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21
Orofacial Manifestations ofSystemic Diseases: An Overview
Philip Atkin
Oral Medicine, School of Dentistry, Cardiff University, Cardiff, United Kingdom
21.1 Introduction: Historical Background
As long ago as the 5th century BCE in ancient Greece, Hippocrates and his school noted a systemic
disease with oral manifestations(1). They described a condition with ulcers in the mouth, genital
ulcers, skin rashes and inflammation of the eyes, among other anatomical sites. This condition was
later described by Behcet, for whom the syndrome is now named(2).
Cheraskin (3) from the Journal of the National Medical Association, in his paper ‘Oral
Manifestations of Systemic Disease’, claimed:
‘…approximately 200 systemic disorders are accompanied by oral symptoms and signs.
Inmany instances, the oral clues are the first and sometimes even the only evidence of a
disturbed state’.
In the published literature, scientific paper titles referring to ‘oral manifestations’ go back more
than a hundred years, with Bloch proposing ‘A Classification of Oral Manifestations of Systemic
Diseases According to Type’ (4). In 1927, there was an account of the ‘Discussion on Oral
Manifestations of Systemic Disease in Children’ at the Royal Society of Medicine in London, where
a patient presenting with an oral manifestation of a skin disorder was described. Mr. FN Doubleday
(dental surgeon) gave an account of one of his patients presenting to the clinic(5):
‘… a woman who said that from childhood onwards, she had suffered from ulceration in her
mouth, which had been attributed to congenital syphilis. She brought with her two papers
showing that, at different times, her Wassermann reaction had been tested and had proved
negative. (…) The dressers were reminded that the mucous membrane of the mouth was
merely part of the skin invaginated to meet the upper end of the oesophagus, and it was
found that she had skin lesions also. On being referred to Dr. Barber of the Dermatological
Department, he sent her back with the diagnosis that the disease was lichen planus, with
unusual lesions of that disease in the mouth’.
Pathological Basis of Oral and Maxillofacial Diseases, First Edition. Edited by S. R. Prabhu, Syed Ali Khurram,
OmarKujan and Merva Soluk Tekkesin.
© 2025 John Wiley & Sons Ltd. Published 2025 by John Wiley & Sons Ltd.
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21.2 Skin Disease
In a 1945 paper from the Yale Journal of Biology and Medicine entitled ‘Oral Manifestations of
Certain Systemic Disorders’, there is a report of a 63- year- old man presenting to the clinic who also
complained of gastrointestinal (GI) upset(6):
‘The oral mucosa showed irregular diffused areas of redness and superficial ulceration,
showing here and there a whitish coating. Near the middle of the right cheek’s mucosa were
two elevated ulceration patches covered with a fibrinous exudate. The physical examination
was negative; gastric analysis revealed achlorhydria, and examination of the blood showed
slight hypochromic anaemia.’
The authors say, ‘One is reminded here that the embryological and functional unity of the gastrointestinal tract includes the oral cavity. Functional changes in the stomach and intestinal tract
may be associated with oral lesions more often than is recognised or suspected.’
Skin and GI disease are some of the more frequent presentations of oral manifestations of systemic disease that present to general dental practitioners, dental and medical specialists, and so
may be referred to oral medicine specialists for further diagnosis and management.
21.2 Skin Disease
21.2.1 Lichen Planus
Lichen planus (LP) is the skin disorder most often seen in the oral mucosal tissues. LP is considered
a T- cell mediated reaction directed against epithelial basal cells, but the target antigen, whether
endogenous or exogenous, is unknown(7). Oral lichen planus (OLP) can present in several ways: the
most common are reticular, atrophic, erosive, ulcerative, plaque- like, papular and rarely, bullous.
Lesions often present with multiple of these descriptors. Skin lesions are typically raised, itchy, violaceous polygonal papules which classically affect the anterior (ventral) surfaces of the wrists and
shins but may also affect the chest, back and scalp. Genital lesions may also be present, and for
females presenting with a pattern of desquamative gingivitis as part of their OLP, vulval lesions are
more common. This has been proposed as a distinct form of lichen planus, vulva- vaginal- gingival
syndrome (VVG)(8).
Lesions of OLP are commonly symmetrical, seen in both buccal mucosae, both lateral borders of
the tongue, or both sides of the hard palate. The sites are typically symmetrical, but the presentations or types (see above) may differ.
OLP has also been proposed as a manifestation of systemic viral diseases, most commonly with
hepatitis C, but also with human papillomavirus (HPV), herpes simplex, Epstein– Barr virus (EBV)
and cytomegalovirus (CMV)(9, 10).
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21.2.2 Lichenoid Reaction
Lichenoid reactions, so- called because of the similarity in appearance to OLP, can be divided
into lichenoid lesions caused by contact with a material which the patient is sensitive to or to a
drug that the patients take for some other condition– similar in many ways to a fixed- drug
eruption presenting on the skin. In the mouth, patients may show mucosal lesions where the
tissue is in contact with a dental restoration, often metal. Similarly, they will have reactions on
the skin to the same materials. A mucosal reaction to a gold crown may be mirrored by a skin
reaction to gold jewellery. There are several families of medications which are known to
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precipitate lichenoid reactions in the mouth and skin. These include antihypertensives
(beta- blockers, ACE inhibitors), hypoglycaemic drugs for managing diabetes (chlorpropamide)
and even familiar and readily available analgesics for managing acute and chronic pain
(NSAIDs)(11).
21.2.3 Graft Versus Host Disease
Graft- versus- host disease (GVHD) occurs following a bone marrow transplant, and the newly
reconstituted immune system reacts to the host tissues. GVHD can appear on the skin, in solid
organs (e.g. the liver) and oral mucosal tissues. The clinical appearances can be very similar to
those of OLP, and the histology also looks similar on biopsy. Except in the case of GVHD, the band
of inflammatory cells, predominantly lymphocytes, found just below the basement membrane in
the oral mucosa will be the grafted cells from the bone marrow transplant(12).
21.2.4 Bullous Diseases
21.2.4.1 Pemphigus
Pemphigus is a blistering disorder affecting the skin and mucosa. The binding between epithelial cells is weakened by an autoimmune inflammatory reaction directed at transmembrane
proteins within the desmosomes, which bind cells together. Several subtypes of pemphigus
include pemphigus vulgaris, pemphigus foliaceous and paraneoplastic pemphigus (now called
paraneoplastic autoimmune multi- organ syndrome/PAMS). Pemphigus vulgaris and paraneoplastic pemphigus are most commonly associated with oral mucosal involvement. Fragile
mucosal blisters break down to leave erosions and ulceration. Desquamative gingivitis is often
seen in association with oral mucosal ulcerations. Diagnosis of the bullous diseases will often
include direct and indirect immunofluorescence studies using patients’ serum and biopsy of
affected tissues.
21.2.4.2 Pemphigoid
Pemphigoid is a sub- epithelial blistering disorder with an autoimmune inflammatory reaction
directed towards transmembrane proteins within the hemidesmosomes binding epithelial cells to
the basement membrane. Blisters in the skin and oral mucosa remain intact longer than those of
pemphigus since the blister roof is composed of the whole thickness of the epithelium. As with
pemphigus, there will typically be a pattern of desquamative gingivitis alongside oral mucosal
ulceration. There may also be conjunctival involvement in the disease, causing damage to the eye
and potentially scarring over the lens(13).
21.2.4.3 IgA Disease and Dermatitis Herpetiformis
IgA antibodies present at the basement membrane zone in linear IgA disease and dermatitis herpetiformis. Linear IgA disease is an autoimmune mucocutaneous disease characterised by linear
deposits of IgA at the basement membrane, in contrast to IgG antibodies seen in pemphigoid.
Dermatitis herpetiformis is linked to gluten intolerance, and a gluten- free diet can eliminate symptoms. In the oral mucosa, ulcerations of affected individuals occur because of tissue fragility from
the disease. Still, they may also appear because the mucosal integrity is compromised secondary to
iron, vitamin B12 and folic acid deficiencies due to malabsorption and small- bowel inflammation
from the gluten enteropathy(14).
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21.3 Gastrointestinal Disease
21.2.4.4 Other Blistering Disorders
Less common bullous diseases affecting the skin and oral tissues include epidermolysis bullosa (EB)
and erythema multiforme (EM). Epidermolysis bullosa is a collection of rare congenital dermatoses
affecting the skin and mucosae. The tissues are extremely fragile, and even very minor trauma can
produce blistering. The severity of the disease can range from mild to fatal(15). Erythema multiforme affects the oral mucosa, causing sometimes extensive oral mucosal blistering, ulceration and
sloughing, often also including the vermillion of the lips. Erythematous, circular skin lesions also
appear, known as target lesions. The skin also suffers from blistering and ulceration. The presentation of EM is similar to that of Stevens– Johnson syndrome (SJS)/toxic epidermolysis, and they were
previously thought to be the same disease but with a spectrum of severity. They are recognised now
as separate conditions with an overlap in aetiology but differences in management. The most common trigger for EM is an infectious cause, typically herpes simplex virus (HSV) or a bacterium
(Mycoplasma pneumoniae). Other triggers include common medications such as non- steroidal anti-
inflammatory analgesics (NSAIDs) and antibiotics, and there are also links to systemic diseases
such as inflammatory bowel disease and Behcet’s disease(16).
21.2.5 Psoriasis
Psoriasis affecting the skin has several well- recognised and recognisable presentations. Psoriatic
patches comprise dry, raised, thickened skin with a silvery white scale on the surface. It typically
presents on the extensor surfaces of knees and elbows, as well as the trunk and scalp. Whether
there are lesions that could be considered ‘oral psoriasis’ has been the subject of ongoing debate for
many years. It is said that geographic tongue and fissured tongue are more common in patients
with known psoriasis, but the converse is not always the case(17, 18).
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21.2.6 Acanthosis Nigricans
Acanthosis nigricans is a rare condition affecting the skin, with the development of velvety black
lesions which may affect the flexor surfaces of joints, posterior neck folds and the axillae. In the
oral cavity, there may be extensive mucosal papillomatous lesions. There is a benign form of acanthosis nigricans, but more importantly, it can be associated with internal malignancies such as
squamous carcinoma of the cervix and lung, adenocarcinomas in the GI tract, breast and
gonads(17, 19).
21.3 Gastrointestinal Disease
21.3.1 Crohn’s Disease
Crohn’s disease is an inflammatory bowel disease which can affect any part of the GI tract, including the mouth. Crohn’s is a granulomatous disease, and on GI mucosal biopsies, granulomas can be
found, helping to confirm the diagnosis. Biopsy of oral tissues is much less likely to demonstrate
granulomas, but the biopsy site will act as a focus of inflammation for months and even years.
Diagnosis of oral Crohn’s is typically made on the clinical presentation associated with GI signs and
symptoms. In the gut, Crohn’s produces full- thickness inflammation from the mucosal lining of the
gut through the submucosa, muscular layers and the covering serosal layer. In the orofacial tissues,
inflammation and erythema of the skin of the face, thickening of the buccal and labial tissues, and
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mucosal inflammation and ulceration mirror the full- thickness inflammation in the rest of the gut.
Other oral mucosal signs of Crohn’s include round/oval aphthous ulcers (either directly as part of
Crohn’s or anaemia following malabsorption and bleeding in the gut), as well as deep linear ulcers
in the buccal sulci, mucosal tags, lip swelling and angular cheilitis. The attached gingival tissues
may also be swollen and erythematous. There is a similar presentation in the orofacial tissues but
without GI symptoms, known as orofacial granulomatosis (OFG). In children, about half progress
from OFG to Crohn’s with a mean time to development of Crohn’s of around 13months(18). With
OFG, in contrast to Crohn’s, some of the flares of inflammation, swelling and ulceration can be
linked to exposure to foods and drinks containing cinnamon and benzoates. So, symptoms can be
managed with dietary manipulation. This is not the case with Crohn’s disease(20).
21.3.2 Ulcerative Colitis andPyostomatitis Vegetans
In contrast to Crohn’s disease, which can affect any part of the GI tract, ulcerative colitis (UC)
affects the colon and occasionally terminal ileum. Also, in contrast to Crohn’s, the inflammation is
of the mucosal luminal lining, where fluid exudates and bleeding will occur. The most common
oral manifestations of UC are due to anaemia, which follows gut lumen inflammation, typically
aphthous ulceration of the oral mucosa. There is a less common oral presentation of both Crohn’s
and UC, pyostomatitis vegetans, where the gingival tissues are inflamed, thickened and display
small pustular eruptions composed of microabscesses in the spinous/prickle cell layer of gingival
epithelium. Other oral mucosal sites may be affected(21).
21.3.3 Coeliac Disease
Gluten sensitivity is the underlying pathology in coeliac disease. Skin manifestations include
vesicular eruptions on the elbows, knees and buttocks. Oral mucosal manifestations include aphthous ulceration. Small bowel inflammation caused by the immune reaction to cereal grain proteins (in wheat, barley and rye) leads to poor absorption of iron, B12 and folic acid, among other
nutrients, and the resulting anaemia may additionally lead to aphthous oral mucosal ulceration,
on top of the ulceration directly associated with the disease(22, 23).
21.3.4 Peutz– Jeghers Syndrome andGardener Syndrome
Both Peutz– Jeghers and Gardener syndromes are associated with the formation of polyps in the GI
tract, which are associated with a high risk of malignant change in patients of all ages. There is also
an increased risk of extra- GI malignancies in both diseases. Peutz– Jeghers syndrome has marked
peri- oral freckling of black, brown or greyish colour and oral mucosal freckling. In Gardner’s syndrome, the main orofacial manifestation is the development of osteomas. These may be seen on
rotational tomograms (more than three should raise suspicion). If they are located in important
anatomical structures such as the temporomandibular joint (TMJ), then movement may be
restricted. Supernumerary teeth and cementomas are also a feature(24).
21.3.5 Gastroesophageal Reflux Disease (GERD) and Eating Disorders
In GERD, there is involuntary regurgitation of the acid content of the stomach into the upper GI
tract. The inflammation and irritation of the oesophagus leads to heartburn. If the acidic fluid
reaches the oral cavity, it can cause typical erosion patterns on the palatal surfaces of upper
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incisors and later occlusal surfaces of molar teeth. It can also cause a burning sensation and altered
taste. In bulimia nervosa, an eating disorder, there is the deliberate triggering of regurgitation of
stomach contents, which produces similar patterns of erosion. The frequent regurgitation of stomach content can also cause Sialosis (sialoadenosis)– a benign enlargement of the salivary glands
with no loss of salivary function. Sialosis is also associated with diabetes, chronic alcohol misuse,
kidney failure and liver cirrhosis(25).
21.4 Salivary Gland Disease
21.4.1 Sjogren’s Syndrome
Sjogren’s syndrome is an autoimmune disease- causing inflammation and scarring of glandular
tissue and a reduction in the secretion of saliva and tears in the relevant glands. Systemic features
of Sjogren’s syndrome include fatigue, dry and itchy skin and morning joint stiffness. Patients with
Sjogren’s syndrome have an increased likelihood of developing lymphoma, particularly nonHodgkin’s lymphoma.
Sjogren’s syndrome has long been divided into primary and secondary forms, where the
secondary form develops after some other, typically also autoimmune, connective tissue
disorderhas manifested conditions such as rheumatoid arthritis, systemic lupus erythematosus
and scleroderma. Diagnosis is with high- resolution ultrasound, serology and labial gland
biopsy(26, 27).
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21.4.2 Salivary Gland Swelling
Persistent salivary gland swelling can occur as a sialosis (as above) or may be associated with
infections such as mumps, hepatitis C and human immunodeficiency virus (HIV). It should be
noted that the most common cause of a dry mouth from reduced saliva production is a result of
medications prescribed for other conditions and radiotherapy to the head and neck in managing
malignancy.
21.5 Oral Mucosal Ulceration fromMineral or Vitamin Deficiency
The oral mucosa, in common with the rest of the GI tract, has a rapid cell turnover and renewal.
Any deficiencies of vitamins or minerals can manifest in the oral soft tissues, often as aphthous
ulcers or sensory changes (e.g. dry mouth, burning mouth).
21.5.1 Iron Deficiency
Iron deficiency, typically measured using serum ferritin levels, can be associated with oral aphthous ulceration. Iron deficiency may result from dietary insufficiency, but where the diet is adequate for iron content, small bowel inflammation through diseases such as Crohn’s or coeliac
disease will reduce absorption. Iron levels will drop from blood loss through inflammatory diseases
such as Crohn’s and ulcerative colitis or malignant diseases such as GI polyps transforming into
adenocarcinomas.
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21.5.2 Vitamin B9 (Folate) and Vitamin B12 (Cyanocobalamin) Deficiency
B9 and B12 deficiency through dietary insufficiency or malabsorption can cause angular cheilitis,
recurrent aphthous ulceration, mucosal thinning and sensitivity and sensory neurological
problems of the tongue and mucosa; sensation of dryness, taste disturbance and numbness. B12
deficiency may also result from a lack of intrinsic factor secretion, partial gastrectomy or an
autoimmune process– pernicious anaemia(28).
21.6 Infective Disease
21.6.1 Oral Flora
The commensal oral flora is typically a mix of bacteria and candida species. Changes in the oral
environment can affect the oral flora and precipitate disease. For example, a dry mouth from drugs,
diabetes or radiotherapy might encourage the development of candida, especially in protected sites
such as beneath a denture. Raised blood sugar from poorly controlled diabetes may do the same.
Broad- spectrum antimicrobials treating systemic infection may also leave candida unopposed
fororal nutrients and cause a candidosis to develop, as may changes to the immune system in
HIV/AIDS. In angular cheilitis, the cracking at the corners of the mouth, which may be secondary
to low iron from dietary insufficiency, malabsorption (GI disease) or blood loss (GI ulceration/
menorrhagia), may become infected with a mixed flora from the oral cavity and skin and cause
additional inflammation and crusting.
21.6.2 Viral Disease
21.6.2.1 Human Papilloma Virus (HPV)
There are over 100 varieties of HPV, most of them causing various forms of warts in numerous
anatomical sites, including the orofacial and head and neck regions. Mostly, they are a short- lived
nuisance, but some types of HPV are associated with malignancy. There are around 14 high- risk
types of HPV, but HPV16 and HPV18 are especially associated with both head and neck cancers
and cervical cancers(29).
21.6.2.2 Herpes Simplex Virus (HSV- 1/HHV- 1)
Herpes simplex viruses are prevalent. HSV- 1 is typically acquired in childhood, transmitted via the
saliva of an infected contact, and may present as a systemic malaise with orofacial blisters and
ulcerations (primary herpetic gingivostomatitis). The virus lies dormant in the dorsal root (sensory) ganglion within the nerves at the site of inoculation– in the case of the orofacial tissues, this
will be the trigeminal ganglion. Reactivation may occur with the presentation of ‘cold sores’ on the
skin of the face or oral mucosa. Reactivation may occur in healthy individuals or when the immune
system is compromised through drugs or illness. HSV- 2 is more commonly associated with sexual
transmission and can affect the perineal and genital areas but may also present in the orofacial
region(30).
21.6.2.3 Varicella Zoster Virus (VZV / HHV- 3)
Chickenpox is the manifestation of the primary infection with VZV. As with HSV, the virus lies
dormant in the spinal column’s dorsal root (sensory) ganglion. For lesions of the face, the virus will
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