Although there remains some confusion regarding the original description of the clinical entity that is currently termed Crohn’s disease, medical historians have cited clinical portrayals of what is likely the disease in the works of Hippocrates, Giovanni Batista Morgagni (1682–1771), John Abercrombie (1780–1844), Charles Combe (1743–1817), and William Saunders (1743–1817) [1–3]. In 1912, T.K. Dalziel of Glasgow described a disease of the intestine termed “chronic interstitial enteritis” in which chronic inflammatory changes associated with characteristic episodes of abdominal pain simulating intestinal obstruction were present [4].

Preceding its seminal description in the Journal of the American Medical Association (JAMA) [5], and references therein, a heterogeneous group of tumor-like inflammatory masses were documented by Tietze in an encyclopedic article in 1920 [6]. By 1923, Moschowitz and Wilenski from Mount Sinai Hospital in New York had described four cases of benign intestinal granuloma, with one having similarity to the original report of regional ileitis [7].

In the first of two presentations in May 1932, Leon Ginzburg presented, before a meeting of the American Gastro-Enterological Association and later published in an expanded form, a description of 52 cases of a granulomatous disease of the intestines without evidence of recognized diseases, including tuberculosis, syphilis, or actinomycosis [7]. A second presentation by Burrill Crohn entitled “Terminal Ileitis: Its Clinical Manifestations,” was delivered to the Section on Gastro-Enterology and Proctology of the American Medical Association in New Orleans, describing 14 patients, predominantly young adults, with stenosis of the distal ileum and fistulous disease to the large intestine or abdominal wall. Clinical symptoms resembled the known entity ulcerative colitis, while pathology demonstrated subacute or chronic necrotizing inflammation beginning abruptly at the ileocecal valve and extending orally for 8–12 inches (c. 20–30 cm), involving the distal ileum alone. In short order, the presentation, entitled “Regional Ileitis,” was published by Crohn, Ginzburg, and Oppenheimer to a wide audience in JAMA on October 15, 1932 [3, 5].

The original description of regional ileitis was timely and accepted by the medical community with immediate additions to the 14 original cases. J.A. Bargen from the Mayo Clinic offered the term “regional” as opposed to “terminal” ileitis, recalling similar cases and recognizing the “agonal” connotation of the descriptor “terminal” [5]. Julius Friedenwald of Baltimore and Louis Hirschman of Detroit added anecdotal cases similar to the descriptions of Crohn, with the addition of a relationship between a previous diagnosis of ulcerative colitis and granulomatous pathology of the terminal [5].

In Volume 1 of the American Journal of Digestive Diseases and Nutrition (and reprinted in part in this issue), Crohn describes in detail three cases of regional ileitis in his publication “The Broadening Conception of Regional Ileitis,” in an attempt to revise and expand the initial concepts of the diagnosis in the face of growing clinical experience [8].

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First, is a case of a 40-year-old male initially undergoing appendectomy for abdominal pain with weight loss, followed by eight operations for recurrent fistulous disease. Crohn comments on the nature of the newly-described disease of the small bowel, focusing on surgical resection as the most appropriate durable therapy. In doing so, he raises concern for appendicitis in the differential diagnosis of the initial clinical manifestations of the disease. Appendectomy and inflammatory bowel disease have continued to be associated to the present day, with some data supporting prior appendectomy as a risk factor [9]. In the single case report, Crohn also describes surgical sequelae, such as the development of recurrent disease and the spontaneous healing of internal fistula following resection, foreshadowing current concepts of the management of post-operative Crohn’s disease [10].

In the second case, Crohn describes the presentation of a 24-year-old attorney with mild diarrhea and weight loss. Following exclusion of ulcerative colitis with sigmoidoscopy, and without the commonly described tender right lower quadrant mass, diagnosis was confirmed by radiographic examination in which rounded and oval ulcerating lesions of the distal ileum were reported. Understanding the role of surgical resection in the management of disease, an exploratory operation was performed based on the radiographic findings, after which the patient expired. On the basis of pathologic examination of the resected intestine and colon, ulcerations and longitudinal ridges with areas of spared mucosa extending from jejunum to distal ileum were described for the first time.

In 1934, the definition of regional ileitis expanded to include not only ileojejunitis but also colitis, although Crohn himself refuted the notion that the colitis and ileitis were of similar etiology. The definition further extended to the duodenum by 1937, and to the stomach by 1949 [11]. Outside of individual cases, the typical radiographic appearance of regional ileitis was described by Kantor in 1934, who first coined the term “string-sign” [11].

The final case describes a 32-year-old female, a sister of a patient in the originally described cohort. While symptoms of generalized and related right upper quadrant pain suggested disease of the gallbladder, development of intestinal obstruction led to resection of the distal ileum, cecum, and ascending colon, with regional ileitis reportedly affecting the distal 8 inches (c. 20 cm) of ileum. In describing this, the first familial involvement of regional ileitis, Crohn suggests a congenital predisposition or transmissible causative agent, although further data supporting a hereditary influence would not be described until 1960 [12].

From the original descriptions of chronic inflammatory changes of the small intestine, to benign granulomas of the gastrointestinal tract, and ultimately the account of regional ileitis, significant advancement has been made in the documentation of the of the clinical manifestations of Crohn’s disease, as highlighted in the early pages of the American Journal of Digestive Diseases and Nutrition. Initial attempts at characterization of the disease entity constricted its phenotypic description. Nonetheless, the heterogeneous clinical manifestations of the disease were soon recognized, necessitating amendments to the original disease description to include post-operative recurrence and familial inheritance, all of which are active topics of research interest today. Although we still think of treatments in non-specific ways among patients with intestinal inflammation, we are moving away from such “lumping” of all the inflammatory appearances of the intestine into “Crohn’s disease” towards more detailed description of phenotypes and the increasing recognition of genetic, serologic, and even microbiome-related distinctions between disease types. Underlying this progress are careful observations and detailed descriptions of individual patients suffering from enigmatic conditions, which is well illustrated with Crohn’s description, republished in this issue [8].