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Original Articles: Gastroenterology

Detailed Follow-up Study of Pediatric Orofacial Granulomatosis Patients

Haaramo, Anu; Alapulli, Heikki†,‡; Aine, Liisa§; Saarnisto, Ulla†,‡; Tuokkola, Jetta; Ruuska, Tarja||; Sipponen, Taina; Pitkäranta, Anne; Kolho, Kaija-Leena

Author Information
Journal of Pediatric Gastroenterology and Nutrition: October 2017 - Volume 65 - Issue 4 - p 388-393
doi: 10.1097/MPG.0000000000001554


What Is Known

  • Orofacial granulomatosis is an inflammatory disease affecting the orofacial area. The connection between Crohn disease and orofacial granulomatosis is debated.
  • Descriptive studies of orofacial granulomatosis, its clinical presentation, management, and long-term behavior, are limited.
  • Some patients with orofacial granulomatosis develop a symptomatic gut disease, and patients with Crohn disease may develop oral lesions. Factors predicting the development of gut disease remain unknown.

What Is New

  • A detailed description of 29 pediatric-onset orofacial granulomatosis patients.
  • Long-term follow-up including otorhinolaryngological examination shows good prognosis. Orofacial granulomatosis does not increase otorhinolaryngological morbidity.
  • Anti–Saccharomyces cerevisiae antibody A may arise as a serological marker detecting underlying Crohn disease in patients with orofacial granulomatosis.

Orofacial granulomatosis (OFG) is an uncommon chronic inflammation presenting in the oral cavity and around the mouth. Most common findings in OFG are persistent or recurrent lip swelling, angular cheilitis, cobblestone formation of the mucosa, and linear ulcers (1,2). Histology shows noncaseating granulomas and lymphedema. Crohn disease (CD) is a chronic inflammatory disease, which can affect any part of the digestive tract including the mouth. Oral lesions in CD cannot be clinically or histologically distinguished from lesions in OFG (3,4). It is being debated whether OFG is an oral manifestation of CD or a separate inflammatory disorder (5,6). A number of patients with OFG develop a symptomatic gut disease, and patients with CD may develop oral lesions. Factors predicting the development of gut disease remain unknown.

Descriptive studies of OFG, its clinical presentation, management, and long-term behavior, are limited and typically consist of small numbers of patients. Otorhinolaryngological findings in OFG patients have not been reported in detail before.

In this comprehensive cross-sectional study, we invited pediatric-onset OFG patients from 2 tertiary care centers to a follow-up visit. A dentist and an otorhinolaryngologist examined the patients in addition to laboratory testing and nutritional evaluation.

The aim of the present study was to describe a cohort of pediatric patients with OFG in detail and to study the long-term outcome of OFG, including dental and otorhinolaryngological status and to evaluate factors associating with CD in patients with OFG.


We invited patients diagnosed with pediatric OFG and treated between January 2000 and March 2014 at Helsinki and Tampere University Hospital, Finland to this follow-up study performed between November 2013 and March 2014. The patients were recruited during their visits at the participating clinics or based on a telephone contact. Of the total of 40 traced patients, 10 patients (3 patients in Helsinki, 7 patients in Tampere) declined the study (the cause was not claimed due to the guidelines of the ethics committee), and 1 was excluded from further analyses due to a wrong primary diagnosis. The diagnosis of OFG was based on typical clinical features assessed by a dentist and gastroenterologist, and in most patients also a mucosal biopsy had been obtained showing granulomatous inflammation. The diagnosis of CD fulfilled the diagnostic Porto criteria including endoscopies with biopsies and small bowel imaging (7).

Study Visits

Patients agreed to a study appointment where they were examined using a structural schema by an otorhinolaryngologist (A.H.) and a dentist (H.A./L.A./U.S.). The otorhinolaryngological examination included fiberoscopic laryngoscopy. Digital photographs of findings in the face and mouth were taken. Orofacial findings were carefully recorded using Oral disease activity score chart for OFG (8). In the score chart each site involved is scored individually for activity and type of lesion, with the total score indicating global severity, maximum total score being 87 (8). The presence of cobblestoning lesions, fibrous banding/scarring, facial swelling, and erythema and staghorning of oral mucosa were recorded. The oral examination was carried out in a dental unit using a dental mirror, a dental and periodontal probe, fiber optic illumination, and appropriate dental lighting. Radiographs were not taken. The oral hygiene level was assessed according to Silness-Löe plaque Index (9). The periodontal condition was assessed by measuring the depth of periodontal pockets and the presence of bleeding after probing in all teeth. Dental caries was recorded with decayed, missing, and filled teeth (DMFT) index (10).


Patients (or their guardians) filled in questionnaires about general health, medications, preceding use of antibiotics, bowel-related symptoms, orofacial symptoms, and special diets. Patients were asked to evaluate the severity of their orofacial symptoms at the time of the examination on a Likert scale with 7 steps, where 1 means no symptoms and 7 means difficult symptoms. Patients were asked to keep a food record for 3 subsequent days before the scheduled appointment. A trained nurse checked the food records upon returning for possible omissions and controversies. A dietitian recorded the food records with a software (AivoDiet, Aivo Finland Oy, Turku, Finland) that makes use of a national database of foods. The use of dietary supplements was also queried in the food records; their compositions were checked from the manufacturers. In addition, patients’ consumption of foods containing cinnamon or benzoic acid (11–13) was recorded. Information about given therapies was collected from patient charts.

Laboratory Investigations

All patients were requested to provide a stool sample for measuring fecal calprotectin. Calprotectin levels were measured in a routine clinical laboratory using a quantitative enzyme immunoassay (PhiCal Test, Calpro AS, Oslo, Norway), and values of <100 μg/g were considered as normal (14,15).

Blood samples were collected from all patients. Laboratory tests included C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), hemoglobin, blood leukocyte count, and anti–Saccharomyces cerevisiae antibodies A (ASCAbA) and G (ASCAbG).

The Ethics Committee of the Helsinki University Hospital approved the study protocol. The patients and/or their guardians signed an informed consent form.

Statistical Analyses

The nonparametric Mann-Whitney and Spearman correlation tests were used to investigate the associations between variables. Statistical analyses were performed using GraphPad Prism 6 for Windows by GraphPad Software, Inc. (San Diego, CA). Differences were considered significant at P value of <0.05.


The study group comprised 29 patients (15 patients in Helsinki and 14 patients in Tampere) with a median duration of follow-up from primary diagnosis of 3.1 years (range 0.1–21.8 years). Background characteristics of the patients are shown in Table 1.

Background characteristics of the study population

Twenty-one patients (72%) had been diagnosed with CD, of whom 11 had an OFG diagnosis before the inflammatory bowel disease diagnosis, and 5 patients got the diagnoses simultaneously (median time from OFG diagnosis to CD diagnosis 0.6 years, range 1 day–4.6 years). Five patients had a CD diagnosis before the OFG diagnosis (median time from CD diagnosis to OFG diagnosis 5.7 years, range 57 days–9.6 years). Eight (28%) patients had not been diagnosed with CD.

Given Therapies for Orofacial Granulomatosis

The given therapies are shown in Table 2. Seventeen patients (59%) had received topical treatment to oral lesions, most commonly tacrolimus gel (n = 15). Five (17%) patients had received more than 1 type of topical treatment. Twelve (41%) patients (10 patients with CD and 2 with OFG only) had not received any topical treatment. One patient with OFG had received methotrexate, and others receiving systemic medication had CD. Seven (24%) patients, all with CD, consumed a specific elimination diet (avoiding milk or lactose, wheat, barley, or gluten) in addition to medication. At study point 3 (10%) patients were using topical tacrolimus, 4 (14%) azathioprine, 3 (10%) anti-TNFα therapy (infliximab), and 2 (7%) methotrexate.

Given therapy for patients with Crohn disease and orofacial granulomatosis (Crohn disease + orofacial granulomatosis) and patients with orofacial granulomatosis only

Oral Findings

The prevalence of typical findings of OFG is shown in Table 3. There was no statistically significant difference in these findings between patients with CD and patients with OFG only. Pictures of typical findings are shown in Figure 1.

Prevalence of typical findings of orofacial granulomatosis and total scores according to Oral disease activity score chart for orofacial granulomatosis in patients with Crohn disease and orofacial granulomatosis (Crohn disease + orofacial granulomatosis) and patients with orofacial granulomatosis only (orofacial granulomatosis only)
Typical lesions in patients with orofacial granulomatosis (OFG): angular cheilitis (A), swelling of the lower lip (B), staghorning (C), and site of disease involvement in OFG patients (D).

Patients’ subjective evaluation regarding orofacial symptoms at study visit varied from 1 (no symptoms, n = 11) to 6 (difficult symptoms, n = 1), median 2 and in CD, regarding bowel-related symptoms between 1 (no symptoms, n = 6) and 5 (rather difficult symptoms, n = 2), median 2.5.

Patients’ total score according to oral disease activity score chart for OFG ranged between 0 and 33 (median 10). The oral mucosa was the most common site of OFG findings in 26 (90%) patients, following lesions in the lower lip (76%, mostly swelling), gingival lesions (66%), and angular cheilitis (48%). Oral findings at study visits are shown in detail in Supplemental Digital Content 1, Table (, and site distribution of lesions in Figure 1. Patients diagnosed with OFG at an older age had more orofacial findings (Spearman r = 0.3812, n = 29, P = 0.0413). Sex did not relate to the severity of oral findings (P = 0.2917), but boys were more often affected (Table 1).

Between patients with CD and patients with OFG only, there was a statistically significant difference only in the number of patients who had upper lip swelling (P = 0.0265), which was more commonly seen in patients with CD (Supplemental Digital Content 1, Table, Orofacial findings were more severe in patients with CD and thus, total scores were higher compared to patients with OFG only (medians 11 and 7.5 respectively, P = 0.0351).

Dental Status

The oral hygiene level was fair (plaque index ≥1.0) in 69% of the patients (median 1.5, range 0–2.67). All patients had gingivitis, and 4 had periodontal pockets (≥4 mm). Untreated dental decay (D > 0) was found in 7 (24.1%), and 13 patients (44.8%) were cavity free (DMFT = 0). None of the dental findings correlated statistically with the severity of the OFG scores.

Otorhinolaryngological Status

The otorhinolaryngological findings of the patients were minor (Supplemental Digital Content 2, Table, Slight enlargement of the cervical lymph nodes was found in 6 (21%) patients. None of the patients had swelling of the major salivary glands. Three (10%) patients had swelling, and 6 (21%) patients had redness of nasal mucosa. Nasal polyps, atrophy of nasal conchae, or septum perforation was not found. Two patients had undergone tonsillectomy, others had gradus I-II tonsils without signs of chronic tonsillitis. All patients had normal findings in the ears. Nasofiberoscopy was successful in 26 patients, of whom all had normal vocal cords. Five patients had either minor swelling or erythema of arytenoid cartilages.

Laboratory Investigations

Five patients had elevated (>5 mg/L) CRP levels (median 9, range 6–29.6 mg/L), all with CD. Seven patients had elevated ESR (median 25, range 13–38 mm/h), 6 with CD.

Twelve patients had elevated levels of ASCAbG (median 32, range 26–95 IU/L). Of these, 10 had CD. All 6 patients with elevated ASCAbA levels (median 45, range 20–167 IU/L) were diagnosed with CD.

There was a significant relationship between elevated ASCAbA and patients’ total score of oral findings (P = 0.0311) but no significant relationship between elevated ASCAbG and patients’ total score (P = 0.0895).

Eighteen (62%) of 29 patients had elevated (>100 μg/g) values of fecal calprotectin (median 954.5, range 116–1833 μg/g). Patients with CD had significantly higher fecal calprotectin values than other patients (P = 0.011). Only 1 patient with elevated calprotectin (367 μg/g) did not have a diagnosed CD.

There was no significant relationship between patients’ fecal calprotectin levels and oral disease activity (Spearman r = 0.03744, n = 29, P = 0.8471).


Thirteen of the 28 patients providing food records had eaten foods containing cinnamon, but only 4 more than once (range 1–3 times). All except 1 patient had eaten food containing benzoic acid either naturally or as an additive (median 8 times, range 3–32 times). The number of cinnamon or benzoic acid consumption did not associate to orofacial findings (Spearman r = –0.2529, P = 28, P = 0.1942 and Spearman r = –0.06313, n = 28, P = 0.7496, respectively).

Nutrient intake and national recommendations are shown in Supplemental Digital Content 3, Table, Most variation was seen in the intake of dietary fiber, but there was no significant correlation between patients’ fiber intake and oral disease activity (P = 0.7154).


The present study indicates that OFG is restricted to the orofacial area and does not seem to increase otorhinolaryngological morbidity. Dental findings did not correlate with the severity of OFG. Long-term follow-up of pediatric-onset OFG patients showed good prognosis, and severe disease exacerbation was not detected. In our study, patients with OFG and CD had more oral findings compared to patients with OFG only. Intriguingly, ASCAbA may serve as a factor predicting underlying or developing CD in patients with OFG.

The largest study to date on OFG included 207 patients with OFG, 22% of which were children (11). In their cohort, the majority of patients did not have CD nor develop it during the follow-up (median 5.5 years) (11). A recent systematic review including 104 child patients reported concurrent CD in approximately 40% of children with OFG, CD usually occurring before the onset of OFG (16). A high prevalence of CD in children with OFG may suggest that OFG and CD are 2 variants of the same chronic inflammatory disease (16). In our study, the frequency of CD in patients with OFG was even higher, because the majority (72%) of patients had been diagnosed with CD. We confirmed the previously reported predominance of OFG in boys (16), with a male to female ratio of 3:1 in all patients with OFG and 2:1 in patients with concurrent CD.

Oral Findings

According to earlier studies, the most common complaints of patients with OFG are lip swelling and facial swelling, reported in >90% of the cases (17,18). Labial swelling was the most common presenting clinical feature at diagnosis found in more than 75% of the 49 patients (19). In our cohort of follow-up patients, some degree of lip swelling, either one- or both sided, occurred in almost 80% of patients. The most common site for lesions was the buccal mucosa, where almost 90% of patients had some findings. The most common individual oral manifestation was, however, swelling of the lower lip, being present in approximately 65% of our patients. This was never the sole presenting clinical feature. The upper lip was affected in clearly fewer patients, in one third of the patients. Facial swelling was found in roughly 10% of our patients. Our patients had received treatment for OFG before the study visit, which may have an effect on the lesions found. Regarding differences between patients with OFG only or OFG with CD, Campbell et al (11) reported that patients with OFG with CD tend to have “posterior pattern” of oral disease and patients without CD “anterior pattern”. In our study, the only statistically significant difference between patients with CD and patients with OFG was the more frequent presence of upper lip swelling in CD.

The high frequency of gingivitis in our patients is most likely partially explained by painful lesions in the oral cavity complicating oral hygiene.

Otorhinolaryngological Findings

The otorhinolaryngological findings in our cohort were minor. Most patients had normal findings in otorhinolaryngological examination including fiberoscopy of nasopharynx and larynx. This strengthens the assumption that OFG is typically restricted in the oral cavity and around the mouth and does not affect the nasal mucosa or the larynx neither the ears. Salivary glands were not affected either. If an OFG patient's salivary glands are affected, sarcoidosis should come to mind as an uncommon cause of orofacial lesions similar to OFG (20).


A study by Al Johani et al (19) showed that combined therapy with topical and intralesional corticosteroids or systemic medications was most effective for control of facial manifestations of OFG. In our cohort, few patients with OFG only did not need any treatment, which indicates that OFG can also present as a mild disease. Approximately 60% of our patients had received topical therapy, mostly tacrolimus gel, for orofacial lesions. Almost 20% of patients had received more than 1 type of topical treatment, which indicates that there is no topical treatment option that would be effective for every patient. Conversely, 40% had not received any topical treatment to OFG. The majority of these patients had CD and a systemic medication that may affect oral lesions as well. Approximately half of the patients who had CD and had received systemic medication for gut symptoms also, however, needed topical treatment for orofacial symptoms. Treatment of OFG is challenging and must be individually tailored to meet the changing clinical presentation and the needs of every individual patient. Criterion standards for treatment are lacking. New treatment options are also emerging. A recent case report suggests that low-dose thalidomide could be a valid treatment option in pediatric OFG (18).

Laboratory Investigations

Savage et al reported that it may be possible to use ASCAbA, a serological marker for CD (21,22) as a marker of coincident gut disease in patients with OFG and as a screening marker of the possible development of CD (23). In our study, patients with elevated ASCAbA were all diagnosed with CD. Patients with elevated ASCAbA, but not those with elevated ASCAbG levels, had more orofacial findings than patients with normal ASCAbA levels. Thus, elevated ASCAbA levels may predict more severe oral disease. Further studies are needed to ensure the connection.

Fecal calprotectin, a surrogate marker of intestinal inflammation, can be useful in identifying underlying gut disease in OFG patients (24,25). As expected, patients with CD had significantly higher fecal calprotectin levels than patients with OFG only. Calprotectin levels did not correlate to more orofacial symptoms. Fecal calprotectin was screened at the study visits in a single stool sample but all patients had provided previously several stool samples. Thus, the possibility of intestinal inflammation in OFG only patients had been considered repeatedly. In our study, 1 patient without diagnosed CD had elevated fecal calprotectin and was referred for further examination for suspicion of underlying CD. In 1 study with 35 patients with OFG and no gut symptoms, 54% of the patients had intestinal abnormalities detected in ileocolonoscopy but only 2 patients had typical features of CD (5). Interestingly, we recently reported that HLA-B44 may associate with the risk of CD in patients with OFG (26).

Only approximately 15% of patients had slightly elevated CRP (median 9 mg/L). Elevated CRP or ESR levels were not connected to higher oral disease activity scores. As previously reported, OFG does not seem to be associated with any significant hematologic abnormalities (5,19).


Patients’ nutrition did not differ markedly from what is nationally recommended (27). In our cohort patients’ fiber intake varied the most but did not associate to disease activity.

Cinnamon and benzoate have reported to be common allergens on patch testing in patients with OFG (13). White et al (8) reported a significant improvement in oral inflammation after a cinnamon- and benzoate-free diet and recommend it as a primary treatment for patients with OFG. There was no significant correlation between cinnamon or benzoic acid consumption and oral findings in our study. Benzoic acid is so commonly used as a food preservative that all except one of our patients had been consuming it during the 3-day food record. It is unclear which patients need dietary modification.

Strengths and Limitations

We consider the small number of patients as a limitation. The cohort is, however, collected from a population of 3 million. Finland is a country of high hygiene standards and national healthcare is provided to everyone. A functional well baby clinic system and school health service system, also providing dental care, cover the whole population regardless of socioeconomic status or place of residence. Therefore, it is likely that severe lesions are detected on routine screening of oral health. All patients diagnosed with OFG in our 2 tertiary care clinics were traced. This indicates that OFG is still a rare condition. Prevalence may grow because the prevalence of CD has been growing during the last years in Western countries (28–30). Dental findings were minor and did not correlate with OFG findings. We, however, consider the lack of a control group matched for age, sex, and socioeconomic status as a limitation in regards assessing the significance of dental findings. We consider it a valid strength that our study is comprehensive, including otorhinolaryngological examination, laboratory tests, and nutritional aspects. To minimize interobserver variation, patient assessment was performed in parallel by an otorhinolaryngologist and a dentist using a structural schema.


OFG is still a rare condition. Long-term follow-up of pediatric-onset OFG patients shows good prognosis. Patients with OFG do not seem to have excess otorhinolaryngological morbidity. Dental findings did not correlate with the severity of OFG. In addition to fecal calprotectin, the serological marker ASCAbA may be a useful factor predicting the presence of underlying CD in patients with OFG. Further studies are needed to examine its utilization in practice.


The authors express their gratitude to research nurse Anne Nikkonen for her superb contribution in organizing the study and recruiting the patients and to nurse Piitu Oksanen for her contribution in organizing the study in Tampere.


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Crohn disease; inflammatory bowel disease; swollen lip

Supplemental Digital Content

Copyright © 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition