Dermatologic Diseases

CLINICAL FEATURES: Perhaps the best known of the ectodermal dysplasia syndromes is hypohidrotic ectodermal dysplasia. In most instances, this disorder seems to show an X-linked inheritance pattern, with the gene mapping to Xq12-q13.1; therefore, a male predominance is usually seen. However, a few families have been identified that show autosomal recessive or autosomal dominant patterns of inheritance.

Affected individuals typically display heat intolerance because of a reduced number of eccrine sweat glands. Sometimes the diagnosis is made during infancy because the baby appears to have a fever of undetermined origin; however, the infant simply cannot regulate body temperature appropriately because of the decreased number of sweat glands. Uncommonly, death results from the markedly elevated body temperature, although this generally happens only when the condition is not identified. Sometimes, as a diagnostic aid, a special impression can be made of the patient’s fingertips and then examined microscopically to count the density of the sweat glands. Such findings should be interpreted in conjunction with appropriate age-matched controls.

Other signs of this disorder include fine, sparse hair, including a reduced density of eyebrow and eyelash hair (Fig. 16-1). The periocular skin may show a fine wrinkling with hyperpigmentation (Fig. 16-2), and midface hypoplasia is frequently observed, often resulting in protuberant lips. Because the salivary glands are ectodermally derived, these glands may be hypoplastic or absent, and patients may exhibit varying degrees of xerostomia. The nails may also appear dystrophic and brittle.

The teeth are usually markedly reduced in number (oligodontia or hypodontia), and their crown shapes are characteristically abnormal (Fig. 16-3). The incisor crowns usually appear tapered, conical, or pointed, and the molar crowns are reduced in diameter. Complete lack of tooth development (anodontia) has also been reported, but this appears to be uncommon.

Female patients may show partial expression of the abnormal gene; that is, their teeth may be reduced in number or may have mild structural changes. This incomplete presentation can be explained by the Lyon hypothesis, with half of the female patient’s X chro mosomes expressing the normal gene, and the other half expressing the defective gene.

HISTOPATHOLOGIC FEATURES: Histopathologic examination of the skin from a patient with hypohidrotic ectodermal dysplasia shows a decreased number of sweat glands and hair follicles. The adnexal structures that are present are hypoplastic and malformed.

TREATMENT AND PROGNOSIS: Management of hypohidrotic ectodermal dysplasia warrants genetic counseling for the parents and the patient. The dental problems are best managed by prosthetic replacement of the dentition with complete dentures, overdentures, or fixed appliances, depending on the number and location of the remaining teeth. With careful site selection, endosseous dental implants may be considered for facilitating prosthetic management of patients older than 5 years of age.

CLINICAL FEATURES: The lesions of white sponge nevus usually appear at birth or in early childhood, but sometimes the condition develops during adolescence. Symmetrical, thickened, white, corrugated or velvety, diffuse plaques affect the buccal mucosa bilaterally in most instances (Fig. 16-4). Other common intraoral sites of involvement include the ventral tongue, labial mucosa, soft palate, alveolar mucosa, and floor of the mouth, although the extent of involvement can vary from patient to patient. Extraoral mucosal sites, such as the nasal, esophageal, laryngeal, and anogenital mucosa, appear to be less commonly affected. Patients are usually asymptomatic.

HISTOPATHOLOGIC FEATURES: The microscopic features of white sponge nevus are characteristic but not necessarily pathognomonic. Prominent hyperparakeratosis and marked acanthosis with clearing of the cytoplasm of the cells in the spinous layer are common features (Figs. 16-5 and 16-6); however, similar microscopic findings may be associated with leukoedema and hereditary benign intra-epithelial dyskeratosis (HBID). In some instances, an eosinophilic condensation is noted in the perinuclear region of the cells in the superficial layers of the epithelium, a feature that is unique to white sponge nevus. Ultrastructurally, this condensed material can be identified as tangled masses of keratin tonofilaments.

Exfoliative cytologic studies may provide more definitive diagnostic information. A cytologic preparation stained with the Papanicolaou method often shows the eosinophilic perinuclear condensation of the epithelial cell cytoplasm to a greater extent than does the histopathologic section (Fig. 16-7).

TREATMENT AND PROGNOSIS: Because this is a benign condition, no treatment is necessary. The prognosis is good.

CLINICAL FEATURES: The lesions of HBID usually develop during childhood, in most instances affecting the oral and conjunctival mucosa. The oral lesions are similar to those of white sponge nevus, with both conditions showing thick, corrugated white plaques involving the buccal and labial mucosa (Fig. 16-8). Milder cases may exhibit the opalescent appearance of leukoedema. Other oral mucosal sites, such as the floor of the mouth and lateral tongue, may also be affected. These oral lesions may exhibit a superimposed candidal infection as well.

The most interesting feature of HBID is the ocular lesions, which begin to develop very early in life. These appear as thick, opaque, gelatinous plaques affecting the bulbar conjunctiva adjacent to the cornea (Fig. 16-9) and sometimes involving the cornea itself. When the lesions are active, patients may experience tearing, photophobia, and itching of the eyes. In many patients, the plaques are most prominent in the spring and tend to regress during the summer or autumn. Sometimes blindness may result from the induction of vascularity of the cornea secondary to the shedding process.

HISTOPATHOLOGIC FEATURES: The histopathologic features of HBID include prominent parakeratin production in addition to marked acanthosis. A peculiar dyskeratotic process, similar to that of Darier’s disease, is scattered throughout the upper spinous layer of the surface oral epithelium (Fig. 16-10). With this dyskeratotic process, an epithelial cell appears to be surrounded or engulfed by an adjacent epithelial cell, resulting in the so-called cell-within-a-cell phenomenon.

TREATMENT AND PROGNOSIS: Because HBID is a benign condition, no treatment is generally required or indicated for the oral lesions. If superimposed candidiasis develops, then an antifungal medication can be used. Patients with symptomatic ocular lesions should be referred to an ophthalmologist. Typically, the plaques that obscure vision must be surgically excised. This procedure, however, is recognized as a temporary measure because the lesions often recur.

CLINICAL FEATURES: Virtually all patients with pachyonychia congenita exhibit characteristic nail changes, either at birth or in the early neonatal period. The free margins of the nails are lifted up because of an accumulation of keratinaceous material in the nail beds. This results in a pinched, tubular configuration. Ultimately, nail loss may occur (Fig. 16-11).

Other skin changes that may occur include marked hyperkeratosis of the palmar and plantar surfaces, producing thick, callouslike lesions (Fig. 16-12). Hyperhidrosis of the palms and soles is also commonly present. The rest of the skin shows punctate papules, representing an abnormal accumulation of keratin in the hair follicles. One disabling feature of the syndrome is the formation of painful blisters on the soles of the feet after a few minutes of walking during warm weather.

The oral lesions seen in the Jadassohn-Lewandowsky form consist of thickened white plaques that involve the lateral margins and dorsal surface of the tongue. Other oral mucosal regions that are frequently exposed to mild trauma, such as the palate, buccal mucosa, and alveolar mucosa, may also be affected (Fig. 16-13). Neonatal teeth have been reported in patients affected by the Jackson-Lawler form, but these individuals do not have oral white lesions. Hoarseness and dyspnea have been described in some patients as a result of laryngeal mucosal involvement.

HISTOPATHOLOGIC FEATURES: Microscopic examination of lesional oral mucosa shows marked hyperparakeratosis and acanthosis with perinuclear clearing of the epithelial cells.

TREATMENT AND PROGNOSIS: Because the oral lesions of pachyonychia congenita show no apparent tendency for malignant transformation, no treatment is required. The nails are often lost or may need to be surgically removed because of the deformity. In addition, the keratin accumulation on the palms and soles can be quite uncomfortable and distressing to many of the affected individuals. Most patients have to pay continuous attention to removal of the excess keratin, and issues related to quality of life often arise. Patients should receive genetic counseling, as an aid in family planning. Identification of the various keratin mutations associated with these disorders is now possible, using molecular techniques to evaluate material obtained from chorionic villus sampling, thereby allowing prenatal diagnosis.

CLINICAL FEATURES: Dyskeratosis congenita usually becomes evident during the first 10 years of life. A reticular pattern of skin hyperpigmentation develops, affecting the face, neck, and upper chest. In addition, abnormal, dysplastic changes of the nails are evident at this time (Fig. 16-14).

Intraorally, the tongue and buccal mucosa develop bullae; these are followed by erosions and, eventually, leukoplakic lesions (Fig. 16-15). The leukoplakic lesions are considered to be premalignant, and approximately one third of them become malignant in a 10- to 30-year period. The actual rate of transformation may be higher, but this may not be appreciated because of the shortened life span of these patients. Rapidly progressive periodontal disease has been reported sporadically.

Thrombocytopenia is usually the first hematologic problem that develops, typically during the second decade of life, followed by anemia. Ultimately, aplastic anemia develops in approximately 70% of these patients (see page 580). Mild to moderate mental retardation may also be present. Generally, the autosomal recessive and X-linked recessive forms show a more severe pattern of disease expression.

HISTOPATHOLOGIC FEATURES: Biopsy specimens of the early oral mucosal lesions show hyperorthokeratosis with epithelial atrophy. As the lesions progress, epithelial dysplasia develops until frank squamous cell carcinoma evolves.

TREATMENT AND PROGNOSIS: The discomfort of the oral lesions is managed symptomatically, and careful periodic oral mucosal ex-aminations are performed to check for evidence of malignant transformation. Routine medical evaluation is warranted to monitor the patient for the development of aplastic anemia. Selected patients may be considered for allogeneic bone marrow transplantation once the aplastic anemia is identified.

As a result of these potentially life-threatening complications, the prognosis is guarded. The average life span for the more severely affected patients is 32 years of age. The parents and the patient should receive genetic counseling, but identification of the DKC1 gene should allow for accurate confirmation of carriers of the gene and for prenatal diagnosis.

CLINICAL FEATURES: During the first few years of life, patients affected by xeroderma pigmentosum show a markedly increased tendency to sunburn. Skin changes, such as atrophy, freckled pigmentation, and patchy depigmentation, soon follow (Fig. 16-16). In early childhood, actinic keratoses begin developing, a process that normally does not take place before 40 years of age. These lesions quickly progress to squamous cell carcinoma, with basal cell carcinoma also appearing; consequently, in most patients a nonmelanoma skin cancer develops during the first decade of life. Melanoma develops in about 5% of patients with xeroderma pigmentosum, but it evolves at a slightly later time. As a consequence of sun exposure, the head and neck region is the site most frequently affected by these cutaneous malignancies. Neurologic manifestations include subnormal intelligence in 80% of affected individuals.

Oral manifestations, which often occur before 20 years of age, include development of squamous cell carcinoma of the lower lip and the tip of the tongue. This latter site is most unusual for oral cancer, and its involvement is again undoubtedly related to the increased sun exposure, however minimal, which this area receives in contrast to the rest of the oral mucosa.

The diagnosis of xeroderma pigmentosum is usually made when the patient is evaluated for the cutaneous lesions, because it is highly unusual for a very young person to have skin cancer. Because xeroderma pigmentosum is an autosomal recessive trait, a family history of the disorder is not likely to be present, but the possibility of a consanguineous relationship of the affected child’s parents should be investigated.

HISTOPATHOLOGIC FEATURES: The histopathologic features of xeroderma pigmentosum are relatively nonspecific, in that the cutaneous premalignant lesions and malignancies that occur are microscopically indistinguishable from those observed in unaffected patients.

TREATMENT AND PROGNOSIS: Treatment of xeroderma pigmentosum is challenging because in most instances significant sun damage has already occurred by the time of diagnosis. Patients are advised to avoid sunlight and unfiltered fluorescent light and to wear appropriate protective clothing and sunscreens if they cannot avoid sun exposure. Before receiving dental treatment, a calibrated UV light meter should be used to evaluate the amount of UV light being emitted from various sources in the dental office, such as the examination light, the radiograph viewbox, computer screens in the area, fiber-optic lights, or lights that are used for curing composite restorations. Some authors have suggested that any reading greater than 0 nm/cm² would be unacceptable. A dermatologist should evaluate the patient every 3 months to monitor the development of cutaneous lesions.

Topical chemotherapeutic agents (e.g., 5-fluorouracil) may be used to treat actinic keratoses. Nonmelanoma skin cancers should be excised conservatively, preferably with microscopically controlled excision (Mohs surgery) to preserve as much normal tissue as possible. Patients should also receive genetic counseling, because a high number of consanguineous marriages have been reported in some series.

The prognosis is still poor. Most patients die 30 years earlier than the normal population, either directly from cutaneous malignancy or from complications associated with the treatment of the cancer.

CLINICAL FEATURES: Hereditary mucoepithelial dysplasia is characterized by both cutaneous and mucosal abnormalities. Patients typically have sparse, coarse hair with nonscarring alopecia. Eyelashes and eyebrows are generally affected (Fig. 16-17). Severe photophobia develops at an early age, and most of these patients will have evidence of cataracts beginning in childhood or early adult life. Corneal vascularization, keratitis, and nystagmus are also commonly described. As would be expected, vision is usually markedly impaired for these patients. Other skin manifestations include a prominent perineal rash that appears during infancy, as well as a widespread rough, dry texture because of follicular keratosis.

Pulmonary complications related to mucoepithelial dysplasia can range in severity, presumably because of the degree of gene expression. In one family, cavitary bullae were reported to form within the lung parenchyma, and these led to recurrent bouts of pneumonia, often resulting in life-threatening complications.

The oral manifestations of hereditary mucoepithelial dysplasia are usually quite striking, appearing as demarcated fiery-red erythema of the hard palate (Fig. 16-18), with generally less involvement of the attached gingivae and tongue mucosa. These mucosal alterations are typically asymptomatic, despite their remarkable clinical appearance. The nasal, conjunctival, vaginal, cervical, urethral, and bladder mucosa may have the same unusual erythematous features.

HISTOPATHOLOGIC FEATURES: Biopsies of the mucosal lesions of hereditary mucoepithelial dysplasia show epithelium with minimal keratinization and a disorganized maturation pattern. The squamous epithelial cells may have a relatively high nuclear/cytoplasmic ratio, but significant nuclear or cellular pleomorphism is not observed. Cytoplasmic vacuoles have been described and may appear as grayish inclusions (Fig. 16-19). These vacuoles also may be observed in exfoliative cytology samples. Ultrastructurally, the lesional cells have been described as having reduced numbers of desmosomes and internalized gap junctions.

TREATMENT AND PROGNOSIS: Given the genetic nature of this disease, supportive care and genetic counseling are typically offered. Affected patients should be monitored for development of pulmonary disease.

CLINICAL FEATURES: The clinical manifestations of incontinentia pigmenti usually begin in the first few weeks of infancy. There are four stages:

CNS abnormalities occur in approximately 30% of affected patients. The most common problems are mental retardation, seizure disorders, and motor difficulties. Ocular problems (e.g., strabismus, nystagmus, cataracts, retinal vascular abnormalities, optic nerve atrophy) may also be identified in nearly 35% of these patients.

The oral manifestations of incontinentia pigmenti, noted in 70% to 95% of the cases, include oligodontia (hypodontia), delayed eruption, and hypoplasia of the teeth (Fig. 16-21). The teeth are small and cone shaped; both the primary and permanent dentitions are affected.

HISTOPATHOLOGIC FEATURES: The microscopic findings in incontinentia pigmenti vary, depending on when a biopsy of the skin lesions is performed.

In the initial vesicular stage, intraepithelial clefts filled with eosinophils are observed. During the verrucous stage, hyperkeratosis, acanthosis, and papillomatosis are noted. The hyperpigmentation stage shows numerous melanin-containing macrophages (melanin incontinence) in the subepithelial connective tissue, the feature from which the disorder derives its name.

TREATMENT AND PROGNOSIS: Treatment of incontinentia pigmenti is directed toward the various abnormalities. Dental management includes appropriate prosthodontic and restorative care, although this is sometimes difficult if CNS problems are severe. Prenatal genetic testing can be performed, but currently this is not widely available.

CLINICAL FEATURES: Patients with Darier’s disease have numerous erythematous, often pruritic, papules on the skin of the trunk and the scalp that develop during the first or second decade of life (Fig. 16-22). An accumulation of keratin, producing a rough texture, may be seen in association with the lesions, and a foul odor may be present as a result of bacterial degradation of the keratin. The process generally becomes worse during the summer months, either because of sensitivity of some patients to UV light or because increased heat results in sweating, which induces more epithelial clefting. The palms and soles often exhibit pits and keratoses. The nails show longitudinal lines, ridges, or painful splits.

The oral lesions are typically asymptomatic and are discovered on routine examination. The frequency of occurrence of oral lesions ranges from 15% to 50%. They consist of multiple, normal-colored or white, flat-topped papules that, if numerous enough to be confluent, result in a cobblestone mucosal appearance (Fig. 16-23). These lesions affect the hard palate and alveolar mucosa primarily, although the buccal mucosa or tongue may be occasionally involved. If the palatal lesions are prominent, then the condition may resemble inflammatory papillary hyperplasia or nicotine stomatitis. Some patients with this condition also experience recurrent obstructive parotid swelling secondary to duct abnormalities.

HISTOPATHOLOGIC FEATURES: Microscopic examination of the cutaneous or mucosal lesions shows a dyskeratotic process characterized by a central keratin plug that overlies epithelium exhibiting a suprabasilar cleft (Fig. 16-24). This intraepithelial clefting phenomenon, also known as acantholysis, is not unique to Darier’s disease and may be seen in conditions such as pemphigus vulgaris (see page 765). In addition, the epithelial rete ridges associated with the lesions appear narrow, elongated, and “test tube”-shaped. Closer inspection of the epithelium reveals varying numbers of two types of dyskeratotic cells, called corps ronds (round bodies) or grains (because they resemble cereal grains).

TREATMENT AND PROGNOSIS: Treatment of Darier’s disease depends on the severity of involvement. Photosensitive patients should use a sunscreen, and all patients should minimize unnecessary exposure to hot environments. For relatively mild cases, keratolytic agents or emollients may be the only treatment required. For more severely affected patients, systemic retinoids are often beneficial, but the side effects of such medications are often quite bothersome to the patient and can be significant; therefore, the physician should carefully monitor their use. Although the condition is not premalignant or otherwise life threatening, genetic counseling is appropriate.

CLINICAL FEATURES: The cutaneous warty dyskeratoma typically appears as a solitary, asymptomatic, umbilicated papule on the skin of the head or neck of an older adult. The intraoral lesion also develops in patients older than age 40, and a slight male predilection has been identified. The intraoral warty dyskeratoma appears as a pink or white, umbilicated papule located on the keratinized mucosa, especially the hard palate and the alveolar ridge (Fig. 16-25). A warty or roughened surface is noted in some lesions. Most warty dyskeratomas are smaller than 0.5 cm in diameter.

HISTOPATHOLOGIC FEATURES: Histopathologically, the warty dyskeratoma appears very similar to keratosis follicularis. Both conditions display dyskeratosis, basilar hyperplasia, and a suprabasilar cleft (Fig. 16-26). The warty dyskeratoma is a solitary lesion, however, and the formation of corps ronds and grains is not a prominent feature.

TREATMENT AND PROGNOSIS: Treatment of the warty dyskeratoma consists of conservative excision. The prognosis is excellent; these lesions have not been reported to recur, and they have no apparent malignant potential. Careful histopathologic evaluation of the tissue should be performed, because some epithelial dysplasias may show a marked lack of cellular cohesiveness, resulting in a similar acantholytic appearance microscopically.

CLINICAL FEATURES: The skin lesions of Peutz-Jeghers syndrome usually develop early in childhood and involve the periorificial areas (e.g., mouth, nose, anus, genital region). The skin of the extremities is affected in about 50% of patients (Fig. 16-27). The lesions resemble freckles, but they do not wax and wane with sun exposure, as do true freckles.

The intestinal polyps, generally considered to be hamartomatous growths, are scattered throughout the mucus-producing areas of the gastrointestinal tract. The jejunum and ileum are most commonly affected. Patients often have problems with intestinal obstruction because of intussusception (“telescoping” of a proximal segment of the bowel into a distal portion), a problem that usually becomes evident during the third decade of life. Most of these episodes are self-correcting, but surgical intervention is sometimes necessary to prevent ischemic necrosis of the bowel, with subsequent peritonitis. Gastrointestinal adenocarcinoma develops in a significant percentage of affected patients, although the polyps themselves do not appear to be premalignant. In one large series of cases, 9% of the patients had developed gastrointestinal malignancy by 40 years of age and 33% by 60 years of age. This compares to 0.1% and 1.0%, respectively, in the general population. Other tumors affecting the pancreas, male and female genital tract, breast, and ovary may also develop. In women, the risk of developing breast cancer approaches 50% by 60 years of age. The increased frequency of malignancy in these patients overall is estimated to be approximately 18 times greater than normal.

The oral lesions essentially represent an extension of the perioral freckling. These 1- to 4-mm brown to blue-gray macules primarily affect the vermilion zone, the labial and buccal mucosa, and the tongue; they are seen in more than 90% of these patients (Fig. 16-28). The number of lesions and the extent of involvement can vary markedly from patient to patient. Some degree of fading of the pigmented lesions may be noted during adolescence.

HISTOPATHOLOGIC FEATURES: The gastrointestinal polyps of Peutz-Jeghers syndrome histopathologically represent benign overgrowths of intestinal glandular epithelium supported by a core of smooth muscle. Epithelial atypia is not usually a prominent feature, unlike the polyps of Gardner syndrome (see page 651).

Microscopic evaluation of the pigmented cutaneous lesions shows slight acanthosis of the epithelium with elongation of the rete ridges. No apparent increase in melanocyte number is detected by electron microscopy, but the dendritic processes of the melanocytes are elongated. Furthermore, the melanin pigment appears to be retained in the melanocytes rather than being transferred to adjacent keratinocytes.

TREATMENT AND PROGNOSIS: Patients with Peutz-Jeghers syndrome should be monitored for development of intussusception or tumor formation. Genetic counseling is also appropriate.

CLINICAL FEATURES: Patients with HHT are often diagnosed initially because of frequent episodes of epistaxis. On further examination, the nasal and oropharyngeal mucosae exhibit numerous scattered red papules, 1 to 2 mm in size, which blanch when diascopy is used. This blanching indicates that the red color is due to blood contained within blood vessels (in this case, small collections of dilated capillaries [telangiectasias] that are close to the surface of the mucosa). These telangiectatic vessels are most frequently found on the vermilion zone of the lips, tongue, and buccal mucosa, although any oral mucosal site may be affected (Figs. 16-29 and 16-30). With aging, the telangiectasias tend to become more numerous and slightly larger.

In many patients, telangiectasias are seen on the hands and feet. The lesions are often distributed throughout the gastrointestinal mucosa, the genitourinary mucosa, and the conjunctival mucosa. The gastrointestinal telangiectasias have a tendency to rupture, which may cause significant blood loss. Chronic iron-deficiency anemia is often a problem for such individu als. Significantly, arteriovenous fistulas may develop in the lungs (30% of HHT patients), liver (30%), or brain (10% to 20%). The brain lesions seem to predispose these patients to the development of brain abscesses. In at least one instance, periodontal vascular malformations were felt to be the cause of septic pulmonary emboli that resolved only after several teeth with periodontal abscesses were extracted.

A diagnosis of HHT can be made if a patient has three of the following four criteria:

In some instances, CREST syndrome (Calcinosis cutis, Raynaud’s phenomenon, Esophageal dysfunction, Sclerodactyly, and Telangiectasia) (see page 801) must be considered in the differential diagnosis. In these cases, serologic studies for anticentromere autoantibodies often help to distinguish between the two conditions because these antibodies typically would be present only in CREST syndrome.

HISTOPATHOLOGIC FEATURES: If one of the telangiectasias is submitted for biopsy, the microscopic features essentially show a superficially located collection of thin-walled vascular spaces that contain erythrocytes (Fig. 16-31).

TREATMENT AND PROGNOSIS: For mild cases of HHT, no treatment may be required. Moderate cases may be managed by selective cryosurgery or electrocautery of the most bothersome of the telangiectatic vessels. Laser ablation of the telangiectatic lesions has also been used, although this approach appears to be most successful for patients with mild to moderate disease. More severely affected patients, particularly those troubled by repeated episodes of epistaxis, may require a surgical procedure of the nasal septum (septal dermoplasty). The involved nasal mucosa is removed and replaced by a skin graft; however, some long-term follow-up studies suggest that the grafts eventually become revascularized, resulting in recurrence of the problem. Nasal closure is another surgical technique that has been performed for patients with severe epistaxis in whom other methods have failed.

Combined progesterone and estrogen therapy may benefit some patients, but because of the potentially serious side effects, this should be limited to the most severely affected individuals. Iron replacement therapy is indicated for the iron-deficient patient, and occasionally blood transfusions may be necessary to compensate for blood loss.

From a dental standpoint, some authors recommend the use of prophylactic antibiotics before dental procedures that might cause bacteremia in patients with HHT and evidence of a pulmonary arteriovenous malformation. For patients with a history of HHT, such antibiotics are advocated until a pulmonary arteriovenous malformation is ruled out because of the 1% prevalence of brain abscesses in affected individuals. Researchers believe that antibiotic coverage, similar to that for endocarditis prophylaxis, may prevent this serious complication. Patients with a history of HHT should be screened for arteriovenous malformations, which can be eliminated by embolization or other vasodestructive techniques using interventional radiologic methods.

The prognosis is generally good, although a 1% to 2% mortality rate is reported from complications related to blood loss. For patients with brain abscesses, the mortality rate is 10%, even with early diagnosis and appropriate therapy.

CLINICAL FEATURES: The pattern of inheritance and the clinical manifestations vary with the type of Ehlers-Danlos syndrome being examined. About 80% of patients have the classical type in either the mild or severe form. Classical Ehlers-Danlos syndrome is inherited as an autosomal dominant trait, and defects of type I collagen have been reported in some families, whereas problems with type V collagen have been identified in others, suggesting genetic heterogeneity. Hyperelasticity of the skin (Fig. 16-32) and cutaneous fragility can be observed. An unusual healing response that often occurs with rela tively minor injury to the skin is termed papyraceous scarring because it resembles crumpled cigarette paper (Fig. 16-33).

Patients with the hypermobility type of Ehlers-Danlos syndrome exhibit remarkable joint hypermobility but no evidence of scarring.

The vascular type of Ehlers-Danlos used to be known as the ecchymotic type because of the extensive bruising that occurs with everyday trauma. Defects in type III collagen have been identified in this disorder. This form is inherited in an autosomal dominant pattern, and the patient may be mistaken for a victim of child abuse. The life expectancy of these patients is often greatly reduced because of the tendency for aortic aneurysm formation and rupture.

One rare form of Ehlers-Danlos syndrome (originally reported as type VIII) was described as having dental manifestations as a hallmark feature, with patients showing marked periodontal disease activity at a relatively early age. Although these patients may have overlapping features with either the classical or vascular forms of the disease, recent studies examining five affected families in Sweden have suggested that this form of Ehlers-Danlos syndrome is linked to a specific mutation of a gene that has been mapped to chromosome 12p13.

The oral manifestations of Ehlers-Danlos syndrome include the ability of 50% of these patients to touch the tip of their nose with their tongue (Gorlin sign), a feat that can be achieved by less than 10% of the general population. Some authors have noted easy bruising and bleeding during minor manipulations of the oral mucosa; others state that oral mucosal friability is present. A tendency for recurrent subluxation of the temporomandibular joint (TMJ) and the development of other TMJ disorders has also been reported.

Most patients with Ehlers-Danlos syndrome have normal teeth. A variety of dental abnormalities have been described, however, including malformed, stunted tooth roots, large pulp stones, and hypoplastic enamel. Although most of these findings have not been consistently correlated with any particular type of the syndrome, pulp stones seem to occur more commonly in patients affected by classical Ehlers-Danlos syndrome.

TREATMENT AND PROGNOSIS: The prognosis for the patient with Ehlers-Danlos syndrome depends on the type. Some forms, such as the vascular type, can be very serious, with sudden death occurring from rupture of the aorta secondary to the weakened, abnormal collagen that constitutes the vessel wall. The mild classical type is generally compatible with a normal life span, although affected women may have problems with placental tearing and hemorrhage during gestation.

Accurate diagnosis is important because it affects the prognosis heavily. Similarly, because the various types of this syndrome show a variety of inheritance patterns, an accurate diagnosis is required so that appropriate genetic counseling can be provided.

CLINICAL FEATURES: Several clinical features characterize tuberous sclerosis. The first of these, facial angiofibromas, used to be called adenoma sebaceum. Because these lesions are neither adenomas nor sebaceous, the use of that term should be discontinued. Facial angiofibromas appear as multiple, smooth-surfaced papules and occur primarily in the nasolabial fold area (Fig. 16-34). Similar lesions, called ungual or periungual fibromas, are seen around or under the margins of the nails (Fig. 16-35).

Two other characteristic skin lesions are connective tissue hamartomas called shagreen patches and ovoid areas of hypopigmentation called ash-leaf spots. Even though approximately 5% of the general population may have an ash-leaf spot, studies have reported that 60% to 97% of children with tuberous sclerosis display these lesions. The shagreen patches, so named because of their resemblance to sharkskin-derived shagreen cloth, affect the skin of the trunk. The ash-leaf spots may appear on any cutaneous surface and may be best visualized using UV (Wood’s lamp) illumination.

CNS manifestations include seizure disorders in 70% to 80% of affected patients and mental retardation in 33% to 45%. In addition, hamartomatous proliferations in the CNS develop into the potato-like growths (“tubers”) seen at autopsy, from which the term tuberous sclerosis is derived (Fig. 16-36). The tuberous hamartomas can best be visualized using T2-weighted magnetic resonance imaging (MRI) and are present in 80% to 95% of these patients.

A relatively rare tumor of the heart muscle, called cardiac rhabdomyoma, is also typically associated with this syndrome. This lesion, which probably represents a hamartoma rather than a true neoplasm, occurs in approximately 30% to 50% of affected patients and is typically identified in childhood. Problems with myocardial function often develop as a result of this process, but many of these tumors undergo spontaneous regression.

Another hamartomatous type of growth related to this disorder is the angiomyolipoma. This is a benign neoplasm composed of vascular smooth muscle and adipose tissue and occurs primarily in the kidney.

Oral manifestations of tuberous sclerosis include developmental enamel pitting on the facial aspect of the anterior permanent dentition in 50% to 100% of patients. These pits are more readily appreciated after applying a dental plaque-disclosing solution to the teeth. Multiple fibrous papules affect 11% to 56% of patients. The fibrous papules are seen predominantly on the anterior gingival mucosa (Fig. 16-37), although the lips, buccal mucosa, palate, and tongue may be involved. Diffuse fibrous gingival enlargement is reported in affected patients who are not taking phenytoin; however, most cases of gingival hyperplasia in these individuals are probably related to medication taken to control seizures. Some patients with tuberous sclerosis may also exhibit radiolucencies of the jaws that represent dense fibrous connective tissue proliferations (Fig. 16-38).

The diagnosis of tuberous sclerosis can be based on finding at least two of the following major features:

The presence of one major and two minor features may also confirm the diagnosis. The minor features include the following:

HISTOPATHOLOGIC FEATURES: Microscopic examination of the fibrous papules of the oral mucosa or the enlarged gingivae shows a nonspecific fibrous hyperplasia. Similarly, the radiolucent jaw lesions consist of dense fibrous connective tissue that resembles desmoplastic fibroma or the simple type of central odontogenic fibroma. The angiofibroma of the skin is a benign aggregation of delicate fibrous connective tissue characterized by plump, uniformly spaced fibroblasts with numerous interspersed thin-walled vascular channels.

TREATMENT AND PROGNOSIS: For patients with tuberous sclerosis, most of the treatment is directed toward the management of the seizure disorder with anticonvulsant agents. Periodic MRI of the head may be done to screen for intracranial lesions, whereas ultrasound evaluation is performed for evaluation of kidney involvement. Mentally retarded patients may have problems with oral hygiene procedures, and poor oral hygiene contributes to phenytoin-induced gingival hyperplasia. Patients affected by this condition have a slightly reduced life span compared with the general population, with death usually related to CNS or kidney disease. Genetic counseling is also appropriate for affected patients, and genetic testing is available for both TSC1 and TSC2 mutations if prenatal or preimplantation family planning is desired.

CLINICAL FEATURES: Cutaneous manifestations are present in almost all patients with multiple hamartoma syndrome, usually developing during the second decade of life. The majority of the skin lesions appear as multiple, small (less than 1 mm) papules, primarily on the facial skin, especially around the mouth, nose, and ears (Fig. 16-39). Microscopically, most of these papules represent hair follicle hamartomas called trichilemmomas. Other commonly noted skin lesions are acral keratosis, a warty-appearing growth that develops on the dorsal surface of the hand, and palmoplantar keratosis, a prominent calluslike lesion on the palms or soles. Cutaneous hemangiomas, neuromas, xanthomas, and lipomas have also been described.

Other problems can appear in these patients as well. Thyroid disease usually appears as either a goiter or a thyroid adenoma, but follicular adenocarcinoma may develop. In women, fibrocystic disease of the breast is frequently observed. Unfortunately, breast cancer occurs with a relatively high frequency (25% to 50%) in these patients. The mean age at diagnosis of breast malignancy is 40 years, which is much younger than usual. In the gastrointestinal tract, multiple benign hamartomatous polyps may be present. In addition, several types of benign and malignant tumors of the female genitourinary tract occur more often than in the normal population.

The oral lesions vary in severity from patient to patient and usually consist of multiple papules affecting the gingivae, dorsal tongue, and buccal mucosa (Figs. 16-40 and 16-41). These lesions have been reported in more than 80% of affected patients and generally produce no symptoms. Other possible oral findings include a high-arched palate, periodontitis, and extensive dental caries, although it is unclear whether the latter two conditions are significantly related to the syndrome.

HISTOPATHOLOGIC FEATURES: The histopathologic features of the oral lesions are rather nonspecific, essentially representing fibroepithelial hyperplasia. Other lesions associated with this syndrome have their own characteristic histopathologic findings, depending on the hamartomatous or neoplastic tissue origin.

DIAGNOSIS: The diagnosis can be based on the finding of two of the following three pathognomonic signs:

A variety of other major and minor diagnostic criteria, as well as a positive family history, are also helpful in confirming the diagnosis. Genetic testing for mutations of the PTEN gene are clinically available, but 20% of patients who otherwise have characteristic multiple hamartoma syndrome will not demonstrate a genetic abnormality; therefore, a negative test does not necessarily preclude the diagnosis of multiple hamartoma syndrome.

TREATMENT AND PROGNOSIS: Treatment of multiple hamartoma syndrome is con-troversial. Although most of the tumors that develop are benign, the prevalence of malignancy is higher than in the general population; therefore, annual physical examinations that focus specifically on anatomic sites of increased tumor prevalence are appropriate. Some investigators recommend bilateral prophylactic mastectomies as early as the third decade of life for female patients because of the associated increased risk of breast cancer.

CLINICAL FEATURES:

HISTOPATHOLOGIC FEATURES: The histopathologic features of epidermolysis bullosa vary with the type being examined. The simplex form shows intraepithelial clefting by light microscopy. Junctional, dystrophic, and hemidesmosomal forms show subepithelial clefting (Fig. 16-46). Electron microscopic examination, which is still considered the diagnostic “gold standard,” reveals clefting at the level of the lamina lucida of the basement membrane in the junctional forms and below the lamina densa of the basement membrane in the dystrophic forms. In contrast, the hemidesmosomal form shows clefting just below the basal cell layer, at its interface with the lamina lucida. Immunohistochemical evaluation of perilesional tissue may help to identify specific defects to classify and subtype the condition further. Molecular genetic analysis is now being used to confirm the diagnosis in some instances.

TREATMENT AND PROGNOSIS: Treatment of epidermolysis bullosa varies with the type. For milder cases, no treatment other than local wound care may be needed. Sterile drainage of larger blisters and the use of topical antibiotics are often indicated in these situations. For the more severe cases, intensive management with oral antibiotics may be necessary if cellulitis develops; despite intensive medical care, some patients die as a result of infectious complications.

The “mitten” deformity of the hands, seen in recessive dystrophic epidermolysis bullosa, can be corrected with plastic surgery, but the problem usually recurs after a period of time, and surgical intervention is required every 2 years on average. With esophageal involvement, dysphagia may be a significant problem, resulting in malnutrition and weight loss. Placement of a gastrostomy tube may be necessary at times. Patients with the recessive dystrophic forms are also predisposed to development of cutaneous squamous cell carcinoma. This malignancy often develops in areas of chronic ulceration during the second through third decades of life and represents a significant cause of death for these patients. Infrequently, the lingual mucosa of affected patients has been reported to undergo malignant transformation as well.

Management of the oral manifestations also depends on the type of the disease. For patients who are susceptible to mucosal bulla formation, dental manipulation should be kept to a minimum. To achieve this, topical 1% neutral sodium fluoride solution should be administered daily to prevent dental caries. A soft diet that is as noncariogenic as possible, as well as atraumatic oral hygiene procedures, should be encouraged. Maintaining adequate nutrition for affected patients is critical to ensure optimal wound healing.

If dental restorative care is required, the lips should be lubricated to minimize trauma. Injections for local anesthesia can usually be accomplished by depositing the anesthetic slowly and deeply within the tissues. For extensive dental care, endotracheal anesthesia may be performed without significant problems in most cases.

Unfortunately, because of the genetic nature of these diseases, no cure exists. Genetic counseling of affected families is indicated. Both prenatal diagnosis and preimplantation diagnosis are available as adjuncts to family planning.

CLINICAL FEATURES: The initial manifestations of pemphigus vulgaris often involve the oral mucosa, typically in adults. The average age at diagnosis is 50 years, although rare cases may be seen in childhood. No sex predilection is observed, and the condition seems to be more common in persons of Mediterranean, South Asian, or Jewish heritage.

Patients usually complain of oral soreness, and examination shows superficial, ragged erosions and ulcerations distributed haphazardly on the oral mucosa (Figs. 16-49 to 16-52). Such lesions may affect virtually any oral mucosal location, although the palate, labial mucosa, buccal mucosa, ventral tongue, and gingivae are often involved. Patients rarely report vesicle or bulla formation intraorally, and such lesions can seldom be identified by the examining clinician, probably because of early rupture of the thin, friable roof of the blisters. More than 50% of the patients have oral mucosal lesions before the onset of cutaneous lesions, sometimes by as much as 1 year or more. Eventually, however, nearly all patients have intraoral involvement. The skin lesions appear as flaccid vesicles and bullae (Fig. 16-53) that rupture quickly, usually within hours to a few days, leaving an erythematous, denuded surface. Infrequently ocular involvement may be seen, usually appearing as bilateral conjunctivitis. Unlike cicatricial pemphigoid, the ocular lesions of pemphigus do not tend to produce scarring and symblepharon formation (see page 772).

Without proper treatment, the oral and cutaneous lesions tend to persist and progressively involve more surface area. A characteristic feature of pemphigus vulgaris is that a bulla can be induced on normal-appearing skin if firm lateral pressure is exerted. This is called a positive Nikolsky sign.

HISTOPATHOLOGIC FEATURES: Biopsy specimens of perilesional tissue show characteristic intraepithelial separation, which occurs just above the basal cell layer of the epithelium (Fig. 16-54). Sometimes the entire superficial layers of the epithelium are stripped away, leaving only the basal cells, which have been described as resembling a “row of tombstones.” The cells of the spinous layer of the surface epithelium typically appear to fall apart, a feature that has been termed acantholysis, and the loose cells tend to assume a rounded shape (Fig. 16-55). This feature of pemphigus vulgaris can be used in making a diagnosis based on the identification of these rounded cells (Tzanck cells) in an exfoliative cytologic preparation. A mild-to-moderate chronic inflammatory cell infiltrate is usually seen in the underlying connective tissue.

The diagnosis of pemphigus vulgaris should be confirmed by direct immunofluorescence examination of fresh perilesional tissue or tissue submitted in Michel’s solution. With this procedure, antibodies (usually IgG or IgM) and complement components (usually C3) can be demonstrated in the intercellular spaces between the epithelial cells (Fig. 16-56) in almost all patients with this disease. Indirect immunofluorescence is also typically positive in 80% to 90% of cases, demonstrating the presence of circulating autoantibodies in the patient’s serum. Enzyme-linked immunosorbent assays (ELISAs) have been developed to detect circulating autoantibodies as well.

It is critical that perilesional tissue be obtained for both light microscopy and direct immunofluorescence to maximize the probability of a diagnostic sample. If ulcerated mucosa is submitted for testing, then the results are often inconclusive because of either a lack of an intact interface between the epithelium and connective tissue or a great deal of nonspecific inflammation.

TREATMENT AND PROGNOSIS: A diagnosis of pemphigus vulgaris should be made as early in its course as possible because control is generally easier to achieve. Pemphigus is a systemic disease; therefore, treatment consists primarily of systemic corticosteroids (usually prednisone), often in combination with other immunosuppressive drugs (so-called steroid-sparing agents), such as azathioprine. Although some clinicians have advocated the use of topical corticosteroids in the management of oral lesions, the observed improvement is undoubtedly because of the absorption of the topical agents, resulting in a greater systemic dose. The potential side effects associated with the long-term use of systemic corticosteroids are significant and include the following:

Ideally, a physician with expertise in immunosuppressive therapy should manage the patient. The most common approach is to use relatively high doses of systemic corticosteroids initially to clear the lesions, then attempt to maintain the patient on as low a dose of corticosteroids as is necessary to control the condition. Often the clinician can monitor the success of therapy by measuring the titers of circulating autoantibodies using indirect immunofluorescence, because disease activity frequently correlates with the abnormal antibody levels. Pemphigus may undergo complete resolution, although remissions and exacerbations are common. One study suggested that up to 75% of patients will have disease resolution after 10 years of treatment.

Before the development of corticosteroid therapy, as many as 60% to 90% of these patients died, primarily as a result of infections and electrolyte imbalances. Even today, the mortality rate associated with pemphigus vulgaris is in the range of 5% to 10%, usually because of the complications of long-term systemic corticosteroid use.

CLINICAL FEATURES: Patients typically have a history of a malignant lymphoreticular neoplasm, or less commonly, a benign lymphoproliferative disorder such as angiofollicular lymph node hyperplasia (Castleman’s disease) or thymoma. In approximately one third of reported cases, paraneoplastic pemphigus developed before a malignancy was identified, thus signaling the presence of a tumor. The neoplastic disease may or may not be under control at the time of onset of the paraneoplastic condition. Signs and symptoms of paraneoplastic pemphigus usually begin suddenly and may appear polymorphous. In some instances, multiple vesiculobullous lesions affect the skin (Fig. 16-57) and oral mucosa. Palmar or plantar bullae may be evident, a feature that is uncommon in pemphigus vulgaris. For other patients, skin lesions can appear more papular and pruritic, similar to cutaneous lichen planus. The lips often show hemorrhagic crusting similar to that of erythema multiforme (Fig. 16-58). The oral mucosa shows multiple areas of erythema and diffuse, irregular ulceration (Fig. 16-59), affecting virtually any oral mucosal surface. If the lesions remain untreated, then they persist and worsen. Some patients may develop only oropharyngeal lesions, without cutaneous involvement.

Other mucosal surfaces are also commonly affected, with 70% of patients having involvement of the conjunctival mucosa. In this area, a cicatrizing (scarring) conjunctivitis develops, similar to that seen with cicatricial pemphigoid (Fig. 16-60). The vaginal mucosa and mucosa of the respiratory tract may be involved.

HISTOPATHOLOGIC FEATURES: The features of paraneoplastic pemphigus on light microscopic examination may be as diverse as the clinical features. In most cases, a lichenoid mucositis is seen, usually with subepithelial clefting (like pemphigoid) or intraepithelial clefting (like pemphigus) (Fig. 16-61).

Direct immunofluorescence studies may show a weakly positive deposition of immunoreactants (IgG and complement) in the intercellular zones of the epithelium and/or a linear deposition of immunoreactants at the basement membrane zone. Indirect immunofluorescence should be conducted using a transitional type of epithelium (e.g., rat urinary bladder mucosa) as the substrate. This shows a fairly specific pattern of antibody localization to the intercellular areas of the epithelium. Immunoprecipitation studies remain the gold standard for the diagnosis of paraneoplastic pemphigus, however, because the various antibodies that characterize this condition can be identified with a considerable degree of specificity. Antibodies directed against desmoplakin I and II, major bullous pemphigoid antigen, envoplakin, and periplakin, in addition to desmoglein 1 and 3, are typically detected. Examples of paraneoplastic pemphigus that show only a lichen oid reaction with no demonstrable autoantibody production have infrequently been described.

TREATMENT AND PROGNOSIS: Paraneoplastic pemphigus is often a very serious condition with a high morbidity and mortality rate. For the infrequent cases associated with a benign lymphoproliferative condition, surgical removal of the tumor may result in regression of the paraneoplastic pemphigus. For those cases associated with malignancy, treatment essentially consists of systemic prednisone, typically combined with another immunosuppressive agent, such as azathioprine, methotrexate, or cyclophosphamide. As with pemphigus vulgaris, the skin lesions usually respond more quickly to treatment than the oral lesions. Unfortunately, although the immunosuppressive therapy often manages to control the autoimmune disease, this immunosuppression often seems to trigger a reactivation of the malignant neoplasm. Thus a high mortality rate is seen, with patients succumbing to complications of the vesiculobullous lesions, complications of immune suppressive therapy, or progression of malignant disease. Occasionally, long-term survivors are reported, but these seem to be in the minority. As more of these patients are identified, therapeutic strategies can be better evaluated and modified for optimal care in the future.

CLINICAL FEATURES: Mucous membrane pemphigoid usually affects older adults, with an average age of 50 to 60 years at the onset of disease. Females are affected more frequently than males by a 2:1 ratio. Oral lesions are seen in most patients, but other sites, such as conjunctival, nasal, esophageal, laryngeal, and vaginal mucosa, as well as the skin (Fig. 16-62), may be involved.

The oral lesions of pemphigoid begin as either vesicles or bullae that may occasionally be identified clinically (Fig. 16-63). In contrast, patients with pemphigus rarely display such blisters. The most likely explanation for this difference is that the pemphigoid blister forms in a subepithelial location, producing a thicker, strong-er roof than the intraepithelial, acantholytic pemphigus blister. Eventually, the oral blisters rupture, leaving large, superficial, ulcerated, and denuded areas of mucosa (Fig. 16-64). The ulcerated lesions are usually painful and persist for weeks to months if untreated.

Often this process is seen diffusely throughout the mouth, but it may be limited to certain areas, especially the gingiva (Fig. 16-65). Gingival involvement produces a clinical reaction pattern termed desquamative gingivitis (see page 162). This pattern may also be seen in other conditions, such as erosive lichen planus or, much less frequently, pemphigus vulgaris.

The most significant complication of mucous membrane pemphigoid, however, is ocular involvement. Although exact figures are not available, up to 25% of patients with oral lesions may eventually develop ocular disease. One eye may be affected before the other. The earliest change is subconjunctival fibrosis, which usually can be detected by an ophthalmologist using slit-lamp examination. As the disease progresses, the conjunctiva becomes inflamed and eroded. Attempts at healing lead to scarring between the bulbar (lining the globe of the eye) and palpebral (lining the inner surface of the eyelid) conjunctivae. Adhesions called symblepharons result (Fig. 16-66). Without treatment the inflammatory changes become more severe, although conjunctival vesicle formation is rarely seen (Fig. 16-67). Scarring can ultimately cause the eyelids to turn inward (entropion). This causes the eyelashes to rub against the cornea and globe (trichiasis) (Fig. 16-68). The scarring closes off the openings of the lacrimal glands as well, and with the loss of tears, the eye becomes extremely dry. The cornea then produces keratin as a protective mechanism; however, keratin is an opaque material, and blindness ensues. End-stage ocular involvement may also be characterized by adhesions between the upper and lower eyelids themselves (Fig. 16-69).

Other mucosal sites may also be involved and cause considerable difficulty for the patient. In females, the vaginal mucosal lesions may cause considerable pain during attempts at intercourse (dyspareunia).

Laryngeal lesions, which are fairly uncommon, may be especially significant because of the possibility of airway obstruction by the bullae that are formed. Patients who experience a sudden change in vocaliza tion or who have difficulty breathing should undergo examination with laryngoscopy.

HISTOPATHOLOGIC FEATURES: Biopsy of perilesional mucosa shows a split between the surface epithelium and the underlying connective tissue in the region of the basement membrane (Fig. 16-70). A mild chronic inflammatory cell infiltrate is present in the superficial submucosa.

Direct immunofluorescence studies of perilesional mucosa show a continuous linear band of immunoreactants at the basement membrane zone in nearly 90% of affected patients (Fig. 16-71). The immune deposits consist primarily of IgG and C3, although IgA and IgM may also be identified. One study has suggested that, when IgG and IgA deposits are found in the same patient, the disease may be more severe. All of these immunoreactants may play a role in the pathogenesis of the subepithelial vesicle formation by weakening the attachment of the basement membrane through a variety of mechanisms, including complement activation with recruitment of inflammatory cells, particularly neutrophils.

Indirect immunofluorescence is positive in only 5% to 25% of these patients, indicating a relatively consistent lack of readily detectable circulating autoanti-bodies. One type of mucous membrane pemphigoid produces low levels of circulating autoantibodies to epiligrin (laminin-5), a component of the basement membrane. Antiepiligrin mucous membrane pemphigoid seems to have more widespread involvement, affecting oral, nasal, ocular, and laryngeal mucosa, compared with other forms of mucous membrane pemphigoid. In contrast, another group of investigators has shown that pemphigoid patients with only oral mucosal involvement have circulating autoantibodies to a6 integrin, a component of the hemidesmosome.

For an accurate diagnosis, perilesional tissue—rather than the ulcerated lesion itself—should be obtained. Often the epithelium in the area of the lesion is so loose that it strips off as the clinician attempts to perform the biopsy. Such tissue is not usually adequate for diagnostic purposes because the interface between the epithelium and connective tissue is no longer intact (although some investigators have shown positive immunofluorescence with this tissue).

Other relatively rare conditions can mimic pemphigoid histopathologically. These include linear IgA bullous dermatosis, angina bullosa hemorrhagica, and epidermolysis bullosa acquisita.

TREATMENT AND PROGNOSIS: Once the diagnosis of mucous membrane pemphigoid has been established by light microscopy and direct immunofluorescence, the patient should be referred to an ophthalmologist who is familiar with the ocular lesions of this condition for a baseline examination of the conjunctivae. This should be done whether or not the patient is experiencing ocular complaints. In addition, if the patient is experiencing symptoms at other anatomic sites, then the appropriate specialist should be consulted.

Because this condition is characterized by heterogeneous pathogenetic mechanisms, it is not surprising that treatments advocated over the years have been varied. In fact, there is no single good therapy for every patient; treatment must be individualized, depending on lesional distribution, disease activity, and therapeutic response. Perhaps as the various forms of pemphigoid are better defined immunopathologically, more specific, directed therapy can be devised.

CLINICAL FEATURES: Bullous pemphigoid typically develops in older people; most patients are between 60 and 80 years of age. No sex or racial predilection is generally reported, although one group of investigators noted that men are overrepresented in this disease by a 2:1 margin when one corrects for the skewing of the aging population toward the female gender. Pruritus may be an early symptom. This is followed by the development of multiple, tense bullae on either normal or erythematous skin (Fig. 16-72). These lesions eventually rupture after several days, causing a superficial crust to form. Eventually, healing takes place without scarring.

Oral mucosal involvement is uncommon, although the reported prevalence in several series of cases has ranged from 8% to 39%. Referral bias may explain the discrepancy in prevalence rates. The oral lesions, like the skin lesions, begin as bullae, but they tend to rupture sooner, probably as a result of the constant low-grade trauma to which the oral mucosa is subjected. Large, shallow ulcerations with smooth, distinct margins are present after the bullae rupture (Fig. 16-73).

HISTOPATHOLOGIC FEATURES: Microscopic examination of tissue obtained from the perilesional margin of a bulla shows separation of the epithelium from the connective tissue at the basement membrane zone, resulting in a subepithelial separation. Modest numbers of both acute and chronic inflammatory cells are typically seen in the lesional area, and the presence of eosinophils within the bulla itself is characteristic.

Direct immunofluorescence studies show a continuous linear band of immunoreactants, usually IgG and C3, localized to the basement membrane zone in 90% to 100% of affected patients. These antibodies may bind to proteins associated with hemidesmosomes, structures that bind the basal cell layer of the epithelium to the basement membrane and the underlying connective tissue. These proteins have been designated as bullous pemphigoid antigens (BP180 and BP230), and immunoelectron microscopy has demonstrated the localization of BP180 to the upper portion of the lamina lucida of the basement membrane.

In addition to the tissue-bound autoantibodies, 50% to 90% of the patients also have circulating autoantibodies in the serum, producing an indirect immunofluorescent pattern that is identical to that of the direct immunofluorescence. Unlike pemphigus vulgaris, the antibody titers seen in bullous pemphigoid do not appear to correlate with disease activity. The antibodies alone do not appear to be capable of inducing bullae in this disease. Instead, binding of the antibodies to the basement membrane initiates the complement cascade, which in turn results in degranulation of mast cells, with recruitment of neutrophils and eosinophils to the area. The damage to the basement membrane is thought to be mediated by elastases and matrix metalloproteinases released by these inflammatory cells.

TREATMENT AND PROGNOSIS: Management of the patient with bullous pemphigoid consists of systemic immunosuppressive therapy. Moderate daily doses of systemic prednisone usually control the condition, after which alternate-day therapy may be given to reduce the risk of corticosteroid complications. If the lesions do not respond to prednisone alone, then another immunosuppressive agent, such as azathioprine, may be added to the regimen. Dapsone, a sulfa derivative, may be used as an alternative therapeutic agent, and tetracycline and niacinamide therapy is reported to be effective for some patients. The more severe, resistant cases require prednisone combined with cyclophosphamide; however, this regimen has the potential for significant side effects.

The prognosis is generally good, with many patients experiencing spontaneous remission after 2 to 5 years. Problems may develop with immunosuppressive therapy in this older adult population, however, and mortality rates of up to 27% have been reported in some series.

CLINICAL FEATURES: Erythema multiforme usually has an acute onset and may display a wide spectrum of clinical disease. On the mild end of the spectrum, ulcerations develop, affect ing the oral mucosa primarily. In its most severe form, diffuse sloughing and ulceration of the entire skin and mucosal surfaces may be seen (toxic epidermal necrolysis or Lyell’s disease).

Patients affected by erythema multiforme are usually young adults in their 20s or 30s. Men are affected more frequently than women.

Prodromal symptoms include fever, malaise, headache, cough, and sore throat, occurring approximately 1 week before onset. Although the disease is self-limiting, usually lasting 2 to 6 weeks, about 20% of patients experience recurrent episodes, usually in the spring and autumn.

Erythematous skin lesions develop in about 50% of cases. A variety of appearances (multiforme means many forms) may be present. Typically, early lesions appear on the extremities and are flat, round, and dusky-red in hue. These become slightly elevated and may evolve into bullae with necrotic centers. Sometimes particular skin lesions develop that are highly characteristic for the disease. These lesions appear as concentric circular erythematous rings resembling a target or bull’s-eye (target lesions) (Fig. 16-74).

The oral lesions begin as erythematous patches that undergo epithelial necrosis and evolve into large, shallow erosions and ulcerations with irregular borders (Fig. 16-75). Hemorrhagic crusting of the vermilion zone of the lips is common (Fig. 16-76). These oral lesions, like the skin lesions, emerge quickly and are uncomfortable. Sometimes patients are dehydrated because they are unable to ingest liquids as a result of mouth pain. The ulcerations often have a diffuse distribution. The lips, labial mucosa, buccal mucosa, tongue, floor of the mouth, and soft palate are the most common sites of involvement. Usually, the gingivae and hard palate are relatively spared.

HISTOPATHOLOGIC FEATURES: Histopathologic examination of the perilesional mucosa in erythema multiforme reveals a pattern that is characteristic but not pathognomonic. Subepithelial or intraepithelial vesiculation may be seen in association with necrotic basal keratinocytes (Fig. 16-81). A mixed inflammatory infiltrate is present, consisting of lymphocytes, neutrophils, and often eosinophils. Sometimes these cells are arranged in a perivascular orientation (Fig. 16-82). Because the immunopathologic features are also nonspecific, the diagnosis is often based on the clinical presentation and the exclusion of other vesiculobullous disorders.

TREATMENT AND PROGNOSIS: Management of erythema multiforme, in many respects, remains controversial. In the past, the use of systemic or topical corticosteroids was often advocated, especially in the early stages of the disease. There is little good clinical evidence that such treatment alters the course of this disease, however. If a causative drug is identified or suspected, then it should be discontinued immediately.

If the patient is dehydrated as a result of an inability to eat because of oral pain, then intravenous rehydration may be necessary along with topical anesthetic agents to decrease discomfort.

If recurrent episodes of erythema multiforme are a problem, then an initiating factor, such as recurrent herpesvirus infection or drug exposure, should be sought. If disease is triggered by herpes simplex, then continuous oral acyclovir or valacyclovir therapy can prevent recurrences.

Generally, erythema multiforme is not life threatening except in its most severe forms. The mortality rate in patients with toxic epidermal necrolysis historically has been approximately 34%; the rate in those with Stevens-Johnson syndrome is 2% to 10%. Corticosteroids should be avoided in the management of toxic epidermal necrolysis because some investigators have found that such drugs may be detrimental. Intravenous administration of pooled human immunoglobulins has been shown in several open-label trials to produce remarkable resolution of toxic epidermal necrolysis, presumably because of blockade of Fas ligand, which is believed to be responsible for inducing epithelial cell apoptosis. Because the lesions of toxic epidermal necrolysis are analogous to those suffered by burn patients, management of these patients in the burn unit of the hospital is recommended.

CLINICAL FEATURES: The characteristic lesions of erythema migrans are seen on the anterior two thirds of the dorsal tongue mucosa. They appear as multiple, well-demarcated zones of erythema (Figs. 16-83 and 16-84), concentrated at the tip and lateral borders of the tongue. This erythema is due to atrophy of the filiform papillae, and these atrophic areas are typically surrounded at least partially by a slightly elevated, yellow-white, serpentine or scalloped border (Fig. 16-85). The patient who is aware of the process is often able to describe the lesions as appearing quickly in one area, healing within a few days or weeks, then developing in a very different area. Frequently, the lesion begins as a small white patch, which then develops a central erythematous atrophic zone and enlarges centrifugally. Often patients with fissured tongue (see page 13) are affected with erythema migrans as well. Some patients may have only a solitary lesion, but this is uncommon. The lesions are usually asymptomatic, although a burning sensation or sensitivity to hot or spicy foods may be noted when the lesions are active. Only rarely is the burning sensation more constant and severe.

Very infrequently, erythema migrans may occur on oral mucosal sites other than the tongue. In these instances, the tongue is almost always affected; however, other lesions develop on the buccal mucosa, on the labial mucosa, and (less frequently) on the soft palate (Figs. 16-86 and 16-87). These lesions typically produce no symptoms and can be identified by a yellow-white serpentine or scalloped border that surrounds an erythematous zone. These features should prevent confusion with such conditions as candidiasis or erythroplakia.

HISTOPATHOLOGIC FEATURES: If a biopsy specimen of the peripheral region of erythema migrans is examined, a characteristic histopathologic pattern is observed. Hyperparakeratosis, spongiosis, acanthosis, and elongation of the epithelial rete ridges are seen (Fig. 16-88). In addition, collections of neutrophils (Munro abscesses) are observed within the epithelium (Fig. 16-89); lymphocytes and neutrophils involve the lamina propria. The intense neutrophilic infiltrate may be responsible for the destruction of the superficial portion of the epithelium, thus producing an atrophic, reddened mucosa as the lesion progresses. Because these histopathologic features are reminiscent of psoriasis, this is called a psoriasiform mucositis. Despite the apparent lack of association between dermatologic conditions and erythema migrans in one recent report, another case-control study of psoriatic patients showed that erythema migrans occurred at a rate of about 10%; only 2.5% of an age-matched and sex-matched population were affected. A Brazilian study determined that both patients with psoriasis and those with benign migratory glossitis were more likely to have the same human leukocyte antigen (HLA) group, namely HLA-Cw6. Whether these findings mean that erythema migrans represents oral psoriasis or that patients with psoriasis are just more susceptible to erythema migrans is open to debate.

TREATMENT AND PROGNOSIS: Generally no treatment is indicated for patients with erythema migrans. Reassuring the patient that the condition is completely benign is often all that is necessary. Infrequently, patients may complain of tenderness or a burning sensation that is so severe that it disrupts their lifestyle. In such cases, topical corticosteroids, such as fluocinonide or betamethasone gel, may provide relief when applied as a thin film several times a day to the lesional areas.

CLINICAL FEATURES: Reactive arthritis is particularly prevalent in young adult men. According to most series, there is a male-to-female ratio of 9:1. The majority (60% to 90%) of these patients are positive for HLA-B27, a haplotype present in only 4% to 8% of the population. The syndrome usually develops 1 to 4 weeks after an episode of dysentery or venereal disease; in fact, two French physicians published a description of this entity affecting four postdysenteric soldiers 1 week before Reiter’s paper appeared.

Urethritis is often the first sign and is seen in both affected males and females. Females may also have inflammation of the uterine cervix. Conjunctivitis usually appears concurrently with the urethritis, and after several days, arthritis ensues. The arthritis usually affects the joints of the lower extremities, although TMJ involvement has been identified in one third of these patients, typically as erosion of the condylar head. Skin lesions often take the form of a characteristic lesion of the glans penis (balanitis circinata). These lesions develop in about 20% to 30% of patients with reactive arthritis, and they appear as well-circumscribed erythematous erosions with a scalloped, whitish linear boundary.

The oral lesions, which occur in slightly less than 20% of patients with this disorder, are described in various ways. Some reports mention painless erythematous papules distributed on the buccal mucosa and palate; other reports describe shallow, painless ulcers that affect the tongue, buccal mucosa, palate, and gingiva. Some authors have even implied that geographic tongue may be a component of reactive arthritis, probably because geographic tongue bears a superficial resemblance to the lesions of balanitis circinata.

The American Rheumatism Association has defined reactive arthritis based on the clinical findings of a peripheral arthritis that lasts longer than 1 month in conjunction with urethritis, cervicitis, or both.

HISTOPATHOLOGIC FEATURES: The histopathologic findings of the cutaneous lesions in patients with reactive arthritis are frequently similar to those found in patients with psoriasis, particularly with respect to the presence of microabscesses within the superficial layers of the surface epithelium. Other features in common with psoriasis include hyperparakeratosis with elongated, thin rete ridges.

TREATMENT AND PROGNOSIS: Some patients with reactive arthritis experience spontaneous resolution of their disease after 3 to 12 months, but many others have chronic symptoms that may wax and wane. Treatment may not be necessary for the milder cases. Nonsteroidal antiinflammatory drugs (NSAIDs) are initially used for managing arthritis, and sulfasalazine may be helpful in resolving cases that do not respond. Immunosuppressive agents, including corticosteroids, azathioprine, and methotrexate, are reserved for the most resistant cases if they are not associated with HIV infection.

Physical therapy probably helps to reduce joint fibrosis associated with arthritis. About 10% to 25% of patients with this disorder have severe disability, usually from arthritis.

CLINICAL FEATURES: Most patients with lichen planus are middle-aged adults. It is rare for children to be affected. Women predominate in most series of cases, usually by a 3:2 ratio over men. Approximately 1% of the population may have cutaneous lichen planus. The prevalence of oral lichen planus is between 0.1% and 2.2%.

The skin lesions of lichen planus have been classically described as purple, pruritic, polygonal papules (Fig. 16-90). These usually affect the flexor surfaces of the extremities. Excoriations may not be visible, despite the fact that the lesions itch, because it hurts the patient when he or she scratches them.

Careful examination of the surface of the skin papules reveals a fine, lacelike network of white lines (Wickham’s striae). Other sites of extraoral involvement include the glans penis, the vulvar mucosa, and the nails (Fig. 16-91). Essentially there are two forms of oral lesions: reticular and erosive.

HISTOPATHOLOGIC FEATURES: The histopathologic features of lichen planus are characteristic but may not be specific, because other conditions, such as lichenoid drug reaction, lichenoid amalgam reaction, oral graft-versus-host disease (GVHD), lupus erythematosus (LE), chronic ulcerative stomatitis, and oral mucosal cinnamon reaction may also show a similar histopathologic pattern. Varying degrees of orthokeratosis and parakeratosis may be present on the surface of the epithelium, depending on whether the biopsy specimen is taken from an erosive or reticular lesion.

The thickness of the spinous layer can also vary. The rete ridges may be absent or hyperplastic, but they classically have a pointed or “saw-toothed” shape (Fig. 16-100).

Destruction of the basal cell layer of the epithelium (hydropic degeneration) is also evident. This is accompanied by an intense, bandlike infiltrate of predominantly T lymphocytes immediately subjacent to the epithelium (Fig. 16-101). Degenerating keratinocytes may be seen in the area of the epithelium and connective tissue interface and have been termed colloid, cytoid, hyaline, or Civatte bodies. No significant degree of epithelial atypia is expected in oral lichen planus, although lesions having a superimposed candidal infection may appear worrisome. These should be reevaluated histopathologically after the candidal infection is treated. On occasion, the chronic inflammatory host response to the atypical cells of epithelial dysplasia can appear virtually indistinguishable histopathologically from lichen planus, particularly in milder cases of epithelial dysplasia. Such ambiguity may contribute to the controversy related to the malignant transformation potential of lichen planus.

The immunopathologic features of lichen planus are nonspecific. Most lesions show the deposition of a shaggy band of fibrinogen at the basement membrane zone.

DIAGNOSIS: The diagnosis of reticular lichen planus can often be made based on the clinical findings alone. The interlacing white striae appearing bilaterally on the posterior buccal mucosa are virtually pathognomonic. Difficulties in diagnosis may arise if candidiasis is superimposed on the lesions because the organism may disturb the characteristic reticular pattern of the lichen planus (Fig. 16-102).

Erosive lichen planus is sometimes more challenging to diagnose (based on clinical features alone) than the reticular form. If the typical radiating white striae and erythematous, atrophic mucosa are present at the periphery of well-demarcated ulcerations on the posterior buccal mucosa bilaterally, then the diagnosis can sometimes be rendered without the support of histopathologic findings. However, a biopsy is often necessary to rule out other ulcerative or erosive diseases, such as lupus erythematosus or chronic ulcerative stomatitis.

Specimens of isolated erosive lichenoid lesions, particularly those of the soft palate, the lateral and ventral tongue, or the floor of the mouth, should be obtained for biopsy to rule out premalignant changes or malignancy. Another condition that may mimic an isolated lesion of lichen planus, both clinically and histopathologically, is a lichenoid reaction to dental amalgam (see page 354).

TREATMENT AND PROGNOSIS: Reticular lichen planus typically produces no symptoms, and no treatment is needed. Occasionally, affected patients may have superimposed candidiasis, in which case they may complain of a burning sensation of the oral mucosa. Antifungal therapy is necessary in such a case. Some investigators recommend annual reevaluation of the reticular lesions of oral lichen planus.

Erosive lichen planus is often bothersome because of the open sores in the mouth. Because it is an immunologically mediated condition, corticosteroids are recommended. The lesions respond to systemic corticosteroids, but such drastic therapy is usually not necessary. One of the stronger topical corticosteroids (e.g., fluocinonide, betamethasone, clobetasol gel) applied several times per day to the most symptomatic areas is usually sufficient to induce healing within 1 or 2 weeks. Some investigators have recommended compounding corticosteroid ointments with an adhesive methylcellulose base, but patient compliance may be reduced because this material is difficult to apply. The patient should be warned that the condition will undoubtedly flare up again, in which case the corticosteroids should be reapplied. In addition, the possibility of iatrogenic candidiasis associated with corticosteroid use should be monitored (Fig. 16-103). Although the use of agents such as topical retinoids, tacrolimus, or cyclosporine has occasionally been advocated for recalcitrant cases of erosive lichen planus, reports of their efficacy have been contradictory. Furthermore, their side effects can be significant, and in the case of cyclosporine, the cost of the drug may be prohibitive. Some investigators suggest that patients with oral erosive lichen planus be evaluated every 3 to 6 months, particularly if the lesions are not typical.

The question of the malignant potential of lichen planus, particularly the erosive form, is yet to be resolved. Most cases of reported malignant transformation are rather poorly documented. Some of these reported cases may not have been true lichen planus, but rather they may have actually been dysplastic leukoplakias with a secondary lichenoid inflammatory infiltrate that mimicked lichen planus (“lichenoid dysplasia”). In addition, the argument can be made that because both lichen planus and squamous cell carcinoma are not rare, some people may have both problems simultaneously, and the two processes may be unrelated to one another. Conversely, some investigators say that the atrophic epithelium of lichen planus may be more susceptible to the action of carcinogens, resulting in an increased risk of malignant transformation. One study examined the molecular characteristics of classic reticular lichen planus, comparing the loss of heterozygosity at purported tumor suppressor gene loci in these lesions with that of varying grades of oral epithelial dysplasia, squamous cell carcinoma, normal oral mucosa, and oral reactive lesions. The molecular profile of oral lichen planus more closely resembled that of normal or reactive oral mucosa, a finding that provides less support for the concept of lichen planus being precancerous. Another study evaluated the malignant transformation rate of typical oral lichen planus compared with oral “lichenoid” lesions. The lichenoid lesions had some features of lichen planus, but were not completely representative, either clinically or histopathologically, of that disease. These investigators found that there was no transformation of characteristic lichen planus, although several of the lichenoid lesions developed into squamous cell carcinoma. Additional prospective clinical studies with strict clinical and histopathologic criteria for the definition of oral lichen planus will need to be performed to resolve this question. If the potential for malignant transformation exists, then it appears to be small. Most of the reported cases have been confined to patients with either the erosive or so-called plaque-type form of lichen planus.