46 Orofacial

granulomatosis

Key Points

■ Orofacial granulomatosis can often present with lip swelling

■ Aetiologies can include orofacial granulomatosis, Crohn
disease, sarcoidosis, infections and lymphoma
■ Accompanying orofacial lesions may include ulcers, mucosal

‘cobblestones’, mucosal tags, gingival enlargements or facial

palsy
■ Diagnosis is confirmed by biopsy and other investigations

■ Treatment depends on the cause

INTRODUCTION
Fig. 46.2  Granulomatous cheilitis (same patient as Fig. 46.1)
Orofacial granulomatosis (OFG) is an uncommon condition
very similar to Crohn disease, due to granulomatous inflam-
mation (Fig.  46.1) and often presents with granulomatous
cheilitis, a rare, chronic swelling of the lip. OFG can also man- GENDER
ifest with angular stomatitis and/or cracked lips (Fig. 46.2), Either gender but males may predominate.
ulcers, mucosal tags, cobble-stoning or gingival hyperplasia.
GEOGRAPHIC
INCIDENCE No known geographic incidence.

It is uncommon.
PREDISPOSING FACTORS
AGE
OFG sometimes arises from an adverse reaction to various
The onset is usually in adolescents and young adult life and foods or additives which include cinnamic aldehyde, ben-
has no known racial predilection. zoates, butylated hydroxyinosole or dodecyl gallate (in
margarine), or menthol (in peppermint oil). Others have
or develop, gastrointestinal Crohn disease or sarcoidosis;
others have a postulated reaction to other antigens (e.g.
metals, such as cobalt), or paratuberculosis or mycobacte-
rial stress ­p rotein mSP65.

AETIOLOGY AND PATHOGENESIS

The cause of OFG is unknown, but it may be related to, or
may be, Crohn disease and there may be a genetic predispo-
sition. A delayed type of hypersensitivity reaction appears to
be involved, although the exact antigen inducing the immu-
nological reaction appears to vary in individual patients. The
inflammatory response is:
Fig. 46.1  Granulomatous cheilitis – persistent painless
diffuse swelling
■ probably mediated by cytokines such as tumour necrosis
298 factor (TNF) alpha, and by protease-activated receptors
 OROFACIAL GRANULOMATOSIS 46
(PARs), matrix metalloproteinases (MMPs) and cyclo-
oxygenases (COXs)
■ submucosal and chronic with many Th1 and mononuclear,
IL-1 producing cells and large, active, dendritic B cells
■ associated with non-caseating granulomas in the lamina
propria, which appear to cause lymphatic obstruction and
lymphoedema, resulting in the clinical swellings (Fig. 46.3).

CLINICAL FEATURES
OFG presents with:
■ Non-tender swelling and enlargement of one or both lips
(Figs 46.1 and 46.2). At the first episode the swelling typi- Fig. 46.4 Granulomatous cobblestoning in palate
cally subsides completely in hours or days, but after recurrent
attacks the swelling may persist, slowly increases in degree
and eventually becomes permanent. The lip involved may
feel soft, firm or nodular on palpation. Swellings involve, in
decreasing order of frequency, the lip and one or both cheeks.
Less commonly, lingual, palatal, gingival and buccal swell-
ings also may occur. The forehead, the eyelids or one side
of the scalp may be involved as well or in isolation. The
normal lip architecture is eventually chronically altered by
the persistence of lymphoedema and non-caseating granu-
lomas in the lamina propria. Once chronicity is established,
the enlarged lip appears cracked and fissured, with reddish
brown discolouration and scaling becomes painful and even-
tually acquires the consistency of firm rubber.
■ Thickening and folding of the oral mucosa produces a ‘cobble-
stone’ type of appearance and mucosal tags (Figs 46.4 – 46.6).
Purple granulomatous enlargements may appear on the
gingiva.
■ Ulcers appear: classically involving the buccal sulcus Fig. 46.5 Granulomatous swelling in floor of mouth
where they appear as linear ulcers, often with granuloma- ("staghorn sign")
tous masses flanking them.
■ The attacks of OFG are sometimes accompanied by:
■ fever and mild constitutional symptoms, including head-

ache and even visual disturbance

■ loss of sense of taste and decreased salivary gland secretion

■ cervical lymph node enlargement

■ central nervous system defects are sometimes reported,

but the significance of the resulting symptoms is easily

Fig. 46.3 OFG; granuloma arrowed Fig. 46.6 OFG mucosal tag
299
46 SECTION 4 COMMON AND IMPORTANT OROFACIAL CONDITIONS

overlooked as they are very variable, sometimes simu- only lymphoedema and perivascular lymphocytic infiltration.
lating disseminated sclerosis, but often with a poorly However, with time, the infiltrate usually becomes more dense
defined association of psychotic and neurological fea- and pleomorphic, and small focal granulomas are formed, which
tures. Autonomic disturbances may occur in OFG are indistinguishable from those of Crohn disease or
■ occasionally, deficits of cranial nerves (olfactory, facial, sarcoidosis. Patch tests and RAST may be indicated to exclude
auditory, glossopharyngeal, vagus and hypoglossal) may reactions to various foodstuffs or additives. Both standard and urti-
arise. Facial palsy occurs in up to 30% of cases, more carial patch testing are used to detect such allergies. Elimination
commonly develops late, but may precede the attacks of diets have also been shown to be diagnostic in some patients.
swelling by months or years. Though intermittent at first, Investigation of the gastrointestinal tract (endoscopy, radi-
the palsy is lower motor neurone type and may become ography and biopsy) is mandatory to exclude Crohn disease;
permanent. It may be unilateral or bilateral, and partial or endoscopic and histologic intestinal abnormalities are common
complete and is part of the Melkersson–Rosenthal syn- in younger patients even when there are no gastrointestinal
drome (see Ch. 56). symptoms. Sarcoidosis may be excluded by chest radiography,
■ A fissured or plicated tongue (seen in 20–40% of cases), serum angiotensin converting enzyme, and a gallium scan, and
which is part of the Melkersson–Rosenthal syndrome, pres- a tuberculin skin test may also be indicated.
ent from birth.
TREATMENT (see also Chs 4 and 5)
DIAGNOSIS Reactions to dietary components should be sought and pos-
The early attacks of OFG may be impossible to clinically sible provoking substances avoided (Table 46.2). Elimination
differentiate from angioedema, but persistence of the swell- diets may be warranted and many patients respond. OFG may
ing between attacks should suggest the diagnosis. Similar be an initial manifestation of Crohn disease and so careful
swelling may also be seen in a range of conditions including: surveillance and specialist care are recommended. Management
is to treat recalcitrant lesions medically. Conservative manage-
■ Melkersson–Rosenthal syndrome (Ch. 56), Miescher chei- ment usually includes topical corticosteroids, intralesional cor-
litis (Ch. 56), Crohn disease or sarcoidosis. ticosteroid injections (such as low-volume, high-concentrate,
■ Lymphomas. extended-release triamcinolone) or topical tacrolimus. Oral
■ Infections: rare cases of lip or oral swelling related to tubercu- clofazimine 100–200 mg daily for 3–6 months (hyperpigmenta-
losis or leprosy have been reported. Agents such as Borrelia tion and raised liver enzymes are adverse effects) may be help-
burgdorferi have been discounted as causes of OFG. ful. Other therapies include NSAIDs, sulfasalazine, antibiotics
■ Liver transplantation – mucosal lesions similar to OFG such as metronidazole, antimalarials such as hydroxychloro-
have been reported. quine, mast cell stabilizers, or low-dose methotrexate. Rarely,
■ Foreign body reactions. cheiloplasty is indicated.
■ Rarely, Ascher syndrome, although the swelling of the lip is
caused by redundant salivary tissue and is associated with EMERGENT TREATMENTS
blepharochalasia and present from childhood (see Ch. 56).
If OFG fails to respond to diet or topical measures, systemic
The many causes of oedema of the lips make the diagnosis one immunomodulators may be required, under specialist supervi-
based on exclusion, on clinical signs and on histological exam- sion. These include anti-TNF therapies such as thalidomide, ada-
ination. This is supported by blood tests, radiology, endoscopy, lumimab or infliximab, but should be used only with caution.
and biopsy to differentiate the above (Table  46.1). Lesional
biopsy is often indicated but, during the early stages, may show
Table 46.2 Regimens that might be helpful in management
of patient suspected of having orofacial granulomatosis
Table 46.1 Aids that might be helpful in diagnosis/
prognosis/management in some patients suspected of Use in secondary
having orofacial granulomatosis* care (severe
oral involvement
In most cases In some cases Use in and/or extraoral
Regimen primary care involvement)
Gastroenterological opinion Patch tests
Biopsy RAST Likely to be Dietary modification Clofazimine
Full blood picture Elimination diet beneficial (antigen exclusion) Corticosteroids
Serum ferritin, vitamin B12 G6PD and TPMT levels Intralesional Thalidomide
and corrected whole blood Blood pressure corticosteroids
folate levels Blood glucose Topical corticosteroids
ESR DEXA (dual-emission X-ray Topical tacrolimus
SACE absorptiometry)
Chest radiography Unproven Topical pimecrolimus Hydroxychloroquine
Gastrointestinal imaging, effectiveness Metronidazole
endoscopy, biopsy Sulfasalazine
Tuberculin testing
Emergent Infliximab
*See text for details and glossary for abbreviations. treatments Adalumimab
300
 OROFACIAL GRANULOMATOSIS 46
■ The cause is unknown but it may be immunological.
FOLLOW-UP OF PATIENTS ■ It is not thought to be inherited.
■ It is not thought to be infectious.
Long-term follow-up as shared care is usually appropriate. ■ It usually has no long-term consequences but related conditions such
as Crohn disease may affect the gut and other tissues.
■ Some patients have food or food additive intolerance or allergy: most
PATIENT INFORMATION SHEET
commonly this is to cinnamaldehyde, carnosine, monosodium gluta-
Orofacial granulomatosis (OFG) mate, cocoa, carbone, or sunset yellow.
▼ Please note this is our provisional diagnosis which must be confirmed ■ Blood tests, X-rays, biopsy, allergy tests and other investigations
by tests. If you have any questions, particularly about the treatment or are often required–mainly to exclude Crohn disease, sarcoidosis and
potential side-effects, please ask. allergies.
■ OFG is an uncommon condition. ■ OFG may be controlled by avoiding allergens, or by using medicines.

USEFUL WEBSITES
Circa, Children with Crohns and Colitis. http://www. Dermnet, N.Z., Orofacial granulomatosis. Emedicine, Cheilitis Granulomatosa (Miescher-
cicra.org/ http://dermnetnz.org/site-age-specific/orofacial- Melkersson-Rosenthal Syndrome). http://emedicine.
granulomatosis.html medscape.com/article/1075333-overview

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