References
Orofacial granulomatosis in children − a review
From Volume 46, Issue 1, January 2019 | Pages 42-48
Article
Orofacial granulomatosis (OFG) is a rare condition affecting both children and adults. It is characterized by granulomatous lesions affecting the orofacial region. It can appear as an isolated condition, the true definition of OFG.1 It is a diagnosis of exclusion as its features can present in conjunction with systemic granulomatous disorders such a Crohn's Disease (CD) and sarcoidosis.2 There has been speculation that OFG may be a predictor of future CD when seen in children.3 This article will focus on the paediatric patient presenting with clinical features of orofacial granulomatous lesions, including those later found to have CD.
History
Orofacial granulomatosis was first described in 1985 by Weisenfeld et al, who reported 60 cases presenting with lymphoedema and the presence of multiple non-caseating giant cell granulomatous lesions.4 It is closely related to Melkersson-Rosenthal syndrome which describes the triad of persistent lip or facial swelling, recurrent facial paralysis and fissured tongue.1
Prevalence
The true prevalence of this condition is unknown due to scant data on this subject,5 yet there has been speculation that the prevalence is greater in the Celtic regions.3 The average age of onset is 11 years within a paediatric population, with males reported to be affected more often than females.6
Clinical presentation
Orofacial granulomatosis can present with a variety of clinical features, which may present in varying number and severity across patients. These include lip swelling (Figures 1−3), full thickness gingival swelling (Figure 4), swelling of the non-labial facial tissues, peri-oral erythema, cobblestone-like appearance of the buccal and/or labial mucosa (Figure 5), linear oral ulceration (Figure 6), mucosal tags, lip fissuring (Figure 7), tongue fissuring and angular cheilitis.5,7
The most common feature of OFG is lip swelling. There are a number of differential diagnoses for lip swellings which should be considered when assessing a patient (Table 1). In the early stages this swelling is recurrent and feels soft and oedematous. Typically, after several recurrent episodes, the lip swelling becomes persistent, firm and indurated with the development of lip fissuring and exfoliation in more severe cases.5,8,9 Intra-oral ulceration consisting of either aphthous-like ulcers or deep linear ulcers in the depth of the buccal sulci (Figure 6) can be a presenting sign of OFG or develop as an additional feature during the course of the disease.10
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Aetiology and pathogenesis
The aetiology and pathogenesis of OFG is largely unknown,11,12,13 with the following factors being proposed in the literature:7
Hereditary and genetic factors
The available literature does not provide sufficient evidence to support a firm genetic link for OFG.14 There have been a small number of studies focusing on hereditary cases, however, no strong HLA associations have been identified when compared to healthy controls.15
Inflammatory/immunological factors
Research into this area remains limited. Current available evidence suggests a more cell-mediated (Th1) response in OFG with strong similarities to the inflammatory reaction seen in gut lesions in CD.16
Hypersensitivity reactions
Numerous allergens have been reported in OFG including dental materials, toothpaste and food substances/additives. The most common reported allergens associated with OFG are cinnamon and benzoate compounds.17,18 In some cases, standard and urticarial cutaneous patch testing can be used to detect such allergens.18 In some of these positive cases, satisfactory symptom improvement can be achieved solely by removing the triggering factors, for example through implementing an elimination diet.19
Interestingly, patients with OFG have much higher IgE-mediated atopy rates when compared with the normal population, meaning that they are more likely to suffer with conditions such as hayfever and asthma.20 The significance of this at present remains unclear.
Microbial factors
There is limited evidence to support a definitive role for microbiological agents in the aetiopathogenesis of OFG. It has been postulated that a microbial agent may be responsible for triggering the immune response that is seen. Infective agents of interest to date include Mycobacterium tuberculosis, Borrelia burgdorferi and Candida albicans.21,22,23
Link to systemic granulomatous disorders
The clinical features seen in OFG are identical to the orofacial manifestations of CD. CD is a chronic inflammatory bowel disease defined by segmental and transmural intestinal inflammation that can involve any part of the gastrointestinal (GI) tract. Bowel symptoms of CD include diarrhoea, abdominal pain and resultant weight loss. Research has shown that 40.4% of children diagnosed with OFG will also have CD, diagnosed either at the time of presentation or in the following months, with an average lag-time being 13 months.6 Therefore, it is recommended that paediatric patients with no GI symptoms are still reviewed by gastroenterology.
Oral granulomas can also occur in sarcoidosis. Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology which is rare in children.24 Oral lesions are uncommon but present as swellings, ulcers and gingivitis.25 Melkersson-Rosenthal syndrome (MRS) is a granulomatous disease of unknown aetiology characterized by a triad of symptoms − orofacial swelling, facial palsy and fissured tongue. Diagnosis of MRS in childhood is a rarity.26
Diagnosis
The diagnosis of OFG is made by the existence of salient clinical features in the absence of a relevant systemic disorder. A lip biopsy can be performed under local anaesthetic to confirm the presence of non-caseating granulomas, however, this is not essential for diagnosis and may not be appropriate for all children.
The investigations commonly performed are to exclude other granulomatous conditions such as those previously discussed. Such investigations will be arranged in secondary or tertiary care and may include serum angiotensin converting enzyme levels (increased in sarcoidosis), chest radiography (bilateral hilar lymphadenopathy in TB and/or sarcoidosis) and GI endoscopy/biopsy to exclude CD in appropriate cases. In primary care, a full blood count, haematinics and a faecal calprotectin could be arranged by the general medical practitioner as a first line investigation for CD.1
Some patients may be referred for various types of skin allergy testing, such as standard patch testing and urticarial testing. This can be useful in identifying any allergens that may act as a trigger for OFG.17
Management
Management of OFG can be difficult, with spontaneous remission being rare.27 The many treatment strategies available have shown varying responses and unpredictability, with no evidence to support the efficacy of one single agent over another. The management can be further complicated by a delay in diagnosis resulting in firm, indurated and cosmetically undesirable lip swelling.28 Persistent and unresponsive cases can cause significant psychological morbidity in young patients, where support may be required for the development of coping strategies to improve quality of life.8
It is important to begin with education; explaining the natural history of the disease and managing expectations of treatment outcome. The main aims of treatment are to reduce and ideally resolve any orofacial swelling, painful oral mucosal lesions and any other disease features, such as peri-oral erythema and angular cheilitis.
Primary care
Orofacial granulomatosis has many features that would be noticed on a routine dental check-up for paediatric patients. The presence of lip swelling may also result in the child seeking medical attention. Early identification is paramount, combined with a referral to the local oral medicine or paediatric dental team. The GDP has an important role to play, and can support the patient by implementing a diet diary to help identify any triggers, provide oral hygiene support to reduce plaque levels, in addition to providing regular professional cleaning. It may also be appropriate to prescribe topical therapies for the management of oral ulceration, such as analgesics, including benzydamine hydrochloride 0.15% (Difflam) in a spray or mouthwash form (Table 2).
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Secondary/tertiary care
It is common practice first to implement a cinnamon- and benzoate-free diet to eliminate any potential allergens.29 This intervention alone may be all that is needed in some patients to reduce the orofacial inflammation. The evidence surrounding the efficacy of such diets, however, is varied and it is not uncommon for additional interventions to be required.29 It is also prudent that any underlying haematinic deficiencies that may be identified during initial screening are addressed, as this may be contributing to any aphthous-like ulceration that may be present.
Selection of treatment methods depends on the severity and extent of the clinical presentation. The use of topical corticosteroid preparations (Table 3) can be useful in promoting reduction of lip swelling and oral ulceration.28 Topical tacrolimus applied to the lips has also been shown to improve lip swelling in some cases.30
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Topical Agents
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Intralesional Corticosteroids
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Systemic Agents
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Short courses of oral prednisolone may be used in severe cases or those unresponsive to topical treatment (Table 3). Systemic corticosteroid therapy, however, is not recommended for long-term use, due to its ability to stunt growth in childhood, as well as the numerous commonly known adverse side-effects.31 Intralesional corticosteroid injections (triamcinolone acetonide 40 mg/ml) (Table 3) have been shown to be effective in reducing lip swelling in some cases.32 The use of systemic steroid sparing agents such as Azathioprine,33 Thalidomide34 and Infliximab35 are used in more severe cases of chronic active OFG or in patients with oral manifestations of CD (Table 3). The need for careful pre-treatment counselling is required with these medications, along with long-term close monitoring.
Surgical procedures, such as cheiloplasty, can be used in those cases of unresponsive long-standing disfiguring swelling. It is recommended that these procedures are performed during a quiescent phase of the disease.36
Conclusion
Although a rare condition, OFG can present in children causing aesthetically unacceptable lip swelling and oral discomfort which has the potential to have deleterious psychological effects if left untreated. The GDP should be well equipped to recognize the signs and refer on to secondary care, as well as providing long-term support.