10_Byard
9/27/05
11:39 AM
Page 215
Forensic Science, Medicine, and Pathology Copyright © 2005 Humana Press Inc. All rights of any nature whatsoever are reserved. ISSN 1547-769X/05/1:215–220/$30.00 eISSN 1556-2891 DOI: 10.1385/Forensic Sci. Med. Pathol.:1:3:215
PRACTICAL PEARL
Total Anomalous Pulmonary Venous Connection Autopsy Considerations Roger W. Byard and John D. Gilbert Forensic Science SA and University of Adelaide, Adelaide, Australia
Address for correspondence and reprints: Roger W. Byard, Forensic Science SA, 21 Divett Place, Adelaide 5000, Australia E-mail: [email protected] Accepted for publication: June 15, 2005
Abstract Total anomalous pulmonary venous connection (TAPVC), where the pulmonary venous circulation drains into the systemic venous circulation rather than into the left atrium, may present a number of problems at autopsy. A 5-week-old infant is reported who died suddenly and unexpectedly who was found at autopsy to have infradiaphragmatic TAPVC into the portal vein. The only associated anomalies were a tri-lobed left lung, a patent ductus arteriosus, and drainage of the inferior vena cava into the both the right and left atria. This case demonstrates particular features that may lead to difficulties in establishing the diagnosis of TAPVC. Sudden death in the absence of symptoms in this age group raises the possibilities of sudden infant death syndrome (SIDS) and inflicted injury, both of which were discounted in this case. An autopsy approach is outlined to maximize chances of diagnosing this entity that includes meticulous inspection and dissection of cardiac vascular connections before evisceration, with photographic documentation of findings. Concurrent cardiovascular abnormalities, including valve atresias, septal defects, and left heart hypoplasia are likely in the presence of asplenia/polysplenia syndrome. Extracardiac anomalies may be present in the form of Holt-Oram, Ellis-van Creveld, and cat eye syndromes. Careful examination of the common draining vein for obstructive features is an important part of the postmortem assessment. The possibility of heritable cases requires referral of the family for genetic evaluation. Key Words: Forensic pathology; total anomalous pulmonary venous connection; TAPVC; sudden death; autopsy. (DOI: 10.1385/Forensic Sci. Med. Pathol.:1:3:215)
INTRODUCTION
CASE REPORT
Anomalous pulmonary venous return refers to a situation where the pulmonary veins do not attach in a normal manner to the left atrium, but instead drain into part of the systemic venous system (1). This may be complete, as in total anomalous pulmonary venous connection (TAPVC), or partial, if only part of the pulmonary venous circulation drains aberrantly. The clinical effects of this congenital anomaly vary depending on the amount of oxygenated blood being delivered to the venous system, and the presence or absence of associated cardiovascular abnormalities. Sudden and unexpected death at an early age is well documented (2). The following case is described to demonstrate typical autopsy features and to outline an approach for the detection and demonstration of lethal aberrant pulmonary venous circulation and its associated features at autopsy.
A 5-week-old girl, who was noted by her father to be “choking,” collapsed in his arms when he picked her up. The father attempted resuscitation before calling an ambulance. When ambulance personnel arrived, the infant was moribund, with a heart rate of 50. She died soon after. The infant’s past history included spontaneous vaginal delivery at 35 weeks gestation with a birthweight of 2700 g. No significant medical problems were noted subsequently. Death while awake raised concerns by attending police that the case may not have been sudden infant death syndrome (SIDS), but may have involved inflicted injury. At autopsy, there were no dysmorphic features and dermatoglyphs were normal. Internal examination revealed a single normally formed and situated spleen (weight = 9.5 g; normal weight = 12–14 g). Although there was levocardia with
215
10_Byard
9/27/05
11:39 AM
Page 216
216 _________________________________________________________________________________Byard and Gilbert
Fig. 1. Posterior view demonstrating the convergence of three left-sided pulmonary veins and two right-sided pulmonary veins to form a common vein that passed through the diaphragm and behind the liver to join the portal vein in a 5-week-old girl who suddenly collapsed.
atrial situs solitus and atrioventricular concordance the heart was noted to be unusually mobile with prominence of the right ventricle (heart weight = 26 g; normal weight = 12–28 g). Examination of the pulmonary venous return showed that three pulmonary veins from the left lung and two pulmonary veins from the right converged to form a common vein that passed through the diaphragm with no connection between the pulmonary venous system and the left atrium. The common vein passed behind the liver and terminated in the portal vein (Figs. 1 and 2). No luminal narrowing could be demonstrated on opening of the common vein. The heart otherwise showed normal venous drainage except for a venous connection between the upper part of the inferior vena cava and the lateral posterior aspect of the left atrium, most likely representing an inferior sinus venosus defect. The vena cavae otherwise terminated normally in the right atrium. Both the right atrium and ventricle were dilated and hypertrophied with a right ventricular free wall thickness of 8 mm. There were no atrial or ventricular septal defects. The foramen
Fig. 2. Demonstration of clear separation of the common vein from the left atrium by rotating the left lung over to the right hand side.
ovale was closed. The left atrium and ventricle were small with a left ventricular free wall thickness of 5 mm. Valves and coronary arteries were normally formed and situated. There was a patent ductus arteriosus with a circumference of 4 mm. The left lung had three lobes. No other abnormalities were detected and there were no other organic diseases present that could have caused or contributed to death. Histopathological examination was unremarkable. There were no significant microbiological, metabolic, electrolyte, or toxicological abnormalities. Full skeletal survey was normal. There was no evidence of intentional or nonintentional trauma. Therefore, death was attributed to the effects of TAPVC.
DISCUSSION TAPVC refers to a rare congenital malformation of the pulmonary venous system in which blood from the lungs drains via the pulmonary veins into the systemic veins or the right atrium (1), resulting in oxygenated blood from the lungs mixing with systemic venous blood. Survival depends on shunting of this blood into the left side of the heart or the aortic outflow tract usually through an atrial septal defect, patent
Forensic Science, Medicine, and Pathology V1–3
10_Byard
9/27/05
11:39 AM
Page 217
Autopsy Considerations of TAPVC ___________________________________________________________________217 foramen ovale, or a patent ductus arteriosus. This condition has also been described in animals (3). TAPVC accounts for 1–2% of all cardiovascular malformations, 2–5% of cases of congenital cardiac defects presenting to autopsy, and occurs in 6.8 cases per 100,000 live births (4–6). Affected infants are more likely to have a birthweight below 2500 g, with intrauterine growth retardation and a gestational age less than 38 weeks, as in the reported case (4). The malformation does not present problems during intrauterine life because of high pulmonary vascular resistance with shunting across the foramen ovale. After birth, clinical symptoms and signs may include tachycardia, tachypnea, diaphoresis, central cyanosis, and features of cardiac failure with feeding difficulties and failure to thrive, however, a significant percentage of affected infants, as in the reported case will be asymptomatic (7,8). The mortality rate in untreated infants is 80% in the first year of life, although survival to adult life has been described (9,10). During embryological development, the primordial lung drains into the splanchnic vascular plexus with communications to the systemic venous circulation through the omphalomesenteric veins, the sinus venosus, and the anterior cardinal veins (11,12). The developing pulmonary vein first appears as an outpouching of the posterior part of the left atrial wall or the sinus venosus and fuses with the pulmonary venous plexus by around 30 weeks gestation. If the common pulmonary vein draining from the pulmonary veins to the left atrium either fails to develop, or involutes, collateral vascular channels may persist, giving rise to anomalous venous drainage either above or below the diaphragm (13). The sites of drainage may be divided into the following four broad categories: Type I:
Type II: Type III: Type IV:
supracardiac, draining into the right or persistent left superior vena cava or their tributaries (45%). cardiac, draining into the right atrium or coronary sinus (25%). infracardiac, draining into the portal vein or its tributaries (25%) draining at multiple sites, for example with the left pulmonary veins connected to the left innominate vein and the right pulmonary veins connected to the right atrium (5%) (6,7).
Although the most common sites of drainage have been reported as the left innominate vein and coronary sinus, this varies depending on the particular series. The worst prognosis has been associated with infradiaphragmatic drainage, partly owing to obstruction at the level of the diaphragm (8,14–17). A variety of different abnormalities may occur with anomalous pulmonary venous connection with, for example, only part of the pulmonary venous return diverting to the systemic circulation in so-called partial anomalous connection.
A specific subset of partial anomalous connection occurs in Scimitar syndrome where there is a hypoplastic right lung with systemic arterial supply and venous drainage. The name derives from the radiographic appearance of the anomalous vein that drains the right lower lung into the inferior vena cava. Partial anomalous pulmonary venous connection is, however, associated with an excellent prognosis and usually a normal life expectancy (18,19). Heredity is variable among the anomalous pulmonary connection syndromes with familial cases described in Scimitar syndrome, other types of partial anomalous pulmonary venous connection and TAPVC (5,18,20,21). Autosomal dominant inheritance of TAPVC with decreased penetrance has been reported in a US family with linkage to 4q12-q13 (22). The proximity of this locus to a vascular epithelial growth factor receptor has raised the possibility of this as being the possible gene locus, although this has not been confirmed. There is an association with a variety of syndromes such as HoltOram, Ellis-van Creveld, asplenia, and cat eye syndromes, the features of which should be looked for at autopsy (22,23). Holt-Oram syndrome is an autosomal dominant condition characterized by upper limb deformities and cardiac abnormalities that are caused by mutations in the long arm of chromosome 12, inactivating the transcription factor TBX5 (24). Ellis-van Creveld syndrome is an autosomal recessive syndrome due to a generalized defect in endochondral ossification characterized by dwarfism, ectodermal dysplasia, a small chest, and congenital cardiac defects (25). Cat eye syndrome or Schmid-Fraccaro syndrome is a rare condition caused by duplication of chromosome 22 (22pter-22q11; arising de novo in a parent) in which there are quite variable phenotypic defects including congenital cardiac anomalies (26). If an underlying syndrome such as these is suspected, the assistance of a medical geneticist at the autopsy may be invaluable, particularly given the heritable nature of some of the associated disorders. Poor clinical outcome has been associated with obstruction or narrowing of the common draining vein and this is something that should be looked for at autopsy (27). Obstruction occurs in 5–10% of cases and is often the result of fibrointimal hyperplasia at the junction of the common vein with draining pulmonary veins, or obstruction at the junction of the common vein with drainage points such as the coronary sinus or portal vein. Narrowing may occur at points where the common vein crosses between the left pulmonary artery and bronchus, or where an attenuated infracardiac common vein passes through the diaphragm (12,28,29). Reduction in luminal cross-section may be demonstrated both angiographically and also by silicone rubber casting (30). Obstruction to drainage may also result from a narrow atrial septal defect or left atrial hypoplasia. There may also be associated hypoplasia of small pulmonary arteries that has a negative effect on prognosis (31). Infants with obstruction have a median age at death of 3 weeks
Forensic Science, Medicine, and Pathology V1–3
10_Byard
9/27/05
11:39 AM
Page 218
218 _________________________________________________________________________________Byard and Gilbert Table 1 An Autopsy Approach to Total Anomalous Pulmonary Venous Connection (TAPVC) Examination of the heart, lungs and associated vasculature in situ looking for: • Unusual mobility of the heart after opening of the pericardial sac • Pulmonary veins not draining to the left atrium • Hypertrophy and dilatation of the right atrium and ventricle • Left heart hypoplasia Consideration of postmortem angiography Identification of site of termination of the pulmonary draining vein: • Supracardiac • Cardiac • Infracardiac • Multiple levels Dissection of aortic branches, pulmonary trunk, and venous tributaries in situ Evaluation of draining vein for stenosis or obstruction Identification of other congenital defects including: • Extracardiac anomalies: asplenia, polysplenia, visceral situs inversus, symmetrical lungs, short main bronchi, other abnormalities including features of Holt-Oram, Ellis-van Creveld, and cat eye syndromes; • Cardiac anomalies: dextrocardia, right atrial isomerism, common arteriovenous canal, ventricular septal defect, double-outlet right ventricle, transposition, valve atresias, tetralogy of Fallot; Consider involving a pediatric cardiologist and a medical geneticist in the autopsy Extensive photographic documentation of vascular and nonvascular abnormalities Consideration of molecular studies Family investigation and follow-up
compared to a median age of 3 months in those without significant narrowing (12). Another factor having a negative impact on prognosis is the presence of associated cardiovascular abnormalities in 30% of cases (7). If there is asplenia or polysplenia there is a higher incidence of a common atrioventricular canal, a double-outlet right ventricle or transposition of the great vessels. Ventricular septal defect may be associated with pulmonary valve hypoplasia or atresia, on occasion constituting complete tetralogy of Fallot (32). Bilateral morphological right atrial auricles (right atrial isomerism), right-sided aortic arch, short main bronchi, and symmetrical tri-lobar lungs may also occur (33). Other cardiovascular anomalies with possible clinical significance include aortic, mitral, and tricuspid valve atresias, truncus arteriosus, and left heart hypoplasia. The presence of pulmonary hypertensive changes in the lung vasculature and thickening of the pulmonary vein media are also associated with a higher mortality rate (12,32,34–36). The prognosis is better for infants with isolated TAPVC who have survived for an average age of 85 days compared with infants with associated abnormalities where deaths occurred at an average of 53 days (12,37). The operative mortality for infants with isolated TAPVC is now less than 10%, whereas that for infants with associated complex congenital cardiac disease is much less favorable (7). There are a number of factors of forensic significance in cases of TAPVC. First, it is a condition that may not have
manifested clinically that may be associated with sudden and unexpected infant death, potentially leading to confusion with other entities such as SIDS if death occurs in association with sleep (38). Although death while awake in the reported case raised concerns that there may have been other causes, including inflicted injury, the latter possibility was subsequently discounted. Twenty-three percent of infants in a series of 52 autopsy cases (n = 12) died suddenly and unexpectedly and had either no, or very nonspecific, symptoms. Overall, the diagnosis was not suspected prior to autopsy in 53% in whom a relevant history was available (26 of 49) (8). Second, given the small size of the dissection field and the need to carefully identify vascular channels before organ removal is undertaken, it is possible that cases could be easily overlooked if it is not considered in the differential diagnosis and en bloc, or particularly piecemeal, removal of organs has occurred prior to proper examination. Edwards previously cited this as a possible reason for a low reported incidence (39). The range of complex cardiovascular malformations that may be associated with TAPVC also highlights the need for meticulous examination and dissection. Finally, the heritable nature of some cases makes correct identification and accurate evaluation imperative so that family genetic counseling can be undertaken if indicated. Steps in the assessment of cases of suspected or known TAPVC are summarized in Table 1.
Forensic Science, Medicine, and Pathology V1–3
10_Byard
9/27/05
11:39 AM
Page 219
Autopsy Considerations of TAPVC ___________________________________________________________________219
Educational Message 1. Total anomalous pulmonary venous connection may be a rare cause of sudden death in asymptomatic infants. 2. To properly evaluate this anomaly, pulmonary venous connections need to be clearly visualized with the organs in situ prior to evisceration. 3. Obstruction to the draining vein is a significant finding contributing to a poor outcome. 4. A variety of cardiovascular malformation and syndromes may also be present. 5. Familial cases occur.
ACKNOWLEDGMENTS We would like to thank Wayne Chivell, the South Australian state coroner, for permission to publish details of this case and Professor Robert Anderson, London, for his opinion on the cardiac malformations. The authors have stated that they do not have a significant financial interest or other relationship with any product manufacturer or provider of services discussed in this article.
REFERENCES 1. Wilson J. XIII. A description of a very unusual formation of the human heart. Phil Trans Roy Soc London 1798;88:346–356. 2. Byard RW, Moore L. Total anomalous pulmonary venous drainage and sudden death in infancy. Forensic Sci Int 1991;51:197–202. 3. Hogan DF, Green HW, Van Alstine WG. Total anomalous pulmonary venous drainage in a dog. J Vet Intern Med 2002;16:303–308. 4. Correa-Villasenor A, Ferencz C, Boughman JA, Neill CA. Total anomalous pulmonary venous return: familial and environmental factors. The Baltimore-Washington Infant Study Group. Teratology 1991;44:415–428. 5. Solymar L, Sabel KJ, Zetterquist P. Total anomalous pulmonary venous connection in siblings: report on three families. Acta Paediatr Scand 1987;76:124–127. 6. Darling RC, Rothney WB, Craig JM. Total pulmonary venous drainage into the right side of the heart: Report of 17 autopsied cases not associated with other major cardiovascular anomalies. Lab Invest 1957;6:44–64. 7. Emmel M, Sreeram N. Total anomalous pulmonary venous connection: diagnosis, management and outcome. Curr Treat Options Cardiovasc Med 2004;6:423–429. 8. James CL, Keeling JW, Smith NM, Byard RW. Total anomalous pulmonary venous drainage (TAPVC) associated with fatal outcome in infancy and early childhood—an autopsy study of 52 cases. Pediatr Pathol 1994;14:665–678. 9. Hawkins JA, Clark EB, Doty DB. Total anomalous pulmonary venous connection. Ann Thorac Surg 1983;36:548–560. 10. Hammon JW Jr., Bender HW Jr. Major anomalies of pulmonary and thoracic systemic veins. In: Sabiston DC, Spencer FC eds. Surgery of the Chest, 5th ed,Vol. 2. Philadelphia: W.B. Saunders, 1990, pp. 1274–1297. 11. Rammos S, Gittenberger-de Groot AC, Oppenheimer-Dekker A. The abnormal pulmonary venous connexion: A developmental approach. Int J Cardiol 1990;29:285–295.
12. Delisle G,Ando M, Calder AL, et al. Total anomalous pulmonary venous connection: report of 93 autopsied cases with emphasis on diagnostic and surgical considerations. Am Heart J 1976;91:99–122. 13. Lamb RK, Qureshi SA, Wilkinson JL, Arnold R, West CR, Hamilton DI. Total anomalous pulmonary venous drainage: seventeen-year surgical experience. J Thorac Cardiovasc Surg 1988;96:368–375. 14. Jensen JB, Blount SB Jr. Total anomalous pulmonary venous return: a review and report of the oldest surviving patient. Am Heart J 1971;82:387–407. 15. Gathman GE, Nadas AS. Total anomalous pulmonary venous connection: clinical and physiologic observations of 75 pediatric patients. Circulation 1970;42:143–154. 16. Bonham-Carter RE, Capriles M, Noe Y. Total anomalous pulmonary venous drainage: A clinical and anatomical study of 75 children. Br Heart J 1969;31:45–51. 17. Sano S, Brown WJ, Mee RBB. Total anomalous pulmonary venous drainage. J Thorac Cardiovasc Surg 1989;97:886–892. 18. Neill CA, Ferenz C, Sabiston DC, Sheldon H. The familial occurrence of hypoplastic right lung with systemic arterial supply and venous drainage “scimitar syndrome.” Bull Johns Hopkins Hosp 1960;107;1–21. 19. Vanderheyden M, Goethals M, Van Hoe L. Partial anomalous pulmonary venous connection or scimitar syndrome. Heart 2003;89:761. 20. Kaufman RL, Boynton RC, Hartmann AF, Morgan BC, McAlister WH. Familial studies in congenital heart disease III: Total anomalous venous connection in two sisters and their female maternal first cousin. Birth Defects 1972;8:88–91. 21. Paz JE, Castilla EE. Familial total anomalous pulmonary venous return. J Med Genet 1971;8:312–314. 22. Bleyl S, Nelson L, Odelberg SJ, et al. A gene for familial total anomalous pulmonary venous return maps to chromosome 4p13-q12. Am J Hum Genet 1995;56:408–415. 23. Byard RW. Vascular conditions. In: Sudden Death in Infancy Childhood and Adolescence. Cambridge: Cambridge University Press, 2004, pp. 249–328. 24. Bossert T, Walther T, Gummert J, Hubald R, Kostelka M, Mohr FW. Cardiac malformations associated with the Holt-Oram syndrome—report on a family and review of the literature. Thorac Cardiovasc Surg 2002;50:312–314. 25. Sergi C, Voigtlander T, Zoubaa S, et al. Ellis-van Creveld syndrome: a generalized dysplasia of endochondral ossification. Pediatr Radiol 2001;31:289–293. 26. Rosias PR, Sijstermans JM, Theunissen PM, et al. Phenotypic variability of the cat eye syndrome. Case report and review of the literature. Gent Couns 2001;12:273–282. 27. Newfeld EA, Wilson A, Paul MH, Reisch JS. Pulmonary vascular disease in total anomalous pulmonary venous drainage. Circulation 1980;61:103–109. 28. Lucas RV Jr., Adams P, Anderson RC, Varco RL, Edwards JE, Lester RG. Total anomalous pulmonary venous connection to the portal venous system:A cause of pulmonary venous obstruction. Am J Roentgenol 1961;86:561–575. 29. Nakib A, Moller JH, Kanjuh VI, Edwards JE. Anomalies of the pulmonary veins. Am J Cardiol 1967;20:77–90. 30. Seo JW, Lee HJ, Choi JY, Choi YH, Lee JR. Pulmonary veins in total anomalous pulmonary venous connection with obstruction: Demonstration using silicone rubber casts. Pediatr Pathol 1991;11:711–720.
Forensic Science, Medicine, and Pathology V1–3
10_Byard
9/27/05
11:39 AM
Page 220
220 _________________________________________________________________________________Byard and Gilbert 31. Maeda K, Yamaki S, Yokota M, Murakami A, Takamoto S. Hypoplasia of the small pulmonary arteries in total anomalous pulmonary venous connection with obstructed pulmonary venous drainage. J Thorac Cardiovasc Surg 2004;127:448–456. 32. Redington AN, Raine J, Shinebourne EA, Rigby ML. Tetralogy of Fallot with anomalous pulmonary venous connections: a rare but clinically important association. Br Heart J 1990;64: 325–328. 33. Devine WA, Debich DE, Anderson RH. Dissection of congenitally malformed hearts, with comments on the value of sequential segmental analysis. Pediatr Pathol 1991;11:235–259. 34. Bharati S, Lev M. Congenital anomalies of the pulmonary veins. Cardiovasc Clin 1973;5:23–41. 35. DeLeon SY, Gidding SS, Ilbawi MN, et al. Surgical management of infants with complex cardiac anomalies associated with
36. 37.
38.
39.
reduced pulmonary blood flow and total anomalous pulmonary venous drainage. Ann Thorac Surg 1987;43:207–211. Murphy JD. Hypoplastic left-heart syndrome in children. Curr Opin Pediatr 1991;3:803–809. Caldarone CA, Behrendt DM. Total anomalous pulmonary venous drainage associated with complex cardiac anatomy. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2000;3:142–152. Krous HF, Beckwith JB, Byard RW, et al. Sudden infant death syndrome (SIDS) and unclassified sudden infant deaths (USID): a definitional and diagnostic approach. Pediatrics 2004;114: 234–238. Edwards JE. Pathologic and developmental considerations in anomalous pulmonary venous connection. Mayo Clin Proc 1953;28:441–462.
Forensic Science, Medicine, and Pathology V1–3
9/27/05
11:39 AM
Page 215
Forensic Science, Medicine, and Pathology Copyright © 2005 Humana Press Inc. All rights of any nature whatsoever are reserved. ISSN 1547-769X/05/1:215–220/$30.00 eISSN 1556-2891 DOI: 10.1385/Forensic Sci. Med. Pathol.:1:3:215
PRACTICAL PEARL
Total Anomalous Pulmonary Venous Connection Autopsy Considerations Roger W. Byard and John D. Gilbert Forensic Science SA and University of Adelaide, Adelaide, Australia
Address for correspondence and reprints: Roger W. Byard, Forensic Science SA, 21 Divett Place, Adelaide 5000, Australia E-mail: [email protected] Accepted for publication: June 15, 2005
Abstract Total anomalous pulmonary venous connection (TAPVC), where the pulmonary venous circulation drains into the systemic venous circulation rather than into the left atrium, may present a number of problems at autopsy. A 5-week-old infant is reported who died suddenly and unexpectedly who was found at autopsy to have infradiaphragmatic TAPVC into the portal vein. The only associated anomalies were a tri-lobed left lung, a patent ductus arteriosus, and drainage of the inferior vena cava into the both the right and left atria. This case demonstrates particular features that may lead to difficulties in establishing the diagnosis of TAPVC. Sudden death in the absence of symptoms in this age group raises the possibilities of sudden infant death syndrome (SIDS) and inflicted injury, both of which were discounted in this case. An autopsy approach is outlined to maximize chances of diagnosing this entity that includes meticulous inspection and dissection of cardiac vascular connections before evisceration, with photographic documentation of findings. Concurrent cardiovascular abnormalities, including valve atresias, septal defects, and left heart hypoplasia are likely in the presence of asplenia/polysplenia syndrome. Extracardiac anomalies may be present in the form of Holt-Oram, Ellis-van Creveld, and cat eye syndromes. Careful examination of the common draining vein for obstructive features is an important part of the postmortem assessment. The possibility of heritable cases requires referral of the family for genetic evaluation. Key Words: Forensic pathology; total anomalous pulmonary venous connection; TAPVC; sudden death; autopsy. (DOI: 10.1385/Forensic Sci. Med. Pathol.:1:3:215)
INTRODUCTION
CASE REPORT
Anomalous pulmonary venous return refers to a situation where the pulmonary veins do not attach in a normal manner to the left atrium, but instead drain into part of the systemic venous system (1). This may be complete, as in total anomalous pulmonary venous connection (TAPVC), or partial, if only part of the pulmonary venous circulation drains aberrantly. The clinical effects of this congenital anomaly vary depending on the amount of oxygenated blood being delivered to the venous system, and the presence or absence of associated cardiovascular abnormalities. Sudden and unexpected death at an early age is well documented (2). The following case is described to demonstrate typical autopsy features and to outline an approach for the detection and demonstration of lethal aberrant pulmonary venous circulation and its associated features at autopsy.
A 5-week-old girl, who was noted by her father to be “choking,” collapsed in his arms when he picked her up. The father attempted resuscitation before calling an ambulance. When ambulance personnel arrived, the infant was moribund, with a heart rate of 50. She died soon after. The infant’s past history included spontaneous vaginal delivery at 35 weeks gestation with a birthweight of 2700 g. No significant medical problems were noted subsequently. Death while awake raised concerns by attending police that the case may not have been sudden infant death syndrome (SIDS), but may have involved inflicted injury. At autopsy, there were no dysmorphic features and dermatoglyphs were normal. Internal examination revealed a single normally formed and situated spleen (weight = 9.5 g; normal weight = 12–14 g). Although there was levocardia with
215
10_Byard
9/27/05
11:39 AM
Page 216
216 _________________________________________________________________________________Byard and Gilbert
Fig. 1. Posterior view demonstrating the convergence of three left-sided pulmonary veins and two right-sided pulmonary veins to form a common vein that passed through the diaphragm and behind the liver to join the portal vein in a 5-week-old girl who suddenly collapsed.
atrial situs solitus and atrioventricular concordance the heart was noted to be unusually mobile with prominence of the right ventricle (heart weight = 26 g; normal weight = 12–28 g). Examination of the pulmonary venous return showed that three pulmonary veins from the left lung and two pulmonary veins from the right converged to form a common vein that passed through the diaphragm with no connection between the pulmonary venous system and the left atrium. The common vein passed behind the liver and terminated in the portal vein (Figs. 1 and 2). No luminal narrowing could be demonstrated on opening of the common vein. The heart otherwise showed normal venous drainage except for a venous connection between the upper part of the inferior vena cava and the lateral posterior aspect of the left atrium, most likely representing an inferior sinus venosus defect. The vena cavae otherwise terminated normally in the right atrium. Both the right atrium and ventricle were dilated and hypertrophied with a right ventricular free wall thickness of 8 mm. There were no atrial or ventricular septal defects. The foramen
Fig. 2. Demonstration of clear separation of the common vein from the left atrium by rotating the left lung over to the right hand side.
ovale was closed. The left atrium and ventricle were small with a left ventricular free wall thickness of 5 mm. Valves and coronary arteries were normally formed and situated. There was a patent ductus arteriosus with a circumference of 4 mm. The left lung had three lobes. No other abnormalities were detected and there were no other organic diseases present that could have caused or contributed to death. Histopathological examination was unremarkable. There were no significant microbiological, metabolic, electrolyte, or toxicological abnormalities. Full skeletal survey was normal. There was no evidence of intentional or nonintentional trauma. Therefore, death was attributed to the effects of TAPVC.
DISCUSSION TAPVC refers to a rare congenital malformation of the pulmonary venous system in which blood from the lungs drains via the pulmonary veins into the systemic veins or the right atrium (1), resulting in oxygenated blood from the lungs mixing with systemic venous blood. Survival depends on shunting of this blood into the left side of the heart or the aortic outflow tract usually through an atrial septal defect, patent
Forensic Science, Medicine, and Pathology V1–3
10_Byard
9/27/05
11:39 AM
Page 217
Autopsy Considerations of TAPVC ___________________________________________________________________217 foramen ovale, or a patent ductus arteriosus. This condition has also been described in animals (3). TAPVC accounts for 1–2% of all cardiovascular malformations, 2–5% of cases of congenital cardiac defects presenting to autopsy, and occurs in 6.8 cases per 100,000 live births (4–6). Affected infants are more likely to have a birthweight below 2500 g, with intrauterine growth retardation and a gestational age less than 38 weeks, as in the reported case (4). The malformation does not present problems during intrauterine life because of high pulmonary vascular resistance with shunting across the foramen ovale. After birth, clinical symptoms and signs may include tachycardia, tachypnea, diaphoresis, central cyanosis, and features of cardiac failure with feeding difficulties and failure to thrive, however, a significant percentage of affected infants, as in the reported case will be asymptomatic (7,8). The mortality rate in untreated infants is 80% in the first year of life, although survival to adult life has been described (9,10). During embryological development, the primordial lung drains into the splanchnic vascular plexus with communications to the systemic venous circulation through the omphalomesenteric veins, the sinus venosus, and the anterior cardinal veins (11,12). The developing pulmonary vein first appears as an outpouching of the posterior part of the left atrial wall or the sinus venosus and fuses with the pulmonary venous plexus by around 30 weeks gestation. If the common pulmonary vein draining from the pulmonary veins to the left atrium either fails to develop, or involutes, collateral vascular channels may persist, giving rise to anomalous venous drainage either above or below the diaphragm (13). The sites of drainage may be divided into the following four broad categories: Type I:
Type II: Type III: Type IV:
supracardiac, draining into the right or persistent left superior vena cava or their tributaries (45%). cardiac, draining into the right atrium or coronary sinus (25%). infracardiac, draining into the portal vein or its tributaries (25%) draining at multiple sites, for example with the left pulmonary veins connected to the left innominate vein and the right pulmonary veins connected to the right atrium (5%) (6,7).
Although the most common sites of drainage have been reported as the left innominate vein and coronary sinus, this varies depending on the particular series. The worst prognosis has been associated with infradiaphragmatic drainage, partly owing to obstruction at the level of the diaphragm (8,14–17). A variety of different abnormalities may occur with anomalous pulmonary venous connection with, for example, only part of the pulmonary venous return diverting to the systemic circulation in so-called partial anomalous connection.
A specific subset of partial anomalous connection occurs in Scimitar syndrome where there is a hypoplastic right lung with systemic arterial supply and venous drainage. The name derives from the radiographic appearance of the anomalous vein that drains the right lower lung into the inferior vena cava. Partial anomalous pulmonary venous connection is, however, associated with an excellent prognosis and usually a normal life expectancy (18,19). Heredity is variable among the anomalous pulmonary connection syndromes with familial cases described in Scimitar syndrome, other types of partial anomalous pulmonary venous connection and TAPVC (5,18,20,21). Autosomal dominant inheritance of TAPVC with decreased penetrance has been reported in a US family with linkage to 4q12-q13 (22). The proximity of this locus to a vascular epithelial growth factor receptor has raised the possibility of this as being the possible gene locus, although this has not been confirmed. There is an association with a variety of syndromes such as HoltOram, Ellis-van Creveld, asplenia, and cat eye syndromes, the features of which should be looked for at autopsy (22,23). Holt-Oram syndrome is an autosomal dominant condition characterized by upper limb deformities and cardiac abnormalities that are caused by mutations in the long arm of chromosome 12, inactivating the transcription factor TBX5 (24). Ellis-van Creveld syndrome is an autosomal recessive syndrome due to a generalized defect in endochondral ossification characterized by dwarfism, ectodermal dysplasia, a small chest, and congenital cardiac defects (25). Cat eye syndrome or Schmid-Fraccaro syndrome is a rare condition caused by duplication of chromosome 22 (22pter-22q11; arising de novo in a parent) in which there are quite variable phenotypic defects including congenital cardiac anomalies (26). If an underlying syndrome such as these is suspected, the assistance of a medical geneticist at the autopsy may be invaluable, particularly given the heritable nature of some of the associated disorders. Poor clinical outcome has been associated with obstruction or narrowing of the common draining vein and this is something that should be looked for at autopsy (27). Obstruction occurs in 5–10% of cases and is often the result of fibrointimal hyperplasia at the junction of the common vein with draining pulmonary veins, or obstruction at the junction of the common vein with drainage points such as the coronary sinus or portal vein. Narrowing may occur at points where the common vein crosses between the left pulmonary artery and bronchus, or where an attenuated infracardiac common vein passes through the diaphragm (12,28,29). Reduction in luminal cross-section may be demonstrated both angiographically and also by silicone rubber casting (30). Obstruction to drainage may also result from a narrow atrial septal defect or left atrial hypoplasia. There may also be associated hypoplasia of small pulmonary arteries that has a negative effect on prognosis (31). Infants with obstruction have a median age at death of 3 weeks
Forensic Science, Medicine, and Pathology V1–3
10_Byard
9/27/05
11:39 AM
Page 218
218 _________________________________________________________________________________Byard and Gilbert Table 1 An Autopsy Approach to Total Anomalous Pulmonary Venous Connection (TAPVC) Examination of the heart, lungs and associated vasculature in situ looking for: • Unusual mobility of the heart after opening of the pericardial sac • Pulmonary veins not draining to the left atrium • Hypertrophy and dilatation of the right atrium and ventricle • Left heart hypoplasia Consideration of postmortem angiography Identification of site of termination of the pulmonary draining vein: • Supracardiac • Cardiac • Infracardiac • Multiple levels Dissection of aortic branches, pulmonary trunk, and venous tributaries in situ Evaluation of draining vein for stenosis or obstruction Identification of other congenital defects including: • Extracardiac anomalies: asplenia, polysplenia, visceral situs inversus, symmetrical lungs, short main bronchi, other abnormalities including features of Holt-Oram, Ellis-van Creveld, and cat eye syndromes; • Cardiac anomalies: dextrocardia, right atrial isomerism, common arteriovenous canal, ventricular septal defect, double-outlet right ventricle, transposition, valve atresias, tetralogy of Fallot; Consider involving a pediatric cardiologist and a medical geneticist in the autopsy Extensive photographic documentation of vascular and nonvascular abnormalities Consideration of molecular studies Family investigation and follow-up
compared to a median age of 3 months in those without significant narrowing (12). Another factor having a negative impact on prognosis is the presence of associated cardiovascular abnormalities in 30% of cases (7). If there is asplenia or polysplenia there is a higher incidence of a common atrioventricular canal, a double-outlet right ventricle or transposition of the great vessels. Ventricular septal defect may be associated with pulmonary valve hypoplasia or atresia, on occasion constituting complete tetralogy of Fallot (32). Bilateral morphological right atrial auricles (right atrial isomerism), right-sided aortic arch, short main bronchi, and symmetrical tri-lobar lungs may also occur (33). Other cardiovascular anomalies with possible clinical significance include aortic, mitral, and tricuspid valve atresias, truncus arteriosus, and left heart hypoplasia. The presence of pulmonary hypertensive changes in the lung vasculature and thickening of the pulmonary vein media are also associated with a higher mortality rate (12,32,34–36). The prognosis is better for infants with isolated TAPVC who have survived for an average age of 85 days compared with infants with associated abnormalities where deaths occurred at an average of 53 days (12,37). The operative mortality for infants with isolated TAPVC is now less than 10%, whereas that for infants with associated complex congenital cardiac disease is much less favorable (7). There are a number of factors of forensic significance in cases of TAPVC. First, it is a condition that may not have
manifested clinically that may be associated with sudden and unexpected infant death, potentially leading to confusion with other entities such as SIDS if death occurs in association with sleep (38). Although death while awake in the reported case raised concerns that there may have been other causes, including inflicted injury, the latter possibility was subsequently discounted. Twenty-three percent of infants in a series of 52 autopsy cases (n = 12) died suddenly and unexpectedly and had either no, or very nonspecific, symptoms. Overall, the diagnosis was not suspected prior to autopsy in 53% in whom a relevant history was available (26 of 49) (8). Second, given the small size of the dissection field and the need to carefully identify vascular channels before organ removal is undertaken, it is possible that cases could be easily overlooked if it is not considered in the differential diagnosis and en bloc, or particularly piecemeal, removal of organs has occurred prior to proper examination. Edwards previously cited this as a possible reason for a low reported incidence (39). The range of complex cardiovascular malformations that may be associated with TAPVC also highlights the need for meticulous examination and dissection. Finally, the heritable nature of some cases makes correct identification and accurate evaluation imperative so that family genetic counseling can be undertaken if indicated. Steps in the assessment of cases of suspected or known TAPVC are summarized in Table 1.
Forensic Science, Medicine, and Pathology V1–3
10_Byard
9/27/05
11:39 AM
Page 219
Autopsy Considerations of TAPVC ___________________________________________________________________219
Educational Message 1. Total anomalous pulmonary venous connection may be a rare cause of sudden death in asymptomatic infants. 2. To properly evaluate this anomaly, pulmonary venous connections need to be clearly visualized with the organs in situ prior to evisceration. 3. Obstruction to the draining vein is a significant finding contributing to a poor outcome. 4. A variety of cardiovascular malformation and syndromes may also be present. 5. Familial cases occur.
ACKNOWLEDGMENTS We would like to thank Wayne Chivell, the South Australian state coroner, for permission to publish details of this case and Professor Robert Anderson, London, for his opinion on the cardiac malformations. The authors have stated that they do not have a significant financial interest or other relationship with any product manufacturer or provider of services discussed in this article.
REFERENCES 1. Wilson J. XIII. A description of a very unusual formation of the human heart. Phil Trans Roy Soc London 1798;88:346–356. 2. Byard RW, Moore L. Total anomalous pulmonary venous drainage and sudden death in infancy. Forensic Sci Int 1991;51:197–202. 3. Hogan DF, Green HW, Van Alstine WG. Total anomalous pulmonary venous drainage in a dog. J Vet Intern Med 2002;16:303–308. 4. Correa-Villasenor A, Ferencz C, Boughman JA, Neill CA. Total anomalous pulmonary venous return: familial and environmental factors. The Baltimore-Washington Infant Study Group. Teratology 1991;44:415–428. 5. Solymar L, Sabel KJ, Zetterquist P. Total anomalous pulmonary venous connection in siblings: report on three families. Acta Paediatr Scand 1987;76:124–127. 6. Darling RC, Rothney WB, Craig JM. Total pulmonary venous drainage into the right side of the heart: Report of 17 autopsied cases not associated with other major cardiovascular anomalies. Lab Invest 1957;6:44–64. 7. Emmel M, Sreeram N. Total anomalous pulmonary venous connection: diagnosis, management and outcome. Curr Treat Options Cardiovasc Med 2004;6:423–429. 8. James CL, Keeling JW, Smith NM, Byard RW. Total anomalous pulmonary venous drainage (TAPVC) associated with fatal outcome in infancy and early childhood—an autopsy study of 52 cases. Pediatr Pathol 1994;14:665–678. 9. Hawkins JA, Clark EB, Doty DB. Total anomalous pulmonary venous connection. Ann Thorac Surg 1983;36:548–560. 10. Hammon JW Jr., Bender HW Jr. Major anomalies of pulmonary and thoracic systemic veins. In: Sabiston DC, Spencer FC eds. Surgery of the Chest, 5th ed,Vol. 2. Philadelphia: W.B. Saunders, 1990, pp. 1274–1297. 11. Rammos S, Gittenberger-de Groot AC, Oppenheimer-Dekker A. The abnormal pulmonary venous connexion: A developmental approach. Int J Cardiol 1990;29:285–295.
12. Delisle G,Ando M, Calder AL, et al. Total anomalous pulmonary venous connection: report of 93 autopsied cases with emphasis on diagnostic and surgical considerations. Am Heart J 1976;91:99–122. 13. Lamb RK, Qureshi SA, Wilkinson JL, Arnold R, West CR, Hamilton DI. Total anomalous pulmonary venous drainage: seventeen-year surgical experience. J Thorac Cardiovasc Surg 1988;96:368–375. 14. Jensen JB, Blount SB Jr. Total anomalous pulmonary venous return: a review and report of the oldest surviving patient. Am Heart J 1971;82:387–407. 15. Gathman GE, Nadas AS. Total anomalous pulmonary venous connection: clinical and physiologic observations of 75 pediatric patients. Circulation 1970;42:143–154. 16. Bonham-Carter RE, Capriles M, Noe Y. Total anomalous pulmonary venous drainage: A clinical and anatomical study of 75 children. Br Heart J 1969;31:45–51. 17. Sano S, Brown WJ, Mee RBB. Total anomalous pulmonary venous drainage. J Thorac Cardiovasc Surg 1989;97:886–892. 18. Neill CA, Ferenz C, Sabiston DC, Sheldon H. The familial occurrence of hypoplastic right lung with systemic arterial supply and venous drainage “scimitar syndrome.” Bull Johns Hopkins Hosp 1960;107;1–21. 19. Vanderheyden M, Goethals M, Van Hoe L. Partial anomalous pulmonary venous connection or scimitar syndrome. Heart 2003;89:761. 20. Kaufman RL, Boynton RC, Hartmann AF, Morgan BC, McAlister WH. Familial studies in congenital heart disease III: Total anomalous venous connection in two sisters and their female maternal first cousin. Birth Defects 1972;8:88–91. 21. Paz JE, Castilla EE. Familial total anomalous pulmonary venous return. J Med Genet 1971;8:312–314. 22. Bleyl S, Nelson L, Odelberg SJ, et al. A gene for familial total anomalous pulmonary venous return maps to chromosome 4p13-q12. Am J Hum Genet 1995;56:408–415. 23. Byard RW. Vascular conditions. In: Sudden Death in Infancy Childhood and Adolescence. Cambridge: Cambridge University Press, 2004, pp. 249–328. 24. Bossert T, Walther T, Gummert J, Hubald R, Kostelka M, Mohr FW. Cardiac malformations associated with the Holt-Oram syndrome—report on a family and review of the literature. Thorac Cardiovasc Surg 2002;50:312–314. 25. Sergi C, Voigtlander T, Zoubaa S, et al. Ellis-van Creveld syndrome: a generalized dysplasia of endochondral ossification. Pediatr Radiol 2001;31:289–293. 26. Rosias PR, Sijstermans JM, Theunissen PM, et al. Phenotypic variability of the cat eye syndrome. Case report and review of the literature. Gent Couns 2001;12:273–282. 27. Newfeld EA, Wilson A, Paul MH, Reisch JS. Pulmonary vascular disease in total anomalous pulmonary venous drainage. Circulation 1980;61:103–109. 28. Lucas RV Jr., Adams P, Anderson RC, Varco RL, Edwards JE, Lester RG. Total anomalous pulmonary venous connection to the portal venous system:A cause of pulmonary venous obstruction. Am J Roentgenol 1961;86:561–575. 29. Nakib A, Moller JH, Kanjuh VI, Edwards JE. Anomalies of the pulmonary veins. Am J Cardiol 1967;20:77–90. 30. Seo JW, Lee HJ, Choi JY, Choi YH, Lee JR. Pulmonary veins in total anomalous pulmonary venous connection with obstruction: Demonstration using silicone rubber casts. Pediatr Pathol 1991;11:711–720.
Forensic Science, Medicine, and Pathology V1–3
10_Byard
9/27/05
11:39 AM
Page 220
220 _________________________________________________________________________________Byard and Gilbert 31. Maeda K, Yamaki S, Yokota M, Murakami A, Takamoto S. Hypoplasia of the small pulmonary arteries in total anomalous pulmonary venous connection with obstructed pulmonary venous drainage. J Thorac Cardiovasc Surg 2004;127:448–456. 32. Redington AN, Raine J, Shinebourne EA, Rigby ML. Tetralogy of Fallot with anomalous pulmonary venous connections: a rare but clinically important association. Br Heart J 1990;64: 325–328. 33. Devine WA, Debich DE, Anderson RH. Dissection of congenitally malformed hearts, with comments on the value of sequential segmental analysis. Pediatr Pathol 1991;11:235–259. 34. Bharati S, Lev M. Congenital anomalies of the pulmonary veins. Cardiovasc Clin 1973;5:23–41. 35. DeLeon SY, Gidding SS, Ilbawi MN, et al. Surgical management of infants with complex cardiac anomalies associated with
36. 37.
38.
39.
reduced pulmonary blood flow and total anomalous pulmonary venous drainage. Ann Thorac Surg 1987;43:207–211. Murphy JD. Hypoplastic left-heart syndrome in children. Curr Opin Pediatr 1991;3:803–809. Caldarone CA, Behrendt DM. Total anomalous pulmonary venous drainage associated with complex cardiac anatomy. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2000;3:142–152. Krous HF, Beckwith JB, Byard RW, et al. Sudden infant death syndrome (SIDS) and unclassified sudden infant deaths (USID): a definitional and diagnostic approach. Pediatrics 2004;114: 234–238. Edwards JE. Pathologic and developmental considerations in anomalous pulmonary venous connection. Mayo Clin Proc 1953;28:441–462.
Forensic Science, Medicine, and Pathology V1–3
