Crohn's Disease and Ulcerative Colitis with Onset in the Same Year in Two Sisters

This is the authors' abstract. We don't add key points for this paper.

The origin and pathogenesis of inflammatory bowel disease (IBD) remain an enigma (1-3). Because the two most typical forms of IBD, Crohn's disease and ulcerative colitis (4,5), have clinical and histologic similarities, they are not always easily distinguishable. The frequently reported association of ulcerative colitis and Crohn's disease in numerous families living in the same town (6,7) within a family (8,9) [monozygotic or dizygotic twins (10-12), in married couples (13-16), or in the same patient (17-20)] suggests that these patients share a genetic background or a causal relation with microbial agents (21,22). We describe two preadolescent sisters, one with Crohn's disease and the other with ulcerative colitis. These children had their first gastrointestinal symptoms within a year of each other, but they had markedly different endoscopic-histologic features. Crohn's disease and ulcerative colitis were diagnosed on the basis of clinical, laboratory, radiologic, and endoscopic findings, including histologic examination of mucosal biopsies. The 9-year follow-up in our two patients illustrates the different location and extent of disease and the different pattern of complications in the two disorders. CASE REPORTS Case 1 This girl was the second-born child of unrelated parents, who had no family history of IBD. At birth she weighed 3,200 g. She was breast fed for 5 months and weaned regularly. She remained healthy until the age of 13 years, July 1983, when she began to have fever, joint pain, and acute bloody diarrhea. Cultures for Salmonella and Shigellae, Campylobacter, Yersinia, and other pathogens had negative results. After a diagnosis of juvenile arthritis, made elsewhere, the patient began oral treatment with penicillin and a short course of corticosteroids, without improvement. Corticosteroid therapy was reinstated when perianal fissures developed. Her gastrointestinal symptoms persisted. One year later, endoscopic, radiologic, and histologic findings led to a diagnosis of ileocolic Crohn's disease. She was in the ≤3rd percentile for weight and height and had elevated inflammatory indices. A colonoscopic examination found a perianal fistula and two small ulcers in the descending colon. A small bowel double-contrast study showed the typical Crohn's disease cobblestoning in a 20-cm segment of the terminal ileum proximal to the ileocecal valve and prestenotic dilatation of the ileum, without other intestinal strictures. Histologic examination of a mucosal specimen from the diseased colon showed no granulomas but numerous inflammatory cells and crypt abscesses that were compatible with Crohn's disease. On discharge, the girl began dietary and pharmacologic treatment, which led to weight recovery and the disappearance of her gastrointestinal symptoms. During the follow-up, she had two severe relapses, treated with corticosteroid therapy, semielemental diet, and metronidazole. Despite the addition of azathioprine to therapy in September 1988, she continued to have mild exacerbations, with bloody mucous diarrhea, abdominal pain, and evening fever. Perineal fistula appeared in October 1989, followed 1 year later by a perivulvar fistula. Subsequent endoscopic follow-up examinations showed only ileocolic involvement. At the last observation, the patient still experienced frequent clinical and biochemical exacerbations, without endoscopic evidence of disease spread, but the perivulvar and perineal fistulas persisted. Case 2 This girl, the third-born child in the family, was born of a normal pregnancy. At birth she weighed 3,800 g. She was breast fed for 6 months and weaned normally. She had a normal growth rate. In May 1984, at the age of 11 years, only 10 months after the onset of her older sister's gastrointestinal symptoms, she began to have bloody diarrhea with five to six bowel movements per day, abdominal pain, and tenesmus. She had weight and height in the 50th percentile and had normal inflammatory markers. At colonoscopy, the epithelial mucosa in the rectum appeared hyperemic and friable. Profuse bleeding and crypt abscesses were uniformly distributed from the rectum, sigmoid, descending and transverse colon, to the right hepatic flexure. The ascending colon and cecum appeared normal. Multiple endoscopic biopsies confirmed the histologic features of ulcerative colitis. A small-bowel barium enema found normal mucosal appearances. Treatment was begun with oral salazopyrin. Within 4 months, the symptoms completely regressed. During follow-up, the girl had two recurrences, with the same symptoms. Recurrences ceased, and she stopped taking salzopyrin 9 years after the diagnosis. DISCUSSION As long as 60 years ago, Crohn (4) noted the correlation between the clinical picture of a 14-year-old boy with the disorder now known as Crohn's disease and that of his 32-year-old sister, in whom this condition developed soon afterward. Although Crohn regarded the association in this case as a chance event, he did propose a congenital predis-position or a causal transmission agent. The enteric pathogens implicated in IBD may colonize and multiply or invade the underlying tissue. Microbial colonization is favored in patients with IBD owing to impairment of the immunologic and nonimmunologic mechanisms that would normally prevent the establishment of an intestinal infection. Although cultures detected neither common bacterial pathogens nor Mycobacterium tuberculosis in our two patients, this does not exclude infection as a concurrent causative agent. Since the first mention of the familial occurrence of ulcerative colitis early in this century (5), numerous reports have described IBD occurring within families. Our two cases are of interest because Crohn's disease and ulcerative colitis occurred in two sisters living in the same family, with onset of IBD in the same year. These cases again underline the similarities between Crohn's disease and ulcerative colitis. As our patients' follow-up shows, despite having elements in common, each of these inflammatory processes has its own distinct course, depending on the location and extent of disease. The genetic factors thought to be among the causes of IBD have never been precisely defined. Shorter et al. (23) suggested that the variant forms of IBD may reflect individual responses to various antigenic stimuli or individual variations in the response to similar antigenic stimuli. The detailed studies from the single series of 353 patients collected by Korelitz in New York City (6) are of great interest. In this study, parent-offspring occurrences were slightly more frequent than sibling-sibling combinations. Because the probands were his own patients, his estimate of the distribution of intrafamilial relationships is based on homogeneous diagnostic criteria, providing reliable data for comparison. Korelitz's findings agree with those of a Cleveland Clinic study (7) of 838 patients with IBD with onset before the age of 21 years, in whom parent-offspring occurrence was ≈9.8%, and sibling-sibling occurrence was 6% in ulcerative colitis and 7.5% in Crohn's disease. Like those of Korelitz, the Cleveland findings argue in favor of the importance of polygenic inheritance in the pathogenesis of IBD. An Italian multicentric study (24) conducted in 14 pediatric gastroenterology centers and comprising 107 patients under 16 years old, 63 with ulcerative colitis and 44 with Crohn's disease, found a familial occurrence of 5% in patients with ulcerative colitis and 9% in patients with Crohn's disease, in contrast to the 12% reported in two earlier studies (25,26). Despite evidence arguing in favor of genetic susceptibility to IBD, the exact gene products remain debatable (1). One suggestion is that the genotypes of patients with ulcerative colitis and Crohn's disease contain three or four common genes, thus making certain individuals susceptible to chronic IBD (27-29). Epidemiologic studies show a higher incidence of IBD among Jews, a lower incidence among blacks (30), and a slight predominance of female over male patients (1.6 to 1). The reported association of ulcerative colitis with Crohn's disease in married couples (13-16) or in whole families could depend partly on environmental agents—such as additives—acting on persons with various genetically determined susceptibilities. Much interest has focused on a possible relation between additives and Crohn's disease (31). This might explain why Crohn's disease has increased over the last 25 years, whereas ulcerative colitis has not. The various distributions of HLA-A and HLA-B antigens sometimes demonstrated in patients with IBD have not always been confirmed (1,2,32-34). In contrast to the strong association of HLA-B8 with celiac disease, attempts to link Crohn's disease and ulcerative colitis to a specific HLA-A or B antigen have failed (1,2). Confirming a reported association (1), HLA typing in our two cases found HLA-A2 antigens in the sister with Crohn's disease (Table 1). This patient and her healthy older sister both had identical HLA-A, -B, -C, -DR, and -DQ antigens. Another notable finding was that the two patients, their mother, and their healthy older sister had HLA-B27 antigens. Although some reports have mentioned the association of HLA-B27 and ankylosing spondylitis, neither of our patients at present have symptoms of this disorder. In contrast to other reports (35-38), in our two patients with IBD, we found no specific association between HLA-DR2 and DR3 antigens. In preadolescent children, the onset and course of IBD might also in part reflect psychologic influences. Research is still needed to assess their importance as determinant etiologic agents (39-41). Our two case reports, patients in whom coincident Crohn's disease and ulcerative colitis occurred not only within the same family but also within an interval of a few months, might further validate the pathogenetic hypothesis that initially, genetic factors interact causing in primis IBD and subsequently, diverse and as yet unspecified environmental factors lead to the onset of one or another form of IBD. Acknowledgment: We are indebted to the Tissue Typing Laboratory of the Immunohematology Department, Italian Red Cross (CRI), Rome, Italy, for the study of the histocompatibility antigens.