Gingival manifestation of Crohn’s disease in a paediatric patient: A case report

Crohn's disease (CD) is a complex multisystemic inflammatory disorder and part of the inflammatory bowel diseases (IBDs). About 20% of the subjects affected by IBDs are paediatric patients and 21% of them present extraintestinal manifestations. Among the extraintestinal manifestations of CD, oral manifestations are rather frequent (20– 50% of affected people) and can be difficult to identify, being frequently aspecific

Extra-intestinal manifestations (EIMs), such as growth and development impairment and perianal disease, occur in 21% of children with IBDs.These non-classical manifestations are often the first signs of IBD.It is calculated that, for this reason, there would be a delay in diagnosis of paediatric CD of 3.4 months. 6ral manifestations (OMs) are part of EIMs of CD.Their prevalence in CD patients is 20-50% of the affected people.Lesions include ulcers, papules and edema of the lips, gingiva and vestibular sulci.In children, aphthous stomatitis occurs in 10-46%. 7Other authors report persistent lip swelling, cobble stoning of the oral mucosa, mucogingivitis, deep linear or serpiginous ulcerations surrounded by epithelial hyperplasia, tissue tags or polyps. 8Jajam et al. 7 classified them into specific oral lesions (labial swelling, cobble stoning of mucosa, mucogingivitis and linear ulcerations) and non-specific oral lesions (aphthous stomatitis, angular cheilitis and pyostomatitis vegetans).OMs can present before or after the diagnosis has been made, but, especially in paediatric patients, they usually precede or coincide with intestinal symptoms, so CD might be considered for paediatric patients with the above-reported oral lesions. 9ecognizing OMs, and EIMs in general, could represent a valuable tool to reduce the delay of CD's diagnosis in paediatric patients.Despite that consideration, in the literature, there are only few case reports about CD's OMs and few reviews about oral lesions in all IBDs.
Therefore, the purpose of this paper is to report an oral manifestation of CD in a paediatric patient.

DE SCR IP TION OF TH E CASE
In November 2020, a 15-year-old girl was referred to our group of Oral Pathology by the department of Paediatric Gastroenterology of Padua University's Hospital.
The patient was diagnosed with "Crohn's disease with pancolitis" in March 2018 and had already undergone several hospitalizations, due to a long history of perianal complications (the first one occurred in 2012).She was placed an ileostomy in March 2018 and had been treated with monthly infusions of Infliximab (IFX, a TNF-inhibitor) since April 2018.This therapy had been suspended only once, in March 2019, because of the appearance of labial herpetic lesions.The patient also suffered from allergic asthma, with respiratory attacks becoming less frequent and lighter.
At the time she came to our clinic, she was being treated with Adalimumab (ADA, a different TNF-inhibitor) and Azathioprine (an immunosuppressant) and the gastrointestinal disease was under control.She was also taking a vitamin D supplement and Levocetirizine (an antihistamine, to be taken when needed), while she was no longer being treated with aerosol of Beclomethasone (a steroid anti-inflammatory medication), since her allergic asthma was improving.
The patient was referred to our attention by her gastroenterologists because of some erythematous intraoral lesions, which they wanted to make sure were OMs of CD.
At the clinical examination, the gingiva and alveolar mucosa, especially in the upper arch, appeared reddened and edematous.(Figure 1) They were not painful, and the patient did not report any particular symptomatology.Angular cheilitis was also present on the left labial commissure.(Figure 2).
No other OMs of CD, such as mucosal tags, ulcers or cobblestoning, were present.The patient showed an ideal condition of oral hygiene, without presence of plaque nor signs of periodontal disease.
We suggested the execution of a histological examination of the lesions, in order to perform a differential diagnosis between an intraoral manifestation of CD and other orofacial granulomatous diseases (such as granulomatosis with polyangiitis, the once called Wegener's granulomatosis) or sarcoidosis.
Under local anaesthesia, a circular sample (5mm diameter) of the buccal alveolar mucosa in the upper right arch was collected through a punch biopsy.

CLINICAL RELEVANCE Scientific Rationale for the Study:
To highlight this gingival manifestation in a paediatric patient affected by Crohn's disease and how the final diagnosis of non-pathognomonic oral lesions should be based on the correlation between the clinical aspect and histopathological features.Principal Findings: Gingival reddening and swelling are not so frequently reported in the literature as an EIM of Crohn's disease (as is, for example, angular cheilitis) and could be easily mistaken with gingival inflammation of another nature.Practical Implications: The authors suggest that clinicians should always consider, in the process of differential diagnosis, that oral lesions could be manifestations of a systemic disease.

F I G U R E 1 Unusual gingival presentation of CD
The histological examination resulted in "fragment of oral mucosa with lymphocyte and monocyte inflammatory infiltration of the submucosa and the squamous epithelium, with formation of granulomatous-like aggregates within the submucosa and the deeper derma.Epithelial ulceration associated with leucocyte infiltration.Gigantic cells were not found.The immunohistochemical characterization found the prevalence of T lymphocytes (CD3 = 70%), B lymphocytes (CD20 = 20%) and macrophages (CD68 = 10%)."(Figures 3-4).
The final diagnosis established that the histological findings were compatible with intraoral manifestations of CD.

DISCUS SION
CD is a complex multisystemic inflammatory disorder in which genetics, microbiota and immune response interact in a complex and unpredictable way.This interaction can produce intestinal and extra-intestinal manifestations, where the second type is often prior or contemporaneous with intestinal symptoms. 8 paediatric patients, there is a higher prevalence of OMs, especially in severe phenotypes. 9Lesions can be painful and are associated with higher risk for tooth decay, since it is difficult for symptomatic patients to maintain a correct oral hygiene.This occurrence could compromise children's oral function and therefore their already impaired quality of life.Short-term therapies with topical corticosteroids for painful lesions and oral hygiene are the only way to treat this pattern. 9ral lesions are often non-specific, such as forms of stomatitis, angular cheilitis and glossitis. 8Most of them could challenge paediatric dentists because they are similar to other orofacial granulomatosis (OFGs) manifestations.OFGs are idiopathic chronic inflammations of the oral mucosa and lips. 10There is a non-well-established connection between OFGs and systemic diseases like CD or sarcoidosis.Evidence is not enough to establish whether OFGs are always specific entities. 10In certain cases, indeed, an OFG can be present together with a systemic disease. 11n our case, we discuss oral lesions in a patient affected by CD, lesions that could also be related to other pathologic entities.Since our patient showed a perfect oral hygiene, with no plaque accumulation nor bleeding on probing, and undergoes periodic dental examinations, we excluded infective/periodontal causes of gingival inflammation and focused on oral manifestations of systemic diseases.Discolouration and swelling of alveolar mucosa can be, indeed, OMs of CD 7 and enter differential diagnosis with manifestations of many other systemic diseases, such as ulcerative colitis, granulomatosis with polyangiitis, leukaemia, celiac disease, gastroesophageal reflux and Plummer-Vinson syndrome.
Being OMs of systemic disease frequently aspecific, diagnosis is based on the correlation between the clinical aspect and histopathological features; therefore, a biopsy of the lesions is necessary.In our case, the patient is orally asymptomatic, so, after diagnosis, we decided not to treat her and keep her monitored, to assure the maintenance of an optimal oral hygiene, which was fundamental to exclude plaque-induced gingivitis from differential diagnosis.
Maintaining a perfect oral hygiene appeared essential also because our patient requested an orthodontic treatment.In the literature, there is only one paper regarding orthodontic treatment in CD patients, 13 where the authors affirm that presence of condylar arthritis or lesions involving the periodontium represents a contraindication for orthodontic treatment and ultimately decided not to treat their patient.Our patient, however, shows no signs of arthritis or periodontal disease, is asymptomatic and keeps an optimal oral hygiene, so, in our opinion, the orthodontic treatment is not contraindicated.We suggested an orthodontic treatment with aligners, to minimize plaque retention and facilitate the maintenance of an optimal oral hygiene.
The decision to report a case of gingival presentation of CD was made to suggest that dentists, and especially pedodontists, can play an essential role for the early diagnosis of CD (and many other systemic diseases 14 ) and can help patients and other specialists manage this complex chronic pathology through time.

AC K NOW L E D GE M E N T
Open Access Funding provided by Universita degli Studi di Padova within the CRUI-CARE agreement.

C ON F L IC T OF I N T E R E S T
No conflict of interest has been declared by the authors.

F I G U R E 2
Angular chelitis F I G U R E 3 Histological examination: evidence of epithelial atrophy and ulceration (arrows).Magnification 10x F I G U R E 4 Immunohistochemistry analysis: Inflammatory cells phenotyping with antibody against CD20+ B-lymphocytes.Magnification 20x 1752248x, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ors.12682by University Of Padova Center Di, Wiley Online Library on [01/03/2023].See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions)on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License