Dermatologic Diseases










457
Ectodermal Dysplasia, 458
White Sponge Nevus, 458
Pachyonychia Congenita, 460
Hereditary Benign Intraepithelial
Dyskeratosis, 462
Hereditary Mucoepithelial
Dysplasia, 462
Dyskeratosis Congenita, 464
Xeroderma Pigmentosum, 464
Darier Disease, 466
Warty Dyskeratoma, 466
Peutz-Jeghers Syndrome, 468
Hereditary Hemorrhagic
Telangiectasia, 468
Tuberous Sclerosis, 470
Multiple Hamartoma Syndrome, 472
Epidermolysis Bullosa, 474
Pemphigus, 476
Paraneoplastic Pemphigus, 478
Mucous Membrane Pemphigoid, 480
Erythema Multiforme, 482
Erythema Migrans, 484
Lichen Planus, 486
Chronic Ulcerative Stomatitis, 490
Graft-Versus-Host Disease, 490
Lupus Erythematosus, 492
Systemic Sclerosis, 494
CREST Syndrome, 496
Psoriasis, 496
Acanthosis Nigricans, 498
16
Dermatologic Diseases

458 16 Dermatologic Diseases
Ectodermal Dysplasia
Figs. 16.1 and 16.2
Approximately 170 dierent, well-dened, heritable conditions make up the group of disorders that fall
under the heading of ectodermal dysplasia. ese disorders are characterized by either aplasia or hypoplasia
of ectodermally derived anatomic structures, including the skin and its appendages, nails, and teeth. Any
of the various types of inheritance patterns may be associated with ectodermal dysplasia, depending on
the particular type. One of the more common and widely known examples is X-linked hypohidrotic
ectodermal dysplasia. ese patients typically have reduced numbers of sweat glands (thus, hypohidrotic);
ne, sparse hair; oligodontia with conically shaped anterior teeth; and saddle nose deformity. Other features
that may be evident include reduced eyebrow and eyelash hairs; brittle, dystrophic nails; ne skin creases
at the lateral aspect of the eyes; and midface hypoplasia.
Because of the reduction in eccrine sweat glands and subsequent decreased sweat production, these
patients are oen intolerant to warm temperatures. e reduction in the number of teeth and the shape
of the teeth results in both functional and aesthetic problems.
Genetic counseling is appropriate for these patients and their families. Management of the dental
problems can be dicult, requiring the expertise of prosthodontists and, potentially, implant specialists.
Fixed and removable appliances, as well as overdentures, can be fabricated. For older children, dental
implant placement may enhance restorative possibilities.
White Sponge Nevus
Fig. 16.3
White sponge nevus is a benign heritable process that is caused by any one of a variety of mutations of
the genes responsible for production of either keratin type 4 or 13. is uncommon autosomal dominant
disorder is characterized by white plaques aecting the oral mucosa, although nasal, vaginal, esophageal,
and anal mucosa also may be aected.
e oral lesions oen are detected in the rst or second decade of life, usually presenting as bilateral
thick, white plaques involving the buccal mucosa. ese lesions typically have blending, indistinct margins,
unlike leukoplakia, which usually exhibits sharply demarcated margins. Other oral mucosal sites can also
be aected, including the labial mucosa, lingual mucosa, oor of the mouth, and palate. Typically the
lesions are asymptomatic, although they may be susceptible to superimposed candidiasis, which could
result in some degree of irritation. A family history of the problem may be present, but this is not absolutely
necessary for diagnosis because the aected patient may have acquired a new gene mutation.
Biopsy of the lesions shows a thick, supercial layer of parakeratin and increased thickness of the
spinous layer, usually with clearing of the cytoplasm of the spinous cells. High-power examination of the
spinous cells oen shows perinuclear eosinophilic condensation of keratin tonolaments, which is a
characteristic feature. Frequently, this nding is more evident upon examination of a Papanicolaou-stained
exfoliative cytologic preparation.
Treatment is generally not necessary because of the benign nature of the condition. However, the clinician
should be aware of white sponge nevus to avoid confusion with leukoplakia, which is a potentially malignant
process.

16 Dermatologic Diseases 459
Figure 16.1
Ectodermal Dysplasia
Sparse scalp hair with absence of eyelashes and eyebrow hair in a patient affected by X-linked hypohidrotic
ectodermal dysplasia. (Courtesy Dr. Marco T. Padilla.)
Figure 16.2
Ectodermal Dysplasia
Same patient as Fig. 16.1, showing a reduced number
of teeth with a conical crown shape. (Courtesy Dr.
Marco T. Padilla.)
Figure 16.3
White Sponge Nevus
Diffuse white plaques found bilaterally on the buccal
mucosa.

460 16 Dermatologic Diseases
Pachyonychia Congenita
Figs. 16.4–16.6
Pachyonychia congenita is a small group of conditions that are considered to be part of the spectrum of
ectodermal dysplasias. is rare disorder is caused by mutation of one of several specic keratin genes,
including keratin 6a, 6b, 16, or 17. In the past, pachyonychia congenita was subdivided into the Jackson-
Lawler type and the Jadassohn-Lewandowsky type; however, modern genetic analysis now reveals that
classication that is based on the specic genetically altered keratin is more accurate and appropriate.
Most patients who have prominent oral lesions show mutations of keratin 6a, although the other mutations
may also have some degree of oral involvement.
In many instances, the cutaneous lesions are the most prominent aspect of this condition, with alterations
in the appearance of the nails being most prominent. Due to the accumulation of keratin under the nail
bed, the nails develop a tubular conguration at a very early age. Eventually this deformity may lead to
loss of the nail. ick, callus-like lesions form on the palmar and plantar surfaces, and the plantar lesions
may become ssured and painful. e plantar changes are particularly symptomatic, presumably due to
the development of blisters that form beneath the thickened keratin layer. Accumulation of keratin within
the hair follicles results in a pattern of cutaneous punctate papules.
Intraorally, white plaques tend to develop on the lateral and dorsal aspects of the tongue, although other
areas that are subject to chronic frictional trauma, such as the palate, buccal mucosa, and alveolar mucosa,
may develop similar keratoses. Patients who have keratin 17 mutations tend to present with neonatal teeth;
however, the keratotic oral mucosal changes are not seen as frequently in these individuals.
As with white sponge nevus, the oral lesions of pachyonychia congenita are harmless and require no
treatment. Management of the nail, palmar, and plantar lesions can be challenging. Removal of infected
nails may be necessary, and attempts at reducing the degree of keratin accumulation have to be continuous.
Retinoids may help in this process, but the side eects of these medications sometimes limit their use.
Genetic counseling is appropriate for patients with this condition, and prenatal diagnosis can be accomplished
by genetic analysis of chorionic villus samples.

16 Dermatologic Diseases 461
Figure 16.4
Pachyonychia Congenita
Thickened, fissured hyperkeratosis of the plantar skin in an affected patient.
Figure 16.5
Pachyonychia Congenita
Tubular, arched toenails and fingernails are the result
of increased inappropriate keratin production.
Figure 16.6
Pachyonychia Congenita
Subtle white plaques are noted on the buccal mucosa
of this patient, although a range of severity may be
present.

462 16 Dermatologic Diseases
Hereditary Benign Intraepithelial Dyskeratosis
Figs. 16.7 and 16.8
Hereditary benign intraepithelial dyskeratosis (HBID) represents a very rare heritable autosomal dominant
condition that aects the oral and conjunctival mucosa. HBID was initially described in an isolated population
of the Haliwa-Saponi Native American people in the northeastern area of North Carolina in the United
States. A handful of aected individuals who do not appear to have a relation to this group also have been
reported. e causative genetic alteration continues to be debated.
Lesions typically begin to develop in childhood, presenting as gelatinous or granular plaques with
pronounced vascularity involving the bulbar conjunctiva. Occasionally the plaques can grow over the
cornea, obstructing vision. Irritation may be associated with the ocular lesions, and some patients report
seasonal variation in their severity.
Oral lesions usually present as asymptomatic thickened white plaques of the buccal and labial mucosae,
oor of the mouth, and tongue. Microscopically these lesions show marked acanthosis and parakeratosis
with dyskeratotic changes, including a “cell-within-a-cell” pattern within the lesional epithelium.
No treatment is typically necessary for this benign condition, particularly with respect to the oral
lesions. Articial tears may provide some relief for patients who develop ocular irritation, but attempts to
remove the gelatinous conjunctival plaques may result in recurrence. However, signicant visual impairment
is relatively uncommon.
Hereditary Mucoepithelial Dysplasia
Fig. 16.9
Hereditary mucoepithelial dysplasia is a rare autosomal dominant condition that also may occur sporadi-
cally. is condition is characterized by epithelial cells that do not develop normally, although the precise
mechanism for this disrupted development is unclear. Skin, hair, and mucosal tissues may be aected,
with atypical cells being found histopathologically, although these do not have any premalignant potential.
Because the mucosal epithelial cells appear atypical microscopically, Papanicolaou-stained cytologic
preparations (Pap smears) of the uterine cervical mucosa may be interpreted as showing cancer or precancerous
changes, and hysterectomy has been performed inappropriately in some cases.
Clinically these patients have alopecia (reduced hair) aecting the scalp, eyebrows, and eyelashes, and
the hair that is present appears coarse. Conjunctival erythema, corneal erosions, cataracts, and nystagmus
may be present, and patients oen have impaired vision. A rash oen develops in the perineal region of
aected infants. Pulmonary complications tend to develop later in life and include disruption of the alveoli,
recurrent pneumonia, pulmonary brosis, and pneumothorax.
Oral mucosal changes consist primarily of a striking bright red appearance of the palatal mucosa, primarily
aecting the anterior hard palate. e gingivae and tongue also may be aected, to a lesser extent. Despite
the erythema, the lesions are essentially asymptomatic. Other mucosal surfaces, including the previously
mentioned vaginal mucosa, may be aected.
Genetic counseling is an important aspect of managing this condition, and women should alert their
healthcare providers to the presence of this disorder so that their Pap smear is not misinterpreted. Periodic
reevaluation for pulmonary complications is appropriate as these patients age.

16 Dermatologic Diseases 463
Figure 16.7
Hereditary Benign Intraepithelial
Dyskeratosis
Thickened white appearance of the buccal mucosa.
(Courtesy Dr. Alice Curran.)
Figure 16.8
Hereditary Benign Intraepithelial
Dyskeratosis
Gelatinous plaque of the bulbar conjunctiva of the
left eye. (Courtesy Dr. Valerie Murrah.)
Figure 16.9
Hereditary Mucoepithelial Dysplasia
Striking red appearance of the attached gingivae and the anterior portion of the hard palate mucosa.

464 16 Dermatologic Diseases
Dyskeratosis Congenita
Figs. 16.10 and 16.11
Dyskeratosis congenita also is considered to be one of the ectodermal dysplasias. is rare condition
is caused by mutation of any one of nine dierent genes that are responsible for producing telomerase
and its associated factors, which are necessary for maintaining the length of chromosomal telomeres.
Telomeres are found on the ends of chromosomes, and normally with each cell division, they tend to
shorten. Telomerase activity adds some of that length back, but eventually the telomeres become too
short and the cell undergoes senescence, as eventually the entire organism does. One of the genes that is
responsible for maintaining the length of the telomeres is DKC1. Because DKC1 was the rst mutation
that was identied in dyskeratosis congenita, and this mutation was inherited as an X-linked recessive
disorder, the assumption was that all cases of dyskeratosis congenita were inherited in this fashion. It is
now known that the other mutations that can cause this disorder can have either autosomal dominant or
recessive inheritance patterns.
e characteristic features of dyskeratosis congenita begin to appear, on average, around 8 years of age.
Oral leukoplakia, nail dystrophy (including loss of nails), and reticular hyperpigmentation and hypopig-
mentation of the skin of the back and trunk comprise a triad of features that are associated with this
disorder. e increased risk of oral squamous cell carcinoma is very high, with the median age of diagnosis
being 32 years. Cutaneous squamous cell carcinoma rates are elevated, as well as gastrointestinal cancers.
Bone marrow failure, so-called myelodysplastic syndrome, is also common, and these patients are at risk
of developing acute myelomonocytic leukemia. In addition, these patients will have increased risk of
pulmonary brosis, probably as a result of degeneration of the lining epithelial cells of the lungs, with
replacement by a broblastic response. Approximately 10% to 15% of individuals with dyskeratosis congenita
will die due to pulmonary brosis.
e diagnosis of dyskeratosis congenita can be made based on the triad of characteristic clinical features,
although these may not be present in every patient. In such cases, molecular genetic studies can identify
shortened telomeres, which are typically less than the rst percentile in length.
Management of this disorder is challenging. Genetic counseling is certainly appropriate. Bone marrow
transplant may be helpful in reducing the risk of hematopoietic malignancies, but the conditioning regimen
prior to the transplant itself may result in tissue damage that leads to complications such as pulmonary
brosis.
Xeroderma Pigmentosum
Fig. 16.12
Xeroderma pigmentosum is a rare autosomal recessive disorder that is characterized by extreme sensitivity
of the skin to ultraviolet light exposure. Aected patients are susceptible to sunburns caused by minimal
sun exposure and by the development of numerous cutaneous malignancies at a very early age, oen
beginning in the rst decade of life. e condition is caused by mutation of any one of seven dierent
genes that participate in nucleotide excision repair of DNA. When cutaneous keratinocytes are exposed
to ultraviolet light, damage to the normal DNA structure will occur. Without recognition, excision, and
repair of this damaged DNA, keratinocyte mutations may result, a process that leads to a greatly increased
risk for malignancy.
e cutaneous changes are oen rst noticed when an aected child is rst exposed to sunlight, resulting
in a severe sunburn aer a small amount of time. Basal cell and squamous cells carcinomas oen develop
in the rst decade of life, and melanoma typically presents in the second decade. Variation in the color of
the skin (poikiloderma) appears as areas with variable amounts of melanin pigmentation. Cataract formation
and other ocular disorders, dwarsm, gonadal hypoplasia, and neurologic degeneration also may be seen.
An increased risk of squamous cell carcinoma of the anterior tongue has been described in these patients.
No cure for xeroderma pigmentosum exists. Patients who avoid all ultraviolet light (sunlight) exposure
will have delayed onset of their cutaneous malignancies. Early tumors can be excised, followed by skin
graing from nonexposed areas of skin. Death is usually related to complications of cutaneous squamous
cell carcinoma or metastatic melanoma.

16 Dermatologic Diseases 465
Figure 16.10
Dyskeratosis Congenita
The tongue appears atrophic and exhibits focal areas of
leukoplakia.
Figure 16.11
Dyskeratosis Congenita
The absence of fingernails is one of several cutaneous manifesta-
tions of this disorder.
Figure 16.12
Xeroderma Pigmentosum
This 21-year-old patient has had several
procedures to remove cutaneous malig-
nancies and actinic keratoses from his
facial skin.

466 16 Dermatologic Diseases
Darier Disease
Figs. 16.13 and 16.14
Darier disease, also known as keratosis follicularis, is an autosomal dominant condition that is caused by
mutation of the ATP2A2 gene. is gene encodes for sarco/endoplasmic reticulum ATPase type 2 (SERCA2),
which is a calcium pump associated with the endoplasmic reticulum. Although this disorder may be seen
in families, as many as 50% of cases may represent new mutations. Currently, the mechanism by which
the altered calcium metabolism causes the changes seen in the surface epithelium is unknown.
Cutaneous lesions of Darier disease usually are noticed during childhood, appearing as erythematous
to brown papules that are sometimes so numerous that they coalesce. e facial skin, as well as the skin
of the trunk and chest, may be aected preferentially. Accumulations of keratin can become malodorous
at times.
Oral lesions present as white, at-topped papules that may be sparse; however, they can be so numerous
that they produce a cobblestone texture. e hard palate and attached gingivae are typically aected.
e cutaneous lesions tend to be uncomfortable in warm temperatures or humid environments, so
minimizing these situations is desirable. Treatment is directed at reducing the amount of keratin. is can
be done by removing the accumulating keratin with mild abrasion or by use of keratolytic agents. Alternatively,
systemic retinoids may be prescribed, and these seem to limit keratin production. However, care must be
exercised with respect to side eects of retinoids.
Warty Dyskeratoma
Fig. 16.15
Warty dyskeratoma, also known as localized Darier disease, is a very uncommon lesion that can develop
on either the skin or oral mucosa. e cause is unknown, although the microscopic features are very
similar to those of Darier disease.
Intraorally, the condition is characterized by the development of a small papule, typically less than
5 mm in diameter, on the keratinized mucosa of the palate or attached gingiva. e papule may show a
central white, keratotic plug, although this plug may be sloughed out, leaving a red central area. e lesion
is generally asymptomatic. e diagnosis is established by excisional biopsy, which is curative.

16 Dermatologic Diseases 467
Figure 16.13
Darier Disease
Confluent erythematous papules and erosions
characterize the cutaneous lesions of this condition.
Figure 16.14
Darier Disease
Numerous umbilicated papules affect the hard palate
and attached gingivae.
Figure 16.15
Warty Dyskeratoma
A solitary papule with a central erythematous erosion that
develops after its keratin plug is lost. (Courtesy Dr. Jeff Barnes.)

468 16 Dermatologic Diseases
Peutz-Jeghers Syndrome
Fig. 16.16
Peutz-Jeghers syndrome is an autosomal dominant condition that is caused by mutation of a tumor
suppressor gene, STK11, which encodes for a serine/threonine kinase. Aected individuals have polyps
that form primarily in the small intestine, but these do not undergo malignant transformation. Because
the polyps may become relatively large, intussusception (the sliding of a proximal segment of bowel into
a distal segment) can cause signicant problems due to potential ischemic necrosis of the involved bowel,
resulting in rupture, spillage of contents, and peritonitis. However, these patients do have an increased
incidence of cancer aecting the gastrointestinal tract (although the polyps do not appear to undergo
malignant transformation), ovary, breast, and male and female reproductive tract.
In many cases, the oral lesions are the rst indication of the disorder. Brown macular lesions that
resemble freckles develop on the skin around body orices, such as the mouth, nose, genitals, and anus.
e lesions can also extend intraorally to involve the buccal mucosa and tongue; the ngers also can be
aected.
ese patients and their families should receive genetic counseling. In addition, periodic evaluation to
monitor for the development of intussusception, as well as malignancy, is recommended.
Hereditary Hemorrhagic Telangiectasia
Figs. 16.17 and 16.18
Hereditary hemorrhagic telangiectasia, also known as Osler-Weber-Rendu syndrome, is an uncommon
autosomal dominant condition that is caused by mutation of either one of two genes, although the clinical
presentation of both mutations is quite similar. HHT1 is caused by mutation of the endoglin (ENG) gene
(located on chromosome 9). On the other hand, HHT2 is caused by mutation of activin receptor-like
kinase-1 (ALK1; ACVRL1) gene, which is located on chromosome 12. ese mutations result in the develop-
ment of multiple supercial vascular malformations involving the nasal mucosa and other mucosal surfaces.
Oen the diagnosis of this disorder is suggested by a history of frequent epistaxis. Further evaluation may
identify additional family members who are aected.
e oral lesions are characterized by multiple, at to slightly elevated, red lesions that are usually 1 to
2 mm in diameter, described as mat-like telangiectasias. Upon diascopy (pressing a clean glass slide against
the lesion), blanching of the lesion should be easily demonstrated, as the blood in the lesional vessels is
pushed into the surrounding vasculature. e oral lesions are usually seen on the lips, labial mucosa,
buccal mucosa, and tongue, but any intraoral site may be aected.
Although these small telangiectatic collections do not present any problems with respect to dental care,
laser ablation of the more cosmetically problematic lesions could be considered. More importantly, a
signicant percentage of these patients, particularly those with HHT1, have been shown to have pulmonary
or cerebral vascular shunts, which may predispose them to cerebral abscess formation. To prevent this
from happening, some investigators have recommended that prophylactic antibiotics be given prior to
dental procedures that cause bacteremia.

16 Dermatologic Diseases 469
Figure 16.16
Peutz-Jeghers Syndrome
Multiple lentigines, ranging from brown to black in color, are often
found in a periorificial pattern, although the oral mucosa is frequently
affected as well. (Courtesy Dr. Asadur Jorge Tchekmedyian.)
Figure 16.17
Hereditary Hemorrhagic Telangiectasia
These erythematous papules and macules on the dorsal
tongue represent focal superficial collections of small
blood vessels.
Figure 16.18
Hereditary Hemorrhagic Telangiectasia
Vascular lesions are noted on this patient’s hard
palate.

470 16 Dermatologic Diseases
Tuberous Sclerosis
Figs. 16.19–16.21
Tuberous sclerosis is an uncommon autosomal dominant condition that is caused by mutations associated
with either one of two tumor suppressor genes—TSC1 and TSC2—which are found on chromosomes 9
and 16, respectively. Mutation of either of these genes results in a characteristic pattern of clinical ndings,
including intellectual disability, a variety of hamartomatous growths, and seizure disorders. e hamartomatous
growths are thought to be induced by disruption of a tumor suppressor pathway that no longer functions
normally. Patients with the TSC2 mutation seem to have a more severe presentation.
Angiobromas of the facial skin are one of the more common lesions seen in tuberous sclerosis, presenting
as multiple small (1 to 3 mm) papules that develop primarily on the perinasal skin, especially in the
nasolabial folds. Similar smooth-surfaced papules, termed periungual bromas, may be found on the skin
adjacent to the nails. Shagreen patches are supercial connective tissue hamartomas that produce velvety
areas of the skin, and their name is derived from the polishing cloths made from shark skin that have this
designation. Small, ovoid areas of hypopigmentation, termed ash leaf spots, are seen commonly in tuberous
sclerosis and are best visualized by using a Wood (ultraviolet) lamp. Other characteristic hamartomas
associated with tuberous sclerosis include angiomyolipoma of the kidney and cardiac rhabdomyoma.
Tuberous sclerosis derives its name from the dense, potato-like hamartomatous growths of the brain
that are oen identied at autopsy of an aected individual. Other central nervous system ndings include
seizure disorders, experienced by many of these patients, and intellectual disability, found in approximately
one-third.
Oral manifestations may include brous papules of anterior facial gingiva, although other oral sites,
such as the tongue, lips, palate, and buccal mucosa also may be aected. e gingival enlargement that
has been reported in these patients is probably caused by treatment of their associated seizure disorder
with phenytoin in most cases. Radiolucencies of the jaws may also develop, and upon biopsy, these typically
contain dense brous connective tissue. Pitting enamel defects are also relatively common in these patients,
especially on the facial aspect of the permanent anterior teeth.
Genetic counseling is recommended for patients and families aected by this disorder. Prenatal genetic
testing for the responsible mutations can be used for family planning, if desired. Management of the seizure
disorder of the tuberous sclerosis patient is important, although monitoring for other potential associated
problems is necessary as well.

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457Ectodermal Dysplasia, 458White Sponge Nevus, 458Pachyonychia Congenita, 460Hereditary Benign Intraepithelial Dyskeratosis, 462Hereditary Mucoepithelial Dysplasia, 462Dyskeratosis Congenita, 464Xeroderma Pigmentosum, 464Darier Disease, 466Warty Dyskeratoma, 466Peutz-Jeghers Syndrome, 468Hereditary Hemorrhagic Telangiectasia, 468Tuberous Sclerosis, 470Multiple Hamartoma Syndrome, 472Epidermolysis Bullosa, 474Pemphigus, 476Paraneoplastic Pemphigus, 478Mucous Membrane Pemphigoid, 480Erythema Multiforme, 482Erythema Migrans, 484Lichen Planus, 486Chronic Ulcerative Stomatitis, 490Graft-Versus-Host Disease, 490Lupus Erythematosus, 492Systemic Sclerosis, 494CREST Syndrome, 496Psoriasis, 496Acanthosis Nigricans, 49816 Dermatologic Diseases 458 16 Dermatologic Diseases Ectodermal DysplasiaFigs. 16.1 and 16.2Approximately 170 dierent, well-dened, heritable conditions make up the group of disorders that fall under the heading of ectodermal dysplasia. ese disorders are characterized by either aplasia or hypoplasia of ectodermally derived anatomic structures, including the skin and its appendages, nails, and teeth. Any of the various types of inheritance patterns may be associated with ectodermal dysplasia, depending on the particular type. One of the more common and widely known examples is X-linked hypohidrotic ectodermal dysplasia. ese patients typically have reduced numbers of sweat glands (thus, hypohidrotic); ne, sparse hair; oligodontia with conically shaped anterior teeth; and saddle nose deformity. Other features that may be evident include reduced eyebrow and eyelash hairs; brittle, dystrophic nails; ne skin creases at the lateral aspect of the eyes; and midface hypoplasia.Because of the reduction in eccrine sweat glands and subsequent decreased sweat production, these patients are oen intolerant to warm temperatures. e reduction in the number of teeth and the shape of the teeth results in both functional and aesthetic problems.Genetic counseling is appropriate for these patients and their families. Management of the dental problems can be dicult, requiring the expertise of prosthodontists and, potentially, implant specialists. Fixed and removable appliances, as well as overdentures, can be fabricated. For older children, dental implant placement may enhance restorative possibilities.White Sponge NevusFig. 16.3White sponge nevus is a benign heritable process that is caused by any one of a variety of mutations of the genes responsible for production of either keratin type 4 or 13. is uncommon autosomal dominant disorder is characterized by white plaques aecting the oral mucosa, although nasal, vaginal, esophageal, and anal mucosa also may be aected.e oral lesions oen are detected in the rst or second decade of life, usually presenting as bilateral thick, white plaques involving the buccal mucosa. ese lesions typically have blending, indistinct margins, unlike leukoplakia, which usually exhibits sharply demarcated margins. Other oral mucosal sites can also be aected, including the labial mucosa, lingual mucosa, oor of the mouth, and palate. Typically the lesions are asymptomatic, although they may be susceptible to superimposed candidiasis, which could result in some degree of irritation. A family history of the problem may be present, but this is not absolutely necessary for diagnosis because the aected patient may have acquired a new gene mutation.Biopsy of the lesions shows a thick, supercial layer of parakeratin and increased thickness of the spinous layer, usually with clearing of the cytoplasm of the spinous cells. High-power examination of the spinous cells oen shows perinuclear eosinophilic condensation of keratin tonolaments, which is a characteristic feature. Frequently, this nding is more evident upon examination of a Papanicolaou-stained exfoliative cytologic preparation.Treatment is generally not necessary because of the benign nature of the condition. However, the clinician should be aware of white sponge nevus to avoid confusion with leukoplakia, which is a potentially malignant process. 16 Dermatologic Diseases 459■ Figure 16.1 Ectodermal Dysplasia Sparse scalp hair with absence of eyelashes and eyebrow hair in a patient affected by X-linked hypohidrotic ectodermal dysplasia. (Courtesy Dr. Marco T. Padilla.)■ Figure 16.2 Ectodermal Dysplasia Same patient as Fig. 16.1, showing a reduced number of teeth with a conical crown shape. (Courtesy Dr. Marco T. Padilla.)■ Figure 16.3 White Sponge Nevus Diffuse white plaques found bilaterally on the buccal mucosa. 460 16 Dermatologic Diseases Pachyonychia CongenitaFigs. 16.4–16.6Pachyonychia congenita is a small group of conditions that are considered to be part of the spectrum of ectodermal dysplasias. is rare disorder is caused by mutation of one of several specic keratin genes, including keratin 6a, 6b, 16, or 17. In the past, pachyonychia congenita was subdivided into the Jackson-Lawler type and the Jadassohn-Lewandowsky type; however, modern genetic analysis now reveals that classication that is based on the specic genetically altered keratin is more accurate and appropriate. Most patients who have prominent oral lesions show mutations of keratin 6a, although the other mutations may also have some degree of oral involvement.In many instances, the cutaneous lesions are the most prominent aspect of this condition, with alterations in the appearance of the nails being most prominent. Due to the accumulation of keratin under the nail bed, the nails develop a tubular conguration at a very early age. Eventually this deformity may lead to loss of the nail. ick, callus-like lesions form on the palmar and plantar surfaces, and the plantar lesions may become ssured and painful. e plantar changes are particularly symptomatic, presumably due to the development of blisters that form beneath the thickened keratin layer. Accumulation of keratin within the hair follicles results in a pattern of cutaneous punctate papules.Intraorally, white plaques tend to develop on the lateral and dorsal aspects of the tongue, although other areas that are subject to chronic frictional trauma, such as the palate, buccal mucosa, and alveolar mucosa, may develop similar keratoses. Patients who have keratin 17 mutations tend to present with neonatal teeth; however, the keratotic oral mucosal changes are not seen as frequently in these individuals.As with white sponge nevus, the oral lesions of pachyonychia congenita are harmless and require no treatment. Management of the nail, palmar, and plantar lesions can be challenging. Removal of infected nails may be necessary, and attempts at reducing the degree of keratin accumulation have to be continuous. Retinoids may help in this process, but the side eects of these medications sometimes limit their use. Genetic counseling is appropriate for patients with this condition, and prenatal diagnosis can be accomplished by genetic analysis of chorionic villus samples. 16 Dermatologic Diseases 461■ Figure 16.4 Pachyonychia Congenita Thickened, fissured hyperkeratosis of the plantar skin in an affected patient. ■ Figure 16.5 Pachyonychia Congenita Tubular, arched toenails and fingernails are the result of increased inappropriate keratin production. ■ Figure 16.6 Pachyonychia Congenita Subtle white plaques are noted on the buccal mucosa of this patient, although a range of severity may be present. 462 16 Dermatologic Diseases Hereditary Benign Intraepithelial DyskeratosisFigs. 16.7 and 16.8Hereditary benign intraepithelial dyskeratosis (HBID) represents a very rare heritable autosomal dominant condition that aects the oral and conjunctival mucosa. HBID was initially described in an isolated population of the Haliwa-Saponi Native American people in the northeastern area of North Carolina in the United States. A handful of aected individuals who do not appear to have a relation to this group also have been reported. e causative genetic alteration continues to be debated.Lesions typically begin to develop in childhood, presenting as gelatinous or granular plaques with pronounced vascularity involving the bulbar conjunctiva. Occasionally the plaques can grow over the cornea, obstructing vision. Irritation may be associated with the ocular lesions, and some patients report seasonal variation in their severity.Oral lesions usually present as asymptomatic thickened white plaques of the buccal and labial mucosae, oor of the mouth, and tongue. Microscopically these lesions show marked acanthosis and parakeratosis with dyskeratotic changes, including a “cell-within-a-cell” pattern within the lesional epithelium.No treatment is typically necessary for this benign condition, particularly with respect to the oral lesions. Articial tears may provide some relief for patients who develop ocular irritation, but attempts to remove the gelatinous conjunctival plaques may result in recurrence. However, signicant visual impairment is relatively uncommon.Hereditary Mucoepithelial DysplasiaFig. 16.9Hereditary mucoepithelial dysplasia is a rare autosomal dominant condition that also may occur sporadi-cally. is condition is characterized by epithelial cells that do not develop normally, although the precise mechanism for this disrupted development is unclear. Skin, hair, and mucosal tissues may be aected, with atypical cells being found histopathologically, although these do not have any premalignant potential. Because the mucosal epithelial cells appear atypical microscopically, Papanicolaou-stained cytologic preparations (Pap smears) of the uterine cervical mucosa may be interpreted as showing cancer or precancerous changes, and hysterectomy has been performed inappropriately in some cases.Clinically these patients have alopecia (reduced hair) aecting the scalp, eyebrows, and eyelashes, and the hair that is present appears coarse. Conjunctival erythema, corneal erosions, cataracts, and nystagmus may be present, and patients oen have impaired vision. A rash oen develops in the perineal region of aected infants. Pulmonary complications tend to develop later in life and include disruption of the alveoli, recurrent pneumonia, pulmonary brosis, and pneumothorax.Oral mucosal changes consist primarily of a striking bright red appearance of the palatal mucosa, primarily aecting the anterior hard palate. e gingivae and tongue also may be aected, to a lesser extent. Despite the erythema, the lesions are essentially asymptomatic. Other mucosal surfaces, including the previously mentioned vaginal mucosa, may be aected.Genetic counseling is an important aspect of managing this condition, and women should alert their healthcare providers to the presence of this disorder so that their Pap smear is not misinterpreted. Periodic reevaluation for pulmonary complications is appropriate as these patients age. 16 Dermatologic Diseases 463■ Figure 16.7 Hereditary Benign Intraepithelial Dyskeratosis Thickened white appearance of the buccal mucosa. (Courtesy Dr. Alice Curran.)■ Figure 16.8 Hereditary Benign Intraepithelial Dyskeratosis Gelatinous plaque of the bulbar conjunctiva of the left eye. (Courtesy Dr. Valerie Murrah.)■ Figure 16.9 Hereditary Mucoepithelial Dysplasia Striking red appearance of the attached gingivae and the anterior portion of the hard palate mucosa. 464 16 Dermatologic Diseases Dyskeratosis CongenitaFigs. 16.10 and 16.11Dyskeratosis congenita also is considered to be one of the ectodermal dysplasias. is rare condition is caused by mutation of any one of nine dierent genes that are responsible for producing telomerase and its associated factors, which are necessary for maintaining the length of chromosomal telomeres. Telomeres are found on the ends of chromosomes, and normally with each cell division, they tend to shorten. Telomerase activity adds some of that length back, but eventually the telomeres become too short and the cell undergoes senescence, as eventually the entire organism does. One of the genes that is responsible for maintaining the length of the telomeres is DKC1. Because DKC1 was the rst mutation that was identied in dyskeratosis congenita, and this mutation was inherited as an X-linked recessive disorder, the assumption was that all cases of dyskeratosis congenita were inherited in this fashion. It is now known that the other mutations that can cause this disorder can have either autosomal dominant or recessive inheritance patterns.e characteristic features of dyskeratosis congenita begin to appear, on average, around 8 years of age. Oral leukoplakia, nail dystrophy (including loss of nails), and reticular hyperpigmentation and hypopig-mentation of the skin of the back and trunk comprise a triad of features that are associated with this disorder. e increased risk of oral squamous cell carcinoma is very high, with the median age of diagnosis being 32 years. Cutaneous squamous cell carcinoma rates are elevated, as well as gastrointestinal cancers. Bone marrow failure, so-called myelodysplastic syndrome, is also common, and these patients are at risk of developing acute myelomonocytic leukemia. In addition, these patients will have increased risk of pulmonary brosis, probably as a result of degeneration of the lining epithelial cells of the lungs, with replacement by a broblastic response. Approximately 10% to 15% of individuals with dyskeratosis congenita will die due to pulmonary brosis.e diagnosis of dyskeratosis congenita can be made based on the triad of characteristic clinical features, although these may not be present in every patient. In such cases, molecular genetic studies can identify shortened telomeres, which are typically less than the rst percentile in length.Management of this disorder is challenging. Genetic counseling is certainly appropriate. Bone marrow transplant may be helpful in reducing the risk of hematopoietic malignancies, but the conditioning regimen prior to the transplant itself may result in tissue damage that leads to complications such as pulmonary brosis.Xeroderma PigmentosumFig. 16.12Xeroderma pigmentosum is a rare autosomal recessive disorder that is characterized by extreme sensitivity of the skin to ultraviolet light exposure. Aected patients are susceptible to sunburns caused by minimal sun exposure and by the development of numerous cutaneous malignancies at a very early age, oen beginning in the rst decade of life. e condition is caused by mutation of any one of seven dierent genes that participate in nucleotide excision repair of DNA. When cutaneous keratinocytes are exposed to ultraviolet light, damage to the normal DNA structure will occur. Without recognition, excision, and repair of this damaged DNA, keratinocyte mutations may result, a process that leads to a greatly increased risk for malignancy.e cutaneous changes are oen rst noticed when an aected child is rst exposed to sunlight, resulting in a severe sunburn aer a small amount of time. Basal cell and squamous cells carcinomas oen develop in the rst decade of life, and melanoma typically presents in the second decade. Variation in the color of the skin (poikiloderma) appears as areas with variable amounts of melanin pigmentation. Cataract formation and other ocular disorders, dwarsm, gonadal hypoplasia, and neurologic degeneration also may be seen. An increased risk of squamous cell carcinoma of the anterior tongue has been described in these patients.No cure for xeroderma pigmentosum exists. Patients who avoid all ultraviolet light (sunlight) exposure will have delayed onset of their cutaneous malignancies. Early tumors can be excised, followed by skin graing from nonexposed areas of skin. Death is usually related to complications of cutaneous squamous cell carcinoma or metastatic melanoma. 16 Dermatologic Diseases 465■ Figure 16.10 Dyskeratosis Congenita The tongue appears atrophic and exhibits focal areas of leukoplakia. ■ Figure 16.11 Dyskeratosis Congenita The absence of fingernails is one of several cutaneous manifesta-tions of this disorder. ■ Figure 16.12 Xeroderma Pigmentosum This 21-year-old patient has had several procedures to remove cutaneous malig-nancies and actinic keratoses from his facial skin. 466 16 Dermatologic Diseases Darier DiseaseFigs. 16.13 and 16.14Darier disease, also known as keratosis follicularis, is an autosomal dominant condition that is caused by mutation of the ATP2A2 gene. is gene encodes for sarco/endoplasmic reticulum ATPase type 2 (SERCA2), which is a calcium pump associated with the endoplasmic reticulum. Although this disorder may be seen in families, as many as 50% of cases may represent new mutations. Currently, the mechanism by which the altered calcium metabolism causes the changes seen in the surface epithelium is unknown.Cutaneous lesions of Darier disease usually are noticed during childhood, appearing as erythematous to brown papules that are sometimes so numerous that they coalesce. e facial skin, as well as the skin of the trunk and chest, may be aected preferentially. Accumulations of keratin can become malodorous at times.Oral lesions present as white, at-topped papules that may be sparse; however, they can be so numerous that they produce a cobblestone texture. e hard palate and attached gingivae are typically aected.e cutaneous lesions tend to be uncomfortable in warm temperatures or humid environments, so minimizing these situations is desirable. Treatment is directed at reducing the amount of keratin. is can be done by removing the accumulating keratin with mild abrasion or by use of keratolytic agents. Alternatively, systemic retinoids may be prescribed, and these seem to limit keratin production. However, care must be exercised with respect to side eects of retinoids.Warty DyskeratomaFig. 16.15Warty dyskeratoma, also known as localized Darier disease, is a very uncommon lesion that can develop on either the skin or oral mucosa. e cause is unknown, although the microscopic features are very similar to those of Darier disease.Intraorally, the condition is characterized by the development of a small papule, typically less than 5 mm in diameter, on the keratinized mucosa of the palate or attached gingiva. e papule may show a central white, keratotic plug, although this plug may be sloughed out, leaving a red central area. e lesion is generally asymptomatic. e diagnosis is established by excisional biopsy, which is curative. 16 Dermatologic Diseases 467■ Figure 16.13 Darier Disease Confluent erythematous papules and erosions characterize the cutaneous lesions of this condition. ■ Figure 16.14 Darier Disease Numerous umbilicated papules affect the hard palate and attached gingivae. ■ Figure 16.15 Warty Dyskeratoma A solitary papule with a central erythematous erosion that develops after its keratin plug is lost. (Courtesy Dr. Jeff Barnes.) 468 16 Dermatologic Diseases Peutz-Jeghers SyndromeFig. 16.16Peutz-Jeghers syndrome is an autosomal dominant condition that is caused by mutation of a tumor suppressor gene, STK11, which encodes for a serine/threonine kinase. Aected individuals have polyps that form primarily in the small intestine, but these do not undergo malignant transformation. Because the polyps may become relatively large, intussusception (the sliding of a proximal segment of bowel into a distal segment) can cause signicant problems due to potential ischemic necrosis of the involved bowel, resulting in rupture, spillage of contents, and peritonitis. However, these patients do have an increased incidence of cancer aecting the gastrointestinal tract (although the polyps do not appear to undergo malignant transformation), ovary, breast, and male and female reproductive tract.In many cases, the oral lesions are the rst indication of the disorder. Brown macular lesions that resemble freckles develop on the skin around body orices, such as the mouth, nose, genitals, and anus. e lesions can also extend intraorally to involve the buccal mucosa and tongue; the ngers also can be aected.ese patients and their families should receive genetic counseling. In addition, periodic evaluation to monitor for the development of intussusception, as well as malignancy, is recommended.Hereditary Hemorrhagic TelangiectasiaFigs. 16.17 and 16.18Hereditary hemorrhagic telangiectasia, also known as Osler-Weber-Rendu syndrome, is an uncommon autosomal dominant condition that is caused by mutation of either one of two genes, although the clinical presentation of both mutations is quite similar. HHT1 is caused by mutation of the endoglin (ENG) gene (located on chromosome 9). On the other hand, HHT2 is caused by mutation of activin receptor-like kinase-1 (ALK1; ACVRL1) gene, which is located on chromosome 12. ese mutations result in the develop-ment of multiple supercial vascular malformations involving the nasal mucosa and other mucosal surfaces. Oen the diagnosis of this disorder is suggested by a history of frequent epistaxis. Further evaluation may identify additional family members who are aected.e oral lesions are characterized by multiple, at to slightly elevated, red lesions that are usually 1 to 2 mm in diameter, described as mat-like telangiectasias. Upon diascopy (pressing a clean glass slide against the lesion), blanching of the lesion should be easily demonstrated, as the blood in the lesional vessels is pushed into the surrounding vasculature. e oral lesions are usually seen on the lips, labial mucosa, buccal mucosa, and tongue, but any intraoral site may be aected.Although these small telangiectatic collections do not present any problems with respect to dental care, laser ablation of the more cosmetically problematic lesions could be considered. More importantly, a signicant percentage of these patients, particularly those with HHT1, have been shown to have pulmonary or cerebral vascular shunts, which may predispose them to cerebral abscess formation. To prevent this from happening, some investigators have recommended that prophylactic antibiotics be given prior to dental procedures that cause bacteremia. 16 Dermatologic Diseases 469■ Figure 16.16 Peutz-Jeghers Syndrome Multiple lentigines, ranging from brown to black in color, are often found in a periorificial pattern, although the oral mucosa is frequently affected as well. (Courtesy Dr. Asadur Jorge Tchekmedyian.)■ Figure 16.17 Hereditary Hemorrhagic Telangiectasia These erythematous papules and macules on the dorsal tongue represent focal superficial collections of small blood vessels. ■ Figure 16.18 Hereditary Hemorrhagic Telangiectasia Vascular lesions are noted on this patient’s hard palate. 470 16 Dermatologic Diseases Tuberous SclerosisFigs. 16.19–16.21Tuberous sclerosis is an uncommon autosomal dominant condition that is caused by mutations associated with either one of two tumor suppressor genes—TSC1 and TSC2—which are found on chromosomes 9 and 16, respectively. Mutation of either of these genes results in a characteristic pattern of clinical ndings, including intellectual disability, a variety of hamartomatous growths, and seizure disorders. e hamartomatous growths are thought to be induced by disruption of a tumor suppressor pathway that no longer functions normally. Patients with the TSC2 mutation seem to have a more severe presentation.Angiobromas of the facial skin are one of the more common lesions seen in tuberous sclerosis, presenting as multiple small (1 to 3 mm) papules that develop primarily on the perinasal skin, especially in the nasolabial folds. Similar smooth-surfaced papules, termed periungual bromas, may be found on the skin adjacent to the nails. Shagreen patches are supercial connective tissue hamartomas that produce velvety areas of the skin, and their name is derived from the polishing cloths made from shark skin that have this designation. Small, ovoid areas of hypopigmentation, termed ash leaf spots, are seen commonly in tuberous sclerosis and are best visualized by using a Wood (ultraviolet) lamp. Other characteristic hamartomas associated with tuberous sclerosis include angiomyolipoma of the kidney and cardiac rhabdomyoma.Tuberous sclerosis derives its name from the dense, potato-like hamartomatous growths of the brain that are oen identied at autopsy of an aected individual. Other central nervous system ndings include seizure disorders, experienced by many of these patients, and intellectual disability, found in approximately one-third.Oral manifestations may include brous papules of anterior facial gingiva, although other oral sites, such as the tongue, lips, palate, and buccal mucosa also may be aected. e gingival enlargement that has been reported in these patients is probably caused by treatment of their associated seizure disorder with phenytoin in most cases. Radiolucencies of the jaws may also develop, and upon biopsy, these typically contain dense brous connective tissue. Pitting enamel defects are also relatively common in these patients, especially on the facial aspect of the permanent anterior teeth.Genetic counseling is recommended for patients and families aected by this disorder. Prenatal genetic testing for the responsible mutations can be used for family planning, if desired. Management of the seizure disorder of the tuberous sclerosis patient is important, although monitoring for other potential associated problems is necessary as well. 16 Dermatologic Diseases 471■ Figure 16.19 Tuberous Sclerosis The papules involving the midfacial skin represent angiofibromas. (Courtesy Dr. Alfredo Aguirre.)■ Figure 16.20 Tuberous Sclerosis Periungual fibromas are a characteristic finding in this condition. ■ Figure 16.21 Tuberous Sclerosis Multiple papules and nodules may occasionally affect the oral mucosa. (Courtesy Dr. Alfredo Aguirre.) 472 16 Dermatologic Diseases Multiple Hamartoma Syndrome (Cowden Syndrome)Figs. 16.22–16.24Multiple hamartoma syndrome, also known as Cowden syndrome, is a rare autosomal dominant disorder that was named aer the rst patient who was identied with this condition. e condition is caused by mutation of the PTEN (phosphatase and tensin homologue deleted on chromosome 10) gene, which has overlapping features with other disorders associated with mutations of this gene, including Proteus-like syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Lhermitte-Duclos disease (a hamartomatous tumor of the cerebellum). Although several dierent benign tumors and hamartomas develop in this syndrome, the most important aspect is that an increased incidence of various malignancies is seen, including breast carcinoma, follicular carcinoma of the thyroid, ovarian and endometrial carcinoma, and gastrointestinal adenocarcinoma.Mucocutaneous manifestations are among the most common signs of this disorder, developing in the rst or second decade of life. Hair follicle hamartomas called trichilemmomas occur as multiple small papules on the facial skin around the eyes, nose, and mouth. Oral broepithelial polyps are very common, aecting the labial mucosa, buccal mucosa, dorsal tongue, and gingivae. Small supercial keratotic plaques, called acral keratoses, can aect the dorsal surface of the hands, and palmar keratoses also can develop.A variety of benign tumors also may develop, such as lipomas, angiomas, polyps of the gastrointestinal tract and urethra, thyroid adenomas, and central nervous system tumors such as meningioma.e diagnosis is based on the clinical presentation and necessitates identication of a certain number of features that have been designated as major and minor criteria. Currently, genetic testing for this disorder, although oen performed, is not completely reliable as a diagnostic tool, primarily because the PTEN mutation cannot be detected in all patients who otherwise have a well-documented diagnosis of this condition.Management includes genetic counseling of patients and their families. Treatment of the benign tumors and hamartomas may be performed on an as-needed basis. Careful monitoring of these patients for malignancies is mandatory, and some investigators have recommended prophylactic mastectomy for aected women due to the high risk of their developing breast cancer. 16 Dermatologic Diseases 473■ Figure 16.22 Multiple Hamartoma Syndrome Multiple papules involving the keratinized and non-keratinized mucosa. (Courtesy Dr. Lynn Wallace.)■ Figure 16.23 Multiple Hamartoma Syndrome Multiple papules of the dorsal tongue. (Courtesy Dr. Lynn Wallace.)■ Figure 16.24 Multiple Hamartoma Syndrome Multiple papules of the hard palate. (Courtesy Dr. Lynn Wallace.) 474 16 Dermatologic Diseases Epidermolysis BullosaFigs. 16.25 and 16.26Epidermolysis bullosa (EB) refers to a group of uncommon inherited disorders that are all characterized by mutation of at least one of the various surface epithelial cell attachment mechanisms. Sometimes the aected target is related to epithelial cell–to–epithelial cell attachment and, in other instances, to epithelial cell–to–connective tissue attachment. All forms of EB have some degree of fragility of the skin. Some forms of the condition are rather mild and merely constitute a nuisance (e.g., EB simplex type), whereas other forms are lethal or severely debilitating (such as EB junctional type). At least 44 dierent subtypes of EB have been described, and these are distributed among four major groups, most having either an autosomal dominant or autosomal recessive inheritance pattern. In addition, there is a rare acquired autoimmune blistering disorder, known as EB acquisita, that is nonhereditary. Discussion will center on the dystrophic group because these have the most relevance to the oral region. Both autosomal dominant and autosomal recessive dystrophic EB have mutations in the COL7A1 gene, which is responsible for production of type VII collagen. e phenotypic expression appears to reect the degree to which the mutation disrupts the production of normal type VII collagen.Patients with dominant dystrophic EB will develop vesicles and bullae with relatively minor injury. ese aect areas of the skin that receive greater than average trauma, such as the ngers, elbows, or knees. e blisters rupture and eventually heal with scarring. Over a period of years, the nails are typically lost as a result of repeated injury. Oral vesicles and bullae may also occur, and it is not unusual for the buccal vestibule to be reduced in depth due to adhesions that develop aer the bullae rupture. However, this condition is usually not life threatening.In contrast, recessive dystrophic EB is a more serious blistering disorder. Aected patients develop bullae with minimal trauma, both on the skin and intraorally. Management of this condition requires minimizing any type of frictional trauma to the skin, although it is virtually impossible to prevent bullae from forming. Treating the denuded cutaneous lesions aer the bullae have ruptured is challenging due to secondary bacterial contamination, and scarring is characteristic aer healing. Eventual development of cutaneous squamous cell carcinoma in these areas is common. e ngers and toes become encased in scar tissue as well, aer multiple episodes of bulla formation, healing, and development of adhesions. is results in the so-called mitten deformity of the hands.Oral vesicles and bullae may develop when the patient ingests any food that has any resistance to chewing and swallowing. Routine toothbrushing results in stripping of the gingival epithelium, and, as a result of decreased oral hygiene and a so diet that is oen rich in carbohydrates, the rate of dental caries is markedly increased. Microstomia and ankyloglossia result aer multiple episodes of perioral and intraoral blistering, with subsequent scarring, contracture, and adhesions.e approach to management depends on the type of EB. Genetic counseling is generally appropriate. Recessive dystrophic EB is one of the more challenging forms of this condition, typically requiring input from various medical specialists, dental specialists, nurses, and physical therapists. Topical uoride treatments and a so, noncariogenic diet should be instituted from a young age. If dental restorative procedures are necessary, they should be carried out in an atraumatic fashion, if possible. 16 Dermatologic Diseases 475A B■ Figure 16.25 Epidermolysis Bullosa (A) Multiple areas of scarring develop after healing of blisters associated with the autosomal recessive form of epidermolysis bullosa. Secondary hypopigmentation and hyperpigmen-tation is evident. (B) So-called mitten deformity of the hand, a result of multiple episodes of blistering and scarring of the fingers. Typically the bones of the fingers are incorporated within the mass of tissue. (With appreciation to Dr. Michelle Ziegler.)■ Figure 16.26 Epidermolysis Bullosa Same patient as Fig. 16.25, showing oral and perioral erosions and shallow ulcerations. (With appreciation to Dr. Michelle Ziegler.) 476 16 Dermatologic Diseases ■ Figure 16.27 Pemphigus Vulgaris Partially collapsed bulla on the skin. PemphigusFigs. 16.27–16.30Although several dierent types of pemphigus have been described, the only one that exhibits signicant oral mucosal involvement is pemphigus vulgaris. ese rare autoimmune disorders are characterized by production of antibodies that are directed against the desmosomal components known as desmoglein 1 and desmoglein 3. Desmoglein 3 is a critical part of the desmosomal attachment mechanism that binds one epithelial cell to another. As a result of this antibody attack on the desmosomes, the surface epithelial cells detach from one another, and an intraepithelial blister is produced clinically. Because this is an intraepithelial process, the roof of the blister is quite thin and fragile.Pemphigus vulgaris mostly aects adults, although there are reports of the disease in childhood. In most cases the oral mucosa is the rst site of involvement. e blisters can develop on virtually any oral mucosal surface, although they are short-lived and rupture very soon aer forming, leaving red erosions and shallow ulcers with ragged margins. ese lesions tend to migrate, healing in one area and developing in another, and usually they are painful. Eventually the blisters begin to form on the skin, where they tend to form accid bullae that rupture within a few hours to days, leaving raw, erythematous erosions and crusts.e diagnosis is made by examining a biopsy sample from the perilesional area microscopically and identifying the intraepithelial cleing that usually develops just above the basal cell layer. Conrmation of the diagnosis is done by performing direct immunouorescence studies on a biopsy taken from adjacent normal-appearing mucosa, submitted in Michel solution. Serum also may be submitted for indirect immunouorescence studies or enzyme-linked immunosorbent assay (ELISA) testing if the patient is at a tertiary care center that performs these tests.Prior to the development of modern immunosuppressive therapy, pemphigus patients typically died of complications of their disease, such as dehydration, infection, and electrolyte imbalance. With treatment today, approximately 90% of these patients will experience remission and control of their disease. Treatment generally consists of systemic corticosteroids that are given with another immune-modulating drug (a so-called steroid-sparing agent) to reduce the dose of corticosteroid while still controlling the patient’s lesions. ese steroid-sparing agents include azathioprine, mycophenolate mofetil, methotrexate, cyclo-phosphamide, and others. Cases that do not respond to this therapy may be treated with rituximab or intravenous immunoglobulin (IVIg). However, complications of the immunosuppressive treatment may result in death, usually from infection. In the past, 60% to 90% of these patients died of this disease; with modern immunosuppressive regimens, the mortality rate is 5% to 10%. 16 Dermatologic Diseases 477■ Figure 16.28 Pemphigus Vulgaris Ragged erosions of the buccal mucosa. ■ Figure 16.29 Pemphigus Vulgaris Erythema and ulceration of the palatal mucosa. ■ Figure 16.30 Pemphigus Vulgaris Erosions of the mandibular buccal attached gingiva. 478 16 Dermatologic Diseases Paraneoplastic PemphigusFigs. 16.31–16.34Paraneoplastic pemphigus is a rare immune-mediated condition that generally seems to be triggered by the presence of a malignant lymphoreticular process, most commonly lymphocytic lymphoma or leukemia. Benign lymphoid proliferations, such as Castleman disease, as well as cancers other than lymphoreticular malignancies, also may be responsible. Although this is an autoimmune process, similar to pemphigus vulgaris, there is a much greater number of antibodies that are directed against many dierent antigenic targets of the oral, respiratory, and genital mucosa, as well as the skin. Cytotoxic T lymphocytes also may play a role in some instances. As a result, the presentation of this disease is much more severe than pemphigus vulgaris. Paraneoplastic pemphigus may have overlapping clinical features with pemphigus, pemphigoid, erythema multiforme, and lichen planus.Aected patients may exhibit erythematous lichenoid cutaneous papules, vesicles, and bullae; severe conjunctivitis that may lead to scarring; and pulmonary symptoms related to bronchiolitis obliterans. A variety of oral lesions can develop, including hemorrhagic crusting of the vermilion zone of the lips, widespread shallow ulcerations preceded by vesicles and bullae, and areas of erythema with lichenoid striae. Typically the patient has already been diagnosed with lymphoma or leukemia, but in one-third of the reported cases, the appearance of paraneoplastic pemphigus resulted in discovery of the neoplasm.e diagnosis of paraneoplastic pemphigus is oen delayed because the patient is usually receiving aggressive chemotherapy for a lymphoreticular malignancy, and this treatment impairs the patient’s ability to ght infection. Consequently, paraneoplastic pemphigus is frequently mistaken for a viral or bacterial infection, and it is only aer weeks of futile antibiotic treatment and negative culture results that the correct diagnosis is entertained and conrmed. Biopsy of perilesional tissue may show a lichenoid mucositis that is combined with both intraepithelial cleing and subepithelial cleing. Although direct immunouorescence may show characteristic features of antibody deposition within the tissue, indirect immunouorescence using rat bladder epithelium as a substrate is considered a more denitive diagnostic test. is should identify diagnostic patterns of intraepithelial and basement membrane deposition of autoantibodies that are circulating in the patient’s serum.If the condition is caused by a benign tumor, such as Castleman disease or thymoma, surgical excision sometimes results in remission of the paraneoplastic pemphigus. Management of cases associated with malignancy can be very challenging because the immunosuppressive therapy that is necessary to control the abnormal antibody production may also allow the patient’s tumor to recur. e additional reduction in the patient’s immune status will increase the risk for serious infections as well. e prognosis generally is considered to be poor, with some series reporting a 90% mortality rate for these patients.■ Figure 16.31 Paraneoplastic Pemphigus Bullae involving the palmar surface of the hand. 16 Dermatologic Diseases 479■ Figure 16.32 Paraneoplastic Pemphigus Cicatrizing conjunctivitis with ulceration and hemor-rhagic crusting of the periocular skin. ■ Figure 16.33 Paraneoplastic Pemphigus Ulceration and hemorrhagic crusting of the vermilion zone of the lips. ■ Figure 16.34 Paraneoplastic Pemphigus Erosions and ulcerations with adjacent white lichenoid striae of the dorsal and lateral tongue. 480 16 Dermatologic Diseases Mucous Membrane PemphigoidFigs. 16.35–16.38Mucous membrane pemphigoid (MMP), also known as cicatricial (scarring) pemphigoid, is a group of autoimmune disorders that are characterized by the formation of vesicles and bullae, mostly involving the mucosal surfaces (oral, conjunctival, laryngeal, nasal, vaginal). Approximately 20% of these patients may have cutaneous lesions as well. is disorder is caused by the production of autoantibodies that are directed against any one of several antigenic targets that comprise the basement membrane of the mucosa. e anatomic sites and severity of the disease are oen dependent on which component of the basement membrane is targeted by the antibody attack.Most patients who develop MMP are older adults, and children are rarely aected. Individuals may notice vesicles or bullae developing on the oral mucosa, particularly the gingiva and palate, although any oral site may be aected. e blisters rupture within several hours, leaving an irregularly shaped, shallow ulceration with smooth borders. As some lesions heal, others will develop at other sites. Intraoral scarring is usually not a prominent feature.Although the oral ulcers are painful and annoying, the most signicant complication of this condition is conjunctival involvement, which may lead to blindness if not identied early and treated appropriately. e earliest sign of conjunctival MMP is subepithelial brosis, a process that requires identication by an ophthalmologic slit-lamp microscopic examination. With continued lesional activity, the brosis causes disruption of the various glands that lubricate the surface of the eye, causing signicant dryness. is leads to conjunctival inammation, and scarring (synechiae) can form between the bulbar (globe of the eye) and the palpebral (eyelid lining) conjunctiva. Eventually blindness ensues.e diagnosis is established by identifying a subepithelial cle upon examination of perilesional mucosa using routine light microscopy. In addition, adjacent normal mucosa should be submitted in Michel solution for direct immunouorescence studies, which should conrm a linear band of immunoreactants (usually C3 and IgG) at the basement membrane zone. Once the diagnosis is established, referral of the patient for ophthalmologic examination is appropriate, and this should be repeated every 6 months.MMP may respond to a variety of treatments, and this may reect the fact that this process is probably a variety of dierent diseases with a common immunopathologic feature. Treatment is initially driven by the presence of ocular involvement, which typically requires systemic immunosuppressive therapy. If there are oral lesions only, then treatment is based on how extensive they are. With limited disease, topical corticosteroids may adequately control the problem. With more extensive disease, medications such as systemic corticosteroids, dapsone, mycophenolate mofetil, or other immune suppressive and immune modulating drugs, such as rituximab, may be appropriate.■ Figure 16.35 Mucous Membrane Pemphigoid Intact bullae and vesicles involving the soft palate mucosa. A shallow ulcer with an erythematous periphery is adjacent to the bullae, representing an area where the roof of the bulla has been lost. 16 Dermatologic Diseases 481■ Figure 16.36 Mucous Membrane Pemphigoid Relatively mild example presenting as erythematous gingivae, the so-called desquamative gingivitis pattern. ■ Figure 16.37 Mucous Membrane Pemphigoid A more severe example of gingival involve-ment, probably exacerbated by bacterial plaque accumulation. ■ Figure 16.38 Mucous Membrane Pemphigoid Involvement of the conjunctival mucosa, demonstrat-ing a band of scar tissue between the bulbar and palpebral conjunctiva (symblepharon formation). 482 16 Dermatologic Diseases Erythema MultiformeFigs. 16.39–16.42Erythema multiforme is an uncommon mucocutaneous disease that is most likely immune mediated, although the precise pathogenetic mechanisms are unclear. Antecedent herpesvirus or mycoplasma infections are oen described, and perhaps these somehow trigger the condition. Less commonly, exposure to a drug seems to initiate the disease. A range of severity is seen, with milder forms designated as erythema multiforme minor, when only the skin or oral mucosa is involved; more severe cases are termed erythema multiforme major, when the skin is involved in addition to at least two mucosal sites.e onset of this condition is usually relatively rapid, with lesions developing within a day or two. e cutaneous lesions are red, palpable, and usually round, initially developing on the extremities. Variation in the appearance of the lesions may be seen (thus the term “multiforme” = “many forms”), with some being macular and some slightly elevated. e target or bull’s-eye lesion is considered a classic sign of erythema multiforme, appearing as concentric red circles, reminiscent of a target. e oral lesions usually present as large, shallow ulcers with irregular margins and an erythematous periphery. ese aect the nonkeratinized mucosa primarily, with only rare examples described as involving the attached gingivae or hard palate. Patients are quite uncomfortable and have trouble eating and drinking, so dehydration may develop.e diagnosis is based on the clinical features, especially if target lesions are present. Although the rapid onset is less characteristic of other immunobullous and erosive conditions, biopsy is oen done to rule out these conditions. e microscopic features of erythema multiforme are suggestive but not pathog-nomonic and require clinical correlation to arrive at the diagnosis.is condition is typically self-limiting, and usually the lesions resolve over a period of several weeks. Chronic erythema multiforme has been described, and this may respond to antiviral medication, presumably because the triggering herpesvirus is suppressed. A short course of systemic corticosteroids at a moderate dose may hasten healing for some individuals. Recurrences happen occasionally, and for unknown reasons, these tend to develop in the spring and autumn.Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) were once thought of as representing severe forms of erythema multiforme, but current opinion places these two conditions in a separate category. e triggering agent for these disorders is usually a drug, rather than infection. ese conditions may be preceded by fever or ulike illness, followed by development of nonpalpable erythematous lesions that initially develop on the trunk. Oral ulcers are common, appearing similar to those of erythema multiforme. TEN is characterized by large cutaneous bullae that slough rapidly, resulting in signicant areas of denuded skin. Patients are susceptible to infection and electrolyte imbalance and typically are managed in the burn unit of a tertiary care center. e mortality rate of TEN oen approaches 30% despite such care.■ Figure 16.39 Erythema Multiforme Characteristic hemorrhagic crusting of the lips. 16 Dermatologic Diseases 483■ Figure 16.40 Erythema Multiforme Erythematous round macular lesions of the palmar skin. ■ Figure 16.41 Erythema Multiforme Shallow ulcers with ragged borders, primarily affect-ing nonkeratinized mucosa. This patient had a history of sulfa drug exposure 1 week earlier. ■ Figure 16.42 Erythema Multiforme Same patient as Fig. 16.41 after 1 week of treatment with prednisolone syrup. 484 16 Dermatologic Diseases Erythema MigransFigs. 16.43–16.46Erythema migrans (benign migratory glossitis; geographic tongue) is a common inammatory condition of unknown etiology. e lesions microscopically resemble those of cutaneous psoriasis, and some studies suggest that patients with psoriasis may have an increased prevalence of oral erythema migrans.e diagnosis of erythema migrans usually does not require biopsy because of its very characteristic clinical features. e lesions appear as sharply demarcated erythematous patches of atrophy of the liform papillae of the dorsal tongue, with a tendency to involve the lateral aspects of the dorsum. Each patch usually has a linear yellow-white border by which it is either partially or completely encompassed. e lesional areas persist for a variable period, then the inammation subsides and the papillae regenerate. Other sites of the dorsal tongue then may develop lesions. Although the dorsal tongue is the most common site of involvement, the lateral and ventral tongue mucosa also are aected rather frequently. Very uncom-monly, the so palate, buccal mucosa, or labial mucosa may develop these lesions, which are characterized by demarcated red patches that are partially or completely surrounded by linear yellow-white borders. In most instances, the lesions are asymptomatic, but some individuals may complain of a mild burning sensation with hot, spicy, or acidic foods when the lesions are active.In most cases, treatment is not necessary. If the burning sensation is severe enough, application of a thin lm of one of the stronger topical corticosteroid gel preparations may provide some relief.■ Figure 16.43 Erythema Migrans Erythematous atrophic patches surrounded by yellow-white linear borders. 16 Dermatologic Diseases 485■ Figure 16.44 Erythema Migrans Ovoid erythematous lesions with slightly raised yellow-white borders on the ventral tongue and floor of the mouth. ■ Figure 16.45 Erythema Migrans Involvement of the mandibular labial mucosa. ■ Figure 16.46 Erythema Migrans Semicircular and ringlike lesion of the soft palate mucosa. (Courtesy Dr. Walter Colon.) 486 16 Dermatologic Diseases Lichen PlanusFigs. 16.47–16.55Lichen planus is an immune-mediated disease that was originally described as a skin condition in 1869. e cause is essentially unknown, although there has been much research performed with respect to the pathogenesis of the disorder. e cutaneous lesions appear as purple, polygonal, pruritic papules that aect the skin of the ankles, base of the spine, and wrists most frequently.Oral involvement can essentially be categorized as reticular and erosive lesions, which probably reect the intensity of the immunologic reaction. Reticular lichen planus is characterized by the symmetric distribu-tion of interlacing white lines, sometimes with small white papule or plaques, on the posterior buccal mucosa. In addition to these sites, the gingivae and dorsal or lateral tongue are common areas of involvement. Less frequently, the vermilion zone of the lips, the labial mucosa, oor of the mouth, and the palatal mucosa may be aected, but the characteristic bilateral buccal mucosal lesions also should be evident. If they are not evident, then other “lichenoid” conditions (things that clinically mimic oral lichen planus) should be considered.Oral lichen planus in the erosive phase is seen as shallow ulcers that can vary in size, surrounded by a zone of erythema with ne radiating white striae at the periphery. Symmetric distribution on the buccal mucosae is expected, and this can be accompanied by gingival involvement (a clinical pattern of so-called desquamative gingivitis) or tongue involvement. As with most immune-mediated disorders, the condition may wax and wane in severity without treatment, and it is not unusual for patients to have reticular lichen planus at one appointment and erosive lichen planus at the next one a few weeks later.Biopsy is oen performed to rule out other immune-mediated disorders and potentially cancerous conditions. Although the microscopic features of oral lichen planus are characteristic, they are not pathog-nomonic, and a variety of other diseases may resemble the pattern of hyperkeratosis, irregular thickness of the spinous layer, pointed rete ridges, disruption of the basal cell layer, and intense subepithelial chronic inammatory inltrate. Clinical correlation is oen required to rule out conditions such as lichenoid amalgam reaction, lichenoid foreign body gingivitis, lichenoid drug reaction, contact stomatitis, gra-versus-host disease, lupus erythematosus, or an early, lichenoid presentation of proliferative verrucous leukoplakia. Direct immunouorescence studies would be necessary to rule out chronic ulcerative stomatitis as well.Whether treatment of lichen planus is necessary depends on the patient’s symptoms. Most cases of reticular lichen planus are asymptomatic and require no treatment. Approximately 25% of oral lichen planus cases will have superimposed candidiasis, and this may cause a burning sensation, as well as blurring of the reticular striae. Treatment with a course of clotrimazole oral troches should relieve symptoms within 1 to 2 days aer initiating a 10-day course of medication, and oen no further treatment is needed. Many patients with erosive lichen planus are symptomatic due to their ulcerations, and they typically complain of pain associated with salty, acidic, or alcoholic foods and drinks. Treatment with one of the stronger topical corticosteroid gel preparations, applied as a thin lm only to the areas that are sore, 4 times daily (aer meals and at bedtime) usually results in resolution of the ulcers. However, periodic re-treatment of lesions usually is necessary because of the recurrent nature of the disease. 16 Dermatologic Diseases 487■ Figure 16.47 Lichen Planus Close-up image of a lesion of cutaneous lichen planus. Note the white lines (Wickham striae) on the surface of the erythematous plaque. ■ Figure 16.48 Lichen Planus Classic example of oral lichen planus in a reticular phase. Bilateral involvement would be expected. ■ Figure 16.49 Lichen Planus Interlacing white linear lesions (reticular phase) that tend to have a fine radiating pattern peripherally in some areas. This process affected the buccal mucosa of a person of color, and benign reactive melanosis is noted. 488 16 Dermatologic Diseases ■ Figure 16.50 Lichen Planus Dorsal tongue involvement, characterized by flat white plaques and peripheral striae. ■ Figure 16.51 Lichen Planus Reticular white striae involving the vermilion zone of the lower lip. ■ Figure 16.52 Lichen Planus Gingival lesions showing erythematous zones with peripheral radiating striae. Buccal mucosal involvement also would be expected. If not, then conditions such as lichenoid foreign body gingivitis or contact stomatitis may have to be considered in the differential diagnosis. 16 Dermatologic Diseases 489■ Figure 16.53 Lichen Planus White striations with central erosions on the right buccal mucosa. ■ Figure 16.54 Lichen Planus Same patient as Fig. 16.53 showing similar lesions on the left buccal mucosa. AB■ Figure 16.55 Lichen Planus (A) Relatively severe reticular and erosive lichen planus involving the buccal mucosa. (B) Same patient 1 month after applying a superpotent topical corticosteroid gel preparation to the lesions four times daily for several weeks. A linea alba is present, but the lichen planus has resolved. 490 16 Dermatologic Diseases Chronic Ulcerative StomatitisFig. 16.56Chronic ulcerative stomatitis, rst described in 1989, is a relatively rare, immune-mediated lichenoid process that primarily aects oral mucosa, although skin involvement also has been described. e condition is oen confused clinically and histopathologically with erosive lichen planus or other lichenoid conditions, and direct immunouorescence studies are necessary to make the diagnosis.is disorder has an adult female predilection and typically involves the tongue, buccal mucosa, and/or the gingivae. A pattern of desquamative gingivitis is not uncommon, but any intraoral site may be aected. Atrophic, eroded, and ulcerated areas with ne peripheral white striae are seen, although usually the striae are not as crisply dened as in lichen planus. ese lesions wax and wane in severity, and tend to heal without scarring in one area, only to develop in another area. Oen the symmetric pattern of distribution seen with oral lichen planus is not present.e diagnostic work-up for this condition oen is initiated when a patient presents with oral lesions that seem resistant to topical corticosteroid therapy. Histopathologic ndings have been reported to be inadequate to distinguish between oral lichen planus and chronic ulcerative stomatitis. When biopsy for direct immunouorescence is performed, there is positive immunoreactivity of the stratied squamous epithelial cell nuclei in the basal and parabasal regions. Indirect immunouorescence studies, using guinea pig or monkey esophagus as a substrate, can provide additional support for the diagnosis.Although some patients may respond suciently to topical application of one of the stronger corticosteroid gel preparations, this is not always the case. In such situations, consideration should be given to treatment with hydroxychloroquine, an antimalarial drug that is oen used for management of other immune-mediated conditions. Periodic ophthalmologic examination and hematologic studies are necessary if this medication is used, due to its potential side eects.Graft-Versus-Host DiseaseFigs. 16.57 and 16.58Gra-versus-host disease (GVHD) is a condition that is seen in a signicant number of patients who have undergone an allogenic bone marrow or stem cell transplant, usually as part of therapy for leukemia or other life-threatening disorders. Cytotoxic drugs and radiation are typically used to destroy the malignant cells, but in the process, the patient’s own hematopoietic cells are wiped out. To restore the patient’s hematopoietic cells, bone marrow or stem cells from an human leukocyte antigen (HLA)-matched donor are obtained and infused into the patient (host). Unfortunately, such matches are oen not perfect. e engraed immune cells can then detect surface antigens of the cells of the host, recognizing them as being “foreign” and subsequently mounting an attack on the host cells. us, the term “gra-versus-host disease” was applied to the disorder that resulted from this attack.Although any tissues of the host patient may be aected, the skin and oral mucosa are commonly involved, producing a pattern that may mimic lichen planus or systemic sclerosis. At times, the oral lesions may be the only manifestation of this disease, presenting in several patterns, including ne white striae or pinpoint white dots that typically aect the labial mucosa, tongue, or buccal mucosa. Erosions and ulcerations also may develop within the areas of white striae, similar to erosive lichen planus; however, various infections, including herpesvirus and deep fungal organisms, may need to be ruled out because of the patient’s immune suppression. Ulceration and crusting of the lips may develop, especially in acute GVHD. In addition, these patients will have an increased risk of developing oral squamous cell carcinoma, so biopsy may be necessary to rule out that process. Patients may complain of a dry mouth, typically as a result of the attack of salivary gland tissue by the engraed immune cells.e diagnosis of oral GVHD is based on the clinical history in conjunction with the histopathologic ndings of lichenoid mucositis, although the intensity of the inammatory inltrate is not as great in GVHD as it is in oral lichen planus. Salivary gland involvement may also be seen, causing destruction of the acinar structures, followed by brosis.Prevention of GVHD is perhaps the best treatment, and closely matching the HLA types of the donor and recipient will decrease the severity of the condition. Patients who develop GVHD are treated with systemic corticosteroids and various steroid-sparing agents, as well as with immune-modulating drugs such as mycophenolate mofetil and cyclosporine. Oral lesions of GVHD are usually treated with one of the stronger topical corticosteroids, and if ulcers are present, then topical anesthetics may be used to allay pain until healing ensues. With signicant involvement of the salivary apparatus, over-the-counter oral lubricants may bring some relief. Salivary stimulants may be useful if enough intact salivary tissue remains. Topical 1% neutral sodium uoride solution should be applied daily to inhibit cervical dental caries. 16 Dermatologic Diseases 491A B■ Figure 16.56 Chronic Ulcerative Stomatitis (A) The erythematous gingival mucosa could suggest pemphigoid or lichen planus, although direct immunofluorescence studies confirmed the diagnosis of chronic ulcerative stomatitis. (B) Atrophic and keratotic changes of the dorsal tongue are also somewhat lichenoid, requiring direct immunofluorescence studies to make the diagnosis. ■ Figure 16.57 Graft-Versus-Host Disease Lichenoid changes are present on the buccal mucosa and tongue. ■ Figure 16.58 Graft-Versus-Host Disease Diffuse ulcerations of the hard palate. 492 16 Dermatologic Diseases Lupus ErythematosusFigs. 16.59–16.62Lupus erythematosus is an immune-mediated disorder that may present as a relatively mild skin disease (chronic cutaneous lupus erythematosus [CCLE]), a serious systemic disease (systemic lupus erythematosus [SLE]), or an intermediate disease (subacute cutaneous lupus erythematosus [SCLE]). SLE is characterized by dysregulation of both the T- and B-cell limbs of the immune system, resulting in signicant damage to a wide range of organ systems, including the skin, kidneys, heart, blood vessels, and joints. CCLE primarily attacks the skin, producing red, scaly patches that may heal with scarring. e features of SCLE lie somewhere between the other two forms.SLE tends to aect young women predominantly, and signs and symptoms can be relatively nonspecic in the initial stages of the disease. Fever, malaise, arthritis, weight loss, and fatigue are oen noted, as well as a characteristic erythematous patch that involves the malar skin and bridge of the nose, termed a “buttery rash.” Kidney involvement develops in 30% to 40% of these patients and may lead to kidney failure. Pericarditis and vegetative endocarditis aect the heart in approximately 50% of SLE patients. e scaly, erythematous patches of CCLE oen appear on the facial skin and frequently worsen with sun exposure. e oral lesions of SLE and CCLE can appear very similar to erosive lichen planus, although in SLE, the lesions may have a nonspecic, or even granulomatous, character. Such lesions occur in a signicant percentage of SLE patients, aecting the lips, tongue, buccal mucosa, and hard palate primarily.e diagnosis of SLE can be challenging in its initial phases, and the American Rheumatism Association has developed a list of laboratory and clinical ndings that, in the appropriate context, could indicate a diagnosis of SLE. e characteristic but not pathognomonic histopathologic features typically show a lichenoid mucositis with perivascular inammation. Serologic studies frequently identify elevated levels of autoantibodies, some of which are nonspecic; however, if autoantibodies directed against double-stranded DNA or Sm protein are identied, this is rather specic for a diagnosis of SLE. ese serologic ndings are usually not present in CCLE or SCLE.Patients with any form of lupus erythematosus should avoid sun exposure if possible. Mild cases of SLE may be managed with nonsteroidal antiinammatory agents in conjunction with hydroxychloroquine, an antimalarial drug that seems to modulate the inammatory response. More severe cases of SLE may require treatment with more potent immune-modulating and immunosuppressive medications. Most cases of CCLE and SCLE can be managed with topical corticosteroids.e prognosis of SLE can vary considerably from person to person, although 95% of these patients are alive 5 years aer their diagnosis. However, by 20 years, the survival rate drops to 75%. e prognosis of CCLE and SCLE is much better, and some of these cases may resolve completely aer several years.■ Figure 16.59 Lupus Erythematosus Red, scaly plaques with areas of regression and postinflammatory melanosis involving sun-exposed skin. 16 Dermatologic Diseases 493■ Figure 16.60 Lupus Erythematosus Scaly, erythematous round (“discoid”) plaques of chronic cutaneous lupus erythematosus. ■ Figure 16.61 Lupus Erythematosus Oral mucosal lesions often appear similar to those of lichen planus, showing areas of erythema in conjunction with white plaques and striae affecting the buccal mucosa. ■ Figure 16.62 Lupus Erythematosus Characteristic lesion showing a mixed red and white plaque involving the mid-posterior hard palate. 494 16 Dermatologic Diseases Systemic SclerosisFigs. 16.63–16.66Systemic sclerosis is an uncommon immune-mediated disorder that is characterized by the abnormal deposition of collagen in a variety of anatomic regions of the body. e precise pathogenesis of systemic sclerosis is unknown. Sometimes the condition seems to remain limited to the skin of the face and extremities and is designated as limited cutaneous systemic sclerosis. In other cases the collagen deposition begins in the skin but becomes more widespread, and this is termed diuse cutaneous systemic sclerosis.Systemic sclerosis commonly aects middle-aged or older women and oen is rst detected due to cutaneous changes that are characterized by very rm, inelastic skin. If the hands are aected, the ngers become xed in a claw-shaped deformity known as sclerodactyly (literally, “hard ngers”). Raynaud phenomenon oen develops in these patients. Renal failure with attendant hypertension is seen with kidney involvement. Collagen deposition in the lungs results in loss of pulmonary elasticity, causing pulmonary hypertension and subsequent cardiac failure.When the facial skin is involved, the face has a smooth appearance with atrophy of the nasal alae and development of microstomia. e skin around the mouth may develop a drawn “purse-string” pattern of radiating furrows. Patients may have trouble inserting dental appliances, and oral hygiene procedures become dicult. Dysphagia occurs due to collagen deposition in the wall of the esophagus, and the rest of the gastrointestinal tract also may be involved.Radiographs typically show generalized widening of the periodontal ligament space. Occasionally resorption of the chin, condyle, coronoid process, or posterior ramus of the mandible is identied.e diagnosis of systemic sclerosis is based on the clinical features, including skin changes and presence of Raynaud phenomenon, combined with the histopathologic and serologic ndings. Biopsy of involved skin or mucosa identies extensive deposition of dense collagen in the supercial connective tissue. Serologic studies may show anticentromere antibodies, consistent with limited cutaneous systemic sclerosis (as well as CREST syndrome), whereas antitopoisomerase antibodies are seen more oen in diuse cutaneous systemic sclerosis.Treatment of this condition can be challenging, and currently there are no medications that will reverse the disease. e complications are generally addressed as they develop. For example, dysphagia is treated with periodic esophageal dilation; Raynaud phenomenon is treated with vasodilators, such as calcium channel blocking drugs, or by discontinuing habits such as cigarette smoking. Antihypertensive medications that are directed at inhibiting angiotensin can be used for treating high blood pressure caused by renal impairment.Oral hygiene procedures can be dicult due to immobility of the ngers and microstomia, so use of an electric toothbrush is recommended. Occasionally specialized dental prosthetic devices are fabricated with features such as hinges to ease their insertion and removal.e prognosis of limited cutaneous systemic sclerosis is better than the diuse form, with 75% to 80% of patients surviving 10 years aer diagnosis, on average. Approximately 55% to 60% of patients with the diuse form can expect to survive 10 years. Mortality is typically related to pulmonary or cardiac complica-tions of the disease.■ Figure 16.63 Systemic Sclerosis Masklike facies, atrophy of the nasal alae, and the “purse-string” perioral wrinkling that typify changes in the facial skin. (Courtesy Dr. Malcolm Miracle.) 16 Dermatologic Diseases 495■ Figure 16.64 Systemic Sclerosis Sclerodactyly and the claw-like deformity of the fingers. (Courtesy Dr. Malcolm Miracle.)■ Figure 16.65 Systemic Sclerosis Generalized widening of the peri-odontal ligament space. (Courtesy Dr. Michele Ravenel.)■ Figure 16.66 Systemic Sclerosis Marked resorption of the mandibular ramus and coronoid process bilaterally, in addition to generalized widening of the periodontal ligament spaces. 496 16 Dermatologic Diseases CREST SyndromeFigs. 16.67 and 16.68CREST syndrome is an uncommon condition that is related to systemic sclerosis, and some investigators feel that this is a form of limited cutaneous systemic sclerosis. e acronym stands for Calcinosis cutis, Raynaud phenomenon, Esophageal dysfunction, Sclerodactyly, and Telangiectasias, which are the hallmark features of the disorder. Calcinosis cutis refers to nontender collections of dystrophic calcications in the supercial dermis. On palpation, these lesions are movable and resemble pebbles, ranging from 0.5 to 2.0 cm, underneath the skin. Raynaud phenomenon is a condition that can occur as an isolated problem but is seen with increased frequency in several immune-mediated disorders. Upon exposure to cold temperatures, vasoconstriction occurs in the arteries that supply the hands, cutting o the blood ow almost completely and causing the ngers to lose their color and turn a pale white. Aer a few minutes, the arterial walls relax, and blood rushes into the ngers, causing congestion that clinically appears bluish. Aer several more minutes of warming, the blood vessels have increased blood ow, resulting in a dusky red color. Varying degrees of pain may accompany the process. Esophageal dysfunction is caused by deposition of collagen in the wall of the esophagus, thereby disrupting normal swallowing. Early stages can be identied with a barium swallow study, and in more advanced cases, the patient has diculty swallowing. Sclerodactyly refers to the changes that occur in the ngers of these patients. e skin becomes tight and shiny, and the ngers curl into a xed claw-like deformity. e telangiectasias that develop in this condition appear similar to those seen in hereditary hemorrhagic telangiectasia, presenting as at or slightly red lesions that are usually only 2 to 3 mm in diameter. ese are oen distributed on the lips and facial skin but also can involve the skin of the ngers.e diagnosis is usually based on the clinical features, although this can be supported by serologic studies that identify characteristic anticentromere antibodies associated with this condition.Management of CREST syndrome is similar to that of localized cutaneous systemic sclerosis. Sometimes the lesions of calcinosis cutis become symptomatic and require excision. Monitoring for pulmonary hypertension and primary biliary cirrhosis is prudent, although these occur less frequently and later in the course of disease, compared with systemic sclerosis.PsoriasisFig. 16.69Psoriasis is one of the most common conditions seen in dermatologic practice, aecting approximately 2% of the US population. is disease can range in severity, with the cutaneous lesions sometimes being quite problematic. e cause is unknown, but according to current concepts, both autoimmune and autoinammatory factors play a role in its pathogenesis, resulting in increased turnover of the epidermis. Psoriasis tends to have a genetic component, although environmental factors also play a role in its pathogenesis.Clinically, the principal lesion of psoriasis consists of an erythematous plaque with a silvery keratotic scale on its surface. e elbows, knees, and scalp are frequently aected, although in some patients the lesions may be more extensive. Pruritus may be a prominent symptom for some patients. In addition, as many as 30% of aected patients will develop psoriatic arthritis, typically approximately one decade aer the skin lesions appear. Oral lesions are quite uncommon and generally asymptomatic. Oen they wax and wane in conjunction with the skin lesions.In most cases, the diagnosis of psoriasis is made clinically, based on the characteristic cutaneous ndings. If the diagnosis is in question, then biopsy shows a characteristic pattern. Intraorally, the lesions may microscopically resemble psoriasis of the skin, but other lesions, such as erythema migrans and cinnamon reaction, also can display a psoriasiform mucositis. For this reason, clinical correlation is necessary, showing the expected waxing and waning that mirrors the activity of the skin lesions.A variety of treatments are available for psoriasis, depending on the severity of involvement. Exposure to sunlight (ultraviolet; UV) may help milder cases, but topical corticosteroids and vitamin D3 analogues are the mainstay of treatment. Systemic therapy may be required for moderate to severe psoriasis, including retinoids, cyclosporine, psoralen and ultraviolet A (PUVA) therapy, or methotrexate. Several new biologic agents (e.g., etanercept, adalimumab, iniximab, ixekizumab) have been developed to block dierent inammatory pathways. Oral lesions of psoriasis usually require no treatment, but therapy for the cutaneous lesions has been reported to improve the oral lesions as well. 16 Dermatologic Diseases 497■ Figure 16.67 CREST Syndrome Pale appearance of the distal phalanges, characteristic of Raynaud phenomenon. (Courtesy Dr. Brent Martin.)■ Figure 16.68 CREST Syndrome Multiple erythematous macules, representing mat-like telangiectasias that have developed on the vermilion zone of the lips. A B■ Figure 16.69 Psoriasis (A) Cutaneous lesions characterized by erythematous plaques surmounted by silvery keratotic scale. (B) Oral lesions characterized by round to serpiginous, faintly erythematous macules with more strikingly red borders involving the keratinized mucosa. (Courtesy Dr. Robert T. Jensen.) 498 16 Dermatologic Diseases Acanthosis NigricansFigs. 16.70 and 16.71Acanthosis nigricans is a cutaneous process that occurs in both benign and malignant forms. Benign acanthosis nigricans is seen commonly in patients who are obese or diabetic, typically aecting the intertriginous areas of the body. Oral lesions are not found in this form of the condition. Malignant acanthosis nigricans also involves the skin but develops in association with internal malignancy, usually a gastrointestinal adenocarcinoma. Malignant acanthosis nigricans occurs much less commonly than the benign form of the condition. Unlike benign acanthosis nigricans, oral lesions have been described in 40% to 50% of the reported cases of malignant acanthosis nigricans.e cutaneous lesions of acanthosis nigricans typically present as velvety areas with a tan, brown, or black color. In the setting of diabetes or obesity, they usually develop in the body folds (intertriginous areas), such as the axillae or groin. Malignant acanthosis nigricans appears identical to benign acanthosis nigricans but can be more widespread. Oral lesions appear as nely papillary areas of the labial and buccal mucosa that show minimal or no pigmentation compared with their cutaneous counterpart. Occasionally the patient is unaware that they have cancer, and for this reason, acanthosis nigricans has been said to represent a cutaneous marker of internal malignancy.e histopathologic features of acanthosis nigricans consist of a papillary pattern of hyperkeratosis and acanthosis, perhaps accompanied by variable degrees of melanin pigmentation. ese ndings should be correlated with the clinical setting of the skin and oral lesions to arrive at the correct diagnosis.Although the process may appear innocuous, it must be determined whether it represents the more common form of acanthosis nigricans that is associated with diabetes mellitus and obesity or if it is an example of malignant acanthosis nigricans. Treatment of the underlying cause (diabetes or obesity) may result in resolution of benign acanthosis nigricans. If malignant acanthosis nigricans is suspected, evaluation to nd a malignancy is appropriate. Some resolution of malignant acanthosis nigricans may be seen aer the malignancy is treated. Oen the responsible tumor is relatively advanced, so the prognosis for these individuals unfortunately is poor. 16 Dermatologic Diseases 499■ Figure 16.70 Acanthosis Nigricans Velvety brown cutaneous alteration of the posterior neck in a woman with malig-nant acanthosis nigricans. (Courtesy Dr. Robert Roddy.)■ Figure 16.71 Acanthosis Nigricans Same patient as Fig. 16.70 with a diffuse, finely papillary alteration of the buccal mucosa. Subsequent to the recognition of her oral lesions, the patient was diagnosed with endometrial adenocarcinoma, which was treated with surgical excision and chemotherapy. However, the tumor quickly recurred and the patient died 11 months later. (Courtesy Dr. Robert Roddy.) 500 16 Dermatologic Diseases 500 16 Dermatologic Diseases BibliographyEctodermal DysplasiaBergendal B. Orodental manifestations in ectodermal dysplasia – a review. 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