Simple SummaryTwo papillon puppies (a stillborn and a live pup) were born with severe syndromic developmental abnormalities, involving incomplete fusion of the chest and abdominal wall with extrusion of internal organs. A similarly affected stillborn pup from the dam’s previous litter was reported, suggesting a possible familial inheritance. This study describes the results of advanced imaging (by computed tomography) and postmortem examinations of the two affected puppies compared to an unaffected stillborn papillon puppy from a separate litter. The results confirmed a diagnosis of Pentalogy of Cantrell, a rare syndrome, which is proposed to be inherited in humans. There are infrequent reports of this congenital condition in domestic animals with variable expression of the typical five signs of this syndrome, without any identified cause or confirmed genetic familial basis.AbstractDevelopmental anomalies are an important cause of stillbirth and early perinatal death in companion animals. Many of these disorders remain poorly understood and provide an opportunity as a spontaneous animal model for human disease. Pentalogy of Cantrell is a rare congenital syndrome described in human neonates. It is a ventral midline closure defect with a proposed familial inheritance in humans. This syndrome involves five defects, including the thoracoabdominal wall, sternal, diaphragmatic, pericardial and cardiac malformations. Diverse expressions of these defects have been described in humans and sporadically in domestic animals. This severe syndrome commonly harbors a poor prognosis, posing an ethical and surgical dilemma. To better understand this syndrome and its presentation in dogs, we describe two rare cases of Pentalogy of Cantrell in a litter of papillon dogs. The affected puppies had anomalies compatible with the Pentalogy of Cantrell, including thoracoabdominal schisis, ectopia cordis, sternal cleft, pericardial agenesis, and diaphragmatic defects. The diagnosis was confirmed by advanced imaging (computed tomography) and postmortem examinations. The family history of this litter was explored and other cases in domestic animals were reviewed. This is the first report of the complete Pentalogy of Cantrell with ectopia cordis in the dog and the only report on papillons. Similar to human cases, possible familial inheritance and suspected male gender bias were observed. Further research on this novel animal model, its pathogenesis and its hereditary basis, may be helpful in better understanding this rare developmental disorder.