Vol. 118 No. 6 December 2014
Unusual gingival swelling in a 4-year-old child Anne-Laure Ejeil, DDS, PhD, Aude Thomas, DDS, Sébastien Mercier, DDS, and Nathan Moreau, DDS Bretonneau Hospital, Paris, France, and Paris Descartes University, Sorbonne Paris Cité, France
(Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:627-631)
CLINICAL PRESENTATION A 4-year-old female patient with gingival swelling was brought to the Department of Oral Surgery. The progressive swelling, present since birth, had been disturbing food intake. Chronic constipation (1 bowel movement every 3 to 4 days, treated with macrogol 3350) associated with intermittent rectal bleeding was also reported by her mother. The patient’s rectal bleeding had been previously diagnosed as “hemorrhoids” by a gastroenterologist. Apart from these gastrointestinal manifestations, the patient appeared to be of normal weight and stature for her age (105 cm/15.7 kg). Clinical extra-oral examination revealed cracked and swollen lips associated with a perioral exfoliating erythematous epidermal reaction (Figure 1). Intra-oral examination revealed a generalized reddish gingival hypertrophy of firm consistency and granulomatous aspect involving the maxilla (Figure 2). Hyperplastic squamous linear lesions of the oral mucosa were also noted (Figure 3). DIFFERENTIAL DIAGNOSIS Differential diagnosis of chronic granulomatous gingival hypertrophies should include sarcoidosis, granulomatosis with polyangiitis (formerly known as Wegener granulomatosis), orofacial granulomatosis, and Crohn disease. Sarcoidosis is a chronic systemic disorder of unknown etiology characterized, in affected organs, by an accumulation of epithelioid granulomas without histopathologic aspects of caseation or presence of infectious agents.1 Peak incidence is found between the ages of 20 and 40. The disease is more common among African Americans and Northern Europeans. Most reported pediatric cases have been described in patients aged 13 to 15. Sarcoidosis affects multiple organs, especially the lungs, lymph nodes, skin, and eyes. In the maxillofacial region salivary gland involvement is common. Clinically, most cases appear as hypertrophic or nodular lesions of firm consistency. Oral forms of sarcoidosis have mostly been described on the lips, hard and soft palate,
buccal mucosa, gingiva, tongue, and tonsils. Oral involvement usually appears in patients with chronic multisystemic sarcoidosis. Patients may also present systemic manifestations such as fever, weight loss, and fatigue. Infants and children under the age of 5 usually present a triad of skin, joint, and eye involvement, without the typical lung disease.1 Because several cases of oral sarcoidosis without systemic involvement have been described, sarcoidosis could not be ruled out of the differential. Nevertheless, gastrointestinal involvement is rare, occurring in about 3% of cases of sarcoidosis. Granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis, is a vasculitis affecting small and medium caliber blood vessels. It results in nasal and pulmonary lesions or significant systemic involvement with renal, cardiac, neurologic, and skin lesions. The peak GPA incidences occur in the 30s and 40s, with a mean age of 41. It is rarely observed in children. Only 15% of cases occur in patients younger than 20, with a female predominance2 and a higher prevalence among Caucasians (especially those from Northern Europe) compared with Asian, African, AfroCaribbean, and African-American populations. Constitutional symptoms of active granulomatosis with polyangiitis are general malaise, myalgia, arthralgia, anorexia, weight loss, and pyrexia. Renal and pulmonary diseases are common findings at time of diagnosis. Cytoplasmic antineutrophil cytoplasmic antibodies (cANCA) and perinuclear anti neutrophil cytoplasmic antibodies (pANCA)-ANCA are considered sensitive and specific markers for GPA.3 Oral involvement classically presents as hyperplastic granular gingivitis.4,5 Atypical oral ulcerations have also been observed.6 Diagnosis is based on a combination of positive ANCA serology and histologic evidence of necrotizing vasculitis, necrotizing glomerulonephritis or granulomatous inflammation from a relevant organ biopsy, such as skin, lung, or kidney. Our patient did not present any signs of systemic involvement suggestive of vasculitis.
Statement of Clinical Relevance Bretonneau Hospital, Department of Oral Surgery, Paris, France, and Paris Descartes University, Sorbonne Paris Cité, France. Received for publication Feb 9, 2014; returned for revision May 21, 2014; accepted for publication May 30, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.05.024
Oral manifestations of Crohn disease may precede the onset of intestinal disease in up to 60% of cases. Knowledge and detection of such manifestations may help in early diagnosis and better management of this disease. 627
CLINICOPATHOLOGIC CONFERENCE 628 Ejeil et al.
OOOO December 2014
Fig. 1. Significant swelling and fissuring involving the upper lip.
Fig. 3. Linear hyperplasic lesions of the oral mucosa.
Fig. 2. Intra-oral photography showing an erythematous and swollen gingiva.
Fig. 4. Gingival biopsy showing giant cell granulomas without necrosis (hematoxylin-eosin, magnification 100; courtesy Tolbiac Laboratory, Dr. F. Le Pelletier).
Orofacial granulomatosis (OFG), which includes Melkersson-Rosenthal syndrome (MRS) and Miescher cheilitis granulomatosa, is a group of chronic inflammatory diseases characterized by noncaseating granulomatous inflammation and affecting oral and maxillofacial soft tissues. MRS has been described as a syndrome of unknown etiology characterized by the triad of persistent lip or facial swelling, recurrent facial paralysis, and fissured tongue. When faced with either facial swelling or cheilitis granulomatosa without the other 2 components of the triad, clinical manifestations should be labeled orofacial granulomatosis. A diagnosis of OFG is made through histopathologic identification of noncaseating granulomas. MRS was ruled out based on the absence of facial paralysis and a tongue of normal clinical aspect, but we could not rule out OFG. Crohn disease (CD) is a chronic, idiopathic, inflammatory, granulomatous disease of unknown etiology involving the gastrointestinal tract. Common symptoms include abdominal pain, diarrhea, fatigue, fever, gastrointestinal bleeding, and weight loss.7 Oral lesions have been described in patients with intestinal CD.8 These
include swelling of the lips and buccal mucosa, gingival hyperplasia, cobblestone appearance of the oral mucosa, mucogingivitis, deep linear ulcerations, and mucosal tags. Colonoscopy, including ileoscopy and biopsy, are often useful in the diagnosis of ileo-colic Crohn disease.7 Diagnosis of CD is made based on histopathologic identification of noncaseating granulomas in association with gastrointestinal manifestations and serologic disturbances. Infectious granulomatous conditions (such as mycosis or tuberculosis) must be excluded by use of special staining methods and cultures. In this case, we favored a granulomatous lesion, not otherwise specified.
DIAGNOSIS AND MANAGEMENT Considering the absence of definitive clinical manifestations, an incisional biopsy of the gingiva was performed. Hematoxylin and eosin staining revealed a non-necrotic giant cell granuloma compatible with Crohn disease and with sarcoidosis (Figure 4). Periodic acideSchiff, Grocott, and Ziehl-Neelsen stains were then applied to biopsy specimens to rule out fungal and
OOOO Volume 118, Number 6
CLINICOPATHOLOGIC CONFERENCE Ejeil et al. 629
Fig. 5. Aspect of the upper lip after 3 months of treatment. Lower lip swelling can be noted.
Fig. 7. Mucosal tags on the cheek with a cobblestone-like appearance still present.
Fig. 6. Aspect of the upper gingiva after 3 months of treatment. Swelling of the lower gingival can be noted.
Fig. 8. Linear ulceration of the floor of the mouth can be noted (arrow).
mycobacterial diseases. Indeed, no signs of fungal or mycobacterial infection were noted. Based on histologic findings and clinical presentation, Crohn disease was suspected. We referred the patient back to the Department of Gastroenterology, where she was first examined. She was hospitalized for 3 days for an endoscopic examination and a full work-up. Investigations included blood tests, abdominal and colic ultrasounds, chest radiography, endoscopy, and colonoscopy. Blood tests revealed a microcytic iron deficiency anemia (hemoglobin: 7.5 g/100 mL; corpuscular volume: 68.4 mm3; iron concentration: 4 mmol/L), which was corrected by a 3-day course of ferric oxide (Veinofer). AntieSaccharomyces cerevisiae antibodies (ASCA) and ANCA assays were performed to differentiate between Crohn disease and ulcerative colitis and to further eliminate vasculitis. The ASCA assay was negative, and pANCA and cANCA were titrated at a dilution of 1:20, which is the detection threshold. Tuberculin intradermal reaction was negative.
A chest radiograph indicated bilateral peribronchovascular thickening without mediastinal lymph node enlargement. Endoscopy was normal, but ileocolonoscopy revealed diffuse lymphoid hyperplasia of the colon and an anal lesion (cracks and inflammatory skin tags). Histologic examination performed on biopsies in different ileocolic and anal regions revealed discrete inflammatory infiltrates of the lamina propria with eosinophils associated with lymphoid hyperplasia. Microgranulomas in the ileum were also noted. After thorough analysis and discussion of all previous examination results, a diagnosis of Crohn disease was established. The patient was treated with a 15-day course of azithromycin, an antibiotic with anti-inflammatory properties, followed by azathioprine, starting at 2 mg/kg. Because of the inter-individual variability in the metabolism of azathioprine explaining significant variability in the clinical response to this drug, genotyping of the thiopurine S-methyltransferase (TPMT) gene was
CLINICOPATHOLOGIC CONFERENCE 630 Ejeil et al.
OOOO December 2014
Fig. 9. (A) Aspect of the upper lip after 6 months of treatment. (B) Aspect of the gingiva after 6 months of treatment. (C) Aspect of the floor of the mouth after 6 months of treatment.
performed to assess possible gene polymorphisms of clinical significance, such as homozygous deficiency (risk of hematologic complications when taking drugs such as azathioprine) or high TPMT activity (leading to excess catabolism of azathioprine, and thus resistance to treatment). In our case, the patient had a normal homozygous expression of the TPMT gene. Three months into treatment, the labial swelling shifted to the lower lip (Figure 5), mandibular gingiva became hypertrophic (Figure 6), whereas the maxillary gingiva had regained a normal appearance. Mucosal tags on the cheeks with a cobblestone-like appearance of the mucosa were still noted (Figure 7). Ulcerations on the anterior portion of the floor of the mouth were also apparent (Figure 8). The patient seemed tired, and her mother said she often fell asleep in class. The gastroenterologists then decided to increase the azathioprine treatment (2 tablets on even days and 1 tablet on odd days) and to replace azithromycin with josamycin. Three months later, all oral symptoms had disappeared (Figure 9) and the patient had gained weight (now weighing 17 kg).
DISCUSSION Crohn disease is a chronic, inflammatory, granulomatous disease of the gastrointestinal tract. The pathogenetic mechanisms involved are still unclear. The incidence of CD is estimated at 3/100,000 children or adolescents.9 Oral manifestations of CD may be more common than previously recognized. The prevalence of oral CD varies between 0.5% and 80.0%, and oral findings may precede the onset of the intestinal disease in up to 60% of patients.10 When oral lesions are present, they may be helpful in establishing the diagnosis of CD.11,12 Oral ulcers, erosions, cobblestone appearance of the mucosa, mucosal tags, orofacial granulomatosis, and lip swelling are the most common oral manifestations, although not pathognomonic. The present case confirms previous reports suggesting that oral CD is associated with ileocolic disease.13-15 Our patient presented
mucosal tags, gingivitis, and swollen lips, as well as an associated anal lesion. Pulmonary involvement is an atypical finding in Crohn disease, unlike sarcoidosis. Estimated prevalence in Crohn disease has been found to be around 0.2%.16 Pediatric cases haven’t been as well described. A review of the English literature found 15 cases of patients (between the ages of 3 and 17 years old) suffering from both Crohn disease and symptomatic pulmonary involvement. Topography of the disease is a key element in the differential diagnosis between CD and sarcoidosis. Sarcoidosis mainly affects the mediastinal lymph nodes and lungs, whereas CD is primarily a gastrointestinal illness. In some cases, however, differential diagnosis can be quite difficult. Nevertheless, intestinal involvement is rare in sarcoidosis, with an incidence of 0.1% to 0.9% of cases.17 Infants and children under the age of 5 usually present a triad of skin, joint, and eye involvement.1 These clinical arguments associated with histology led to the diagnosis of Crohn disease in our patient. The European Crohn’s and Colitis Organisation (ECCO) Consensus states that all children suspected of Crohn disease should have a complete work-up at the time of diagnosis.9 A physical examination must include oral and perianal inspection. Oral lesions can be the initial and primary finding for patients with CD.18-20 Treatment should be oriented toward induction and maintenance of clinical remission. Infliximab is effective for induction and maintenance of remission in pediatric Crohn disease.9 Infliximab is a chimeric monoclonal antibody human/murine IgG1 produced in mouse hybridoma cells using recombinant DNA. In France, infliximab is indicated for treatment of active severe Crohn disease in patients aged 6 to 17 who have not responded to conventional therapy comprising a corticosteroid, an immunomodulator, and primary nutrition therapy. The ECCO Consensus considers that medical treatment of CD in children should be more aggressive upon disease outbreak compared with adult treatment, and that early introduction of
OOOO Volume 118, Number 6
immunomodulators such as azathioprine should be sought to prevent disease progression in such patients. Azathioprine and 6-mercaptopurine have been proven to be effective treatments to prevent relapses in Crohn disease. Azathioprine is prescribed at an initial dose of 2 to 2.5 mg/kg/24 h with generally good tolerance. Beneficial effects are not immediate and appear only several months after initiation of treatment. Budesonide is a new corticosteroid rapidly metabolized by the liver, thereby reducing adverse drug effects often associated with corticosteroids. Recent research demonstrating the efficacy of budesonide in treating active Crohn disease was followed by trials examining the effects of budesonide on the reduction of recurrences in inactive Crohn disease. Said trials found that the use of budesonide (3 mg and 6 mg daily) in patients with inactive Crohn disease was not effective in maintaining remission for up to 12 months. Budesonide is thus not recommended in the maintenance treatment of inactive Crohn disease. Delayed growth is a unique complication of pediatric inflammatory bowel diseases, which needs to be addressed in such cases. In general, the use of corticosteroids as induction treatment is avoided in children because of its additional inhibitory effects on growth. Severe oral manifestations seldom occur and can be difficult to treat.8 Close collaboration between gastroenterologists and dentists is useful for appropriate management of these patients. In the present case, the gingival hypertrophy and the ulceration of the mouth floor disappeared after treatment with josamycin and azathioprine, thus allowing our patient to regain adequate oral hygiene. Such treatment effectiveness is a strong argument favoring our diagnosis of Crohn disease. In conclusion, studies have shown that systematic oral evaluation by an experienced dental practitioner undoubtedly plays a substantial role in accurately identifying oral CD lesions.11 The oral cavity provides an easily accessible region for diagnosis when CD is suspected. Dentists can thus play a critical role in the early diagnosis of CD. REFERENCES 1. Shetty AK, Gedalia A. Childhood sarcoidosis: a rare but fascinating disorder. Pediatr Rheumatol. 2008;6:16. 2. Akikusa JD, Schneider R, Harvey EA, et al. Clinical features and outcome of pediatric Wegener’s granulomatosis. Arthritis Rheum. 2007;57:837-844. 3. Kallenberg CG. Pathogenesis of ANCA-associated vasculitides. Ann Rheum Dis. 2011;70:i59-63.
CLINICOPATHOLOGIC CONFERENCE Ejeil et al. 631 4. Staines KS, Higgins B. Recurrence of Wegener’s granulomatosis with de novo intraoral presentation treated successfully with rituximab. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108:76-80. 5. Samson J, El Hage M, Lombardi T. Des fraises ou des framboises? Med Buccale Chir Buccale. 2010;16:125-126. 6. Xing X, Zhang T, Wang X. Pediatric Wegener’s granulomatosis with oral ulcers and progressive periodontitis: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;112:1-5. 7. Wilkins T, Jarvis K, Patel J. Diagnosis and management of Crohn’s disease. Am Fam Physician. 2011;84(12):13651375. 8. Rowland M, Fleming P, Bourke B. Looking in the mouth for Crohn’s disease. Inflamm Bowel Dis. 2010;16:332-337. 9. Van Assche G, Dignass A, Reinisch W, et al. ECCO Consensus on CD: Special situations. J Crohns Colitis. 2010;4:63-101. 10. Plauth M, Jenss H, Meyle J. Oral manifestations of Crohn’s disease. An analysis of 79 cases. J Clin Gastroenterol. 1991;13: 29-37. 11. Pittock S, Drumm B, Fleming P, et al. The oral cavity in Crohn’s disease. J Pediatr. 2001;138(5):767-771. 12. Michailidou E, Arvanitidou S, Lombardi T, Kolokotronis A, Antoniades D, Samson J. Oral lesion leading to the diagnostic of Crohn disease: report of 5 cases. Quintescence Int. 2009;40: 581-588. 13. Basu MK, Asquith P. Oral manifestations of inflammatory bowel disease. Clin Gastroenterol. 1980;9:307-321. 14. Harty S, Fleming P, Rowland M, et al. A prospective study of the oral manifestations of Crohn’s disease. Clin Gastroenterol Hepatol. 2005;3:886-891. 15. Jose FA, Heyman MB. Extraintestinal manifestations of inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2008;46: 124-133. 16. Vadlamudi NB1, Navaneethan U, Thame KA, Kelly DR, Dimmitt RA, Harris WT. Crohn’s disease with pulmonary manifestations in children: 2 case reports and review of the literature. J Crohns Colitis. 2013;7:85-92. 17. Friedman M, Ali MA, Borum ML. Gastric sarcoidosis: a case report and review of the literature. South Med J. 2007;100: 301-303. 18. Salek H, Amir Balouch A, Sedghizadeh PP. Oral manifestation of Crohn’s disease without concomitant gastrointestinal involvement. Odontology; 2013:Available at: http://link.springer.com/ article/10.1007/s10266-013-0108-3#page-1. 19. Bruscino N, Arunachalam M, Galeone M, Scarfì F, Maio V, Difonzo EM. Lip swelling as initial manifestation of Crohn’s disease. Arch Dis Child. 2012;97:647. 20. Boirivant M, Cossu A. Inflammatory bowel disease. Oral Dis. 2012;18:1-15.
Reprint requests: Dr. Anne-Laure Ejeil Faculté de Chirurgie Dentaire 1 rue Maurice Arnoux 92120 Montrouge France [email protected]
Unusual gingival swelling in a 4-year-old child Anne-Laure Ejeil, DDS, PhD, Aude Thomas, DDS, Sébastien Mercier, DDS, and Nathan Moreau, DDS Bretonneau Hospital, Paris, France, and Paris Descartes University, Sorbonne Paris Cité, France
(Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:627-631)
CLINICAL PRESENTATION A 4-year-old female patient with gingival swelling was brought to the Department of Oral Surgery. The progressive swelling, present since birth, had been disturbing food intake. Chronic constipation (1 bowel movement every 3 to 4 days, treated with macrogol 3350) associated with intermittent rectal bleeding was also reported by her mother. The patient’s rectal bleeding had been previously diagnosed as “hemorrhoids” by a gastroenterologist. Apart from these gastrointestinal manifestations, the patient appeared to be of normal weight and stature for her age (105 cm/15.7 kg). Clinical extra-oral examination revealed cracked and swollen lips associated with a perioral exfoliating erythematous epidermal reaction (Figure 1). Intra-oral examination revealed a generalized reddish gingival hypertrophy of firm consistency and granulomatous aspect involving the maxilla (Figure 2). Hyperplastic squamous linear lesions of the oral mucosa were also noted (Figure 3). DIFFERENTIAL DIAGNOSIS Differential diagnosis of chronic granulomatous gingival hypertrophies should include sarcoidosis, granulomatosis with polyangiitis (formerly known as Wegener granulomatosis), orofacial granulomatosis, and Crohn disease. Sarcoidosis is a chronic systemic disorder of unknown etiology characterized, in affected organs, by an accumulation of epithelioid granulomas without histopathologic aspects of caseation or presence of infectious agents.1 Peak incidence is found between the ages of 20 and 40. The disease is more common among African Americans and Northern Europeans. Most reported pediatric cases have been described in patients aged 13 to 15. Sarcoidosis affects multiple organs, especially the lungs, lymph nodes, skin, and eyes. In the maxillofacial region salivary gland involvement is common. Clinically, most cases appear as hypertrophic or nodular lesions of firm consistency. Oral forms of sarcoidosis have mostly been described on the lips, hard and soft palate,
buccal mucosa, gingiva, tongue, and tonsils. Oral involvement usually appears in patients with chronic multisystemic sarcoidosis. Patients may also present systemic manifestations such as fever, weight loss, and fatigue. Infants and children under the age of 5 usually present a triad of skin, joint, and eye involvement, without the typical lung disease.1 Because several cases of oral sarcoidosis without systemic involvement have been described, sarcoidosis could not be ruled out of the differential. Nevertheless, gastrointestinal involvement is rare, occurring in about 3% of cases of sarcoidosis. Granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis, is a vasculitis affecting small and medium caliber blood vessels. It results in nasal and pulmonary lesions or significant systemic involvement with renal, cardiac, neurologic, and skin lesions. The peak GPA incidences occur in the 30s and 40s, with a mean age of 41. It is rarely observed in children. Only 15% of cases occur in patients younger than 20, with a female predominance2 and a higher prevalence among Caucasians (especially those from Northern Europe) compared with Asian, African, AfroCaribbean, and African-American populations. Constitutional symptoms of active granulomatosis with polyangiitis are general malaise, myalgia, arthralgia, anorexia, weight loss, and pyrexia. Renal and pulmonary diseases are common findings at time of diagnosis. Cytoplasmic antineutrophil cytoplasmic antibodies (cANCA) and perinuclear anti neutrophil cytoplasmic antibodies (pANCA)-ANCA are considered sensitive and specific markers for GPA.3 Oral involvement classically presents as hyperplastic granular gingivitis.4,5 Atypical oral ulcerations have also been observed.6 Diagnosis is based on a combination of positive ANCA serology and histologic evidence of necrotizing vasculitis, necrotizing glomerulonephritis or granulomatous inflammation from a relevant organ biopsy, such as skin, lung, or kidney. Our patient did not present any signs of systemic involvement suggestive of vasculitis.
Statement of Clinical Relevance Bretonneau Hospital, Department of Oral Surgery, Paris, France, and Paris Descartes University, Sorbonne Paris Cité, France. Received for publication Feb 9, 2014; returned for revision May 21, 2014; accepted for publication May 30, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.05.024
Oral manifestations of Crohn disease may precede the onset of intestinal disease in up to 60% of cases. Knowledge and detection of such manifestations may help in early diagnosis and better management of this disease. 627
CLINICOPATHOLOGIC CONFERENCE 628 Ejeil et al.
OOOO December 2014
Fig. 1. Significant swelling and fissuring involving the upper lip.
Fig. 3. Linear hyperplasic lesions of the oral mucosa.
Fig. 2. Intra-oral photography showing an erythematous and swollen gingiva.
Fig. 4. Gingival biopsy showing giant cell granulomas without necrosis (hematoxylin-eosin, magnification 100; courtesy Tolbiac Laboratory, Dr. F. Le Pelletier).
Orofacial granulomatosis (OFG), which includes Melkersson-Rosenthal syndrome (MRS) and Miescher cheilitis granulomatosa, is a group of chronic inflammatory diseases characterized by noncaseating granulomatous inflammation and affecting oral and maxillofacial soft tissues. MRS has been described as a syndrome of unknown etiology characterized by the triad of persistent lip or facial swelling, recurrent facial paralysis, and fissured tongue. When faced with either facial swelling or cheilitis granulomatosa without the other 2 components of the triad, clinical manifestations should be labeled orofacial granulomatosis. A diagnosis of OFG is made through histopathologic identification of noncaseating granulomas. MRS was ruled out based on the absence of facial paralysis and a tongue of normal clinical aspect, but we could not rule out OFG. Crohn disease (CD) is a chronic, idiopathic, inflammatory, granulomatous disease of unknown etiology involving the gastrointestinal tract. Common symptoms include abdominal pain, diarrhea, fatigue, fever, gastrointestinal bleeding, and weight loss.7 Oral lesions have been described in patients with intestinal CD.8 These
include swelling of the lips and buccal mucosa, gingival hyperplasia, cobblestone appearance of the oral mucosa, mucogingivitis, deep linear ulcerations, and mucosal tags. Colonoscopy, including ileoscopy and biopsy, are often useful in the diagnosis of ileo-colic Crohn disease.7 Diagnosis of CD is made based on histopathologic identification of noncaseating granulomas in association with gastrointestinal manifestations and serologic disturbances. Infectious granulomatous conditions (such as mycosis or tuberculosis) must be excluded by use of special staining methods and cultures. In this case, we favored a granulomatous lesion, not otherwise specified.
DIAGNOSIS AND MANAGEMENT Considering the absence of definitive clinical manifestations, an incisional biopsy of the gingiva was performed. Hematoxylin and eosin staining revealed a non-necrotic giant cell granuloma compatible with Crohn disease and with sarcoidosis (Figure 4). Periodic acideSchiff, Grocott, and Ziehl-Neelsen stains were then applied to biopsy specimens to rule out fungal and
OOOO Volume 118, Number 6
CLINICOPATHOLOGIC CONFERENCE Ejeil et al. 629
Fig. 5. Aspect of the upper lip after 3 months of treatment. Lower lip swelling can be noted.
Fig. 7. Mucosal tags on the cheek with a cobblestone-like appearance still present.
Fig. 6. Aspect of the upper gingiva after 3 months of treatment. Swelling of the lower gingival can be noted.
Fig. 8. Linear ulceration of the floor of the mouth can be noted (arrow).
mycobacterial diseases. Indeed, no signs of fungal or mycobacterial infection were noted. Based on histologic findings and clinical presentation, Crohn disease was suspected. We referred the patient back to the Department of Gastroenterology, where she was first examined. She was hospitalized for 3 days for an endoscopic examination and a full work-up. Investigations included blood tests, abdominal and colic ultrasounds, chest radiography, endoscopy, and colonoscopy. Blood tests revealed a microcytic iron deficiency anemia (hemoglobin: 7.5 g/100 mL; corpuscular volume: 68.4 mm3; iron concentration: 4 mmol/L), which was corrected by a 3-day course of ferric oxide (Veinofer). AntieSaccharomyces cerevisiae antibodies (ASCA) and ANCA assays were performed to differentiate between Crohn disease and ulcerative colitis and to further eliminate vasculitis. The ASCA assay was negative, and pANCA and cANCA were titrated at a dilution of 1:20, which is the detection threshold. Tuberculin intradermal reaction was negative.
A chest radiograph indicated bilateral peribronchovascular thickening without mediastinal lymph node enlargement. Endoscopy was normal, but ileocolonoscopy revealed diffuse lymphoid hyperplasia of the colon and an anal lesion (cracks and inflammatory skin tags). Histologic examination performed on biopsies in different ileocolic and anal regions revealed discrete inflammatory infiltrates of the lamina propria with eosinophils associated with lymphoid hyperplasia. Microgranulomas in the ileum were also noted. After thorough analysis and discussion of all previous examination results, a diagnosis of Crohn disease was established. The patient was treated with a 15-day course of azithromycin, an antibiotic with anti-inflammatory properties, followed by azathioprine, starting at 2 mg/kg. Because of the inter-individual variability in the metabolism of azathioprine explaining significant variability in the clinical response to this drug, genotyping of the thiopurine S-methyltransferase (TPMT) gene was
CLINICOPATHOLOGIC CONFERENCE 630 Ejeil et al.
OOOO December 2014
Fig. 9. (A) Aspect of the upper lip after 6 months of treatment. (B) Aspect of the gingiva after 6 months of treatment. (C) Aspect of the floor of the mouth after 6 months of treatment.
performed to assess possible gene polymorphisms of clinical significance, such as homozygous deficiency (risk of hematologic complications when taking drugs such as azathioprine) or high TPMT activity (leading to excess catabolism of azathioprine, and thus resistance to treatment). In our case, the patient had a normal homozygous expression of the TPMT gene. Three months into treatment, the labial swelling shifted to the lower lip (Figure 5), mandibular gingiva became hypertrophic (Figure 6), whereas the maxillary gingiva had regained a normal appearance. Mucosal tags on the cheeks with a cobblestone-like appearance of the mucosa were still noted (Figure 7). Ulcerations on the anterior portion of the floor of the mouth were also apparent (Figure 8). The patient seemed tired, and her mother said she often fell asleep in class. The gastroenterologists then decided to increase the azathioprine treatment (2 tablets on even days and 1 tablet on odd days) and to replace azithromycin with josamycin. Three months later, all oral symptoms had disappeared (Figure 9) and the patient had gained weight (now weighing 17 kg).
DISCUSSION Crohn disease is a chronic, inflammatory, granulomatous disease of the gastrointestinal tract. The pathogenetic mechanisms involved are still unclear. The incidence of CD is estimated at 3/100,000 children or adolescents.9 Oral manifestations of CD may be more common than previously recognized. The prevalence of oral CD varies between 0.5% and 80.0%, and oral findings may precede the onset of the intestinal disease in up to 60% of patients.10 When oral lesions are present, they may be helpful in establishing the diagnosis of CD.11,12 Oral ulcers, erosions, cobblestone appearance of the mucosa, mucosal tags, orofacial granulomatosis, and lip swelling are the most common oral manifestations, although not pathognomonic. The present case confirms previous reports suggesting that oral CD is associated with ileocolic disease.13-15 Our patient presented
mucosal tags, gingivitis, and swollen lips, as well as an associated anal lesion. Pulmonary involvement is an atypical finding in Crohn disease, unlike sarcoidosis. Estimated prevalence in Crohn disease has been found to be around 0.2%.16 Pediatric cases haven’t been as well described. A review of the English literature found 15 cases of patients (between the ages of 3 and 17 years old) suffering from both Crohn disease and symptomatic pulmonary involvement. Topography of the disease is a key element in the differential diagnosis between CD and sarcoidosis. Sarcoidosis mainly affects the mediastinal lymph nodes and lungs, whereas CD is primarily a gastrointestinal illness. In some cases, however, differential diagnosis can be quite difficult. Nevertheless, intestinal involvement is rare in sarcoidosis, with an incidence of 0.1% to 0.9% of cases.17 Infants and children under the age of 5 usually present a triad of skin, joint, and eye involvement.1 These clinical arguments associated with histology led to the diagnosis of Crohn disease in our patient. The European Crohn’s and Colitis Organisation (ECCO) Consensus states that all children suspected of Crohn disease should have a complete work-up at the time of diagnosis.9 A physical examination must include oral and perianal inspection. Oral lesions can be the initial and primary finding for patients with CD.18-20 Treatment should be oriented toward induction and maintenance of clinical remission. Infliximab is effective for induction and maintenance of remission in pediatric Crohn disease.9 Infliximab is a chimeric monoclonal antibody human/murine IgG1 produced in mouse hybridoma cells using recombinant DNA. In France, infliximab is indicated for treatment of active severe Crohn disease in patients aged 6 to 17 who have not responded to conventional therapy comprising a corticosteroid, an immunomodulator, and primary nutrition therapy. The ECCO Consensus considers that medical treatment of CD in children should be more aggressive upon disease outbreak compared with adult treatment, and that early introduction of
OOOO Volume 118, Number 6
immunomodulators such as azathioprine should be sought to prevent disease progression in such patients. Azathioprine and 6-mercaptopurine have been proven to be effective treatments to prevent relapses in Crohn disease. Azathioprine is prescribed at an initial dose of 2 to 2.5 mg/kg/24 h with generally good tolerance. Beneficial effects are not immediate and appear only several months after initiation of treatment. Budesonide is a new corticosteroid rapidly metabolized by the liver, thereby reducing adverse drug effects often associated with corticosteroids. Recent research demonstrating the efficacy of budesonide in treating active Crohn disease was followed by trials examining the effects of budesonide on the reduction of recurrences in inactive Crohn disease. Said trials found that the use of budesonide (3 mg and 6 mg daily) in patients with inactive Crohn disease was not effective in maintaining remission for up to 12 months. Budesonide is thus not recommended in the maintenance treatment of inactive Crohn disease. Delayed growth is a unique complication of pediatric inflammatory bowel diseases, which needs to be addressed in such cases. In general, the use of corticosteroids as induction treatment is avoided in children because of its additional inhibitory effects on growth. Severe oral manifestations seldom occur and can be difficult to treat.8 Close collaboration between gastroenterologists and dentists is useful for appropriate management of these patients. In the present case, the gingival hypertrophy and the ulceration of the mouth floor disappeared after treatment with josamycin and azathioprine, thus allowing our patient to regain adequate oral hygiene. Such treatment effectiveness is a strong argument favoring our diagnosis of Crohn disease. In conclusion, studies have shown that systematic oral evaluation by an experienced dental practitioner undoubtedly plays a substantial role in accurately identifying oral CD lesions.11 The oral cavity provides an easily accessible region for diagnosis when CD is suspected. Dentists can thus play a critical role in the early diagnosis of CD. REFERENCES 1. Shetty AK, Gedalia A. Childhood sarcoidosis: a rare but fascinating disorder. Pediatr Rheumatol. 2008;6:16. 2. Akikusa JD, Schneider R, Harvey EA, et al. Clinical features and outcome of pediatric Wegener’s granulomatosis. Arthritis Rheum. 2007;57:837-844. 3. Kallenberg CG. Pathogenesis of ANCA-associated vasculitides. Ann Rheum Dis. 2011;70:i59-63.
CLINICOPATHOLOGIC CONFERENCE Ejeil et al. 631 4. Staines KS, Higgins B. Recurrence of Wegener’s granulomatosis with de novo intraoral presentation treated successfully with rituximab. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108:76-80. 5. Samson J, El Hage M, Lombardi T. Des fraises ou des framboises? Med Buccale Chir Buccale. 2010;16:125-126. 6. Xing X, Zhang T, Wang X. Pediatric Wegener’s granulomatosis with oral ulcers and progressive periodontitis: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;112:1-5. 7. Wilkins T, Jarvis K, Patel J. Diagnosis and management of Crohn’s disease. Am Fam Physician. 2011;84(12):13651375. 8. Rowland M, Fleming P, Bourke B. Looking in the mouth for Crohn’s disease. Inflamm Bowel Dis. 2010;16:332-337. 9. Van Assche G, Dignass A, Reinisch W, et al. ECCO Consensus on CD: Special situations. J Crohns Colitis. 2010;4:63-101. 10. Plauth M, Jenss H, Meyle J. Oral manifestations of Crohn’s disease. An analysis of 79 cases. J Clin Gastroenterol. 1991;13: 29-37. 11. Pittock S, Drumm B, Fleming P, et al. The oral cavity in Crohn’s disease. J Pediatr. 2001;138(5):767-771. 12. Michailidou E, Arvanitidou S, Lombardi T, Kolokotronis A, Antoniades D, Samson J. Oral lesion leading to the diagnostic of Crohn disease: report of 5 cases. Quintescence Int. 2009;40: 581-588. 13. Basu MK, Asquith P. Oral manifestations of inflammatory bowel disease. Clin Gastroenterol. 1980;9:307-321. 14. Harty S, Fleming P, Rowland M, et al. A prospective study of the oral manifestations of Crohn’s disease. Clin Gastroenterol Hepatol. 2005;3:886-891. 15. Jose FA, Heyman MB. Extraintestinal manifestations of inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2008;46: 124-133. 16. Vadlamudi NB1, Navaneethan U, Thame KA, Kelly DR, Dimmitt RA, Harris WT. Crohn’s disease with pulmonary manifestations in children: 2 case reports and review of the literature. J Crohns Colitis. 2013;7:85-92. 17. Friedman M, Ali MA, Borum ML. Gastric sarcoidosis: a case report and review of the literature. South Med J. 2007;100: 301-303. 18. Salek H, Amir Balouch A, Sedghizadeh PP. Oral manifestation of Crohn’s disease without concomitant gastrointestinal involvement. Odontology; 2013:Available at: http://link.springer.com/ article/10.1007/s10266-013-0108-3#page-1. 19. Bruscino N, Arunachalam M, Galeone M, Scarfì F, Maio V, Difonzo EM. Lip swelling as initial manifestation of Crohn’s disease. Arch Dis Child. 2012;97:647. 20. Boirivant M, Cossu A. Inflammatory bowel disease. Oral Dis. 2012;18:1-15.
Reprint requests: Dr. Anne-Laure Ejeil Faculté de Chirurgie Dentaire 1 rue Maurice Arnoux 92120 Montrouge France [email protected]
