Congenital Intestinal Aganglionosis in White Foals

Transcription

1 Vet. Pathol. 20: (1983) Congenital Intestinal Aganglionosis in White Foals S.L. VONDERFECHT, A. TROMMERSHAUSEN BOWLING, AND M. COHEN Veterinary Medical Teaching Hospital, University of California, Davis, Calif., and Department of Reproduction, School of Veterinary Medicine, University of California, Davis, Calif. Abstract. A congenital and probably hereditary neurological defect has been identified in the intestinal tract ofsix foals produced from the breeding of overo (a type of spotting pattern) horses. The foals had white hair and pink skin with the exception of occasional pigmented foci about the muzzle, ventral abdomen, and hindquarters. The foals appeared normal at birth, but within a few hours developed symptoms of colic. At necropsy, the only significant finding was a narrow, pale segment of large intestine. This abnormality either was confined to the small colon and rectum or involved the entire colon and rectum. Microscopically, myenteric and submucosal neuronal plexuses were absent throughout the large intestine and extensive portions of the small intestine. The only other significant finding was the lack of melanin in the skin. Two recognized spotting patterns, tobiano (fig. 1) and overo (fig. 2) are eligible for registration in stud books of the American Paint Horse Association and the Pinto Horse Association of America. These patterns also occur in several other breeds of horses (16]. The mating of two overo horses occasionally results in the production of a white foal which appears normal at birth; however, the foal fails to pass meconium, quickly develops colic, and dies. Stenosis of the colon [7], rectal atresia (15], and a paucity of ganglia in the transverse colon [15] have been reported in these foals. A recent report describes aganglionosis of colon and terminal ileum in white foals from overo parents [6]. This paper describes the clinical and pathologic findings in six white foals. Case Histories Clinical histories ofthe foals in this study are summarized in table I. All foals were produced by overo X overo matings with the exception of foal I. Initial records indicated this foal had an overo dam and was sired by a tobiano stallion which had been sired by an overo stallion. Unfortunately, the owner could not be contacted to confirm this. Foals 2 and 6 had the same dam; however, each was sired by a different stallion. The foals had white hair and pink skin with the exception ofoccasional black tail 65

2 66 Vonderfecht et al. 3 Fig. 1: Tobiano. An autosomal dominant pattern characterized by white patches, underlain by pink skin, extending from the neck crest, withers, or top of the croup in a dorsal to ventral distribution. White areas may merge to form an extensive white pattern of smooth outline. The legs are white but the head usually is dark. Fig. 2: Overo. This pattern is characterized by white hair patches, underlain by pink skin, on the ventral or lateral surface of the midsection extending dorsally up to, but not including, the midline of the back. White also may occur on the lateral surface of the neck and flank. Large white areas characteristically have a jagged outline. At least one, and usually all four legs are colored, but conventional white leg markings may be present. The pattern of inheritance is not known. Fig. 3: Cecum and colon from foal 6 with distended cecum (c) and small, pale large colon (lc) and small colon (sc). Bar = 6 em.

3 Congenital Intestinal Aganglionosis 67 Table I. Clinical histories of white foals Foal number Sex Age at onset of Parentage signs(hours) Sire Dam I F 3 Tobiano (?) Overo 2 M 10 Overo Overo 3 M 8-12 Overo Overo 4 M 3 Overo Overo 5 F 8-12 Overo Overo 6 M 12 Overo Overo hairs (foals 2 and 5), black spots about the muzzle (foals 4 and 5) or pale-brown to yellow foci in the dorsal gluteal and ventral abdominal regions (foal 4). The irides of all eyes were pale blue. The foals were normal at birth and able to stand and suckle; however, all developed signs ofcolic within 12 hours. None was observed to have passed meconium. Digital rectal examination failed to detect feces. Foal 6 did not respond to sudden loud noises or to cries ofthe mare when the foal and mare were separated. Otoscopic examination revealed no abnormalities. A variety of clinical parameters were examined. Complete blood counts showed an elevated number of white cells and an altered neutrophil to lymphocyte ratio. These variations were attributed to the stresses ofcolic, transportation, and handling. No abnormalities in other hematologic parameters were noted. Serum chemistry values were within normal limits for horses of this age. Due to intractable pain of colic and poor prognoses, all foals were killed before 30 hours old. Materials and Methods Tissues from all major organs, sympathetic trunk, celiaco-mesenteric ganglia, dorsal root ganglia, and vagus nerve were fixed in 10% buffered formalin, dehydrated, embedded in paraffin, cut at 6 p.m, and stained with hematoxylin and eosin. Results Significant findings at necropsy were confined to the gastrointestinal tract. The jejunum and ileum were distended moderately by watery, green-yellow to thick, mucinous, green material. The serosal and mucosal surfaces ofjejunum and ileum were patchily or diffusely reddened. The small colon and rectum of each foal were pale, of small diameter, and tortuous. The lumen always was patent; however, the mucosa was folded extensively. In addition to the small colon changes, foal 6 had a narrow, pale transverse colon, dorsal colon, and left ventral colon (fig. 3). In all foals, the cecum and portions ofthe colon, which were not narrow and pale, were distended by meconium. A consistent abnormality in all foals was the absence ofsubmucosal and myenteric ganglia throughout the large intestine and various portions of the small intestine.

4 68 Vonderfecht et al. The ileum and the major portion of the jejunum in foals 1 to 5 lacked ganglia. Ganglia were present in the small intestine of the third foal 180 em distal to the pylorus; however, at 240 em, ganglia were absent and none were found in more distal portions of the intestines. Foal 6 had ganglia throughout the proximal ileum. Nerve fibers were seen in the intestinalwall and mesentery in all areas ofthe gastrointestinal tract. Occasional large nerve fibers were observed between muscle layers ofthe small colon. Ganglia were found in the esophagus, stomach, and duodenum of all foals. Melanin-containing cells were found in the skin only in the areas which were observed grossly to be pigmented. The posterior layer of the iris, ciliary body, and retinal pigment epithelium ofthe eyes contained melanin granules. Adrenal medulla, sympathetic trunk, celiaco-mesenteric ganglia, dorsal root ganglia, and vagus nerve were within normal limits. No significant lesions were present in other tissues. Sections ofsmall intestine, cecum, and colon were examined from three, one-dayold foals which died from causes unrelated to the gastrointestinal tract. In every section, submucosal and myenteric ganglia were numerous and easily observed. Discussion A paucity ofganglia in the transverse colon was reported in a white foal sired by an overo Paint [15J. The dam of this foal was a buckskin mare sired by an overo Paint. This is similar to foal 1 of the present study, i.e., one parent was not an overo but had been sired by an overo. It is not clear from the previous report whether intrinsic ganglia were sought in other portions of the intestine of the affected foal. Abnormalities in the origin and distribution of various branches of the cranial mesenteric artery were described. These features were examined specifically in foals 5 and 6 ofthe present study, but no abnormalities were observed. Rectal atresia [15J and colonic stenosis [7J have been described in white foals from overo breeding. No histological findings were described in these reports. A recent report described aganglionosis in the colon and terminal ileum ofwhite foals [6J. In the present study, aganglionosis of the small intestine of five foals was more extensive, involving both jejunum and ileum. At least three additional syndromes of congenital intestinal aganglionosis have been reported. The most thoroughly studied is congenital aganglionic megacolon or Hirschsprung's disease in man. Hirschsprung's disease is characterized by the absence of ganglia from all layers of the bowel, the presence of large nerve fibers between longitudinal and circular muscle layers, and abnormalities in the number and distribution ofcholinergic and adrenergic nerve fibers in the affected bowel [4, 5, 12, l7j. Aganglionosis is limited to the rectum and sigmoid colon in at least 75% of patients with Hirschsprung's disease; however, a small percentage of patients lack ganglia throughout the large intestine and various portions of the small intestine. This subclass of Hirschsprung's disease, which is similar to the white foal syndrome, is referred to as total colonic aganglionosis or the Zuelzer-Wilson syndrome [2, 10, l2j. Congenital colonic aganglionosis also has been described in piebald lethal mice

5 Congenital Intestinal Aganglionosis 69 [I). The recessive lethal allele (s') of the gene for piebald spotting (s) results in aganglionosis of the distal large intestine when present in the homozygous state. The si / si mice have black eyes and white coats with a few small patches of pigmentation about ears, eyes, and tail. All of these mice die with megacolon due to colonic aganglionosis. Another recessive spotting gene, the lethal spotting (Is) gene, is not allelic with s but resembles its effect on coat pigmentation. A few Is/Is mice have lived to reproduce; however, all eventually die with megacolon as a result of aganglionosis of the distal colon [8, II). The association ofaganglionosis with a deficiency ofpigment cells in hair and skin is interesting in view of the embryologic origins of the intrinsic ganglion cells and melanocytes; both cells are derived from the neural crest. It is possible that a defect in neural crest cell migration, either through deficiency in number, failure to migrate or improper local environment could account for the association between coat color and aganglionosis. Studies with chick embryos have shown that incomplete removal of the cervical neural crest results in deficiencies of enteric ganglia in the posterior intestine (18). Other studies have shown that the enteric ganglia arise from vagal and lumbosacral neural crest (9). Other tissues of neural crest origin including adrenal medulla, sympathetic trunk, celiaco-mesenteric ganglia, ganglia in esophagus and stomach, and dorsal root ganglia were within normal limits in the affected foals. The pathophysiology of aganglionic megacolon is still a matter of active investigation. Present evidence suggests that the intrinsic ganglia integrate excitatory, cholinergic input with inhibitory adrenergic and probably serotonergic stimuli to produce coordinated movement from the intrinsic contractile activity of the intestinal smooth muscle. The absence of enteric ganglia and normal patterns of innervation releases the inherently excitable smooth muscle from nervous control. Thus, coordinated peristaltic movement is lost and a hyperexcitable, contracted intestinal segment results (14). The presence ofmeconium so far distally in the aganglionic intestine ofthese foals is not explained readily. Equally difficult to explain is how occasional patients with a form ofhirschsprung's disease in which a major portion ofthe colon is aganglionic manage to have prolonged periods of normal bowel movements in the initial stages of the disease (3). Some correlation has been found between the age at clinical presentation and the number of cholinergic nerves within the distal aganglionic bowel in the common type of Hirschsprung's disease. Patients who present later in life with lesser degrees of obstruction have aganglionic segments with fewer cholinergic nerves (4). Powerful contractions from the proximal, normal bowel may be able to overcome the resistance of the contracted, aganglionic bowel (3). Finally, small intestinal and colonic aganglionosis in white foals of overo backgrounds should not be confused with the syndrome associated with the lethal dominant white gene. This gene, which is not associated with white spotting, produces embryonic death when present in the homozygous state. The heterozygous whites are viable and have no detectable abnormalities [l3).

6 70 Vonderfecht et al. References BIELSCHOWSKY, M.; SCHOFIELD, G.e.: Studies on megacolon in piebald mice. Aust J Exp Bioi Med Sci 40: , EHRENPREIS, T.: Hirschsprung's Disease, pp Medical Publishers Inc., Chicago, EHRENPREIS, T.: Hirschsprung's Disease. Am J Dig Dis 16: , GARRETI, J.R.; HOWARD, E.R.; NIXON, H.H.: Autonomic nerves in rectum and colon in Hirschsprung's disease. A cholinesterase and catecholamine histochemical study. Arch Dis Child 44: , HOWARD, E.R.: Hirschsprung's disease: A review of the morphology and physiology. Postgrad Med J 48: , HULTGREN, B.D.: Ileocolonic aganglionosis in white progeny of overo spotted horses. J Am Vet Med Assoc 180: , JONES, W.E.: The overo white foal syndrome. J Equine Med Surg 3:54-56, LANE, P.W.: Association of megacolon with two recessive spotting genes in the mouse. J Hered 57:29-31, LEDoUARIN, N.M.; TEILLET, M.: The migration of neural crest cells to the walls of the digestive tract in avian embryo. J Embryol Exp Morphol30:31-48, Louw, J.H.: Total colonic aganglionosis. Can J Surg 21: , 1978 II MAYER, T.e.; MALTBY, E.L.: An experimental investigation of pattern development in lethal spotting and belted mouse embryos. Dev Bioi 9: , MEIER-RuGE, W.: Hirschsprung's disease: Its etiology, pathogenesis and differential diagnosis.currtoppathoi59: ,1974 i 13 PuLOS, W.L.; HUTI, E.B.: Lethal dominant white in horses. J Hered 60:59-63, ROGAWASKI, M.A.; GOODRICH, J.T.; GERSHON, M.D.; TOULOUKIAN, R.J.: Hirschsprung's disease: Absence of serotonergic neurons in the aganglionic colon. J Pediatr Surg 13: , SCHNEIDER, J.E.; LEIPOLD, H.W.: Recessive lethal white in two foals. J Equine Med Surg 2: , TROMMERSHAUSEN-SMITH, A.: Lethal white foals in matings of overo spotted horses. Theriogenology 8: , WEINBERG, A.G.: Hirschsprung's disease-a pathologist's view. In: Perspectives in Pediatric Pathology, ed. Rosenberg and Bolande, pp , vol. 2. Yearbook Medical Publishers Inc., Chicago, YNTEMA, C.L.; HAMMOND, W.S.: The origin ofintrinsic ganglia oftrunk viscera from vagal neural crest in the chick embryo. J Comp Neuroll0l: , 1954 Request reprints from Dr. S.L. Vonderfecht, Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD (USA).