Infantile Colonic Crohn's Disease: A Report of Four Cases in One Family

Crohn's disease, primarily a disease of adolescents and young adults, is uncommonly encountered in childhood and is extremely rare in infants less than 1 year of age (1). It may involve any segment of the gastrointestinal tract. The small bowel is involved in approximately 90% of the cases, and in 70% it is in the terminal ileum. Isolated involvement of the large intestine occurs in 5% to 10% of affected patients (2,3). Familial occurrence is well known (4–6), and several genetic factors have been implicated (7,8). In Crohn's colitis unresponsive to medical treatment, subtotal colectomy with an ileostomy appears to be the procedure of choice (9,10), improving the child's clinical condition and growth. Infantile Crohn's disease is very rare and has been described usually as a severe illness with poor prognosis. Data in the literature regarding the best therapeutic approach in these infants are very limited (1–3). CASE REPORTS Between 1990 and 1998, three siblings and their first-degree cousin of Bedouin origin, were admitted to the pediatric department with bloody diarrhea, failure to thrive, anemia, and severe perianal disease. Their respective ages on admission were 3 weeks, 2 weeks, 3 months, and 2 months. On physical examination, all infants were pale, ill looking, and malnourished (i.e., below the 3rd percentile for weight). The most prominent signs were severe perianal disease consisting of ulcerations, mucosal and skin tags, fistulae, and fissures. Significant laboratory data included a hemoglobin level between 7.5 and 9 g/dl, white blood cell count between 19,000 and 27,000/mm3, and erythrocyte sedimentation rate (ESR) between 85 and 95 mm/hr. Stool specimens for culture and parasite examination, including Yersinia and amoeba, were negative, and a Mantoux test result was negative. In all infants, blood test results for total lymphocytes, immunoglobulins, and nitroblue tetrazolium were within normal limits. Scans obtained after barium enemas revealed patchy changes with cobblestone appearance and ulcer formation, characteristic of Crohn's disease involving the entire colon, in three infants and in only the rectosigmoid region in one infant. Colonoscopy showed severe patchy inflammation with small superficial aphthous ulcerations and cobblestone appearance. The two older brothers were operated on at the age of 9 months and 8 months, respectively, after a poor response to prolonged conservative treatment including steroids, 5-acetylsalicylic acid, metronidazole, and total parenteral nutrition. The younger sister and the cousin had a similar course. Based on our previous experience and the poor response of the two older brothers to conservative treatment, the sister and cousin were operated on earlier, at the age of 5 months and 4 months, respectively. The three siblings underwent subtotal colectomy with ileostomy and preservation of the rectal stump. The cousin underwent rectosigmoidectomy with colostomy. The macroscopic appearance of the resected bowel in all four cases demonstrated patchy changes consisting of inflammation, ulcerations, and fibrosis, with a typical cobblestone appearance and transmural involvement (Fig. 1). The histologic lesion consisted of epithelial necrosis and multiple ulcerations that had variable depth, reaching the submucosal layer and, in some parts, destruction of the muscularis propria with transmural involvement. The inflammatory response was characterized by neutrophils and, more deeply, the lesions were typically chronic with plasma cells, histiocytes, and giant cells (Fig. 2). In the two older brothers, a few granulomas were detected in the specimen. In the third sibling and the cousin, no granulomas were seen. There was no histologic evidence of any tuberculosis or mycotic infection.FIG. 1.: The pathologic appearance of the resected colon (patient 1) showing stenosis of the lumen, marked edema, and friable mucosa. Ulceration and fissures were noted, surrounded by tissue of a cobblestone appearance (long arrow). Transmural involvement was demonstrated (short arrow).FIG. 2.: Microscopic section of the ascending colon (patient 1) demonstrating chronic inflammatory infiltrate involving all layers with granulomata formation. A fissure is shown (arrow). In the upper right corner a typical granuloma is demonstrated.The second sibling died 7 months after surgery, at the age of 1 year, 4 months, after hypovolemic shock developed associated with acute diarrhea and delayed referral to medical care. There was no clinical evidence of any relapse of Crohn's disease at that time. The other two siblings are presently receiving complete enteral feedings and are thriving well, with good, formed stools from the ileostomy. They are now 8 and 2.5 years old. Repeated rectoscopy and rectal biopsy specimens from the 8-year-old boy still show histologic features of mild chronic inflammation. The cousin is now 1 year old, 8 months after surgery, and is receiving enteral feedings with supplementary parenteral nutrition. She has some feeding problems and loose stools. In all patients, the severe perianal disease healed completely, after surgery. By means of blood DNA, the present patients and their families were genotyped in search of risk loci on chromosomes 3, 7, 12, and 16 (8), and the results were negative. The clinical details, management, and outcome of all infants are summarized in the Table 1.TABLE 1: Familial infantile Crohn's disease: summary of clinical details and outcomeDISCUSSION Crohn's disease has rarely been observed in infancy. The first known infant affected by this disease was reported in 1947 by Koop et al. (11) Miller and Larsen (12) in 1971 reviewed the literature and summarized 12 cases of Crohn's disease occurring in the newborn period, including 6 of their cases. In 8 of the cases reviewed, the disease involved the small bowel, whereas in 3 the disease involved the right colon and the terminal ileum. One patient had only colonic involvement. Seven of 12 patients reviewed by Miller and Larsen died after surgery (12). In our series the inflammatory process involved the anorectum and colon extensively, with sparing of the small bowel and with typical histologic changes (13). The most prominent clinical signs in our patients were severe perianal disease consisting of ulcerations, fissures, and fistulas. Surprisingly, none of those previously reviewed and infants reported by Miller and Larsen had any perianal involvement (12). Mezoff et al. (2) reported a 4-week-old infant with signs and symptoms suggesting Crohn's disease that initially was associated with central nervous system thrombosis and later, at the age of 6 months, with severe perianal inflammation. Furthermore, our patients' clinical course was different from those reported previously. The patients reported by Koop et al. (11) and Miller and Larsen (12) had a prodromal period of diarrhea lasting from 2 days to several weeks, followed by signs of intestinal obstruction. All but two infants required emergency surgery with resection of the involved bowel. Our patients initially showed severe perianal disease, failure to thrive, diarrhea, and anemia and were operated on electively. Two of them were operated on after a prolonged period of unsuccessful conservative treatment. The remaining two patients were operated on earlier after a short period of medical therapy, in view of our early experience. Although steroids and 5-acetylsalicylic acid are reported to be very useful in most Crohn's patients (14), all our patients failed to respond. Immunosuppressive agents, such as azathioprine or cyclosporine as suggested by some (15), were not used in our patients. The previously reported cases of infantile Crohn's disease (12) have not had conservative treatment before surgery because they were mostly treated for undiagnosed diarrhea and had surgery due to mechanical obstruction. When the colon is severely involved with Crohn's disease, the surgical options include: fecal diversion, subtotal colectomy with ileostomy, subtotal colectomy with ileorectal anastomosis, and segmental resection with anastomosis. In our opinion, as well as those of others (9,10), in Crohn's colitis, subtotal colectomy with an ileostomy appears to be the procedure of choice. Ileorectal anastomosis at a later date is possible. Long-term follow-up is necessary to ascertain the validity of this concept. Ritchie (10) compared results in 182 patients who underwent subtotal colectomy and ileostomy with 78 patients who underwent subtotal colectomy with ileorectal anastomosis. The patients who underwent ileorectal anastomosis had a much higher recurrence rate. Occasionally, Crohn's colitis may be limited to one area, as it occurred in our fourth patient in whom only the rectosigmoid was involved. In this case, sigmoidectomy and colostomy were performed. Crohn's disease occurs with variable frequency in different populations. Epidemiologic data show that the Jewish Ashkenazi population has a higher risk of development of inflammatory bowel disease (IBD) than do other ethnic groups (16). An epidemiologic and clinical study of IBD performed in the Bedouin-Arab population of southern Israel between 1981 and 1990 (17), showed clearly the rarity of the disease in this population. In complete contradistinction, all our cases occurred in one extended Bedouin family who had classic findings of colonic Crohn's disease. Familial occurrence of colonic Crohn's disease is well known (4–6). Genetic factors have been implicated in the origin of the disease (7,8). Linkage data derived from genome-wide scans of sibling-pair families with IBD have identified four loci on chromosomes 3, 7, 12, and 16 as potential sites for susceptibility genes (8,18). So far, we have found no supportive evidence for these linkages in our patients. To the best of our knowledge, this is the first report of Crohn's disease in siblings (not twins) in early infancy. In conclusion, based on the present study, infants with colonic Crohn's disease respond poorly to conservative drug therapy and may present a better outcome, after early surgical intervention.