Orofacial granulomatosis (OFG) is a condition characterized by persistent enlargement of the

soft tissue Soft tissue connective tissue, connects and surrounds or supports internal organs and bones, and includes muscle, tendons, ligaments, Adipose tissue, fat, fibrous tissue, Lymphatic vessel, lymph and blood vessels, fasciae, and synovial membranes.� ...

s of the mouth, lips and the area around the mouth on the face. The enlargement does not cause any pain, but the best treatment and the prognosis are uncertain. The mechanism of the enlargement is

granulomatous inflammation A granuloma is an aggregation of macrophages (along with other cells) that forms in response to chronic inflammation. This occurs when the immune system attempts to isolate foreign substances that it is otherwise unable to eliminate. Such subst ...

. The underlying cause of the condition is not completely understood, and there is disagreement as to how it relates to

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...

and

sarcoidosis Sarcoidosis (; also known as Besnier–Boeck–Schaumann disease) is a disease involving abnormal collections of White blood cell, inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph n ...

Signs and symptoms

Signs and symptoms may include: * Persistent or recurrent enlargement of the lips, causing them to protrude. If recurrent, the interval during which the lips are enlarged may be weeks or months. The enlargement can cause midline fissuring of the lip ("median cheilitis") or

angular cheilitis Angular cheilitis (AC) is inflammation of one or both corners of the mouth. Often the corners are red with skin breakdown and crusting. It can also be itchy or painful. The condition can last for days to years. Angular cheilitis is a type of ch ...

(sores at the corner of the mouth). The swelling is non-pitting (cf.

pitting edema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may inclu ...

) and feels soft or rubbery on

palpation Palpation is the process of using one's hands to check the body, especially while perceiving/diagnosing a disease or illness. Usually performed by a health care practitioner, it is the process of feeling an object in or on the body to determine ...

. The

mucous membrane A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It ...

of the lip may be

erythema Erythema (, ) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not associated with pathology inc ...

tous (red) and granular. One or both lips may be affected. *

Oral ulceration A mouth ulcer (aphtha), or sometimes called a canker sore or salt blister, is an ulcer that occurs on the mucous membrane of the oral cavity. Mouth ulcers are very common, occurring in association with many diseases and by many different mechanis ...

(mouth ulcers) which may be aphthous like, or be more chronic and deep with raised margins. Alternatively, lesions similar to pyostomatitis vegetans may occur in OFG, but this is uncommon. * "Full width" gingivitis (compare with marginal gingivitis). *

Gingival enlargement Gingival enlargement is an increase in the size of the gingiva (gums). It is a common feature of gingival disease. Gingival enlargement can be caused by a number of factors, including inflammatory conditions and the side effects of certain medica ...

(swelling of the gums). *

Fissured tongue Fissured tongue is a Benignity, benign condition characterized by deep grooves (fissure (anatomy), fissures) in the Dorsum (anatomy), dorsum of the tongue. Although these grooves may look unsettling, the condition is usually painless. Some individ ...

(grooves in the tongue). * Enlargement of the mucous membrane of the mouth, which may be associated with cobblestoning and mucosal tags (similar lesions often occur on the intestinal mucosa in Crohn disease). * Enlargement of the perioral and periorbital soft tissues (the tissues of the face around the mouth and the eyes). The facial skin may be dry, exfoliative (flaking) or erythematous. *

Cervical lymphadenopathy Cervical lymphadenopathy refers to lymphadenopathy of the cervical lymph nodes (the glands in the neck). The term ''lymphadenopathy'' strictly speaking refers to disease of the lymph nodes, though it is often used to describe the enlargement of th ...

(enlarged

lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...

s in the neck). *

Facial palsy Facial nerve paralysis is a common problem that involves the paralysis of any structures innervated by the facial nerve. The pathway of the facial nerve is long and relatively convoluted, so there are a number of causes that may result in facial ...

(weakness and altered sensation of the face). The enlargement of the tissues of the mouth, lips and face seen in OFG is painless.

Melkersson–Rosenthal syndrome Melkersson–Rosenthal syndrome is a rare neurological disorder characterized by recurring facial paralysis, swelling of the face and lips (usually the upper lip: cheilitis granulomatosis) and the development of folds and furrows in the tongue ( ...

is where OFG occurs with fissured tongue and

paralysis Paralysis (: paralyses; also known as plegia) is a loss of Motor skill, motor function in one or more Skeletal muscle, muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory d ...

of the

facial nerve The facial nerve, also known as the seventh cranial nerve, cranial nerve VII, or simply CN VII, is a cranial nerve that emerges from the pons of the brainstem, controls the muscles of facial expression, and functions in the conveyance of ta ...

. The cause of the facial paralysis is thought to be caused by the formation of granulomas in the facial nerve, which supplies the

muscles of facial expression The facial muscles are a group of striated skeletal muscles supplied by the facial nerve (cranial nerve VII) that, among other things, control facial expression. These muscles are also called mimetic muscles. They are only found in mammals, alth ...

Causes

The cause of the condition is unknown. The disease is characterized by non-caseating granulomatous inflammation. That is, the granulomas do not undergo the caseating ("cheese-like")

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...

typical of the granulomas of

tuberculosis Tuberculosis (TB), also known colloquially as the "white death", or historically as consumption, is a contagious disease usually caused by ''Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can al ...

. There is disagreement as to whether OFG represents an early form of

, or whether it is a distinct, but similar clinical entity. Crohn disease can affect any part of gastrointestinal tract, from mouth to anus. When it involves the mouth alone, some authors refer to this as "oral Crohn disease", distinguishing it from OFG, and others suggest that OFG is the same condition as Crohn disease when it presents in the oral cavity. OFG may represent a delayed

hypersensitivity reaction Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes im ...

, but the causative

antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

(s) is not identified or varies form one individual to the next. Suspected sources of antigens include metals, e.g.

cobalt Cobalt is a chemical element; it has Symbol (chemistry), symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. ...

, or additives and preservatives in foods, including

benzoate Benzoic acid () is a white (or colorless) solid organic compound with the formula , whose structure consists of a benzene ring () with a carboxyl () substituent. The benzoyl group is often abbreviated "Bz" (not to be confused with "Bn," which ...

benzoic acid Benzoic acid () is a white (or colorless) solid organic compound with the formula , whose structure consists of a benzene ring () with a carboxyl () substituent. The benzoyl group is often abbreviated "Bz" (not to be confused with "Bn," which ...

cinnamaldehyde Cinnamaldehyde is an organic compound with the formula or . Occurring naturally as predominantly the ''trans'' (''E'') isomer, it gives cinnamon its flavor and odor. It is a phenylpropanoid that is naturally synthesized by the shikimate pathway ...

, metabisulfates,

butylated hydroxyanisole Butylated hydroxyanisole (BHA) is a synthetic, waxy, solid petrochemical. Its antioxidant properties have caused it to be widely used as a preservative in food, food packaging, animal feed, cosmetics, pharmaceuticals, rubber, and petroleum product ...

dodecyl gallate Dodecyl gallate, or lauryl gallate, is the ester of dodecanol and gallic acid. As a food additive it is used under the E number E312 as an antioxidant and preservative A preservative is a substance or a chemical that is added to products such ...

tartrazine Tartrazine is a synthetic lemon yellow azo dye primarily used as a food coloring. It is also known as E number E102, C.I. 19140, FD&C Yellow 5, Yellow 5 Lake, Acid Yellow 23, Food Yellow 4, and trisodium 1-(4-sulfonatophenyl)-4-(4-sulfonato ...

, or

menthol Menthol is an organic compound, specifically a Monoterpene, monoterpenoid, that occurs naturally in the oils of several plants in the Mentha, mint family, such as Mentha arvensis, corn mint and peppermint. It is a white or clear waxy crystallin ...

, Examples of foods which may contain these substances include margarine, cinnamon, eggs, chocolate or peppermint oil. Some suggest that infection with atypical mycobacteria could be involved, (

paratuberculosis Paratuberculosis is a contagious, chronic and sometimes fatal infection that primarily affects the small intestine of ruminants. It is caused by the bacterium ''Mycobacterium avium'' subspecies ''paratuberculosis''. Infections normally affect r ...

), and that OFG is a reaction to mycobacterial stress protein mSP65 acting as an antigen. In response to an antigen, a chronic, submucosal,

T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...

mediated inflammatory response occurs, which involves

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

s (e.g.

tumor necrosis factor alpha Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...

protease-activated receptor Protease-activated receptors (PAR) are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, and also on endothelial cells, fibroblasts ...

matrix metalloproteinase Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs be ...

s and

cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such a ...

s. The granulomas in OFG form in the

lamina propria The lamina propria is a thin layer of connective tissue that forms part of the moist linings known as mucous membranes or mucosae, which line various tubes in the body, such as the respiratory tract, the gastrointestinal tract, and the urogenital ...

, and may form adjacent to or within lymphatic vessels. This is thought to cause obstruction of lymphatic drainage and

lymphedema Lymphedema, also known as lymphoedema and lymphatic edema, is a condition of localized edema, swelling caused by a compromised lymphatic system. The lymphatic system functions as a critical portion of the body's immune system and returns inters ...

which is manifest as swelling clinically. There may be a genetic predisposition to the condition. People who develop OFG often have a history of

atopy Atopy is the tendency to produce an exaggerated immunoglobulin E (IgE) immune response to otherwise harmless substances in the environment. Allergic diseases are clinical manifestations of such inappropriate, atopic responses. Atopy may have ...

, such as childhood

asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...

eczema Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...

Diagnosis

The diagnosis is usually made by tissue

biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, an interventional radiologist, or an interventional cardiology, interventional cardiologist. The process involves the extraction of sampling (medicine), sample ...

, however this cannot reliably distinguish between the granulomas of OFG and those of Crohn disease or sarcoidosis. Other causes of granulomatous inflammation are ruled out, such as sarcoidosis, Crohn disease,

allergic Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, alle ...

foreign body reaction A foreign body reaction (FBR) is a typical tissue response to a foreign body within biological tissue. It usually includes the formation of a foreign body granuloma. Tissue encapsulation of an implant is an example, as is inflammation around a spl ...

s and mycobacterial infections.

Classification

OFG could be classified as a type of

cheilitis Cheilitis also called and known as chapped lips, is a medical condition characterized by inflammation of the lips. The inflammation may include the perioral skin (the skin around the mouth), the vermilion border, or the Oral mucosa#Types, labial ...

(lip inflammation), hence the alternative names for the condition using the word cheilitis, and a granulomatous condition.

Treatment

Anti-tumour necrosis factor α drugs (e.g.

infliximab Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing ...

) Dietary restriction of a particular suspected or proven antigen may be involved in the management of OFG, such as cinnamon or benzoate-free diets.

Epidemiology

OFG is uncommon, but the incidence is increasing. The disease usually presents in adolescence or young adulthood. It may occur in either sex, but males are slightly more commonly affected.

Signs and symptoms

Causes

Diagnosis

Classification

Treatment

Epidemiology

History

References

External links