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Young Children with Behçet Disease Have More Intestinal Involvement

Hung, Chien-Hui*; Lee, Jyh-Hong; Chen, Szu-Ta; Yang, Yao-Hsu; Lin, Yu-Tsan; Wang, Li-Chieh; Yu, Hsin-Hui; Chiang, Bor-Luen

Journal of Pediatric Gastroenterology and Nutrition: August 2013 - Volume 57 - Issue 2 - p 225–229
doi: 10.1097/MPG.0b013e3182936ec4
Original Articles: Gastroenterology

Objective: Gastrointestinal (GI) involvement in childhood Behçet disease (BD) is not well understood. We aimed to clarify the intestinal presentation in children with BD.

Methods: Medical records of 85 children with recurrent oral ulcers between 1990 and 2010 at the National Taiwan University Hospital were reviewed retrospectively. Twenty of them who fulfilled the Mason and Barnes criteria for the diagnosis of childhood BD were enrolled. The clinical and laboratory characteristics were analyzed.

Results: Among 20 patients, the median age at diagnosis was 13.2 years. The common presentations included oral ulcers (100%), genital ulcers (70%), skin lesions (65%), and GI symptoms (50%). Five of 10 patients with GI symptoms received endoscopic examinations and all had ulcers. Divided by the age of 10, patients younger than 10 years tended to have higher rates of GI symptoms initially and intestinal ulcers (P = 0.002 and 0.015, respectively). Platelet count was significantly lower in young patients (P = 0.0151). Patients without GI symptoms had higher rates of skin involvement than patients with GI symptoms (P = 0.019).

Conclusions: Young children with BD tended to have more GI presentations. For children with BD younger than 10 years having GI symptoms, endoscopic examinations may be considered.

*Department of Pediatrics, Taichung Hospital Department of Health, Taiching

Department of Pediatrics, National Taiwan University Hospital, Taipei

Department of Pediatrics, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan.

Address correspondence and reprint requests to Bor-Luen Chiang, MD, PhD, Department of Pediatrics, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei 100, Taiwan (e-mail:

Received 27 November, 2012

Accepted 20 March, 2013

The authors report no conflicts of interest.

Behçet disease (BD) was first described by a Greek ophthalmologist, Benediktos Adamantiades. He presented a case of relapsing iritis with hypopyon in 1930. Then, a Turkish dermatologist, Dr Hulusi Behçet, integrated with the triad of aphthous stomatitis, genital ulceration, and uveitis in 1937 (1). BD is an inflammatory disorder involving multisystems and tends to wax and wane, although the causes are still unknown. Microscopically, BD is a vascular disease affecting vessels of variable types, sizes, and localizations. Several diagnostic criteria based on variable manifestations have been proposed. The universal diagnostic criteria, defined by the International Study Group for Behçet's Disease, comprise recurrent oral ulceration and at least 2 of 4 symptoms, including recurrent genital ulcerations, eye lesions, skin lesions, and a positive pathergy test (2). The Mason and Barnes diagnostic criteria include 3 major or 2 major plus 2 minor criteria. The major criteria include buccal ulceration, gastrointestinal (GI) lesions, thrombophlebitis, eye lesions, and skin lesions. The minor criteria include cardiovascular lesions, arthritis, central nervous system symptoms, and a family history of BD. Only 1 of the above criteria, along with oral ulceration, is defined as incomplete or partial BD.(3).

BD usually occurs between the second and fourth decades of life. Patients who have initial symptoms at age 16 years or before are considered to have childhood-onset BD. Several previous studies have reported that the expression and severity of manifestations in children are different from adults. The childhood study by Treudler et al (4) showed that delayed development of the complete symptom complex and lower prevalence of severe complications were detected in juvenile-onset disease. Karincaoglu et al (5) reported that there were no differences in the frequency of disease manifestations between childhood-onset and adult-onset BD, except for higher neurological and GI involvement in childhood-onset BD. Krause et al (6) also reported significantly more GI symptoms, arthralgia, and central nervous system involvement in children than in adults.

GI symptoms, including nonspecific abdominal pain, diarrhea, vomiting, and bleeding, are common in childhood and are usually considered to be acute gastroenteritis, constipation, or food allergy. In addition, Crohn disease and ulcerative colitis are the most common intestinal ulcerative diseases. Thus, BD can be easily neglected without a detailed history and physical examination. The frequency of GI symptoms in BD is relatively lower than other typical symptoms, including oral aphthous ulceration, genital ulceration, and ocular symptoms. Krause et al (6) reported significantly more nonspecific GI symptoms in children than in adults. Fujikawa and Suemitsu (7) also suggested that there was a higher frequency of intestinal signs and symptoms in children with BD compared with adults. A rigorous diagnosis of intestinal BD can be made if the typical clinical findings of BD plus typical oval-shaped large ulcers in the terminal ileum or lesions in the small or large intestine are found. In addition, tuberculosis, Crohn disease, nonspecific colitis, and drug-associated colitis should be excluded before final diagnosis (8). The aim of this study was to clarify the clinical characteristics of children with BD, especially in the GI manifestations.

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This study was a retrospective review of 85 patients younger than 16 years with recurrent oral ulcers between 1990 and 2010 from National Taiwan University Hospital, which is a tertiary referral center. Data from medical files and patient interviews were collected. The records included clinical history, physical examination, family history, endoscopy, radiology, surgery, and pathology findings. Because many patients did not have a record of a pathergy test, we used the Mason and Barnes criteria to define the diagnosis. Twenty patients met the criteria for the diagnosis of BD, and there were 10 boys and 10 girls. These patients were originally diagnosed as having BD by clinicians. Sixteen patients who had recurrent oral ulcerations plus only 1 symptom met the criteria for the diagnosis of incomplete BD. The other 49 patients did not meet the criteria of BD and were excluded. All of the patients were Taiwanese.

We further divided the cases of complete-type BD into a young age group (10 years or younger) and an older child age group (older than 10 years), and analyzed the frequency of each symptom between the 2 groups. We also analyzed the difference between patients with and without those symptoms.

Patients with GI discomfort with or without endoscopic examinations were categorized as having intestinal-type BD. Six patients had severe GI symptoms or malnutrition and received gastroscopy, ileoscopy, or colonoscopy to exclude the possibility of other inflammatory bowel diseases or infection-related ulceration; the other 4 patients only had mild GI symptom without endoscopy examination.

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Statistical Analysis

Statistical analysis was done using STATA statistical software (version 10; StataCorp, College Station, TX). Associations of categorical variables were tested by the Pearson χ 2 test. Differences of medians were tested by the rank sum test. For non-Gaussian data, differences were compared using the nonparametric Mann-Whitney U test. All tests were 2-sided, and significance was accepted at a P value ≤0.05.

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We analyzed 20 patients with the complete type of BD. The median (range) age at initial onset was 13.0 (0.0–16.0) years, and the median age at diagnosis was 13.2 (0.0–18.0) years. Recurrent oral ulceration was the most common manifestation (100%), followed by genital ulcers (70%), skin lesions (65%), GI symptoms (50%), and arthralgia (30%) (Table 1). In the initial presentation, recurrent oral ulceration was the most frequent (70%), followed by GI involvement (20%) and ocular involvement (10%).



There were no differences in the frequency of clinical presentations between age groups (Table 2); however, oral ulceration as an initial symptom was more common in the older children (P = 0.052), and GI symptoms were more common in the younger children (P = 0.002) (Table 2). The younger children had a higher platelet count (P = 0.0151) and higher complement component 4 (C4) level (P = 0.0547) compared with the older children. Only 1 patient had a family history of BD.



Oral aphthous ulceration was the most common symptom and also the most common initial presentation. Genital ulcers were mostly located on the scrotum, penis, and perineum in boys, and vulvae, labia majora, and minora in girls. Perianal ulceration was also noted in some patients. The most common cutaneous lesions in our patients included folliculitis, erythema nodosum, and papulopustular lesions. One patient even had severe ulcerative carbuncles. The lesions were usually located over the lower extremities, face, and back. Six patients complained of having monoarthralgia or polyarthralgia, mainly involving the knees, elbows, wrists, and small joints of the fingers in our population. Four patients had ocular complications. Two of them had uveitis, 1 had photophobia with postinflammatory change in examination, and the last had iritis for a long time, but an examination showed no uveitis or retinal lesions. Fourteen patients received ophthalmoscopic examinations, and only 3 of them (21.4%) had positive findings. Only 1 patient had central nervous system symptoms, which presented as myoclonic jerk. One patient had chronic nephritis without a biopsy examination. No major vessel involvement was noted.

Ten patients had GI symptoms and were defined as having intestinal-type childhood-onset BD, and 10 patients did not have GI symptoms. The male-to-female ratio of those with GI symptoms was 6:4, and the age ranged from 16 days to 16 years. Four patients had GI symptom at initial onset, and were diagnosed as having childhood-onset BD after the presentation of other symptoms. The clinical symptoms included nonspecific abdominal pain, diarrhea, vomiting, and bloody stools. Six patients received gastroscopy, ileoscopy, or colonoscopy examinations because of severe GI discomfort or poor nutrition. Three patients had typical endoscopic findings, including ulcers over the colon, terminal ileum, and duodenum. One had ulceration over esophagus, tongue, and pharynges. One had an antral gastric ulcer. The last one had negative findings. The pathology reports did not show any characteristics, and most showed chronic inflammation with lymphoplasma cells with or without neutrophil and eosinophil infiltration in the GI tract. Patients with GI symptoms had fewer skin lesions (P = 0.019) (Table 3). The younger children had more GI symptoms (P = 0.160), and 80% of those symptoms presented at initial presentation (P = 0.02) (Table 2). In 5 younger children with intestinal-type childhood-onset BD, 4 had severe GI discomfort, vomiting, chronic diarrhea, and malnutrition, and so on, as the initial symptom and all received endoscopic examinations. Three of them had ulceration over the ileum, colon, and duodenum, and the last one had a gastric ulcer. None of the 5 older children presented with abdominal pain as the initial symptom. Most of them had unspecific abdominal pain. One patient with mild watery diarrhea received an endoscopic examination without positive finding. Two older patients experienced GI bleeding. One patient only had mild, blood-tinged stool passage without endoscopy examination and the other had tarry stool; endoscopy revealed esophageal erosion and pharyngeal ulcers. Endoscopy examination showed younger patients had more typical appearance of BD than older ones (Table 4) (9).





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BD is a vasculitis with chronic multisystemic inflammation. The etiology remains unknown. The characteristics of BD include recurrent oral ulcers, genital ulcers, uveitis, and skin lesions. Other clinical manifestations include arthritis, GI symptoms, central nervous system disorders, vasculitis, and cardiovascular lesions. The usual course in any organ system includes exacerbations and remissions; however, the overall prognosis may decline because of episodes of inflammation. The disease may be confused with other common diseases such as herpetic gingivostomatitis and herpangina, making diagnosis of childhood-onset BD difficult. BD clusters along the ancient Silk Road, which extends from eastern Asia to the Mediterranean. From a literature review (5,6,8,10–15), the most common symptom in each study was recurrent oral ulcers. The frequency of genital ulcers ranged from 32% to 91% and that of skin lesions from 55% to 92%. Ocular lesions, joint symptoms, and central nervous system disorders were less common in eastern Asians than western Asians or Europeans. The frequency of GI symptom ranged from 0% to 50%, with no ethnic differences. Our data included patients with mild GI discomfort to severe upset, and we performed endoscopy in those who had severe vomiting, diarrhea, bleeding, or malnutrition.

GI manifestations are not rare in BD. The frequency of GI manifestations of BD has been reported to be 3% to 25% in adults (16) and 0% to 50% in children (6,7,10–15,17). Jung et al (18) reported that diagnosis before the age of 40 years was associated with a more severe intestinal course and poorer prognosis. Fujikawa et al (7) also found that children with BD had a higher frequency of intestinal signs and symptoms than adults. Krause et al (6) also reported higher GI involvement in childhood-onset BD. The most common symptoms include abdominal pain, diarrhea, vomiting, and bleeding; however, the symptoms are not specific for the diagnosis of intestinal BD. Thus, Kobayashi et al (8) used a modified Delphi approach to diagnosis in this category, in which typical clinical findings of BD plus typical oval-shaped large ulcers in the terminal ileum or ulceration or inflammation of the small or large intestine are considered. In addition, tuberculosis, Crohn disease, nonspecific colitis, and drug-associated colitis should be excluded. They also suggested that colonoscopy with a biopsy, double-contrast barium enema, and laboratory tests are necessary to make a diagnosis. Esophagogastroduodenoscopy and enteroclysis were also required to determine the extent of the lesions. The most common sites of lesions are the terminal ileum, followed by the cecum, ascending colon, transverse colon, and anus (9); however, esophageal and stomach involvement are uncommon. In our study, 6 of 10 patients with intestinal BD received gastroscopy, ileoscopy, or colonoscopy examinations because of severe discomfort or poor nutrition. Three of 4 younger children had ulceration over the ileum, colon, and duodenum, and the other had a gastric ulcer. One older child had ulceration over the esophagus, tongue, and pharynx, and another older child had negative findings. Younger children seemed to have more positive rates of ulceration and typical presenting areas. Furthermore, we also noticed that younger patients had more GI discomfort as the initial presentation (P = 0.002) and that older patients presented with recurrent oral ulceration (P = 0.052). There is no evidence-based treatment that can be recommended for the management of intestinal BD. Agents such as sulfasalazine, corticosteroids, azathioprine, tumor necrosis factor-α antagonists, or thalidomide should be tried first (19). Surgery should be considered in those patients with perforation or intractable bleeding or poor response to medical treatment.

Inflammatory bowel disease is a group of disorders with inflammation of the small intestine and colon. The major types of inflammatory bowel disease include ulcerative colitis and Crohn disease. BD also belongs to the category of an inflammatory bowel disease; however, it is difficult to distinguish BD from Crohn disease. Both of them have a young age at onset, nonspecific GI manifestations including oral ulceration and extraintestinal symptoms, and a chronic course of exacerbations and remissions; however, Lee et al (9) reported several differences in endoscopy examinations. Few focal discrete round-shaped ulcerations tend to be the manifestations of intestinal BD. Crohn disease has a more diffuse or segmental distribution, and a large number of irregular or longitudinal, ill-defined ulcers, and typical cobblestone appearance. In our study, 6 patients received endoscopic examinations and excluded the possibility of Crohn disease because of a lack of the typical cobblestone appearance; however, further studies are needed to clarify the pathogenesis and mechanism of inflammatory bowel disease, and to establish protocols to distinguish BD from Crohn disease.

Neonatal BD is another special type of BD, which presents before the age of 1 month. The etiology is probably the result of the transplacental passage of maternal antibodies, and the symptoms usually diminish after a few months with or without medication (20). The pathogenesis is probably different from classic BD. In our study, 2 patients had initial presentation before the age of 1 month, and both had GI disorders; however, 1 of them who fit the criteria of BD at 1 year 2 months of age had recurrent episodes of oral ulceration and bloody stools. The other, who initially had severe vomiting followed by diarrhea and failure to thrive and fit the criteria at the neonatal stage, did not have recurrent episodes after 3 months of age.

The exact underlying cause of BD is still unknown. Several possible pathogenic mechanisms of BD were declared, including genetic influences, bacterial antigens with cross-reactivity to human peptides (molecular mimicry), altered innate immune function, abnormal autoantibody and immune complex formation, and vascular endothelial activation and hypercoagulability. The integrity of intestinal epithelium with its tight junctions is a physical barrier to the uptake of foreign antigens and the penetration of pathogens. An immature intestinal mucosa barrier in young children cannot properly defend against antigens or pathogens in the GI tract; thus, antigens or pathogens can easily cross the barrier and cause oral intolerance and even induce molecular mimicry. Children with more GI manifestations may be explained by the mechanism; however, further studies are still needed to verify the hypothesis.

Platelet count was another interesting finding. From our data, the younger children seemed to have a higher platelet count (P = 0.0151). No patients experienced thrombotic events or major vascular disease. No previous studies have reported the differences in the hemogram data of patients with BD by age. Younger children had increased thrombocyte counts (174.0–915.0 K/μL) and 5 of them had thrombocytosis; they also had increased ESR. This may be the result of inflammation; however, the older children had normal thrombocyte counts, except 1, who had thrombocytopenia. Furthermore, whether the inflammatory condition of vessels in younger patients is more severe than in older patients and whether this condition increases the risk of coagulopathy still require further studies to elucidate.

Because of a limited follow-up duration, we did not analyze the prognosis of younger children and older children. The severity and prognosis tend to differ from case to case; however, Jung et al (18) reported a more severe clinical course and poorer prognosis in those of younger age (younger than 40 years). An increased mortality rate among patients younger than 35 years has also been reported, with male sex, arterial involvement, and a high number of BD flares being the associated risk factors.

There are some limitations to our study. First, a retrospective review may include errors in the medical records, and the data of pathergy tests were incomplete. Thus, there are potential errors with regard to the included population; however, we used the Mason and Barnes criteria, which have a high sensitivity and specificity of diagnosis to correct the selection bias. Second, the frequency of recurrent oral ulcers may be overestimated because of the initial screening with positive recurrent oral ulcer. From other reports and International Study Group for Behçet's Disease criteria, recurrent oral ulcer was always the first clinical presentation. Furthermore, it is difficult to predict the prognosis because of the short follow-up duration.

In conclusion, in this study, the most common presentations of childhood BD were recurrent oral ulceration, genital ulcers, skin lesions, and GI symptoms. Young patients had more GI symptoms at presentation and GI ulceration. Regarding BD children younger than 10 years having GI symptoms, endoscopic examination may be considered to clarify the intestinal involvement and to differentiate it from Crohn disease. Endoscopic examination should be considered in patients with BD with severe vomiting, diarrhea, or malnutrition. If patients only have nonspecific mild abdominal pain, supportive treatment and observation are considered and endoscopic examination could be undertaken.

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Behçet disease; children; intestine

© 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,