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Unusual vascular ring anomaly associated with a persistent right aortic arch and an aberrant left subclavian artery in German pinschers
The Veterinary Journal 187 (2011) 352–355
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Unusual vascular ring anomaly associated with a persistent right aortic arch and an aberrant left subclavian artery in German pinschers Julia Menzel, Ottmar Distl * Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Bünteweg 17p, 30559 Hannover, Germany
a r t i c l e
i n f o
Article history: Accepted 15 December 2009
Keywords: German pinscher Dog Persistent right aortic arch Left subclavian artery Vascular ring anomaly Inheritance
a b s t r a c t The objective of this study was to describe a specific form of persistent right aortic arch (PRAA) in three German pinscher dogs and to analyse the mode of inheritance in the breed. This type of PRAA is characterised by a left retro-oesophageal subclavian artery in combination with a ligamentum arteriosum originating at the aberrant left subclavian artery (PRAA-SA-LA). This rare combination of anomalies has only been reported in two isolated cases in other dog breeds and the occurrence of any form of PRAA was not previously known to occur in the German pinscher. In the present study, 18 cases of this congenital anomaly were ascertained and their high degree of relatedness and inbreeding could be shown through pedigree analysis. Three of the affected dogs underwent further clinical investigations, and post-mortem examination (two cases) and findings at surgery (one case) verified the diagnosis of PRAA-SA-LA. A monogenic autosomal recessive mode of inheritance was not likely. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Vascular ring anomalies (VRAs) are developmental irregularities of the embryonic aortic arches that result in a complete or partial circle around the trachea and the oesophagus formed by blood vessels and associated structures, which may lead to a compression of the encircled structures. Persistent right aortic arch (PRAA) is recognised as the most common VRA (Helphrey, 1979; Ellison, 1980; Muldoon et al., 1997), representing 95% of all VRAs diagnosed in dogs (Buchanan, 2004). In PRAA-affected dogs, the aorta is formed by the right fourth aortic arch instead of the left fourth aortic arch (Kim et al., 2006). PRAA is a common cause of regurgitation and usually results in a dilated oesophagus in young dogs (Muldoon et al., 1997; Kim et al., 2006). The ligamentum arteriosum typically joins the pulmonary artery to the abnormally positioned aorta and creates the VRA around the oesophagus and the trachea. PRAA with an aberrant left subclavian artery (PRAA-SA) is observed in 33% of all dogs with PRAA (Buchanan, 2004). In cases of a PRAA-SA, the oesophagus is compressed by the vascular ring comprised of the persistent right aortic arch with left subclavian artery and by a partial ring formed by the aberrant left subclavian artery (Ellison, 1980). In only two reported cases of PRAA-SA, the ligamentum arteriosum extended from the main pulmonary artery to the aberrant left sub* Corresponding author. Tel.: +49 511 9538875; fax: +49 511 9538582. E-mail address: [email protected] (O. Distl). 1090-0233/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2009.12.016
clavian artery instead of the aortic arch (PRAA-SA-LA) (House et al., 2005). This rare course of the ligamentum arteriosum enforces the compression of the oesophagus by the aberrant left subclavian artery. The first clinical symptoms seen in newborn puppies affected by PRAA, PRAA-SA or PRAA-SA-LA appear with the ingestion of solid food and consist of postprandial regurgitation of food in all three types of vascular ring anomalies (Buchanan, 2004; VanGundy, 1989). Contrast radiographies of the thorax show oesophageal dilatation cranial to the heart with constriction at the level of the heart base (Buchanan, 1968; VanGundy, 1989). Surgical treatment is required to eliminate the constriction (Ellison, 1980). Epidemiological as well as breeding studies have shown that German shepherds, Irish Setters and Greyhounds are genetically predisposed to the development of PRAA (Patterson, 1968; Gunby et al., 2004), but the mode of inheritance is complex and polygenic in its basis (Patterson, 1989). There are no reports of any forms of PRAA in German pinschers. However, in the last 6 months PRAA-SA-LA has been diagnosed in three German pinscher puppies from Germany and The Netherlands. Fifteen other cases of PRAA have been reported by breeders or veterinarians and therefore have to be regarded partly as presumptive diagnoses. This is a high prevalence in the German pinscher and raises the suspicion of a genetic cause. The objectives of this study were to describe the congenital conotruncal anomalies and to examine if PRAA could be an inherited defect in German pinschers.
J. Menzel, O. Distl / The Veterinary Journal 187 (2011) 352–355
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Materials and methods The Pinscher-Schnauzer-Klub (PSK) in Germany contacted the Institute for Animal Breeding and Genetics of the University of Veterinary Medicine, Hannover because of several recent cases of PRAA in the breed. A total of 18 cases from 16 different litters had been reported in the last 10 years. Three underwent further investigations at the Hannover Institute for Animal Breeding and Genetics and it was found that the cause of oesophageal constriction was a persistent right aortic arch, an aberrant left subclavian artery and a left ligamentum arteriosum with its origin on the left subclavian artery (PRAA-SA-LA). The 15 remaining cases were reported by veterinarians or breeders and dog owners. One puppy was examined in a private institute for pathology and PRAASA-LA was diagnosed. Another dog underwent corrective surgery at the Faculty of Veterinary Medicine at the Ludwig-Maximilians-University in Munich 10 years previously with a diagnosis of PRAA without further specification. In the other 13 dogs, diagnoses were made on the basis of clinical signs, radiographies and contrast oesophagrams, and therefore could be regarded as presumptive diagnoses. One female dog, at 7 years of age, had survived since the age of 8 months with the presumptive diagnosis of PRAA (not specified) using radiography, clinical symptoms and contrast oesophagram. The owner started to feed this dog about 6–8 times daily with small amounts of pureed soft dog food mixed with water with the animal in an upright position and maintained the feeding regime up to the time we saw it. The dog appeared reasonably well with this treatment, although regurgitation occurs up to twice a month. In total, 2/18 dogs we ascertained underwent a corrective surgery, 15/18 were euthanised as puppies mainly because of poor body condition, and 1/18 dog is living without surgical treatment. The pedigrees of the affected dogs were used for segregation analysis to test whether the data were compatible with the respective simple Mendelian model, a recessive mode of inheritance. The Singles method is a straightforward method of simple segregation analysis (Davie, 1979). The test involves a statistical comparison of the estimated segregation frequency P (probability that an offspring is affected by the respective disease) with the hypothesised value (P0) arising from the particular model of inheritance being tested. If a recessive mode of inheritance is assumed, both parents in each of a set of full sib families are unaffected, the null hypothesis is that the true value of P0 = 0.25. The most straightforward use of the Singles method can be made when the investigator is certain that all families with affected offspring are included in the data. Then the segregation frequency can be estimated as P = (A A1)/(T A1) and its estimated variance is given by Est. Var. (P) = (T A)/(T A1)3 [A A1+2A2(T A)/(T A1)] where A is the total number of affected offspring in the available data, T is the total number of all examined offspring in the available data, A1 is the total number of families with just one affected offspring, and A2 is the total number of families with two affected offspring. Then the null hypothesis is tested using: Z2 = (P P0)2/Est. Var. (P). If the calculated value Z2 is not significant at a = 0.05, the data are consistent with a simple recessive mode of inheritance. The mean coefficient of relationship was calculated using OPTI-MATE (Wrede and Schmidt, 2003) for the group of German pinschers with PRAA-affected offspring (n = 27) and a contemporary group of dogs born in 2008 (n = 555). The mean coefficient of inbreeding was compared among PRAA-affected dogs and the same contemporary group of dogs. Pedigree information over eight generations was considered, the completeness of pedigrees was larger than 95% in all eight generations. The mean number of puppies per litter was calculated for the group of litters with PRAA-affected offspring (n = 16) and a contemporary group of all litters in 2005– 2009 (n = 415). P was calculated using t tests.
Fig. 1. Contrast oesophagram of puppy 2 (ventro-dorsal projection): highly dilated oesophagus (A) cranial to the heart base.
striction was the aberrant left subclavian artery in combination with the ligamentum arteriosum. In cases 2 and 3, a breeder of German pinschers contacted the Hannover Institute for Animal Breeding and Genetics because of two suspected PRAA-affected male puppies (puppies 2 and 3) in one litter. The referral veterinarian had undertaken radiography and contrast oesophagrams of both puppies at an age of 4 weeks and suspected PRAA because of the radiographic findings and the typical clinical signs. The two puppies were presented to the Hannover Small Animal Clinic where a complete clinical examination, radiography, contrast oesophagrams, and ultrasonography of the heart were performed. The contrast oesophagram of puppy 2 showed that the oesophagus was highly dilated cranial to the heart base (Fig. 1) but the contrast oesophagram of puppy 3 showed only a mild dilatation cranial to the heart base. In the ultrasonographic examination of puppy 2, a ventricle septum defect was also diagnosed. The ultrasonographic examination of puppy 3 revealed no abnormalities. Because of the complicated medical findings in puppy 2 and the poor prognosis for the ventricle septum defect, puppy 2 was euthanised and sent for post-mortem examination. Puppy 3 was submitted for surgical treatment the following day. The oesophagus was found compressed by a complete ring formed with an
Results Case reports The first case was a 3 week-old female German pinscher puppy (puppy 1) that was euthanised because of constant regurgitation and poor body condition. Contrast oesophagram with barium sulfate by the referral veterinarian revealed a precardiac megaoesophagus and oesophageal constriction at the level of the heart base. After euthanasia, puppy 1 was presented to the Hannover Institute for Pathology to investigate the cause of the constriction. A severe dilatation of the oesophagus cranial to the heart base and constriction at the level of the heart base were found. The diameter of the oesophagus cranial to the heart was four times larger than that at the level of the heart base. The oesophagus was present between a persistent right aortic arch, a left subclavian artery, the heart base and the ligamentum arteriosum, which extended from the main pulmonary artery to the left subclavian artery, attaching approximately 1 cm cranial to the point of origin of the aberrant left subclavian artery. The main cause of the con-
Fig. 2. Findings in the necropsy of puppy 2. The oesophagus (A) is highly dilated cranial to the heart. The left subclavian artery (B) originated in the distal right aortic arch (C), coursed dorsal to the oesophagus and crossed over to the left side. The ligamentum arteriosum (D) joins the pulmonary artery with the aberrant subclavian artery.
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J. Menzel, O. Distl / The Veterinary Journal 187 (2011) 352–355
Fig. 3. Pedigree showing the German pinschers affected by PRAA. In puppies 1–3 the specific form of PRAA with an aberrant left subclavian artery with a ligamentum arteriosum joining the left subclavian artery and the main pulmonary artery was diagnosed.
Table 1 Comparison of coefficients of inbreeding among PRAA-affected and a contemporary group of German pinschers as well as and relationship coefficients among parents with PRAAaffected progeny and a contemporary group of German pinschers. Parameter
Contemporary group
PRAA-affected or German pinschers with PRAA-affected offspring
P
Mean coefficient of relationship (%) Mean coefficient of inbreeding (%)
7.44 ± 7.45 3.56 ± 2.98
11.04 ± 10.14 6.76 ± 4.86
0.088 0.005
aberrant persistent left ligamentum arteriosum joining the left subclavian artery and the pulmonary artery and their left subclavian artery. After ligation and transsection of the ligamentum arteriosum, the oesophagus was no more compressed by the aberrant left subclavian artery so the vessel was not manipulated. Regurgitation was not noticed either during the upright position feeding interval during the first few days after surgery or subsequently up to the time of this report (6 months after surgery). The necropsy findings of puppy 2 (Fig. 2), were very similar to those in puppy 1. The oesophagus was highly dilated in the precardiac region; the diameter in this region was five times larger than at the level of the heart base. The oesophagus was found in the same position as in puppy 1, with the ligamentum arteriosum attaching the aberrant left subclavian artery 1.5 cm cranial to the point of its origin.
Pedigree analysis Investigation of the pedigrees showed relationships among all 18 affected dogs (Fig. 3). The mean coefficient of inbreeding of PRAA-affected German pinschers was significantly higher than the mean coefficient of inbreeding of the contemporary group (Table 1). The mean coefficient of relationship among parents with at least one PRAA-affected progeny was also higher than the mean coefficient of relationship of the contemporary group. The mean number of puppies per litter calculated for the group of litters with PRAA-affected offspring was 6.20 ± 2.33 which was not significantly different from the mean number of puppies per litter calculated for the contemporary group (6.47 ± 2.59). All affected dogs had unaffected parents and the proportion of affected males (n = 8) and females (n = 7) was almost equal (sex unknown: n = 3). Therefore, an X-linked mode of inheritance was
excluded as well as a monogenic autosomal dominant mode and a mitochondrial mode. The result of the simple segregation analysis using the Singles method did not support a monogenic autosomal recessive mode of inheritance. The calculated value for Z2 = 29.51 was significant at a = 0.05 (P < 0.001), therefore the data are not consistent with a simple recessive mode of inheritance. Assuming a penetrance of <0.5, the data fit to a monogenic autosomal recessive inheritance (P > 0.05).
Discussion The left retro-oesophageal subclavian artery in combination with the left ligamentum arteriosum with its origin on the left subclavian artery was the main cause of oesophageal constriction in the three German pinscher puppies examined. Even if the other cases reported could not be verified in post-mortem examinations, the close relationships among the cases suggest that the same VRA may have caused the dilatation of the oesophagus. Misdiagnoses are unlikely because we were able to collect veterinary and radiography reports for many of the 18 cases reported here. The extremely rare combination of anomalies that occurred in the three German pinscher puppies has been described in dogs in only two cases before, in one German shepherd and in one Great Dane (House et al., 2005). The combination of anomalies is similar to an inherited anomaly reported in humans for which a diverticulum is present at the origin of the left subclavian artery (Kommerell’s diverticulum) (Cina et al., 2000). The only definitive treatment for VRAs is surgery. Medical therapy alone without surgery, consisting of feeding in an upright position and using a slurry diet, is not considered effective and in most cases leads to worsening of oesophageal dilation with the risk of aspiration pneumonia. Nevertheless, the 7 year-old female
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German pinscher reported here has survived since the age of 8 months with the presumptive diagnosis of PRAA. The dog has a normal weight for its size and aspiration pneumonia has not occurred. The six most commonly reported heart defects in dogs have been all proven to be heritable through genetic studies (Patterson, 1989). In the case of PRAA, breeding studies (German shepherds) as well as epidemiological studies (German shepherds, Irish setters) have demonstrated that German shepherds and Irish setters are genetically predisposed to the condition and the mode of inheritance of PRAA is most likely complex and polygenic (Patterson, 1968; Patterson, 1989). Investigation of the heritability of congenital heart diseases first started with epidemiological studies. Results indicated that the number of PRAA-affected dogs in the German shepherd and Irish setter breeds was significantly higher than in other breeds. In breeding studies involving matings between two German shepherd dogs with PRAA, there was a higher frequency of the anomaly in the offspring, and the type of PRAA in those puppies was identical or closely related to that of the parents (Patterson, 1968). The close relationship and high inbreeding coefficients suggest that PRAA in German pinschers is an inherited defect and the same specific form of PRAA may be transmitted from the parents. The higher the coefficient of inbreeding, the more likely an inherited recessive defect may be evident in the offspring. The coefficient of inbreeding of the group of German pinschers with PRAA-affected offspring is significantly higher than in the contemporary group but we could not determine the exact mode of inheritance for PRAA in German pinschers. Using the Singles method for segregation analysis, a monogenic autosomal recessive inheritance could be rejected. The proportion of affected puppies per litter was clearly below 0.25 and in only two litters was this proportion close to 0.25 (2/7 = 0.286 and 2/9 = 0.22). Even differences in sizes among litters with PRAA-affected and without PRAA-affected puppies were small and did not seem to influence the segregation ratio of affected individuals. Therefore, this mode of inheritance did not appear plausible. Thus, an oligogenic or polygenic mode of inheritance or the contribution of a larger number of mutations of a genomic region appeared to be more likely. Conclusions A monogenic autosomal recessive mode of inheritance is unlikely in these cases of PRAA-SA-LA. A whole genome scan for linkage analysis could help clarify which genomic regions are associated with this anomaly. The reported German pinscher fami-
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lies may be useful in the quest to unravel genes involved in PRAALA-SA. Conflict of interest statement None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper. Acknowledgements We thank the Pinscher-Schnauzer-Klub e. V. (PSK) in Germany for support in collecting pedigrees and cases of PRAA and all German pinscher breeders for providing data and diagnoses from their dogs. References Buchanan, J.W., 2004. Tracheal signs and associated vascular anomalies in dogs with persistent right aortic arch. Journal of Veterinary Internal Medicine 18, 510– 514. Buchanan, J.W., 1968. Patent ductus arteriosus and persistent right aortic arch surgery in dogs. Journal of Small Animal Practice 9, 409–428. Cina, C.S., Arena, G.O., Bruin, G., Clase, C.M., 2000. Kommerell’s diverticulum and aneurismal right sided aortic arch: a case report and review of literature. Journal of Vascular Surgery 32, 1208–1214. Davie, A.M., 1979. The singles method for segregation analysis under incomplete ascertainment. Annals of Human Genetics 42, 507–512. Ellison, G.W., 1980. Vascular ring anomalies in the dog and cat. Compendium on Continuing Education for the Practicing Veterinarian 2, 693–705. Gunby, J.M., Hardie, R.J., Bjorling, D.E., 2004. Investigation of the potential heritability of persistent right aortic arch in Greyhounds. Journal of the American Veterinary Medical Association 224, 1120–1121. Helphrey, M.L., 1979. Vascular ring anomalies in the dog. Veterinary Clinics of North America 9, 207–218. House, A.K., Summerfield, N.J., German, A.J., Noble, P.J.M., Ibbarola, P., Brockmann, D.J., 2005. Unusual vascular ring anomaly associated with a persistent right aortic arch in two dogs. Journal of Small Animal Practice 6, 585–590. Kim, N.S., Alam, M.R., Choi, I.H., 2006. Persistent right aortic arch and aberrant left subclavian artery in a dog: a case report. Veterinarni Medicina 51, 156–160. Muldoon, M., Birchard, S.J., Ellison, G.W., 1997. Long-term results of surgical correction of persistent right aortic arch in dogs: 25 cases (1980–1995). Journal of the American Veterinary Medical Association 210, 1761–1763. Patterson, D.F., 1968. Epidemiologic and genetic studies of congenital heart disease in the dog. Circulation Research 23, 171–2002. Patterson, D.F., 1989. Hereditary congenital heart defects in dogs. Journal of Small Animal Practice 30, 153–165. VanGundy, T., 1989. Vascular ring anomalies. Compendium on Continuing Education for the Practicing Veterinarian 2, 36–48. Wrede, J., Schmidt, T., 2003. OPTI-MATE version 3.81. A management programme useful to minimize inbreeding in endangered populations. Programme Manual. Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Germany.
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Unusual vascular ring anomaly associated with a persistent right aortic arch and an aberrant left subclavian artery in German pinschers Julia Menzel, Ottmar Distl * Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Bünteweg 17p, 30559 Hannover, Germany
a r t i c l e
i n f o
Article history: Accepted 15 December 2009
Keywords: German pinscher Dog Persistent right aortic arch Left subclavian artery Vascular ring anomaly Inheritance
a b s t r a c t The objective of this study was to describe a specific form of persistent right aortic arch (PRAA) in three German pinscher dogs and to analyse the mode of inheritance in the breed. This type of PRAA is characterised by a left retro-oesophageal subclavian artery in combination with a ligamentum arteriosum originating at the aberrant left subclavian artery (PRAA-SA-LA). This rare combination of anomalies has only been reported in two isolated cases in other dog breeds and the occurrence of any form of PRAA was not previously known to occur in the German pinscher. In the present study, 18 cases of this congenital anomaly were ascertained and their high degree of relatedness and inbreeding could be shown through pedigree analysis. Three of the affected dogs underwent further clinical investigations, and post-mortem examination (two cases) and findings at surgery (one case) verified the diagnosis of PRAA-SA-LA. A monogenic autosomal recessive mode of inheritance was not likely. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Vascular ring anomalies (VRAs) are developmental irregularities of the embryonic aortic arches that result in a complete or partial circle around the trachea and the oesophagus formed by blood vessels and associated structures, which may lead to a compression of the encircled structures. Persistent right aortic arch (PRAA) is recognised as the most common VRA (Helphrey, 1979; Ellison, 1980; Muldoon et al., 1997), representing 95% of all VRAs diagnosed in dogs (Buchanan, 2004). In PRAA-affected dogs, the aorta is formed by the right fourth aortic arch instead of the left fourth aortic arch (Kim et al., 2006). PRAA is a common cause of regurgitation and usually results in a dilated oesophagus in young dogs (Muldoon et al., 1997; Kim et al., 2006). The ligamentum arteriosum typically joins the pulmonary artery to the abnormally positioned aorta and creates the VRA around the oesophagus and the trachea. PRAA with an aberrant left subclavian artery (PRAA-SA) is observed in 33% of all dogs with PRAA (Buchanan, 2004). In cases of a PRAA-SA, the oesophagus is compressed by the vascular ring comprised of the persistent right aortic arch with left subclavian artery and by a partial ring formed by the aberrant left subclavian artery (Ellison, 1980). In only two reported cases of PRAA-SA, the ligamentum arteriosum extended from the main pulmonary artery to the aberrant left sub* Corresponding author. Tel.: +49 511 9538875; fax: +49 511 9538582. E-mail address: [email protected] (O. Distl). 1090-0233/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2009.12.016
clavian artery instead of the aortic arch (PRAA-SA-LA) (House et al., 2005). This rare course of the ligamentum arteriosum enforces the compression of the oesophagus by the aberrant left subclavian artery. The first clinical symptoms seen in newborn puppies affected by PRAA, PRAA-SA or PRAA-SA-LA appear with the ingestion of solid food and consist of postprandial regurgitation of food in all three types of vascular ring anomalies (Buchanan, 2004; VanGundy, 1989). Contrast radiographies of the thorax show oesophageal dilatation cranial to the heart with constriction at the level of the heart base (Buchanan, 1968; VanGundy, 1989). Surgical treatment is required to eliminate the constriction (Ellison, 1980). Epidemiological as well as breeding studies have shown that German shepherds, Irish Setters and Greyhounds are genetically predisposed to the development of PRAA (Patterson, 1968; Gunby et al., 2004), but the mode of inheritance is complex and polygenic in its basis (Patterson, 1989). There are no reports of any forms of PRAA in German pinschers. However, in the last 6 months PRAA-SA-LA has been diagnosed in three German pinscher puppies from Germany and The Netherlands. Fifteen other cases of PRAA have been reported by breeders or veterinarians and therefore have to be regarded partly as presumptive diagnoses. This is a high prevalence in the German pinscher and raises the suspicion of a genetic cause. The objectives of this study were to describe the congenital conotruncal anomalies and to examine if PRAA could be an inherited defect in German pinschers.
J. Menzel, O. Distl / The Veterinary Journal 187 (2011) 352–355
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Materials and methods The Pinscher-Schnauzer-Klub (PSK) in Germany contacted the Institute for Animal Breeding and Genetics of the University of Veterinary Medicine, Hannover because of several recent cases of PRAA in the breed. A total of 18 cases from 16 different litters had been reported in the last 10 years. Three underwent further investigations at the Hannover Institute for Animal Breeding and Genetics and it was found that the cause of oesophageal constriction was a persistent right aortic arch, an aberrant left subclavian artery and a left ligamentum arteriosum with its origin on the left subclavian artery (PRAA-SA-LA). The 15 remaining cases were reported by veterinarians or breeders and dog owners. One puppy was examined in a private institute for pathology and PRAASA-LA was diagnosed. Another dog underwent corrective surgery at the Faculty of Veterinary Medicine at the Ludwig-Maximilians-University in Munich 10 years previously with a diagnosis of PRAA without further specification. In the other 13 dogs, diagnoses were made on the basis of clinical signs, radiographies and contrast oesophagrams, and therefore could be regarded as presumptive diagnoses. One female dog, at 7 years of age, had survived since the age of 8 months with the presumptive diagnosis of PRAA (not specified) using radiography, clinical symptoms and contrast oesophagram. The owner started to feed this dog about 6–8 times daily with small amounts of pureed soft dog food mixed with water with the animal in an upright position and maintained the feeding regime up to the time we saw it. The dog appeared reasonably well with this treatment, although regurgitation occurs up to twice a month. In total, 2/18 dogs we ascertained underwent a corrective surgery, 15/18 were euthanised as puppies mainly because of poor body condition, and 1/18 dog is living without surgical treatment. The pedigrees of the affected dogs were used for segregation analysis to test whether the data were compatible with the respective simple Mendelian model, a recessive mode of inheritance. The Singles method is a straightforward method of simple segregation analysis (Davie, 1979). The test involves a statistical comparison of the estimated segregation frequency P (probability that an offspring is affected by the respective disease) with the hypothesised value (P0) arising from the particular model of inheritance being tested. If a recessive mode of inheritance is assumed, both parents in each of a set of full sib families are unaffected, the null hypothesis is that the true value of P0 = 0.25. The most straightforward use of the Singles method can be made when the investigator is certain that all families with affected offspring are included in the data. Then the segregation frequency can be estimated as P = (A A1)/(T A1) and its estimated variance is given by Est. Var. (P) = (T A)/(T A1)3 [A A1+2A2(T A)/(T A1)] where A is the total number of affected offspring in the available data, T is the total number of all examined offspring in the available data, A1 is the total number of families with just one affected offspring, and A2 is the total number of families with two affected offspring. Then the null hypothesis is tested using: Z2 = (P P0)2/Est. Var. (P). If the calculated value Z2 is not significant at a = 0.05, the data are consistent with a simple recessive mode of inheritance. The mean coefficient of relationship was calculated using OPTI-MATE (Wrede and Schmidt, 2003) for the group of German pinschers with PRAA-affected offspring (n = 27) and a contemporary group of dogs born in 2008 (n = 555). The mean coefficient of inbreeding was compared among PRAA-affected dogs and the same contemporary group of dogs. Pedigree information over eight generations was considered, the completeness of pedigrees was larger than 95% in all eight generations. The mean number of puppies per litter was calculated for the group of litters with PRAA-affected offspring (n = 16) and a contemporary group of all litters in 2005– 2009 (n = 415). P was calculated using t tests.
Fig. 1. Contrast oesophagram of puppy 2 (ventro-dorsal projection): highly dilated oesophagus (A) cranial to the heart base.
striction was the aberrant left subclavian artery in combination with the ligamentum arteriosum. In cases 2 and 3, a breeder of German pinschers contacted the Hannover Institute for Animal Breeding and Genetics because of two suspected PRAA-affected male puppies (puppies 2 and 3) in one litter. The referral veterinarian had undertaken radiography and contrast oesophagrams of both puppies at an age of 4 weeks and suspected PRAA because of the radiographic findings and the typical clinical signs. The two puppies were presented to the Hannover Small Animal Clinic where a complete clinical examination, radiography, contrast oesophagrams, and ultrasonography of the heart were performed. The contrast oesophagram of puppy 2 showed that the oesophagus was highly dilated cranial to the heart base (Fig. 1) but the contrast oesophagram of puppy 3 showed only a mild dilatation cranial to the heart base. In the ultrasonographic examination of puppy 2, a ventricle septum defect was also diagnosed. The ultrasonographic examination of puppy 3 revealed no abnormalities. Because of the complicated medical findings in puppy 2 and the poor prognosis for the ventricle septum defect, puppy 2 was euthanised and sent for post-mortem examination. Puppy 3 was submitted for surgical treatment the following day. The oesophagus was found compressed by a complete ring formed with an
Results Case reports The first case was a 3 week-old female German pinscher puppy (puppy 1) that was euthanised because of constant regurgitation and poor body condition. Contrast oesophagram with barium sulfate by the referral veterinarian revealed a precardiac megaoesophagus and oesophageal constriction at the level of the heart base. After euthanasia, puppy 1 was presented to the Hannover Institute for Pathology to investigate the cause of the constriction. A severe dilatation of the oesophagus cranial to the heart base and constriction at the level of the heart base were found. The diameter of the oesophagus cranial to the heart was four times larger than that at the level of the heart base. The oesophagus was present between a persistent right aortic arch, a left subclavian artery, the heart base and the ligamentum arteriosum, which extended from the main pulmonary artery to the left subclavian artery, attaching approximately 1 cm cranial to the point of origin of the aberrant left subclavian artery. The main cause of the con-
Fig. 2. Findings in the necropsy of puppy 2. The oesophagus (A) is highly dilated cranial to the heart. The left subclavian artery (B) originated in the distal right aortic arch (C), coursed dorsal to the oesophagus and crossed over to the left side. The ligamentum arteriosum (D) joins the pulmonary artery with the aberrant subclavian artery.
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Fig. 3. Pedigree showing the German pinschers affected by PRAA. In puppies 1–3 the specific form of PRAA with an aberrant left subclavian artery with a ligamentum arteriosum joining the left subclavian artery and the main pulmonary artery was diagnosed.
Table 1 Comparison of coefficients of inbreeding among PRAA-affected and a contemporary group of German pinschers as well as and relationship coefficients among parents with PRAAaffected progeny and a contemporary group of German pinschers. Parameter
Contemporary group
PRAA-affected or German pinschers with PRAA-affected offspring
P
Mean coefficient of relationship (%) Mean coefficient of inbreeding (%)
7.44 ± 7.45 3.56 ± 2.98
11.04 ± 10.14 6.76 ± 4.86
0.088 0.005
aberrant persistent left ligamentum arteriosum joining the left subclavian artery and the pulmonary artery and their left subclavian artery. After ligation and transsection of the ligamentum arteriosum, the oesophagus was no more compressed by the aberrant left subclavian artery so the vessel was not manipulated. Regurgitation was not noticed either during the upright position feeding interval during the first few days after surgery or subsequently up to the time of this report (6 months after surgery). The necropsy findings of puppy 2 (Fig. 2), were very similar to those in puppy 1. The oesophagus was highly dilated in the precardiac region; the diameter in this region was five times larger than at the level of the heart base. The oesophagus was found in the same position as in puppy 1, with the ligamentum arteriosum attaching the aberrant left subclavian artery 1.5 cm cranial to the point of its origin.
Pedigree analysis Investigation of the pedigrees showed relationships among all 18 affected dogs (Fig. 3). The mean coefficient of inbreeding of PRAA-affected German pinschers was significantly higher than the mean coefficient of inbreeding of the contemporary group (Table 1). The mean coefficient of relationship among parents with at least one PRAA-affected progeny was also higher than the mean coefficient of relationship of the contemporary group. The mean number of puppies per litter calculated for the group of litters with PRAA-affected offspring was 6.20 ± 2.33 which was not significantly different from the mean number of puppies per litter calculated for the contemporary group (6.47 ± 2.59). All affected dogs had unaffected parents and the proportion of affected males (n = 8) and females (n = 7) was almost equal (sex unknown: n = 3). Therefore, an X-linked mode of inheritance was
excluded as well as a monogenic autosomal dominant mode and a mitochondrial mode. The result of the simple segregation analysis using the Singles method did not support a monogenic autosomal recessive mode of inheritance. The calculated value for Z2 = 29.51 was significant at a = 0.05 (P < 0.001), therefore the data are not consistent with a simple recessive mode of inheritance. Assuming a penetrance of <0.5, the data fit to a monogenic autosomal recessive inheritance (P > 0.05).
Discussion The left retro-oesophageal subclavian artery in combination with the left ligamentum arteriosum with its origin on the left subclavian artery was the main cause of oesophageal constriction in the three German pinscher puppies examined. Even if the other cases reported could not be verified in post-mortem examinations, the close relationships among the cases suggest that the same VRA may have caused the dilatation of the oesophagus. Misdiagnoses are unlikely because we were able to collect veterinary and radiography reports for many of the 18 cases reported here. The extremely rare combination of anomalies that occurred in the three German pinscher puppies has been described in dogs in only two cases before, in one German shepherd and in one Great Dane (House et al., 2005). The combination of anomalies is similar to an inherited anomaly reported in humans for which a diverticulum is present at the origin of the left subclavian artery (Kommerell’s diverticulum) (Cina et al., 2000). The only definitive treatment for VRAs is surgery. Medical therapy alone without surgery, consisting of feeding in an upright position and using a slurry diet, is not considered effective and in most cases leads to worsening of oesophageal dilation with the risk of aspiration pneumonia. Nevertheless, the 7 year-old female
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German pinscher reported here has survived since the age of 8 months with the presumptive diagnosis of PRAA. The dog has a normal weight for its size and aspiration pneumonia has not occurred. The six most commonly reported heart defects in dogs have been all proven to be heritable through genetic studies (Patterson, 1989). In the case of PRAA, breeding studies (German shepherds) as well as epidemiological studies (German shepherds, Irish setters) have demonstrated that German shepherds and Irish setters are genetically predisposed to the condition and the mode of inheritance of PRAA is most likely complex and polygenic (Patterson, 1968; Patterson, 1989). Investigation of the heritability of congenital heart diseases first started with epidemiological studies. Results indicated that the number of PRAA-affected dogs in the German shepherd and Irish setter breeds was significantly higher than in other breeds. In breeding studies involving matings between two German shepherd dogs with PRAA, there was a higher frequency of the anomaly in the offspring, and the type of PRAA in those puppies was identical or closely related to that of the parents (Patterson, 1968). The close relationship and high inbreeding coefficients suggest that PRAA in German pinschers is an inherited defect and the same specific form of PRAA may be transmitted from the parents. The higher the coefficient of inbreeding, the more likely an inherited recessive defect may be evident in the offspring. The coefficient of inbreeding of the group of German pinschers with PRAA-affected offspring is significantly higher than in the contemporary group but we could not determine the exact mode of inheritance for PRAA in German pinschers. Using the Singles method for segregation analysis, a monogenic autosomal recessive inheritance could be rejected. The proportion of affected puppies per litter was clearly below 0.25 and in only two litters was this proportion close to 0.25 (2/7 = 0.286 and 2/9 = 0.22). Even differences in sizes among litters with PRAA-affected and without PRAA-affected puppies were small and did not seem to influence the segregation ratio of affected individuals. Therefore, this mode of inheritance did not appear plausible. Thus, an oligogenic or polygenic mode of inheritance or the contribution of a larger number of mutations of a genomic region appeared to be more likely. Conclusions A monogenic autosomal recessive mode of inheritance is unlikely in these cases of PRAA-SA-LA. A whole genome scan for linkage analysis could help clarify which genomic regions are associated with this anomaly. The reported German pinscher fami-
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lies may be useful in the quest to unravel genes involved in PRAALA-SA. Conflict of interest statement None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper. Acknowledgements We thank the Pinscher-Schnauzer-Klub e. V. (PSK) in Germany for support in collecting pedigrees and cases of PRAA and all German pinscher breeders for providing data and diagnoses from their dogs. References Buchanan, J.W., 2004. Tracheal signs and associated vascular anomalies in dogs with persistent right aortic arch. Journal of Veterinary Internal Medicine 18, 510– 514. Buchanan, J.W., 1968. Patent ductus arteriosus and persistent right aortic arch surgery in dogs. Journal of Small Animal Practice 9, 409–428. Cina, C.S., Arena, G.O., Bruin, G., Clase, C.M., 2000. Kommerell’s diverticulum and aneurismal right sided aortic arch: a case report and review of literature. Journal of Vascular Surgery 32, 1208–1214. Davie, A.M., 1979. The singles method for segregation analysis under incomplete ascertainment. Annals of Human Genetics 42, 507–512. Ellison, G.W., 1980. Vascular ring anomalies in the dog and cat. Compendium on Continuing Education for the Practicing Veterinarian 2, 693–705. Gunby, J.M., Hardie, R.J., Bjorling, D.E., 2004. Investigation of the potential heritability of persistent right aortic arch in Greyhounds. Journal of the American Veterinary Medical Association 224, 1120–1121. Helphrey, M.L., 1979. Vascular ring anomalies in the dog. Veterinary Clinics of North America 9, 207–218. House, A.K., Summerfield, N.J., German, A.J., Noble, P.J.M., Ibbarola, P., Brockmann, D.J., 2005. Unusual vascular ring anomaly associated with a persistent right aortic arch in two dogs. Journal of Small Animal Practice 6, 585–590. Kim, N.S., Alam, M.R., Choi, I.H., 2006. Persistent right aortic arch and aberrant left subclavian artery in a dog: a case report. Veterinarni Medicina 51, 156–160. Muldoon, M., Birchard, S.J., Ellison, G.W., 1997. Long-term results of surgical correction of persistent right aortic arch in dogs: 25 cases (1980–1995). Journal of the American Veterinary Medical Association 210, 1761–1763. Patterson, D.F., 1968. Epidemiologic and genetic studies of congenital heart disease in the dog. Circulation Research 23, 171–2002. Patterson, D.F., 1989. Hereditary congenital heart defects in dogs. Journal of Small Animal Practice 30, 153–165. VanGundy, T., 1989. Vascular ring anomalies. Compendium on Continuing Education for the Practicing Veterinarian 2, 36–48. Wrede, J., Schmidt, T., 2003. OPTI-MATE version 3.81. A management programme useful to minimize inbreeding in endangered populations. Programme Manual. Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Germany.