DISEASES OF SKIN

ECTODERMAL DYSPLASIA
A group of inherited conditions in which 2 or more ectodermally derived structures fail to develop Aplasia or hypoplasia of skin, hair, nails, teeth & sweat glands can occur Estimated 121 different subtypes with several patterns of inheritance including auto. dominant, auto. recessive, sex-linked

ECTODERMAL DYSPLASIA (HYPOHIDROTIC) Clinical Features: This type appears to show a X-linked pattern thus a male predominance Usually display heat intolerance due to reduced number of sweat glands; dx may be made in infancy due to fever of unknown origin; rare deaths due to elevated body temperature Other features include: sparse, fine, blond hair including eyelashes & eyebrows; fine wrinkling & hyperpigmentation of skin around eye; mid-face hypoplasia; dystrophic, brittle nails & varying degrees of xerostomia due to diminished numbers of salivary glands Hypodontia or oligodontia, if present crowns may be tapered, pointed & smaller than normal Females may show partial expression of abnormal gene ie. fewer teeth with mild structural defects; this can be explained by Lyon hypothesis, ie. half of females X chromosomes having defective gene Histologic Features: Skin shows decreased numbers of sweat glands & hair follicles Other adnexal structures are hypoplastic & malformed Treatment & Prognosis: Dental problems best managed by prosthetic replacement, ie. complete, overdentures, fixed appliance depending on number of teeth present; implants ok in older patients Genetic counseling is warranted

WHITE SPONGE NEVUS

Synonyms: Cannons Disease & Familial White Folded Dysplasia Autosomal dominant skin disorder with high degree of penetrance & variable expressivity Present at birth or by adolescence Clinical Features: Appears as symmetric, thickened, white, corrugated/velvety plaque Primarily affects buccal mucosa but also may involve tongue, buccal mucosa, alveolar ridge or floor Other mucous membranes such as nasal, esophageal, anogenital may be involved Patients are usually asymptomatic Histologic Features: Prominent hyperparakeratosis & acanthosis with clearing of cytoplasm of cells in spinous layer; similar to leukoedema, HBID Eosinophilic condensation of keratin tonofilaments in perinuclear region; this best seen in cytologic preparations Treatment & Prognosis: No treatment necessary for this benign condition; prognosis excellent

EPIDERMOLYSIS BULLOSA
Describes a group of inherited blistering mucocutaneous disorders which have in common defects in the attachment mechanisms of the epithelial cells There are three broad categories: Simplex, Junctional and Dystrophic A variety of inheritance patterns are seen Simplex: a relatively mild form Junctional: Due to the sloughing of the skin during passage through the birth canal many of these patients die Dystrophic: Oral lesions occur primarily in this form; dental anomalies (anodontia, enamel hypoplasia, neonatal teeth & caries) are associated with several types of EB Clinical Features: Autosomal dominant dystrophic forms are non-life threatening but may be disfiguring Vesicles/bullae develop in areas of low-grade, chronic trauma such as knuckles or knees; bullae rupture leaving ulcers which heal with scarring Oral lesions are mild & consist of gingival erythema, tenderness and recession Recessive dystrophic forms are more debilitating with vesicles/bullae developing with minor trauma; secondary infection is a major problem; if pt. survives into their 20s, scarring may result in fusion of the fingers Oral problems are very severe; foods with any texture may cause bullae/vesicles to form; scarring may lead to microstomia Histologic Features: Simplex form shows intraepithelial clefting Junctional & Dystrophic forms show subepithelial clefting EM reveals clefting at level of lamina lucida of basement membrane in junctional forms and below in dystrophic forms Immunohistochemistry helpful in diagnosis Treatment & Prognosis: Mild cases need no treatment other than wound care Severe cases require sterile drainage and antibiotic therapy Mitten deformity can be corrected via plastic surgery; gastrostomy tube may be necessary with esophageal involvement Dystrophic forms predisposes pts. to squamous cell carcinoma Management of oral lesions: dental manipulations should be minimal; pts. on soft diet require topical fluoride & other oral hygiene procedures There is no cure for the disease

PEMPHIGUS
The condition represents 4 autoimmune diseases: p. vulgaris, p. vegetans, p. erythematosus & p. foliaceus While pemphigus vulgaris is the most common type, pemphigus is rare (1-5 cases per million) Pemphigus vulgaris, if untreated, may lead to death Oral lesions of pemphigus vulgaris are often the first sign; they are often the most difficult to treat & thus are often described as the first to show & the last to go The blistering that is seen with this disease results from autoantibodies directed against epidermal cell surface glycoprotein a component of desmosomes Clinical Features: The average age is 50 yrs. with the sex predilection being equal Vesicles, erosions & ulcerations occur on any mucosal or skin surface Patients usually complain of pain or soreness with the palate, labial/buccal mucosa, ventral tongue & gingivae the more frequent sites of involvement Clinicians rarely see vesicles/bullae intraorally but these are thin-walled & rupture quickly Approx. 50% of pts. have oral lesions first & almost all pts. will develop oral lesions Skin vesicles/bullae rupture quickly leaving a red ulcerated surface Positive Nikolsky sign Histologic Features: Biopsy of perilesional tissue shows the characteristic intraepithelial separation just above the basal cell layer The superficial layers of epithelium may have been sloughed leaving only the basal cells which have been described as a row of tombstones The separation of the individual epithelial cells is termed acantholysis & the loose cells tend to become rounded (Tzanck cells) The underlying connective tissue shows a chronic inflammatory infiltrate Direct immunofluorescence is helpful in the diagnosis Treatment & Prognosis: Early diagnosis is important to achieve control Systemic corticosteroids (usually prednisone) often in combination with immunosuppressive drugs (azathioprine) Rarely undergoes complete resolution; 5-10% mortality rate; steroid therapy contributes to morbidity & mortality

ERYTHEMA MULTIFORME Is a vesiculobullous, ulcerative condition of uncertain etiology & pathogenesis Probably is immunologically mediated 50% of cases are preceded by infection such as Herpes simplex or Mycoplasma pneumoniae or one of a variety of drugs Direct & indirect immunofluorescence studies are nonspecific; not diagnostic Clinical Features: Usually an acute onset with a wide spectrum of presentation ranging from ulcerations affecting the oral cavity primarily to a severe form with diffuse sloughing & ulceration of the entire skin & mucosal surfaces (toxic epidermal necrolysis or Lyells disease Most patients in 20s-30s; male predilection Prodromal symptoms: fever, malaise, headache, cough & sore throat approx. 1 wk before Mild form usually lasts from 2-6 wks. but about 20% of pts. have recurrences often in spring or fall Skin lesions take on many forms (multiforme) Early skin lesions are usually flat, round & dark red & more common on arms/legs; these may evolve into bullae with necrotic centers Target (bulls eye) lesions are highly characteristic; these show concentric circular erythematous rings Oral lesions begin as erythematous patches, become necrotic and form large shallow ulcers with irregular borders; may crust on lips Ulcers have a diffuse distribution but gingivae & hard palate may be spared Ulcers are painful & pt. may not want to eat or drink

ERYTHEMA MULTIFORME MAJOR (STEVENS-JOHNSON SYNDROME) More severe form usually triggered by drug Ocular & genital lesions must accompany oral & skin lesions for diagnosis to be made Severe ocular lesions may lead to scarring (symblepharon) TOXIC EPIDERMAL NECROLYSIS CONSIDERED MOST SEVERE FORM OF ERYTHEMA MULTIFORME Almost always triggered by drug Female predilection & pts. usually older Characterized by diffuse & significant sloughing of skin & mucosal surfaces In this rare form, the skin lesions heal in 2-4 wks. if pt. survives; oral lesions usually take longer to heal & pt. may have residual ocular damage Histologic Features: Subepithelial vesiculation associated with necrotic basal cells is usually observed Mixed inflammatory infiltrate often with perivascular orientation Immunopathologic features are nonspecific & only help to exclude other vesiculobullous disorders Treatment & Prognosis: Management for minor & major forms includes systemic corticosteroids Dehydrated pts. may require IV fluids and topical anesthetic agents for oral discomfort With recurrent herpes infection: antivirals Mortality 2-10% in Stevens-Johnson; up to 34% in toxic epidermal necrolysis

LICHEN PLANUS
A relatively common, chronic dermatologic disease, often affecting the oral mucosa; current evidence indicates it is an immunologically mediated disorder; the relationship to stress is controversial A variety of drugs are known to induce similar appearing lesions for which the term lichenoid mucositis is used Clinical Features: 1-2% of population has cutaneous L.P.; majority of patients are middle-aged with a 3:2 female predilection Skin lesions appear as pruritic, purple, polygonal papules with a fine, lace-like network of white lines known as Wickhams striae; oral & other mucous membranes may be involved as well as nails While many forms are recognized by some authors, there are essentially two forms of oral lesions:

RETICULAR LICHEN PLANUS More common form Usually asymptomatic & occurs most frequently on buccal mucosa bilaterally; may also affect tongue, gingivae & palate So named because of interlacing white lines but may also appear as plaques Lesions typically wax & wane over wks./mos. EROSIVE LICHEN PLANUS Patients usually symptomatic Lesions appear atrophic, erythematous with central areas of ulceration; usually the fine, white radiating striae can be seen at edge of lesion; with gingival involvement, this form is part of a group of specific disease entities which produce a reaction pattern called desquamative gingivitis

Histologic Features: Characteristic but not pathognomonic because lichenoid drug reactions & other lesions can appear similar Ortho/Parakeratosis seen with reticular form; spinous layer may be atrophic or hyperplastic with saw-toothed rete ridges; basal layer may show hydropic degeneration A band-like infiltrate of predominantly T lymphocytes adjacent to the epithelium is usually present Degenerating keratinocytes (colloid, cytoid, hyaline or Civatte bodies) may be seen at interface of epithelium & connective tissue Immunopathologic features are nonspecific Diagnosis: The diagnosis of reticular form can often be made on clinical findings alone Biopsy is often necessary to rule out other vesiculoerosive diseases in cases of erosive lichen planus Treatment & Prognosis: Reticular form typically produces no symptoms & requires no treatment Erosive form is usually treated by topical (or systemic if necessary) corticosteroids With steroid treatment, pt. should be monitored for candidal infection Potential malignant transformation is small

PSORIASIS
Common(I-2%ofpopulation)chronic skin disease Characterized by increased proliferation of cutaneous keratinocytes; etiopathogenesis poorly understood; probably caused by abnormal production of cytokines; genetic factors may have some role but may/must be influenced by environmental agents Clinical Features: After 2"d decade onset tends to persist for years with periods of exacerbation & quiescence; lesions worse during winter; scalp, elbows & knees favorite sites; appear as well-demarcated erythematous plaques with silvery scale; usually asymptomatic these lesions may itch; approx. 4% develop psoriatic arthritis Psoriatic arthritis may affect TMJ Oral lesions are uncommon & range from white plaques to red plaques to ulcers Some authors refer to erythema migrans (geographic tongue) as intraoral psoriasis but direct correlation has been difficult to prove Histologic Features: Surface epithelium shows marked parakeratin with elongation of rete ridges; connective tissue papillae approach epithelial surface closely; a chronic, perivascular, inflammatory cell infiltrate may be noted around the capillaries; Munro abscesses in parakeratin layer may also be seen Treatment & Prognosis: Mild lesions require no treatment Moderate involvement may be treated by corticosteroids, coal tar derivatives, keratolytic agents & UV light may help Severe disease treated by Psoralen & Ultraviolet A, methotrexate or cyclosporine No increase in mortality rate; sq. cell ca ?

LUPUS ERYTHEMATOSUS
Immunologically mediated condition

SLE: serious multisystem disease with variety of skin & oral manifestations; related to increased B lymphocyte activity and abnormal T cell function; cause is unknown but genetic factors may play a role Chronic cutaneous lupus erythematosus: primarily affects skin & oral mucosa

SYSTEMIC LUPUS ERYTHEMATOSUS Clinical Features: Often difficult dx as early stages are nonspecific & vague; females 8- 1 0: 1; average age 3 1 yrs.; common findings: fever, wt. loss, arthritis & malaise; 40-50% have butterfly rash which gets worse with sunlight; 40-50% have kidney problems; approx. 50% have Libman-Sacks endocarditis 5-25% have oral lesions Palate, buccal mucosa & gingivae usually involved Lesions may have lichenoid appearance but may vary from nonspecific to granulomatous to ulcerative Ulceration, pain, erythema and hyperkeratosis may occur CHRONIC CUTANEOUS LUPUS ERYTHEMATOSUS Pts. have few, if any, of systemic signs of SLE; the skin lesions of CCLE are known as discoid lupus erythematosus Skin lesions begin as scaly erythematous patches which are made worse by sunlight; atrophy, scarring & hypopigmentation or hyperpigmentation seen Oral lesions resemble erosive lichen planus SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS Form of LE with clinical manifestations between SLE & CCLE Skin lesions are most prominent feature & while photosensitive, pts. usually do not show induration & scarring as those with CCLE Like SLE, arthritis is usually present but not renal, cardiac or neurologic problems Histologic Features: Skin lesions show hyperkeratosis with follicular plugging in CCLE while all forms demonstrate degeneration of basal cell layer; a dense chronic inflammatory infiltrate with a perivascular location in deeper connective tissue

Histologic Features (Continued): Oral lesions demonstrate hyperkeratosis, alternating atrophy & thickening of spinous layer, degeneration of basal cell layer & a subepithelial lymphocytic infiltrate Diagnosis is made based upon information from clinical, microscopic and immunological findings Treatment: Pts. with SLE should avoid ultraviolet light which may precipitate disease activity; systemic corticosteroids alone or combined with other immunosuppresive drugs are given for acute episodes; topical steroids may be enough for CCLE; antimalarial drugs have been effective in CCLE and subacute forms Prognosis: SLE: Variable with 5-yr. survival of approx. 95% in pts. receiving therapy; 75% 15 yr. survival; survival depends upon organs affected with renal failure the most common cause of death CCLE: Some cases transform to SLE (5%); some resolve in time

SYSTEMIC SCLEROSIS

Synonyms: Scleroderma; Hide-Bound Disease Probably immunologically mediated Characterized by dense coliagen deposits in tissues of body; reason not understood Skin is dramatically effected but most other organs may be also Clinical & Radiographic Features: Often insidious onset; most pts. are adults with female predilection, 3:1 First sign often Raynaud's phenomenon which is not specific for scleroderma Resorption of terminal phalanges (acro-osteolysis) & flexion contractions may produce shortened, claw-like fingers Skin develops a diffuse, hard, usually smooth texture & surface; "mast-like" & 66 mouse" facies Fibrosis of lungs, heart, kidneys & GI tract may lead to organ failure Microstomia with limitation of mouth opening seen in approx. 70% of pts.; c 4pursestring" appearance; gingival recession may occur and loss of tongue mobility may lead to dysphagia Diffuse widening of PDL is often seen Resorption of posterior ramus, coronoid and condyle may occur (approx. 20% of pts.) Mild form of disease called localized seteroderma usually affects only a patch of skin; "coup de sabre" (scar-like lesion) Histologic Features: Diffuse deposition of dense collagen replacing and destroying normal tissue is the characteristic feature Diagnosis is suggested by clinical stiffening of skin and Raynaud's phenomenon; skin biopsy and immunological studies are supportive Treatment & Prognosis: Management is difficult: D-penicillamine may be given to inhibit collagen production; nifedipine may help blood flow & thus Raynaud's phenomenon; corticosteroids are little help Esophageal dilation ; microstomia causes several oral problems; prognosis is poor; survival drops with time, 30% at 12 yrs

ACANTHOSIS NIGRANS
Acquired dermatologic condition characterized by velvety, brownish alterations of the skin In some cases it is a marker of GI cancer and this form is termed malignant acanthosis nigricans; etiology of this form is unknown but malignant cells may produce a cytokine-like peptide which affects sq. cells Most cases are not associated with malignancy & are termed benign acanthosis nigricans; pseudo-acanthosis nigricans may be seen in obese patients Some benign forms may be inherited or occur in association with endocrinopathies such as diabetes mellitus, Addison's disease, acromegaly, & hypothyroidism Benign form also associated with certain syndromes (Crouzon) or drugs (oral contraceptives, corticosteroids); these forms are typically associated with insulin tissue resistance Clinical Features: Malignant form associated with internal malignancy particularly adenoca of GI tract; approx. 20% of cases dxed before malignancy found In both forms flexural areas of skin are most affected Lesions appear as finely papillary, hyperkeratotic, usually asymptomatic brown patches; texture is either velvety or leathery Oral lesions seen in 25-50% of affected pts. especially those with malignant form; lesions appear as finely papillary, usually non-pigmented areas of tongue & lips Histologic Features: Epidermis exhibits hyperorthokeratosis and papillomatosis; usually some degree of increased melanin deposition; acanthosis is usually mild Oral lesions usually show more acanthosis & minimal melanin pigmentation Treatment & Prognosis: Acanthosis nigricans itself is harmless; pt. evaluated for possible associated diseases Malignant form has very poor prognosis; the acanthosis nigricans may disappear when cancer is treated Keratolytic agents may improve appearance of the benign form

CICATRICIAL PEMPHIGOID
Synonym: Benign mucous membrane pemphigoid Is a chronic, blistering, mucocutaneous, autoimmune disease which clinically may resemble pemphigus hence -oid suffix; however prognosis & histology different Cicatricial from word for scar; conjunctival involvement may lead to scarring/blindness Clinical Features: Pts. average 60 yrs. at onset; 2:1 female predilection Primarily mucosal lesions Oral lesions begin as vesicles/bullae which eventually rupture leaving large ulcers; the ulcers are painful and may persist for wks/mos. without treatment; gingival lesions part of desquamative gingivitis Ocular involvement occurs in approx. 25% of pts. with oral lesions & is very significant Ocular: symblepharons (adhesions), entropion (scar turns eyelid in), trichiasis (eyelashes rub cornea & globe); eyes are dry due to closing of lacrimal duct orifices Other mucosal sites may be involved Histologic Features: Perilesional mucosa shows subepithelial clefting with mild chronic inflammatory infiltrate in connective tissue Direct immunofluorescence shows linear band at basement membrane zone in approx. 90% of pts.; immunoreactants consists primarily of IgG and C3 Cicatricial pemphigoid separated from linear IgA disease because IgG & C3 are primary immune deposits in pemphigoid and from epidermolysis bullosa acquisita because in this disease the IgG autoantibodies are at the floor of the bullae while in cicatricial pemphigoid they are localized in roof Treatment & Prognosis: Pt. should be sent to ophthalmologist for eye exam &/or care Potent topical corticosteroids may control oral lesions; oral hygiene important with gingival lesions May require systemic steroids and/or other immunosuppressive drugs; dapsone has been effective in some cases; no cure

BULLOUS PEMPHIGOID
Autoimmune disease characterized by autoantibodies directed against a component of the basement membrane Resembles cicatricial pemphigoid but has a more limited clinical course Clinical Features: Most patients between 60-80 yrs.; no racial or sexual predilection Pruritus is often an early symptom to be followed by the development of multiple bullae with either a normal or erythematous skin background Bullae rupture, crust & heal without scarring Oral involvement is not common ranging from 8-39% of cases Oral lesions begin as bullae which then rupture to form large, shallow ulcers with smooth, well-demarcated margins Histologic Features: Separation of the epithelium from the connective tissue is at the basement membrane & thus subepithelial; acute & chronic inflammatory infiltrate including eosinophils seen Direct immunofluorescence shows linear band (usually IgG & C3) localized to basement membrane in 90%+ pts. Antibodies may bind to a protein associated with hemidesmosomes; hemidesmosomes bind the basal cell layer to basement membrane & underlying connective tissue 40-70% of patients have circulating autoantibodies in serum Treatment & Prognosis: Management consists of systemic immunosuppressive therapy usually prednisone In patients not responding azathioprine or methotrexate may be added to regimen; dapsone may be alternative Prognosis is good & many patients have spontaneous remission in 2-3 yrs.