To understand the historical evolution of the disease, a review of its initial definition is critical. In 1932, Crohn, Ginzburg, and Oppenheimer identified 14 cases of inflammatory disease of the terminal ileum which they believed to be a newly defined entity called “regional ileitis.”  The key diagnostic findings outlined by the authors included - 1) a mass in the right iliac region, 2) evidence of fistula formation, 3) emaciation and anemia,  4)  the scar of previous appendectomy, and 5) evidence of intestinal obstruction”. The mass in the right iliac region was inflamed, thickened ileum.  Fistula was near universal finding and was noted to form readily to adjacent bowel, often sigmoid, or ascending colon. In at least half of the cases, the appendix had been removed at a prior operation indicating likely previous diagnostic confusion, but not definitively ruled out as a potential causative factor in pathogenesis.

Lastly, the ultimate presentation was that of intestinal obstruction noted to be occasionally “visible through the emaciated abdominal wall.”  In his comments,  Crohn noted the great lengths to which Dr. Paul Klemperer, the pathologist, had gone to painstakingly exhaust alternative diagnoses such as tuberculosis, symphilis, actinomycosis, Hodgkin’s disease, and lymphosarcoma.

An important contribution to the definition of the disease was published in JAMA by Kantor in 1934,  which created a more formal roentgenographic description of disease .  Dr.  Kantor endowed the term “string sign”  to the stricture often seen roentgenographically in the terminal ileum of advanced cases.  Additional “chief changes”  as described by Kantor included filling defect just proximal to the cecum,  abnormality in contour of the last filled loop of ileum, and dilation of ileum proximal to the lesion. 

Throughout the remainder of the 1930s into the early 1940s, numerous case reports and small case series began to emerge,  confirming and expanding upon the findings of Crohn et al. The early experience was clouded by uncertainty as to the correct operation and high mortality associated with the stage of presentation. In 1935, Mixter published 11 operative cases from the Beth Israel Hospital in Boston. Six patients were treated with a single stage ileocecal resection,  while five required staged resection all of which were complicated by fistula or abscesses postoperatively. In 1937, Pemberton et al. published the Mayo Clinic series of 39 cases (36 operative) with 47 major surgical procedures and an associated mortality rate of 4.2 % .
Amongst these early reports,  operations commonly performed included bypass procedures (ileo-ileostomy,  ileocolostomy,  ileosigmoidostomy), resection and ileo-colonic anastomosis, or drainage alone without resection. These early series included patients with proximal small bowel lesions in addition to the terminal ileum, beginning the expansion of the clinical definition. With additional cases being brought to the literature, the clinical spectrum and epidemiology became elucidated. These early case reports were encouraging for the success of surgical management as gross recurrence was rarely encountered in the early experience and surgery was believed to be curative. 

Despite the initial description that the pathology was limited to the distal ileum, early series of Crohn’s disease soon revealed more widespread gastrointestinal tract disease. Dr. Ralph Colp at The Mount Sinai Hospital is credited with the first description implicating Crohn’s colitis as an associated entity in 1934 .  Two years later Crohn reported being “loath to accept the fact that ileitis of any type could involve the colon in an analogous inflammatory process” however did ultimately accept this association later in his career .  In a 1954 publication,  Crohn described the finding of both ileitis and colitis as a “bewildering combination of two disease processes” .  Associated colonic inflammation was believed to be either an innocent bystander from disease “spread,” or a separate synchronous illness such as ulcerative colitis. It was not until the late 1950s and early 1960s that there was acceptance of Crohn’s (granulomatous)  colitis as a distinct entity .  In 1952, Wells was the first to definitively use the description “Crohn’s disease of the colon” .

Differentiation between alternative forms of colitis was challenging. In 1960, Lockhart-Mummery described 25 cases of regional enteritis of the large intestine with criteria to differentiate it from ulcerative colitis .  By the 1970s,  Crohn’s colitis was a well-established entity .
Descriptions of involvement of other portions of the intestinal tract followed in parallel, including that of perianal disease, and gastroduodenal disease. Bissell, in 1934, reported an association between regional ileitis and perianal disease. Penner and Crohn in 1938 expanded upon this significantly with a series of patients with regional ileitis who also had perianal and rectovaginal fistula. While no etiology was suggested,  they astutely recognized that in a series of 56 patients, 14 % were diagnosed with fistula in ano. This was a rate which far exceeded any known association with routine diarrheal illnesses. In 1950, Comfort et al. reported the first accounts of gastroduodenal granulomatous inflammation and its relationship with regional ileitis .  In the early 1950s,  extraintestinal manifestations of the disease were noted, specifically the association with arthritis which was later expanded upon in larger retrospective reviews in the 1970s.