Epidermolysis Bullosa
Etiology
• A diverse group of
predominantly cutaneous, but also mucosal, mechanobullous diseases
• Inherited form:
autosomal dominant or recessive patterns may occur
• Acquired form
(acquisita): autoimmune from autoantibodies (immunoglobulin G [IgG]) to type
VII collagen deposited within the basement membrane zone and upper dermis or
lamina propria
Clinical Presentation
• Variable, depending
upon the specific form of many subtypes recognized
• Mucosal lesions
range in severity from mild to debilitating, depending on subtype:
• Inherited forms have
wide range of oral mucosal involvement, with most severe form (autosomal
recessive, dermolytic) also demonstrating enamel hypoplasia and caries
• Acquisita form with
mucous membrane pemphigoid variant shows oral and conjunctival
erosions/blisters
• Mucosal involvement
absent in several variants
• Scarring and
stricture formation common in severe recessive forms
• Mucosa is often
friable, but it may be severely blistered, eroded, or ulcerated.
• Loss of oral
anatomic landmarks may follow severe scarring (eg, tongue mucosa may become
smooth and atrophic with episodes of blistering and scarring).
• Obliteration of
vestibules, reduction of oral opening, ankyloglossia
• Scarring can be
associated with atrophy and leukoplakia, with increased risk for squamous cell
carcinoma development.
Microscopic Findings
• Bullae vary in
location depending upon the form that is present:
• Intraepithelial in
nonscarring forms
• At
epithelial–connective tissue junction in dystrophic forms
•
Subepithelial/intradermal in scarring forms
• Ultrastructural
findings are as follows:
• Intraepithelial
forms associated with defective cytokeratin groups
• Junctional forms
associated with defective anchoring filaments at hemidesmosomal sites
(epithelial–connective tissue junction)
• Dermal types
demonstrate anchoring fibril or collagen destruction.
Diagnosis
• Distribution of
lesions
• Family history
• Microscopic
evaluation
• Ultrastructural
evaluation
• Immunohistochemical
evaluation of basement membrane zone using specific labeled antibodies as
markers for site of blister formation
Differential Diagnosis
• Varies with specific
form
• Generally includes
the following:
• Bullous pemphigoid
• Mucous membrane
(cicatricial) pemphigoid
• Erosive lichen
planus
• Dermatitis
herpetiformis
• Porphyria cutanea
tarda
• Erythema multiforme
• Bullous impetigo
• Kindler syndrome
• Ritter’s disease
Treatment
• Acquisita form:
• Some recent success
with colchicine and dapsone
• Immunosuppressive
agents including azathioprine, methotrexate, and cyclosporine may be effective
• Acquisita and
inherited forms:
• Avoidance of trauma
• Dental prevention
strategies including extra-soft brushes, daily topical fluoride applications,
dietary counseling
Prognosis
• Widely variable
depending on subtype
Erythema Multiforme
Etiology
• Many cases preceded
by infection with herpes simplex; less often with Mycoplasma pneumoniae or other organisms
• May be related to
drug consumption, including sulfonamides, other antibiotics, analgesics, phenolphthalein-containing
laxatives, barbiturates
• Another trigger may
be radiation therapy.
• Essentially an
immunologically mediated reactive process, possibly related to circulating
immune complexes
Clinical Presentation
• Acute onset of
multiple, painful, shallow ulcers and erosions with irregular margins
• Early mucosal
lesions are macular, erythematous, and occasionally bullous.
• May affect oral mucosa
and skin synchronously or metachronously
• Lips most commonly
affected with eroded, crusted, and hemorrhagic lesions (serosanguinous exudate)
known as Stevens-Johnson syndrome when severe
• Predilection for
young adults
• As many as one-half
of oral cases have associated erythematous to bullous skin lesions.
• Target or iris skin
lesions may be noted over extremities.
• Genital and ocular
lesions may occur.
• Usually
self-limiting; 2- to 4-week course
• Recurrence is
common.
Diagnosis
• Appearance
• Rapid onset
• Multiple site
involvement in one-half of cases
• Biopsy results often
helpful, but not always diagnostic
Differential Diagnosis
• Viral infection, in
particular, acute herpetic gingivostomatitis (Note: Erythema multiforme rarely
affects the gingiva.)
• Pemphigus vulgaris
• Major aphthous
ulcers
• Erosive lichen
planus
• Mucous membrane
(cicatricial) pemphigoid
Treatment
• Mild (minor) form:
symptomatic/supportive treatment with adequate hydration, liquid diet, analgesics,
topical corticosteroid agents
• Severe (major) form:
systemic corticosteroids, parenteral fluid replacement, antipyretics
• If evidence of an
antecedent viral infection or trigger exists, systemic antiviral drugs during the
disease or as a prophylactic measure may help.
• See “Therapeutics”
section for details.
Prognosis
• Generally excellent
• Recurrences common
Hand-Foot-and-Mouth
Disease
Etiology
• A very common
enterovirus infection (coxsackievirus A10 or A16), which may occur in mild epidemic
proportion, chiefly in children
• Incubation period is
short, usually less than 1 week
Clinical Presentation
• Oral mucosal lesions
with focal herpes simplex–like appearance, usually involving nonkeratinized
tissue (soft palate, floor of mouth, labial-buccal mucosa)
• Accompanying palmar,
plantar, and digital lesions are deeply seated, vesicular, and erythematous
• Short course with
mild symptoms
Diagnosis
• Concomitant oral and
cutaneous lesions
• Skin lesions
commonly involve hands and feet.
• Skin lesions may
involve buttocks.
• Antibody-titer
increase measured between acute and recovery phases
Differential Diagnosis
• Herpangina
• Herpes simplex
infection
• Acute lymphonodular
pharyngitis
Treatment
• Symptomatic
treatment only
• Patient should be
cautioned against the use of aspirin to manage fever.
Prognosis
• Excellent
• Lifelong immunity,
but it is strain specific
Herpangina
Etiology
• Most often by
members of coxsackievirus group A (7, 9, 10, and 16) or group B (1–5)
• Occasionally due to
echovirus 9 or 17
Clinical Presentation
• Incubation period of
5 to 9 days
• Acute onset
• Usually endemic in
young children; usually occurs in summer
• Often subclinical
• Posterior oral
cavity, tonsillar pillars involved
• Macular erythematous
areas precede short-lived vesicular eruption, followed by superficial
ulceration
• Accompanied by
pharyngitis, dysphagia, fever, malaise, headache, lymphadenitis, and vomiting
• Self-limiting
course, usually under 2 weeks
Diagnosis
• Other viral
illnesses to be ruled out or separated
• Course, time of
year, location of lesions, contact with known infected individual
Differential Diagnosis
• Hand-foot-and-mouth
disease
• Varicella
• Acute herpetic
gingivostomatitis
Treatment
• Soft diet
• Hydration
• Antipyretics
• Chlorhexidine rinses
• Compounded mouth
rinses
Prognosis
• Excellent
Herpetic Stomatitis:
Primary
Etiology
• Herpes simplex virus
(HSV)
• Over 95% of oral primary herpes due to HSV-1
• Physical contact is
mode of transmission
Clinical Presentation
• 88% of population
experience subclinical infection or mild transient symptoms
• Most cases occur in
those between 0.5 and 5 years of age.
• Incubation period of
up to 2 weeks
• Abrupt onset in
those with low or absent antibody to HSV-1
• Fever, anorexia,
lymphadenopathy, headache, in addition to oral ulcers
• Coalescing, grouped,
pinhead-sized vesicles that ulcerate
• Ulcers show a
yellow, fibrinous base with an erythematous halo
• Both keratinized and
nonkeratinized mucosa affected
• Gingival tissue with
edema, intense erythema, pain, and tenderness
• Lips, perioral skin
may be involved
• 7- to 14-day course
Diagnosis
• Usually by clinical
presentation and pattern of involvement
• Cytology preparation
to demonstrate multinucleate virusinfected giant epithelial cells
• Biopsy results of
intact macular area show intraepithelial vesicles or early virus-induced
epithelial (cytopathic) changes
• Viral culture or
polymerase chain reaction (PCR) examination of blister fluid or scraping from
base of erosion
Differential Diagnosis
• Herpangina
• Hand-foot-and-mouth
disease
• Varicella
• Herpes zoster
(shingles)
• Erythema multiforme
(typically no gingival lesions)
Treatment
• Soft diet and hydration
• Antipyretics (avoid
aspirin)
• Chlorhexidine rinses
• Systemic antiviral
agents (acyclovir, valacyclovir) if early in course or in immunocompromised
patients
• Compounded mouth
rinse
Prognosis
• Excellent in
immunocompetent host
• Remission/latent
phase in nearly all those affected who have adequate antibody titers
Impetigo
Etiology
• Cutaneous bacterial
infection: Streptococcus and Staphylococcus species
• Is spread through
direct contact
• Highly contagious
Clinical Presentation
• Honey-colored,
perioral crusts preceded by vesicles
• Flaccid bullae less
common (bullous impetigo)
Diagnosis
• Clinical features
• Culture of organism
(usually group A, â-hemolytic
streptococci or group II Staphylococcus
aureus)
• Herpes simplex
(recurrent)
• Exfoliative
cheilitis
• Drug eruptions
• Other
vesiculobullous diseases
Treatment
• Topical antibiotics
(mupirocin, clindamycin)
• Systemic antibiotics
Prognosis
• Excellent
• Rarely,
poststreptococcal glomerulonephritis may develop.
Mucous Membrane
Pemphigoid
Etiology
• Autoimmune; trigger
unknown
• Autoantibodies
directed against basement membrane zone antigens
Clinical Presentation
• Vesicles and bullae
(short lived) followed by ulceration
• Multiple intraoral
sites (occasionally gingiva only)
• Usually in older
adults
• 2:1 female
predilection
• Ocular lesions noted
in one-third of cases
• Proclivity for
scarring in ocular, laryngeal, nasopharyngeal, and oropharyngeal tissues
Microscopic Findings
• Subepithelial cleft
formation
• Linear pattern IgG
and complement 3 (C3) along basement membrane zone; less commonly IgA
• Direct
immunofluorescence examination positive in 80% of cases
• Indirect
immunofluorescence examination usually negative
• Immunoreactants
deposited in lamina lucida in most patients
Diagnosis
• Biopsy
• Direct immunofluorescent
examination
Differential Diagnosis
• Pemphigus vulgaris
• Erythema multiforme
• Erosive lichen planus
• Lupus erythematosus
• Epidermolysis bullosa acquisita
Treatment
• Topical corticosteroids
• Systemic prednisone,
azathioprine, or cyclophosphamide
•
Tetracycline/niacinamide
• Dapsone
• See “Therapeutics”
section for details.
Prognosis
• Morbidity related to
mucosal scarring (oropharyngeal, nasopharyngeal, laryngeal, ocular, genital)
• Management often
difficult due to variable response to corticosteroids
• Management often
requires multiple specialists working in concert (dental, dermatology,
ophthalmology, otolaryngology)
Paraneoplastic Pemphigus
Etiology
• Autoimmune,
triggered by malignant or benign tumors
• Autoantibodies
directed against a variety of epidermal antigens including desmogleins 3 and 1,
desmoplakins I and II, and other desmosomal antigens, as well as basement
membrane zone antigens
Clinical Presentation
• Short-lived vesicles
and bullae followed by erosion and ulceration; resembles oral pemphigus
• Multiple oral sites
• Severe hemorrhagic,
crusted erosive cheilitis
• Painful lesions
• Cutaneous lesions
are polymorphous; may resemble lichen planus, erythema multiforme, or bullous
pemphigoid
• Underlying neoplasms
such as non-Hodgkin’s lymphoma, leukemia, thymoma, spindle cell neoplasms,
Waldenström’s macroglobulinemia, and Castleman’s disease
Microscopic Findings
• Suprabasilar
acantholysis, keratinocyte necrosis, and vacuolar interface inflammation
• Direct
immunofluorescent testing is positive for epithelial cell surface deposition of
IgG and C3 and a lichenoid tissue reaction interface deposition pattern
• Indirect
immunofluorescent testing is positive for epithelial cell surface IgG
antibodies
• Special testing with
mouse and rat bladder, cardiac muscle, and liver may demonstrate paraneoplastic
pemphigus antibodies that bind to simple columnar and transitional epithelia
Diagnosis
• Biopsy of skin or
mucosa
• Direct
immunofluorescent examination of skin or mucosa
• Indirect
immunofluorescent examination of sera including special substrates
Differential Diagnosis
• Pemphigus vulgaris
• Erythema multiforme
• Stevens-Johnson
syndrome
• Mucous membrane
(cicatricial) pemphigoid
• Erosive oral lichen
planus
Treatment
• Identification of
concurrent malignancy
• Immunosuppressive
therapy
Prognosis
• Good with excision
of benign neoplasms
• Grave, usually
fatal, with malignancies
• Management is very
challenging.
Pemphigus Vulgaris
Etiology
• An autoimmune
disease where antibodies are directed toward the desmosome-related proteins
desmoglein 3 or desmoglein 1
• A drug-induced form
exists with less specificity in terms of immunologic features, clinical
presentation, and histopathology
Clinical Presentation
• Over 50% of cases
develop oral lesions as the initial manifestation
• Oral lesions develop
in 70% of cases
• Painful, shallow
irregular ulcers with friable adjacent mucosa
• Nonkeratinized sites
(buccal, floor, ventral tongue) often are initial sites affected
• Lateral shearing
force on uninvolved skin or mucosa can produce a surface slough or induce
vesicle formation (Nikolsky sign)
Microscopic Findings
• Separation or
clefting of suprabasal from basal layer of epithelium
• Intact basal layer
of surface epithelium
• Vesicle forms at
site of epithelial split
• Nonadherent spinous
cells float in blister fluid (Tzanck cells)
• Direct
immunofluorescence examination positive in all cases
• IgG localization to
intercellular spaces of epithelium
• C3 localization to
intercellular spaces in 80% of cases
• IgA localization to
intercellular spaces in 30% of cases
• Indirect
immunofluorescence examination positive in 80% of cases
• General correlation
with severity of clinical disease
Diagnosis
• Clinical appearance
• Mucosal
manifestations
• Direct/indirect
immunofluorescent studies
Differential Diagnosis
• Mucous membrane
(cicatricial) pemphigoid
• Erythema multiforme
• Erosive lichen
planus
• Drug reaction
• Paraneoplastic
pemphigus
Treatment
• Systemic
immunosuppression
• Prednisone, azathioprine,
mycophenolate mofetil, cyclophosphamide
• Plasmapheresis plus
immunosuppression
• IVIg for some
recalcitrant cases
• See “Therapeutics”
section for details.
Prognosis
• Guarded
• Approximately a 5%
mortality rate secondary to long-term systemic corticosteroid–related
complications
Recurrent Herpetic
Stomatitis: Secondary
Etiology
• Herpes simplex virus
• Reactivation of
latent virus
Clinical Presentation
• Prodrome of
tingling, burning, or pain at site of recurrence
• Multiple, grouped,
fragile vesicles that ulcerate and coalesce
• Most common on
vermilion border of lips or adjacent skin
• Intraoral
recurrences characteristically on hard palate or attached gingiva (masticatory
mucosa)
• In immunocompromised
patients, lesions may occur in any oral site and are more severe (herpetic
geometric glossitis).
Diagnosis
• Characteristic
clinical presentation and history
• Viral culture or PCR
examination of blister fluid or scraping from base of erosion
• Cytologic smear
• Direct
immunofluorescence examination of smear
Differential Diagnosis
• Erythema multiforme
• Herpes zoster
(shingles)
• Herpangina
• Hand-foot-and-mouth
disease
Treatment
• Acyclovir or
valacyclovir early in prodrome
• Supportive
• Acyclovir may be
used for prophylaxis for seropositive transplant patients
• Ganciclovir may be
used for human immunodeficiency virus (HIV)-positive patients, especially those
co-infected with cytomegalovirus.
• For recurrent herpes
labialis, see “Therapeutics” section.
Prognosis
• Excellent
• Healing without
scarring within 10 to 14 days
• Protracted healing
in HIV-positive patients
Stevens-Johnson
Syndrome
Etiology
• A complex mucocutaneous
disease affecting two or more mucosal sites simultaneously
• Most common trigger:
antecedent recurrent herpes simplex infection
• Infection with Mycoplasma also may serve as a trigger.
• Medications may
serve as initiators in some cases.
• Sometimes referred
to as “erythema multiforme major”
Clinical Presentation
• Labial vermilion and
anterior portion of oral cavity usually affected initially
• Early phase is
macular followed by erosion, sloughing, and painful ulceration
• Lip ulcers appear
crusted and hemorrhagic.
• Pseudomembrane;
foul-smelling presentation as bacterial colonization supervenes
• Posterior oral
cavity and oropharyngeal involvement leads to odynophagia, sialorrhea, drooling
• Eye (conjunctival)
involvement may occur.
• Genital involvement
may occur.
• Cutaneous
involvement may become bullous.
• Iris or target
lesions are characteristic on skin.
Microscopic Findings
• Subepithelial
separation with basal cell liquefaction
• Intraepithelial
neutrophils
• Epithelial and
connective tissue edema
• Perivascular
lymphocytic infiltrate
Diagnosis
• Usually made on
clinical grounds
• Histopathology is
not diagnostic.
Differential Diagnosis
• Pemphigus vulgaris
• Paraneoplastic
pemphigus
• Mucous membrane
(cicatricial) pemphigoid
• Bullous pemphigoid
• Acute herpetic
gingivostomatitis
• Stomatitis
medicamentosa
Treatment
• Hydration and local
symptomatic measures
• Topical compounded
oral rinses
• Systemic
corticosteroid use controversial
• Recurrent, virally
associated cases may be reduced in frequency with use of daily, low-dose
antiviral prophylactic therapy (acyclovir, famciclovir, valacyclovir).
• May require
admission to hospital burn unit
Prognosis
• Good; self-limiting
usually
• Recurrences not
uncommon
Varicella and Herpes
Zoster
Etiology
• Primary and recurrent forms
due to varicella-zoster virus (VZV)
• Primary VZV (chickenpox): a
childhood exanthem
• Secondary (recurrent) VZV
(herpes zoster/shingles) infection: most common in elderly or immunocompromised
adults
Clinical Presentation
• Varicella
(chickenpox)
• Fever, headache,
malaise, and pharyngitis with a 2-week
incubation
• Skin with widespread
vesicular eruption
• Oral mucosa with
short-lived vesicles that rupture forming shallow, defined ulcers
• Herpes zoster
(shingles)
• Unilateral, dermatomal, grouped vesicular eruption of skin and/or oral mucosa
• Vesicles may
coalesce prior to ulceration and crusting.
• Lesions are painful.
• Prodromal symptoms
along affected dermatome may occur.
• Pain, paresthesia,
burning, tingling
• Postherpetic pain
may be severe.
Diagnosis
• Clinical appearance
and symptoms
• Cytologic smear with
cytopathic effect present (multinucleated giant cells)
• Viral culture or PCR
examination of blister fluid or scraping from base of erosion
• Serologic evaluation
of VZV antibody
• Biopsy with direct
fluorescent examination using fluoresceinlabeled VZV antibody
Differential Diagnosis
• Primary herpes
simplex/acute herpetic gingivostomatitis
• Recurrent intraoral
herpes simplex
• Pemphigus vulgaris
• Mucous membrane
(cicatricial) pemphigoid
Treatment
• Symptomatic
management in primary infection
• Antiviral drugs
(especially acyclovir) in immunocompromised patients or patients with extensive
disease
• Systemic
corticosteroids may be used to help control/prevent postherpetic neuralgia.
• Pain control to
prevent “CNS imprinting”
Prognosis
• Generally good
• Recurrences more
likely in immunosuppressed patients
