} Reference Elsea and Girirajan ³¹⁹ Craniofacial features include broad face with hypertelorism and upslanting eyes, prognathism, low-set ears, cleft lip/palate, and ocular abnormalities.Reference Edelman, Girirajan and Finucane ³²⁰ Mild-to-moderate developmental delay is often observed along with characteristic neurobehavioural features such as sleep disturbance with inverted circadian rhythm and predilection for self-injury.Reference Edelman, Girirajan and Finucane ³²⁰ CHD is present in ~30–40% and includes ventricular septal defect, atrial septal defect, right-sided lesions including tetralogy of Fallot, and total anomalous pulmonary venous return.Reference Edelman, Girirajan and Finucane ^{320 –} Reference Myers and Challman ³²² The cardiovascular risk profile includes predisposition for dyslipidaemia, including hypercholesterolaemia.Reference Smith, Gropman and Bailey-Wilson ³²³ Post-operative ischaemic stroke in a young adult with premature cerebrovascular atherosclerosis has been reported.Reference Chaudhry, Schwartz and Singh ³²⁴ Immunoglobulin levels are low in ~20%.Reference Greenberg, Lewis and Potocki ³²¹ Hypothyroidism presents in ~30%.Reference Greenberg, Lewis and Potocki ³²¹ Epileptiform abnormalities are present in ~50%, and clinical seizures develop in ~20–30%.Reference Edelman, Girirajan and Finucane ^{320 ,} Reference Goldman, Potocki and Walz ³²⁵ Renal and urinary tract anomalies are present in ~15% and include renal dysplasia, small kidney, vesicoureteral reflux, renal agenesis, and ureteral duplication.Reference Edelman, Girirajan and Finucane ^{320 ,} Reference Myers, Challman and Bock ³²⁶

Wolf–Hirschhorn syndrome

Wolf–Hirschhorn syndrome has a prevalence of approximately one in 20,000 live births and is associated with the deletion of 4p16.3.Reference Maas, Van Buggenhout and Hannes ^{327 ,} Reference Battaglia, Filippi and Carey ³²⁸ Patients characteristically have the appearance of a “Greek warrior helmet” with high forehead, prominent glabella, and protruding eyes with hypertelorism.Reference Battaglia, Filippi and Carey ³²⁸ Micrognathia, forehead haemangioma, and cleft lip/palate also occur with increased frequency. Severe developmental delay is uniformly observed, and seizures occur in ~90% of individuals starting at a young age.Reference Battaglia, Filippi, South and Carey ³²⁹ CHD is present in ~50%, most commonly atrial septal defect, pulmonary stenosis, ventricular septal defect, and patent ductus arteriosus, but more complex lesions have been reported.Reference Battaglia, Filippi and Carey ^{328 ,} Reference von Elten, Sawyer, Lentz-Kapua, Kanis and Studer ^{330 ,} Reference Tautz, Veenma and Eussen ³³¹ Defects in humoral immunity, including common variable immunodeficiency and isolated IgA deficiency, are frequently observed.Reference Hanley-Lopez, Estabrooks and Stiehm ³³² Renal and urinary tract defects are observed in ~30% and include vesicoureteral reflux, renal agenesis, dysplasia, or hypoplasia, and horseshoe kidney.Reference Battaglia, Filippi and Carey ³²⁸

Cornelia de Lange syndrome

Cornelia de Lange syndrome, also known as Brachmann–de Lange syndrome, has a prevalence of approximately one in 10,000 live births and is caused by mutations in the NIPBL, SMC1A, or SMC3 genes, which encode gene products involved in the function of cohesin, a protein complex involved in cell division.Reference Liu and Krantz ³³³ Patients have consistent craniofacial features including short neck, low posterior hairline, hirsute forehead, arched and confluent eyebrows, and thick and long eyelashes.Reference Jackson, Kline, Barr and Koch ³³⁴ Mild-to-moderate intellectual disability is frequent.Reference Kline, Stanley and Belevich ³³⁵ CHD is present in ~30% and includes pulmonary valve stenosis, peripheral pulmonary artery stenosis, atrial septal defect, ventricular septal defect, left-sided obstructive lesions, and tetralogy of Fallot; there is also risk for progressive atrioventricular valve dysplasia.Reference Selicorni, Colli and Passarini ^{336 ,} Reference Chatfield, Schrier and Li ³³⁷

Airway management may be complicated by micrognathia, cleft palate, sub-mucous cleft, short, stiff neck, and restricted mouth opening.Reference August and Sorhabi ³³⁸ Recurrent infections including fungal infections are reported at increased frequency, and humoral deficiency and T-cell abnormalities have been observed.Reference Jyonouchi, Orange, Sullivan, Krantz and Deardorff ³³⁹ Thrombocytopaenia has been observed in ~20%.Reference Lambert, Jackson and Clark ³⁴⁰ Renal and urinary tract anomalies are observed in ~40% of patients and most frequently renal dysplasia, pelvic dilation, and vesicoureteral reflux are observed.Reference Selicorni, Sforzini and Milani ³⁴¹ Seizures, often partial type, occur in ~25%.Reference Verrotti, Agostinelli and Prezioso ³⁴²

Holt–Oram syndrome

Holt–Oram syndrome, which is characterised by the triad of atrial septal defect, conduction abnormality, and upper limb malformation – most commonly thumb – has a prevalence of approximately one in 100,000 live births and is caused by mutations in the cardiac transcription factor TBX5.Reference Bossert, Walther and Gummert ³⁴³ Cardiac lesions include atrial septal defect, which is most common, ventricular septal defect, and more complex lesions such as conotruncal defects, atrioventricular canal defects, and left-sided obstructive lesions.Reference Bossert, Walther and Gummert ³⁴³ The most frequent conduction abnormality is atrioventricular block, most commonly first degree, which may be present in the absence of structural CHD.Reference Newbury-Ecob, Leanage, Raeburn and Young ³⁴⁴ Aside from the risk of atrioventricular block or other conduction disturbances, there are typically no other significant co-morbidities expected to complicate peri-operative care.

Goldenhar syndrome

Goldenhar syndrome, also known as oculo-auriculo-vertebral spectrum, occurs in up to one in 6000 live births.Reference Digilio, Calzolari and Capolino ³⁴⁵ Although suspected to be due to abnormal development of the first and second branchial arches, the genetic cause is presently unknown; however, 22q11 deletion was recently reported in patients diagnosed with this disorder.Reference Digilio, McDonald-McGinn and Heike ³⁴⁶ The defining features include unilateral microtia, hemifacial microsomia with mandibular hypoplasia, ocular epibulbar dermoid, and cervical vertebral malformations.Reference Rollnick, Kaye, Nagatoshi, Hauck and Martin ³⁴⁷ CHD is present in ~30% of cases and includes conotruncal defects, ventricular septal defect, and atrial septal defect.Reference Digilio, Calzolari and Capolino ³⁴⁵ Significant craniofacial distortion and cervical vertebral anomalies may complicate airway management.Reference Ozlu, Simsek, Alacakir and Yigitkanli ³⁴⁸ Renal and urinary tract anomalies include ectopic or fused kidneys, renal agenesis, and vesicoureteral reflux.Reference Ritchey, Norbeck, Huang, Keating and Bloom ³⁴⁹