- Email: [email protected]
Cantrell Syndrome (Thoracoabdominal Ectopia Cordis; Anomalous Umbilical Cord; Diaphragmatic, Pericardial and Intracardiac Defects) in the Pig (Sus scrofa domesticus)
J. Comp. Path. 2020, Vol. 174, 99e103
Available online at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/jcpa
SPONTANEOUSLY ARISING DISEASE
Cantrell Syndrome (Thoracoabdominal Ectopia Cordis; Anomalous Umbilical Cord; Diaphragmatic, Pericardial and Intracardiac Defects) in the Pig (Sus scrofa domesticus) N. Martı´n-Alguacil* and L. Avedillo† * Departmental Section of Anatomy and Embryology, School of Veterinary Medicine, Universidad Complutense de Madrid, Avda. Puerta de Hierro s/n and † Private Practitioner, Clı´nica Veterinaria Salud Animal, Gri~non, Madrid, Spain
Summary Pentalogy of Cantrell (PC) is a complex body wall defect, involving the abdominal wall, sternum, diaphragm, pericardium and heart. We report on six stillborn piglets with anomalous umbilical cord (UC), cranioumbilical abdominal defect, cleft sternum, incomplete diaphragm and pericardium, ectopia cordis and intracardiac anomalies. Anomalous UC was defined as a single umbilical artery (SUA) and/or short cord, or as an UC with atypical coiling pattern. The embryonic period, in which all the anomalies found in these piglets develops, coincides with that of UC formation in the pig. We propose that anomalous UC should be considered a sixth defect in Cantrell syndrome (CS), considering that the insult leading to the classical malformations of PC and UC abnormalities is the same or that the sequence of malformations itself may alter the early fetoplacental blood flow and therefore the normal development of the UC angioarchitecture. CS has not been reported previously in animals. Ó 2019 Elsevier Ltd. All rights reserved. Keywords: anomalous umbilical cord; body wall defect; Cantrell syndrome; pig
Cantrell syndrome (CS) is a complex body wall defect (BWD) presenting as thoracoabdominoschisis, with no spinal or limb anomalies. but the presence of multiple congenital defects such as distal sternal cleft, a defect in the ventral diaphragm and pericardium, as well as intracardiac malformations (Cantrell et al., 1958). A characteristic feature of this syndrome is ectopia cordis (EC) with omphalocoele (Chandran and Ari, 2013). Thoracoabdominal EC is commonly associated with pentalogy of Cantrell (PC; Duan et al., 2009). All malformations included in this study were found sporadically during 2002e2018. Animals were from a swine farming association from Toledo (Spain), comprised of 15 pig production facilities Correspondence to: (e-mail: [email protected]). 0021-9975/$ - see front matter https://doi.org/10.1016/j.jcpa.2019.11.005
with an annual average census of 6,500 breeding sows in close production cycle. Three females and three males (Landrace e large white e Pietrain) presenting with anomalies suggestive of CS were selected for the study. All piglets were stillborn and were the only abnormal members of their litters. The study was conducted in the Laboratory for the Study of Congenital Malformations (Anatomy and Embryology Department), School of Veterinary Medicine, Universidad Complutense de Madrid, Madrid, Spain. Detailed gross evaluation of the six animals was carried out using conventional anatomical methods. Special attention was paid to possible abnormalities within the heart, diaphragm and pericardium. A summary of the anomalies detected in the six piglets, as well as the size of the midline defect is given in Ó 2019 Elsevier Ltd. All rights reserved.
100
N. Martı´n-Alguacil and L. Avedillo
Table 1. A ventral midline fissure was observed in the thoracoabdominal wall, extending from the cranial part of the thorax to the umbilical region (Fig. 1) in all piglets. The amniotic membrane covered all of the exposed organs and was connected distally with the umbilical cord (UC) (Fig. 2). The UC was anomalous in all piglets (Table 1). The heart was ectopic and not covered by the pericardium (Fig. 2). The great vessels were positioned anomalously and were oriented dorsally. There was no anal atresia or spinal or craniofacial defects. All limbs were normal in length and shape. There was normal hepatic lobulation and the lungs appeared to be normal, with the exception of animal P264 in which the liver was an amorphous mass with no lobulation. The ventral insertion of the diaphragm was absent (Fig. 1). Internal inspection of the hearts revealed intracardiac defects in specimens (Table 1, Fig. 3). The full spectrum of CS consists of five anomalies: (1) a midline supraumbilical abdominal wall defect, (2) a deficiency of the ventral diaphragm and (3) diaphragmatic pericardium, (4) several congenital intracardiac malformations, and (5) a defect of the caudal sternum (Cantrell et al., 1958). In all the six piglets in this study, the full spectrum with the five anomalies characteristic of PC (Cantrell et al., 1958) were identified. An additional sixth defect, anomalous UC, was identified in all cases. The UC in all cases was shortened, showing an atypical coiling pattern. The UC in P264, the most affected animal, had a single umbilical artery (SUA) and one umbilical vein. UC pathologies as SUA, short cord or UC with atypical coiling pattern have been identified in PC (M€ uller Brochut et al., 2011). In human studies of this syndrome, there is male dominance with a male to female ratio of 2.7:1 (Barisic et al., 2001). We did not notice a gender pre-
Fig. 1. Ventral view of the wall defect in P264. The diaphragm musculature is barely visible (arrows) and its ventral insertion is absent. D, diaphragm; H, heart; SUA, single umbilical artery; UV, umbilical vein.
Fig. 2. In P267, the ectopic heart is visible and it was not covered by the pericardium. Except for the heart, all exposed organs are covered by the amniotic membrane. H, heart; I, intestine.
disposition; in contrast, the male to female ratio was 3:3. Affected human males also have more severe symptoms (Barisic et al., 2001), and in the present study the most severely affected animal (P264) was male. An associated intracardiac defect (e.g. septal defects) is frequent in PC and in the present cases there were two ventricular septal defects, three auricular septal defects and one atrioventricular septal defect. In addition, hypoplastic auricles, intracardiac valve atresia and the absence of one of the coronary arteries were also found. In PC, sternal malformations include bifid sternum (26%), absent xiphoid (10%) and absent caudal 2/3 of sternum (9%) (V azquezJimenez et al., 1998). The six pigs had a bifid sternum. In PC, the most common ventral abdominal wall defect is an omphalocoele (63%) (Vazquez-Jimenez et al., 1998). In all of the present cases, the exposed organs were covered by the amniotic membrane, as occurs in omphalocoele. A ventral retrosternal defect of the diaphragm occurs in 91% of human cases (Vazquez-Jimenez et al., 1998), a defect that was demonstrated in all six piglets. Notter (1927) and Hofliger (1936) described similar cases of two piglets with the heart and part of the intestine protruding through a ventral body wall fissure involving the sternum, except the manubrium, and the abdominal wall cranial to the prepuce. Gruys et al. (1978) described a case of complicated umbilical hernia in a pig, in which organs protruded through a fissure and were covered by a thin membrane. The fissure extended from the sternum, that was cleft, as far as and including the umbilicus, and the umbilical vessels were situated in the wall of the sac. Freeman and McGovern (1984) described a case of ectopia cordis thoracoabdominalis in a piglet. We believe that these three cases are similar to the six piglets presented in this study. Freeman and McGovern (1984) described a body
Table 1 Summary of the internal and external anomalies of the piglets Externally exposed organs
Diaphragm defect
Sternum
Ventral pericardium
Abdominal defect size
P227 M
Heart, ventral part of liver, ventral part of stomach, part of spleen, small intestine and caecum Heart, ventral part of liver, jejunum and ileum
Ventral
Midline splitting of the five more caudal sternebrae
Absent
6.1 cm
Ventral
Midline splitting except for the two first sternebrae
Absent
7.2 cm
Ventral
Midline splitting of the most caudal sternebrae
Absent
6.0 cm
Midline splitting of the four more caudal sternebrae
Absent
6.5 cm
Ventral
Midline splitting of the most caudal sternebrae
Absent
4.5 cm
Ventral
Midline splitting of the most caudal sternebrae
Absent
7 cm
P226 F
P228 M
Heart, some small intestine
P264 M
Heart, liver, stomach, spleen, small intestine, colon and caecum Heart, part of ileum and caecum
P267 F
P283 F
Heart, part of small intestine
Malformed musculature barely visible
Umbilical cord
Intracardiac defects
Other defects
Shorter, abnormal coiling pattern, dispersed vessels, two arteries (one hypoplastic) and one vein
Auricular septal defect
Ectopic caecum
Shorter, abnormal coiling pattern, dispersed vessels, two arteries and one vein Shorter, abnormal coiling pattern, dispersed vessels, two arteries and one vein Shorter, abnormal coiling pattern, dispersed vessels, SUA and one vein
Ventricular septal defect
Heart globous shape with right auricle dilation and ectopic liver
Ventricular septal defect
Heart globous shape with right auricle dilation
Large interatrial defect, atresia of the mitral valve, one coronary artery
Liver amorphous mass without lobulation
Shorter, abnormal coiling pattern, dispersed vessels, two arteries and one vein Shorter, abnormal coiling pattern, dispersed vessels, two arteries and one vein
Hypoplastic auricles, great vessel transposition, ventricular septal defect Auricular septal defect
Cantrell Syndrome in the Pig
Case and sex
M, male; F, female; SUA, single umbilical artery.
101
102
N. Martı´n-Alguacil and L. Avedillo
Fig. 3. Heart (P267) with great vessel translocation. The pulmonary trunk is connected with the left ventricle (note the location of the probe). LV, left ventricle; PT, pulmonary trunk.
wall defect consisting of a ventral midline fissure, which also involved all of the sternum, except for the manubrium, and which extended caudally as far as the umbilicus. They also observed a similar UC defect, a distal union of the UC with the body wall. In addition, there was absence of the ventral part of the diaphragm and pericardium as occurred in the present six cases. However, they did not record any abnormality in the chambers of the heart. The embryogenesis of the body wall in the pig begins at about day 12 of gestation and is finished by day 15 (Marrable, 1971). A defect in development of the somatopleure explains firstly the anomalous development of the septum transversum and malformation of the diaphragm and pericardia and, secondly, the malformations of the sternum and thoracoabdominal wall. A defect in the development of the splancnopleure can also account for the epicardial and cardiac defects. These phenomena are present in PC, and they appear to arise during blastogenesis. Diaphragmatic, pericardial and intracardiac defects in PC are the result of failure of development of a segment of mesoderm, while abdominal wall and sternal defects result from failure of paired primordial structures to migrate to their proper loca-
tions (Cantrell et al., 1958). In PC, midline defects in the thoracic wall began to show at E14.5. The sternum does not fuse and the heart protrudes at the midline through the body wall (Snowball et al., 2015). A failure in the ventral thoracic wall closure will affect the ventral part of the pericardium. All of the abnormalities present in the present cases may be attributed to a defect in the process of migration or fusion of the ventral midline of the body. All of the present cases had UC abnormalities, such as short cord or abnormal coiling pattern. One case also had a SUA. M€ uller Brochut et al. (2011) described three cases of human PC with UC defects. After reviewing the literature they found that nine of 24 reported cases had some abnormality of the UC. Of the 24 cases, a SUA was found in seven (29.2%). The embryonic time in which PC develops coincides with that of UC formation and the spiral display of the umbilical vessels. An early insult may, in theory, interfere with the characteristic switch from a predominantly uncoiled to the typical twisted structure of the umbilical vessels. We propose that anomalous UC be included as an additional characteristic feature of PC, which would define a ‘hexalogy of Cantrell’. The porcine UC forms a characteristic a twisted structure containing the allantoic stalk and the vessels (two arteries and one vein). As the embryo grows, the amnion expands and the connecting stalk lengthens. The allantoic vessels continue with the placental villi and form the vessels of the UC. The differentiation of the UC in pig begins during the second postconceptional week. The main changes are evident during the first 4 weeks of gestation, during which the UC vessels transform from a parallel course to their characteristic helical disposition. The fact that the UC was malformed in all of the present cases led us to include the UC defect as part of the syndrome. Therefore, we consider, as do some other authors (M€ uller Brochut et al., 2011), CS to be a sequence of developmental anomalies that start during blastogenesis, generating a polytopic field defect affecting the UC. The presentation of CS in the pig is similar to that described in man. Its pathogenesis remains unknown to date. Further comparative studies carried out on affected pigs could be of value for improved understanding of this condition.
Acknowledgments No funding sources supported this work.
References Barisic I, Clementi M, H€ ausler M, Gjergja R, Kern J et al. (2001) Evaluation of prenatal ultrasound diagnosis of
Cantrell Syndrome in the Pig
fetal abdominal wall defects by 19 European registries. Ultrasound in Obstetrics and Gynecology, 18, 309e316. Cantrell JR, Haller JA, Ravitch MM (1958) A syndrome of congenital defects involving the abdominal wall, sternum, diaphragm, pericardium, and heart. Surgery Gynecology & Obstetrics, 107, 602e614. Chandran S, Ari D (2013) Pentalogy of Cantrell: an extremely rare congenital anomaly. Journal of Clinical Neonatology, 2, 95e97. Duan QJ, Gao Z, Zhang ZW, Li JH, Ma LL, Ying LY (2009) Correct definition of pentalogy of Cantrell. Journal of Perinatal Medicine, 37, 426. Freeman LE, McGovern PT (1984) Ectopia cordis thoracoabdominalis in a piglet. The Veterinary Record, 115, 431e433. Gruys E, Jansingh J, vd Linde-Sipman JS (1978) [Umbilical hernia and ectopia cordis in a piglet]. Tijdschrift Voor Diergeneeskunde, 103, 498e500. € Hofliger H (1936) Uber Organdystopien bei Haustieren mit besonderer Ber€ ucksichtigung der Ectopie cordis und der sog. Zwerchfellbr€ uche. Virchows Archiv: Pathological Anatomy, 297, 627e644.
103
Marrable AW (1971) The Embryonic Pig: A Chronological Account. Pitman Publishing, New York, pp. 20e89. M€ uller Brochut AC, Baumann MU, Kuhn A, Di Naro E, Tutschek B et al. (2011) Pentalogy or hexalogy of Cantrell? Pediatric and Developmental Pathology, 14, 396e401. Notter C (1927) Scistosomen beim schweine. Virchows Archiv: Pathological Anatomy, 264, 280e298. Snowball J, Ambalavanan M, Cornett B, Lang R, Whitsett J et al. (2015) Mesenchymal Wnt signaling promotes formation of sternum and thoracic body wall. Developmental Biology, 401, 264e275. V azquez-Jimenez JF, Muehler EG, Daebritz S, Keutel J, Nishigaki K et al. (1998) Cantrell’s syndrome: a challenge to the surgeon. The Annals of Thoracic Surgery, 65, 1178e1185.
June 29th, 2019 ½ Received, Accepted, November 20th, 2019
Available online at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/jcpa
SPONTANEOUSLY ARISING DISEASE
Cantrell Syndrome (Thoracoabdominal Ectopia Cordis; Anomalous Umbilical Cord; Diaphragmatic, Pericardial and Intracardiac Defects) in the Pig (Sus scrofa domesticus) N. Martı´n-Alguacil* and L. Avedillo† * Departmental Section of Anatomy and Embryology, School of Veterinary Medicine, Universidad Complutense de Madrid, Avda. Puerta de Hierro s/n and † Private Practitioner, Clı´nica Veterinaria Salud Animal, Gri~non, Madrid, Spain
Summary Pentalogy of Cantrell (PC) is a complex body wall defect, involving the abdominal wall, sternum, diaphragm, pericardium and heart. We report on six stillborn piglets with anomalous umbilical cord (UC), cranioumbilical abdominal defect, cleft sternum, incomplete diaphragm and pericardium, ectopia cordis and intracardiac anomalies. Anomalous UC was defined as a single umbilical artery (SUA) and/or short cord, or as an UC with atypical coiling pattern. The embryonic period, in which all the anomalies found in these piglets develops, coincides with that of UC formation in the pig. We propose that anomalous UC should be considered a sixth defect in Cantrell syndrome (CS), considering that the insult leading to the classical malformations of PC and UC abnormalities is the same or that the sequence of malformations itself may alter the early fetoplacental blood flow and therefore the normal development of the UC angioarchitecture. CS has not been reported previously in animals. Ó 2019 Elsevier Ltd. All rights reserved. Keywords: anomalous umbilical cord; body wall defect; Cantrell syndrome; pig
Cantrell syndrome (CS) is a complex body wall defect (BWD) presenting as thoracoabdominoschisis, with no spinal or limb anomalies. but the presence of multiple congenital defects such as distal sternal cleft, a defect in the ventral diaphragm and pericardium, as well as intracardiac malformations (Cantrell et al., 1958). A characteristic feature of this syndrome is ectopia cordis (EC) with omphalocoele (Chandran and Ari, 2013). Thoracoabdominal EC is commonly associated with pentalogy of Cantrell (PC; Duan et al., 2009). All malformations included in this study were found sporadically during 2002e2018. Animals were from a swine farming association from Toledo (Spain), comprised of 15 pig production facilities Correspondence to: (e-mail: [email protected]). 0021-9975/$ - see front matter https://doi.org/10.1016/j.jcpa.2019.11.005
with an annual average census of 6,500 breeding sows in close production cycle. Three females and three males (Landrace e large white e Pietrain) presenting with anomalies suggestive of CS were selected for the study. All piglets were stillborn and were the only abnormal members of their litters. The study was conducted in the Laboratory for the Study of Congenital Malformations (Anatomy and Embryology Department), School of Veterinary Medicine, Universidad Complutense de Madrid, Madrid, Spain. Detailed gross evaluation of the six animals was carried out using conventional anatomical methods. Special attention was paid to possible abnormalities within the heart, diaphragm and pericardium. A summary of the anomalies detected in the six piglets, as well as the size of the midline defect is given in Ó 2019 Elsevier Ltd. All rights reserved.
100
N. Martı´n-Alguacil and L. Avedillo
Table 1. A ventral midline fissure was observed in the thoracoabdominal wall, extending from the cranial part of the thorax to the umbilical region (Fig. 1) in all piglets. The amniotic membrane covered all of the exposed organs and was connected distally with the umbilical cord (UC) (Fig. 2). The UC was anomalous in all piglets (Table 1). The heart was ectopic and not covered by the pericardium (Fig. 2). The great vessels were positioned anomalously and were oriented dorsally. There was no anal atresia or spinal or craniofacial defects. All limbs were normal in length and shape. There was normal hepatic lobulation and the lungs appeared to be normal, with the exception of animal P264 in which the liver was an amorphous mass with no lobulation. The ventral insertion of the diaphragm was absent (Fig. 1). Internal inspection of the hearts revealed intracardiac defects in specimens (Table 1, Fig. 3). The full spectrum of CS consists of five anomalies: (1) a midline supraumbilical abdominal wall defect, (2) a deficiency of the ventral diaphragm and (3) diaphragmatic pericardium, (4) several congenital intracardiac malformations, and (5) a defect of the caudal sternum (Cantrell et al., 1958). In all the six piglets in this study, the full spectrum with the five anomalies characteristic of PC (Cantrell et al., 1958) were identified. An additional sixth defect, anomalous UC, was identified in all cases. The UC in all cases was shortened, showing an atypical coiling pattern. The UC in P264, the most affected animal, had a single umbilical artery (SUA) and one umbilical vein. UC pathologies as SUA, short cord or UC with atypical coiling pattern have been identified in PC (M€ uller Brochut et al., 2011). In human studies of this syndrome, there is male dominance with a male to female ratio of 2.7:1 (Barisic et al., 2001). We did not notice a gender pre-
Fig. 1. Ventral view of the wall defect in P264. The diaphragm musculature is barely visible (arrows) and its ventral insertion is absent. D, diaphragm; H, heart; SUA, single umbilical artery; UV, umbilical vein.
Fig. 2. In P267, the ectopic heart is visible and it was not covered by the pericardium. Except for the heart, all exposed organs are covered by the amniotic membrane. H, heart; I, intestine.
disposition; in contrast, the male to female ratio was 3:3. Affected human males also have more severe symptoms (Barisic et al., 2001), and in the present study the most severely affected animal (P264) was male. An associated intracardiac defect (e.g. septal defects) is frequent in PC and in the present cases there were two ventricular septal defects, three auricular septal defects and one atrioventricular septal defect. In addition, hypoplastic auricles, intracardiac valve atresia and the absence of one of the coronary arteries were also found. In PC, sternal malformations include bifid sternum (26%), absent xiphoid (10%) and absent caudal 2/3 of sternum (9%) (V azquezJimenez et al., 1998). The six pigs had a bifid sternum. In PC, the most common ventral abdominal wall defect is an omphalocoele (63%) (Vazquez-Jimenez et al., 1998). In all of the present cases, the exposed organs were covered by the amniotic membrane, as occurs in omphalocoele. A ventral retrosternal defect of the diaphragm occurs in 91% of human cases (Vazquez-Jimenez et al., 1998), a defect that was demonstrated in all six piglets. Notter (1927) and Hofliger (1936) described similar cases of two piglets with the heart and part of the intestine protruding through a ventral body wall fissure involving the sternum, except the manubrium, and the abdominal wall cranial to the prepuce. Gruys et al. (1978) described a case of complicated umbilical hernia in a pig, in which organs protruded through a fissure and were covered by a thin membrane. The fissure extended from the sternum, that was cleft, as far as and including the umbilicus, and the umbilical vessels were situated in the wall of the sac. Freeman and McGovern (1984) described a case of ectopia cordis thoracoabdominalis in a piglet. We believe that these three cases are similar to the six piglets presented in this study. Freeman and McGovern (1984) described a body
Table 1 Summary of the internal and external anomalies of the piglets Externally exposed organs
Diaphragm defect
Sternum
Ventral pericardium
Abdominal defect size
P227 M
Heart, ventral part of liver, ventral part of stomach, part of spleen, small intestine and caecum Heart, ventral part of liver, jejunum and ileum
Ventral
Midline splitting of the five more caudal sternebrae
Absent
6.1 cm
Ventral
Midline splitting except for the two first sternebrae
Absent
7.2 cm
Ventral
Midline splitting of the most caudal sternebrae
Absent
6.0 cm
Midline splitting of the four more caudal sternebrae
Absent
6.5 cm
Ventral
Midline splitting of the most caudal sternebrae
Absent
4.5 cm
Ventral
Midline splitting of the most caudal sternebrae
Absent
7 cm
P226 F
P228 M
Heart, some small intestine
P264 M
Heart, liver, stomach, spleen, small intestine, colon and caecum Heart, part of ileum and caecum
P267 F
P283 F
Heart, part of small intestine
Malformed musculature barely visible
Umbilical cord
Intracardiac defects
Other defects
Shorter, abnormal coiling pattern, dispersed vessels, two arteries (one hypoplastic) and one vein
Auricular septal defect
Ectopic caecum
Shorter, abnormal coiling pattern, dispersed vessels, two arteries and one vein Shorter, abnormal coiling pattern, dispersed vessels, two arteries and one vein Shorter, abnormal coiling pattern, dispersed vessels, SUA and one vein
Ventricular septal defect
Heart globous shape with right auricle dilation and ectopic liver
Ventricular septal defect
Heart globous shape with right auricle dilation
Large interatrial defect, atresia of the mitral valve, one coronary artery
Liver amorphous mass without lobulation
Shorter, abnormal coiling pattern, dispersed vessels, two arteries and one vein Shorter, abnormal coiling pattern, dispersed vessels, two arteries and one vein
Hypoplastic auricles, great vessel transposition, ventricular septal defect Auricular septal defect
Cantrell Syndrome in the Pig
Case and sex
M, male; F, female; SUA, single umbilical artery.
101
102
N. Martı´n-Alguacil and L. Avedillo
Fig. 3. Heart (P267) with great vessel translocation. The pulmonary trunk is connected with the left ventricle (note the location of the probe). LV, left ventricle; PT, pulmonary trunk.
wall defect consisting of a ventral midline fissure, which also involved all of the sternum, except for the manubrium, and which extended caudally as far as the umbilicus. They also observed a similar UC defect, a distal union of the UC with the body wall. In addition, there was absence of the ventral part of the diaphragm and pericardium as occurred in the present six cases. However, they did not record any abnormality in the chambers of the heart. The embryogenesis of the body wall in the pig begins at about day 12 of gestation and is finished by day 15 (Marrable, 1971). A defect in development of the somatopleure explains firstly the anomalous development of the septum transversum and malformation of the diaphragm and pericardia and, secondly, the malformations of the sternum and thoracoabdominal wall. A defect in the development of the splancnopleure can also account for the epicardial and cardiac defects. These phenomena are present in PC, and they appear to arise during blastogenesis. Diaphragmatic, pericardial and intracardiac defects in PC are the result of failure of development of a segment of mesoderm, while abdominal wall and sternal defects result from failure of paired primordial structures to migrate to their proper loca-
tions (Cantrell et al., 1958). In PC, midline defects in the thoracic wall began to show at E14.5. The sternum does not fuse and the heart protrudes at the midline through the body wall (Snowball et al., 2015). A failure in the ventral thoracic wall closure will affect the ventral part of the pericardium. All of the abnormalities present in the present cases may be attributed to a defect in the process of migration or fusion of the ventral midline of the body. All of the present cases had UC abnormalities, such as short cord or abnormal coiling pattern. One case also had a SUA. M€ uller Brochut et al. (2011) described three cases of human PC with UC defects. After reviewing the literature they found that nine of 24 reported cases had some abnormality of the UC. Of the 24 cases, a SUA was found in seven (29.2%). The embryonic time in which PC develops coincides with that of UC formation and the spiral display of the umbilical vessels. An early insult may, in theory, interfere with the characteristic switch from a predominantly uncoiled to the typical twisted structure of the umbilical vessels. We propose that anomalous UC be included as an additional characteristic feature of PC, which would define a ‘hexalogy of Cantrell’. The porcine UC forms a characteristic a twisted structure containing the allantoic stalk and the vessels (two arteries and one vein). As the embryo grows, the amnion expands and the connecting stalk lengthens. The allantoic vessels continue with the placental villi and form the vessels of the UC. The differentiation of the UC in pig begins during the second postconceptional week. The main changes are evident during the first 4 weeks of gestation, during which the UC vessels transform from a parallel course to their characteristic helical disposition. The fact that the UC was malformed in all of the present cases led us to include the UC defect as part of the syndrome. Therefore, we consider, as do some other authors (M€ uller Brochut et al., 2011), CS to be a sequence of developmental anomalies that start during blastogenesis, generating a polytopic field defect affecting the UC. The presentation of CS in the pig is similar to that described in man. Its pathogenesis remains unknown to date. Further comparative studies carried out on affected pigs could be of value for improved understanding of this condition.
Acknowledgments No funding sources supported this work.
References Barisic I, Clementi M, H€ ausler M, Gjergja R, Kern J et al. (2001) Evaluation of prenatal ultrasound diagnosis of
Cantrell Syndrome in the Pig
fetal abdominal wall defects by 19 European registries. Ultrasound in Obstetrics and Gynecology, 18, 309e316. Cantrell JR, Haller JA, Ravitch MM (1958) A syndrome of congenital defects involving the abdominal wall, sternum, diaphragm, pericardium, and heart. Surgery Gynecology & Obstetrics, 107, 602e614. Chandran S, Ari D (2013) Pentalogy of Cantrell: an extremely rare congenital anomaly. Journal of Clinical Neonatology, 2, 95e97. Duan QJ, Gao Z, Zhang ZW, Li JH, Ma LL, Ying LY (2009) Correct definition of pentalogy of Cantrell. Journal of Perinatal Medicine, 37, 426. Freeman LE, McGovern PT (1984) Ectopia cordis thoracoabdominalis in a piglet. The Veterinary Record, 115, 431e433. Gruys E, Jansingh J, vd Linde-Sipman JS (1978) [Umbilical hernia and ectopia cordis in a piglet]. Tijdschrift Voor Diergeneeskunde, 103, 498e500. € Hofliger H (1936) Uber Organdystopien bei Haustieren mit besonderer Ber€ ucksichtigung der Ectopie cordis und der sog. Zwerchfellbr€ uche. Virchows Archiv: Pathological Anatomy, 297, 627e644.
103
Marrable AW (1971) The Embryonic Pig: A Chronological Account. Pitman Publishing, New York, pp. 20e89. M€ uller Brochut AC, Baumann MU, Kuhn A, Di Naro E, Tutschek B et al. (2011) Pentalogy or hexalogy of Cantrell? Pediatric and Developmental Pathology, 14, 396e401. Notter C (1927) Scistosomen beim schweine. Virchows Archiv: Pathological Anatomy, 264, 280e298. Snowball J, Ambalavanan M, Cornett B, Lang R, Whitsett J et al. (2015) Mesenchymal Wnt signaling promotes formation of sternum and thoracic body wall. Developmental Biology, 401, 264e275. V azquez-Jimenez JF, Muehler EG, Daebritz S, Keutel J, Nishigaki K et al. (1998) Cantrell’s syndrome: a challenge to the surgeon. The Annals of Thoracic Surgery, 65, 1178e1185.
June 29th, 2019 ½ Received, Accepted, November 20th, 2019