Original Articles: Gastroenterology
Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by episodic fever and polyserositis attacks. The gene causing FMF (MEFV) is located on the short arm of chromosome 16, and many disease-associated mutations have been identified after cloning the gene in 1997 (1). Homozygosis for the M694 V mutation is associated with a more severe form of FMF (2). The disease is frequently encountered in Turks, Jews, and Asians (3). Diagnostic criteria for FMF disease and timing for genetic investigations are well described in the literature. The hallmark of FMF is abdominal pain and patients may have various gastrointestinal symptoms. Consequently, >50% patients with FMF are seen by a gastroenterologist before the disease is diagnosed (4). In this report, we described 11 patients who presented with gastrointestinal symptoms and eventually diagnosed as having FMF. Gastrointestinal mucosal involvement without amyloidosis is documented by endoscopic and histopathologic investigation in these patients.
The medical files of the patients who were diagnosed as having FMF at the Department of Pediatric Gastroenterology, Gazi University School of Medicine, between 2007 and 2012 were examined retrospectively. FMF diagnosis was made through performing clinical, laboratory, colonoscopy, endoscopy, and genetic analysis. Tel-Hashomer criteria were used for the diagnosis of FMF. For definitive diagnosis, 2 major criteria or 1 major criterion and 2 minor criteria are required. For a probable diagnosis, 1 major criterion and 1 minor criterion are sufficient. The patients were investigated for age, sex, family history, admission complaints, accompanying perianal lesions, nutritional status, colonoscopic and endoscopic findings, biopsies, and FMF mutations in detail. Infections, food allergies, immunodeficiencies, and Behçet disease were excluded by stool culture, skin prick test and elimination diet, immune tests, ophthalmic examination, and HLA B5 analyses. Endoscopy and/or colonoscopy and histopathologic examination of endoscopic biopsies were performed in patients presenting with diarrhea or vomiting.
Thirty-six patients were diagnosed as having FMF during this period. Among them, 11 patients were admitted with vomiting or diarrhea. Demographic characteristics of patients are shown in Table 1. Ten of these patients had diarrhea (6 of them bloody) and 1 had vomiting. Perianal lesions were remarkable in 5 patients with diarrhea. All of the patients had fever except 1. Abdominal pain was present in 6 patients. Four patients had restlessness (Table 2). Periodicity was a major characteristic of these complaints. Laboratory characteristics and FMF mutation analyses are shown in Table 3. Stool analyses indicated noninfectious inflammation of the bowel in patients with diarrhea. Colonoscopy and upper gastrointestinal endoscopy were performed in 10 patients, all of whom showed inflammation of the colonic mucosa. Pangastritis was reported in 2 patients. Multiple aphthous ulcers were shown in the gastric mucosa by endoscopy in patients presenting with vomiting. Endoscopic and histopathologic characteristics of patients are shown in Table 4.
The diagnosis of FMF is based on clinical grounds. Diagnostic difficulties occur especially in patients with atypical features, in younger age groups, and in patients with overlapping or associated diseases such as vasculitis and inflammatory bowel disease (IBD) (4). Genetic testing should be reserved for such patients. Gastrointestinal involvement of FMF continues to be one of the most popular topics. In addition to acute abdominal attacks, other gastrointestinal symptoms are noted in patients with FMF. These symptoms may be classified in several groups: acute attack and attack-related manifestations such as acute peritonitis, pelvic attacks, and intestinal obstruction; manifestation not related to attacks, such as functional bowel disease; amyloidosis-related manifestation, such as constipation and diarrhea. Ischemic colitis and perforation may be seen because of amyloid deposition in large intestine; FMF-associated diseases affecting the gastrointestinal tract, such as IBD and vasculitis (4); however, in 2011, we reported 3 patients with FMF between 3 months and 4 years of age presented with colitis without amyloidal deposition in intestines (5). Infectious causes, immunodeficiencies, and vasculitis syndromes were excluded in these patients. Although colonoscopic views resembled IBDs (Fig. 1), clinical, endoscopic, and histological recovery was achieved only with colchicine therapy. Thus, we were aware of clinical colitis states without amyloidal deposits in FMF, independent from IBDs or vasculitis. After this awareness, all patients with noninfectious chronic or recurrent colitis-type diarrhea were evaluated for FMF in our center.
Following these 3 patients, 7 more similar patients were admitted to our clinic and they were diagnosed as having FMF by mutation analyses. As a result, a total of 10 patients with colitis-type diarrhea were diagnosed as having FMF. Reviewing the endoscopic evaluations, 3 patients showed views compatible with total lymphoid nodular hyperplasia, whereas colonic mucosal hyperemia and partly ulcerated areas covered with white exudates were seen in 7 patients. Colonoscopic views were not different from IBDs or Behçet disease. All cases were evaluated one by one for immunodeficiencies, Crohn disease, Behçet disease, infectious causes, and food allergies. None of the 10 patients showed small bowel involvement. Endoscopic evaluations of these 10 patients were clear for duodenal lesions and also amyloid deposition was not detected in biopsies. All patients were treated with colchicine alone.
Another striking feature in our series was accompanying perianal lesions in 5 of 10 patients (Fig. 2). Perianal lesions are known to be monitored in immunodeficiencies, Behçet disease, and Crohn disease. One of the patients (#7) had perianal abscess drainage twice in another center before admission to our clinic. Perianal lesions were cleaned; antibiotic and antifungal solutions were applied and followed up, mostly without dressing. Lesions healed with some scars and did not recur after local care and colchicine treatment (Fig. 3).
Our 11th patient was admitted with a different clinical state. A 10-month-old boy was admitted with periodic vomiting, fever, and restlessness. His weight was 9100 g. The patient had a 650-g weight loss and a significant percentile loss in the last 3 months. Urinary tract infections, metabolic diseases, and anatomic abnormalities of the upper gastrointestinal tract and food allergies were excluded. The patient did not benefit from gastroesophageal reflux treatment. Hyperemia and widespread aphthous ulcerations were noted in stomach and bulbus during endoscopy (Fig. 4). The family was questioned again for herbals, analgesics, caustic material, and anti-inflammatory drugs. The mother had FMF and FMF mutation analysis was performed. The result was positive and reported as M694 V/E148Q. Symptoms resolved after colchicine treatment and all lesions were seen to be healed in subsequent endoscopy. Thus, we observed a patient presenting with upper gastrointestinal symptoms and lesions without small or large bowel involvement and amyloidal deposition. This patient was 17 months old and had been undergoing colchicine treatment for 4 months. The patient's body weight was 11.0 kg and had no complaints. Involvement of the upper gastrointestinal tract in FMF has not been reported in the literature. Vomiting and refusal of breast-feeding are frequently encountered during infancy. Considering chronic vomiting of infancy, urinary tract infections, food intolerance, food allergies, metabolic diseases, anatomical abnormalities of the gastrointestinal tract, and intracranial pathologies have to be kept in mind. Periodicity of the symptoms and family history guided us to FMF; thus, mutation analysis was performed. The patient's symptoms suddenly disappeared and weight gain was observed following initiation of colchicine treatment. Disappearance of lesions in control endoscopy proved that symptoms and endoscopic lesions were caused by FMF. This patient had FMF with upper gastrointestinal tract involvement; however, association of esophagitis, gastric, or bulbar aphthous ulcerations was never defined in the literature before. Similar aphthous lesions may be seen in Behçet disease, thus, Behçet disease was taken into consideration; however, pathergy test was negative and uveitis was not present.
Abdominal imagings (x-ray, ultrasound, computed tomography, or gastrointestinal series) are useful especially for differential diagnosis during FMF attacks. These imaging methods show various degrees of small or large bowel dilatation during this period. Dilatations, nodular lesions, filling defects, ischemic ulcerations, narrowing, and rigidity are shown by gastrointestinal series in patients with FMF in the presence of amyloidosis. There is no knowledge about endoscopic and histopathologic evaluation of gastrointestinal mucosa in children with FMF in the literature. Endoscopic findings and mucosal involvement of the gastrointestinal tract without amyloidosis was established as a main characteristic of the disease in our patients by endoscopic procedures (6–8).
In conclusion, FMF may present in children with unusual symptoms, such as colitis and aphthous ulcerations in bulbus. Another important feature of the 11 patients we studied was the presence of gastrointestinal presentation without renal involvement and amyloid deposition. To date, gastrointestinal involvement of FMF has been explained by bacterial overgrowth related to dysmotility and malabsorption caused by amyloid deposition; however, colitis and aphthous bulbitis in our patients are not related to amyloid deposition. Mucosal involvement of the upper and lower gastrointestinal tract may be related to FMF attacks in these patients and it should be investigated by endoscopy or colonoscopy and histopathology. With these patients, we are sure that FMF will continue to amaze us.
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Keywords:© 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
amyloidosis; aphthous bulbitis; aphthous gastritis; colitis; familial Mediterranean fever