Dermatology

CHAPTER 26
Cutaneous Manifestations
of Internal Disease
CHAPTER CONTENTS
CUTANEOUS MANIFESTATIONS OF DIABETES CUTANEOUS PARANEOPLASTIC SYNDROMES

MELLITUS
FAMILIAL CANCER SYNDROMES
NECROBIOSIS LIPOIDICA
COWDEN DISEASE (MULTIPLE HAMARTOMA
GRANULOMA ANNULARE SYNDROME)
ACANTHOSIS NIGRICANS MUIR-TORRE SYNDROME
XANTHOMAS AND DYSLIPOPROTEINEMIA GARDNER’S SYNDROME
NEUROFIBROMATOSIS BIRT-HOGG-DUBÉ SYNDROME AND RENAL
CARCINOMA
TUBEROUS SCLEROSIS
INTERNAL CANCER AND SKIN DISEASE
Certain cutaneous diseases are frequently associated with • Perforating disorders

internal disease. The skin disease itself may be inconse- • Eruptive xanthomas
quential, but its presence should prompt investigation of
possible related internal disorders. A selected group of
such diseases is discussed in this chapter. Pigmentary skin NECROBIOSIS LIPOIDICA
changes associated with internal diseases are also dis-
cussed in Chapter 19. Necrobiosis lipoidica (NL) is a disease of unknown ori-
gin, but more than 50% of the patients with NL are gen-
erally insulin dependent. The average age at onset is 30
CUTANEOUS MANIFESTATIONS years. It is frequently associated with diabetes. More than
OF DIABETES MELLITUS 75% of patients with NL either have or will develop dia-
betes mellitus. However, it is seen in only 0.3% to 0.7%
Approximately 30% of patients with diabetes mellitus de- of the entire diabetic population. The skin lesions may
velop a skin disorder sometime during the course of disappear years before the onset of diabetes, and most pa-
ease. A list of these disorders follows: tients with diabetes do not develop NL. The disease may
• Candida infections (mouth, genital) occur at any age, but it most commonly appears in the
• Carotenodermia (yellow skin) third and fourth decades. Most of the patients are females,
• Diabetic bullae and in most cases the lesions are confined to the anterior
• Diabetic dermopathy (shin spots) surfaces of the lower legs (Figure 26-1).
• Diabetic thick skin The eruption begins as an oval, violaceous patch and
• Erythema (face, lower legs, feet) expands slowly. The advancing border is red, and the cen-
• External otitis tral area turns yellow-brown. The central area atrophies
• Finger pebbles and has a waxy surface; telangiectasias become prominent
• Foot ulcers (Figure 26-1). Ulceration occurs, particularly following
• Acanthosis nigricans (insulin resistance syndromes) trauma, in 13% of cases. In many instances the clinical
• Gas gangrene (nonclostridial) presentation is so unique that biopsy is not required.
• Granuloma annulare (localized or generalized)
• Insulin lipodystrophy Treatment. Currently, there are no evidence-based
• Necrobiosis lipoidica guidelines for the treatment of necrobiosis lipoidica. A
• Yellow nails
986
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26 Cutaneous Manifestations of Internal Disease 987
NECROBIOSIS LIPOIDICA
B C
D E F
FIGURE 26-1 Necrobiosis lipoidica. A, Erythematous violaceous plaques on the ante-

rior surface of the lower legs. B, The central area atrophies and has a waxy surface
with prominent telangiectasias. C, The mid lower legs are most often affected. D, The
central area is waxy yellow with prominent telangiectasia. E, End-stage disease with
severe atrophy and telangiectasia. F, Severe disease with dense fibrosis and ulceration.
988 Clinical Dermatology
complete review of all treatments is found in the follow- Clinical Presentation. Granuloma annulare is charac-
ing reference: PMID: 23969033 terized by a ring of small, firm, flesh-colored or red pap-
Topical and Intralesional Steroids. Topical and intra- ules. The localized form, most common in young adult
lesional steroids arrest inflammation but promote further females, is most frequently found on the lateral or dorsal
atrophy. Clobetasol propionate under occlusion has suc- surfaces of the hands and feet (Figure 26-2, A-F ). The
cessfully treated thick plaques. Intralesional injections ef- disease begins with an asymptomatic, flesh-colored pap-
fectively control small areas of NL, but the concentration ule that undergoes central involution. Over months,
of triamcinolone acetonide (10 mg/ml) should be diluted a ring of papules slowly increases in diameter to 0.5 to
with saline or Xylocaine to 2.5 mg/ml to avoid atrophy. 5 cm. The duration of the disease is highly variable. Many
Systemic Corticosteroids. A 3- to 5-week course of sys- lesions undergo spontaneous involution without scarring,
temic corticosteroids may arrest the disease; however, whereas others last for years. The familial occurrence of
restitution of atrophic skin lesions is not achieved. Ulcer- GA is uncommon but has been noted in siblings, twins,
ation of NL can at times be successfully treated with oral and successive generations.
prednisolone. Disseminated GA occurs in adults and appears with
Pentoxifylline. Pentoxifylline (Trental) 400 mg three numerous flesh-colored or erythematous papules, some
times a day is reported to result in significant improve- of which form annular rings. The papules may be accen-
ment after 1 month of treatment. Ulcerating NL is re- tuated in sun-exposed areas. The course is variable; many
ported to respond within 8 weeks of administration of lesions persist for years.
400 mg of pentoxifylline twice a day. Pentoxifylline is Generalized perforating GA is characterized by 1- to
thought to decrease blood viscosity by increasing fibrino- 4-mm umbilicated papules on the extremities and is most
lysis and red blood cell deformability and also to inhibit commonly seen in children and young adults. Biopsy
platelet aggregation. shows transepithelial elimination of degenerating colla-
Aspirin and Dipyridamole. Low-dose aspirin and di- gen fibers. GA occurred during anti–tumor necrosis fac-
pyridamole are thought to inhibit platelet aggregation, tor (anti-TNF) therapy (4.5% of 119 patients) (infliximab,
but reports concerning their efficacy in healing ulcers in adalimumab, etanercept) for rheumatoid arthritis. PMID:
plaques of NL are conflicting. The recommended treat- 17728330 Patients who develop GA usually heal, remain
ment is aspirin 3.5 mg/kg every 48 hours, which for the remarkably healthy, and do not ordinarily develop other
average patient is 325 gm daily (one tablet); or dipyri- odd diseases. PMID: 17638746
damole (Persantine) (25-, 50-, or 75-mg tablets) 2 to Subcutaneous GA occurs in children. Painless subcu-
3 mg/kg/day, which for the average patient is 150 to 200 taneous nodules in the lower anterior tibial region or foot
mg daily in divided doses. For effective control of ulcer- and in the scalp, typically in the occiput, are the most
ation, platelet inhibition therapy must be used for a mini- common presenting features. The mean age at presenta-
mum of 3 to 7 months. Recommended treatment sched- tion is 3.9 years. Diagnosis requires an excisional biopsy.
ules should be followed because there is evidence that Lesions may recur after excision. Lesions may resolve
higher dosages can decrease treatment effectiveness. spontaneously and recur after excision. No record of pro-
Other Treatments. Cyclosporine, tacrolimus ointment gression to systemic illness is reported.
0.1%, etanercept, mycophenolate mofetil, fumaric acid
esters, photochemotherapy with topical psoralen plus ul- Diagnosis. The clinical presentation is characteristic,
traviolet A (PUVA), chloroquine (200 mg/day), hydroxy- and biopsy may not be required. Histologic examination
chloroquine (400 mg/day), inflixamab, and thalidomide shows collagen degeneration, a feature similar to that
(150 mg/day) are reported to be effective. seen in necrobiosis lipoidica.
Skin Grafting. Skin grafting is effective for extensive
disease. Treatment. Localized lesions are asymptomatic and are
best left untreated. Those patients troubled by appear-
ance may be treated with intralesional injections of triam-
GRANULOMA ANNULARE cinolone acetonide (2.5 to 5 mg/ml). The solution should
be injected only into the elevated border. Topical steroids
There are conflicting reports about the association of have little effect. Localized lesions have responded to im-
granuloma annulare (GA) with diabetes mellitus. Most iquimod cream. Disseminated GA has been reported to
patients with the localized form of granuloma annulare respond to dapsone, isotretinoin, etretinate, hydroxychlo-
do not have clinical or laboratory evidence of diabetes. roquine, niacinamide (1.5 gm/day), fumaric acid esters,
The association between disseminated granuloma annu- hydroxyurea, narrow-band ultraviolet B therapy, and pso-
lare and diabetes has been established, but the frequency ralen and ultraviolet A therapy (PUVA). Four patients
is unknown. In a retrospective study 12% of patients with with disseminated GA were treated with a cycle of cyclo-
GA had diabetes mellitus. Those patients suffered signifi- sporine therapy for 6 weeks. Cyclosporine was started at
cantly more often from chronic relapsing GA than non- a dose of 4 mg/kg/day for 4 weeks, and subsequently re-
diabetic patients. Granuloma annulare can be associated duced by 0.5 mg/kg/day every 2 weeks. The lesions re-
with human immunodeficiency virus (HIV) and can pre- solved within 3 weeks and there were no relapses. PMID:
sent at all stages of HIV infection. Generalized GA is the 16831309
most common clinical pattern in HIV infection.
GRANULOMA ANNULARE
A B
C D
E F
FIGURE 26-2 Granuloma annulare. A, A classic lesion with papules on the border.
B, Classic presentation showing evolution and atrophy in the center. C, Mid lower
back lesion consists only of papules. D, Symmetrical disease on the calves. Papules
and small irregular rings are present. E, Classic lesions most commonly involve sites
about the foot and ankles. F, Several rings have coalesced on the forearm.
ACANTHOSIS NIGRICANS tance. There is a high prevalence of AN in obese adults.

There is a positive correlation between the development
Acanthosis nigricans (AN) is a nonspecific reaction pat- of AN and the severity of the obesity. AN is a common
tern that may accompany obesity; diabetes; excess corti- finding in overweight youth. Nearly 40% of Native
costeroids; pineal tumors; other endocrine disorders (Box American teenagers, 13% of black people, 6% of His-
26-1); multiple genetic variants; drugs such as nicotinic panic people, and less than 1% of white, non-Hispanic
acid, estrogens, and corticosteroids; and adenocarcinoma. children between the ages of 10 and 19 have AN. AN
AN is classified into malignant and benign forms (Box identifies a subgroup within an ethnic group that has the
26-2). highest insulin concentration, the most severe insulin re-
sistance, and the highest risk for the development of type
Clinical Characteristics. In all cases the disease presents 2 diabetes.
with symmetric, brown thickening of the skin. In time the The interaction between excessive amounts of circu-
skin may become quite thickened as the lesion develops a lating insulin with insulin-like growth factor receptors on
leathery, warty, or papillomatous surface (Figure 26-3). keratinocytes may lead to the development of acanthosis
The lesions range in severity from slight discoloration of nigricans.
a small area to extensive involvement of wide areas. The In rare instances AN may occur as an autosomal domi-
most common site of involvement is the axilla (Figure nant trait with no obesity, associated endocrinopathies, or
26-4), but the changes may be observed in the flexural congenital abnormalities; it may appear at birth or during
areas of the posterior neck (Figure 26-5) and groin, along childhood and is accentuated at puberty.
the belt line, over the dorsal surfaces of the fingers, in the
mouth, and around the areolae of the breasts (Figure Drug-Induced Acanthosis Nigricans. Drug-induced
26-6) and umbilicus. During the disease process, there is acanthosis nigricans has occurred with the use of nico-
papillary hypertrophy, hyperkeratosis, and an increased tinic acid and, rarely, with other agents.
number of melanocytes in the epidermis.
Endocrine Syndromes with Acanthosis Nigricans. In
Benign Acanthosis Nigricans. The majority of cases are a large and heterogeneous group of conditions, insulin
idiopathic and are associated with obesity; this process is action at the cellular level is markedly reduced (see Box
referred to as pseudo–acanthosis nigricans. Most patients 26-1). AN appears to represent a cutaneous marker of tis-
with AN have either clinical or subclinical insulin resis- sue insulin resistance, irrespective of its cause (antibodies
to the insulin receptor or congenital or acquired defects
of receptor or postreceptor function). These patients may
not require insulin therapy, and many do not have diabe-
tes. For patients without diabetes, insulin resistance is es-
tablished by the documentation of high levels of circulat-
BOX 26-1 Endocrine Syndromes with ing insulin or by the observation of an impaired response
Acanthosis Nigricans* to exogenous insulin. Prolonged hypersecretion of insu-
lin may lead to pancreatic exhaustion, glucose intoler-
Insulin-resistant states ance, and type 2 diabetes.
• Type A syndrome Two syndromes of insulin resistance and AN are
• Type B syndrome
of special interest. Type A syndrome, also called the
• Lipoatrophic diabetes
• Leprechaunism HAIR-AN syndrome, is characterized by hyperandro-
• Acral hypertrophy syndrome genemia (HA), extreme insulin resistance (IR), and acan-
• Pinealoma thosis nigricans (AN) occurring in the absence of obesity
• Pineal hyperplasia syndrome or lipoatrophy. It is distinguished from type B insulin re-
Hyperandrogenic states sistance by a lack of antibodies to the insulin receptor or
• Type A and B syndromes other evidence of autoimmune disease. It is familial and
• Polycystic ovary disease affects mainly black women, who have the onset of AN in
• Ovarian hyperthecosis infancy or childhood.
• Stromal luteoma
• Ovarian dermoid cysts
Acromegaly
Cushing’s disease
Pituitary basophilism
Obesity
Hypothyroidism BOX 26-2 Classification of Acanthosis
Addison’s disease Nigricans
Hypogonadal syndrome with insulin resistance
Prader-Willi syndrome BENIGN
Alström syndrome Obesity related
Hereditary (many syndromes)
Adapted from Lowella EE, Fenske NA: J Am Acad Dermatol 34:892, Endocrine syndromes
1996. PMID: 8621823
*Most have insulin resistance plus hyperinsulinemia plus acanthosis MALIGNANT
nigricans.
Treatment. Lesions are usually asymptomatic and do

not require treatment. Reducing thicker lesions in areas
of maceration may decrease odor and promote comfort. A
12% ammonium lactate cream, applied as needed, may
soften lesions. Retinoic acid (Retin-A cream or gel) ap-
plied each day, or less often if irritation occurs, is effec-
tive.
Malignant Acanthosis Nigricans. The cases of greatest

concern are those originating in nonobese adult patients.
These cases may result from secretion of tumor products
with insulin-like activity or transforming growth factor
alpha, which stimulates keratinocytes to proliferate.
These patients must be evaluated for internal malignancy.
The stomach is the most common site for the tumor, but
cancer in several other areas has been reported. Malig-
nant AN has a different clinical appearance. Lesions de-
velop rapidly and tend to be more severe and extensive.
FIGURE 26-3 Acanthosis nigricans. The skin is brown
Hyperpigmentation is prominent and is not limited to
and thickened and has a papillomatous surface.
the hyperkeratotic areas. Mucous membrane involvement
and thickening of the palms and soles occur more fre-
quently. Itching is common. The presence of AN in con-
junction with tripe palms and the sign of Leser-Trélat is
highly suggestive of an internal malignancy. In approxi-
mately one third of patients, the skin lesions precede the
clinical manifestations of cancer, and in several cases they
have disappeared with successful removal of the tumor. A
recurrence of acanthosis nigricans may mark the recur-
rence or metastasis of the previously treated cancer. In
patients with malignant acanthosis, chemotherapy may
relieve many of the distressing cutaneous symptoms.
FIGURE 26-4 Acanthosis nigricans. The axilla is the most

common site of involvement. The skin is thickened and
hyperpigmented.
FIGURE 26-5 Acanthosis nigricans of the neck. The pa- FIGURE 26-6 Acanthosis nigricans. The areola may be
tient was obese. affected.
as cofactors for plasma enzymes and interact with cell

XANTHOMAS AND surface receptors. Lipoproteins are divided into five ma-
DYSLIPOPROTEINEMIA jor classes: chylomicrons, very-low-density lipoproteins
(VLDL), intermediate-density lipoproteins (IDL), low-
The plasma lipids and lipoprotein levels are under the density lipoproteins (LDL), and high-density lipopro-
control of a number of genetic and environmental influ- teins (HDL). LDL and HDL have each been divided into
ences. Abnormalities in a number of these lipids or sub- two subfractions.
fractions result in dyslipoproteinemias and xanthomas.
Xanthomas are lipid deposits in the skin and tendons that Classification: Primary versus Secondary Hyperlipo-
occur secondary to a lipid abnormality. These localized proteinemia. Dyslipoproteinemias are categorized as
deposits are yellow and are frequently very firm. Although primary or secondary. Primary conditions (Table 26-2) are
certain types of xanthomas are characteristic of certain genetically determined and were grouped by Fredrickson
lipid abnormalities, none is absolutely specific because into five or six types on the basis of specific lipoprotein
the same form of xanthomas occurs in many different dis- elevations. This classification recognizes elevations of
eases; further investigation is always required. The mo- chylomicrons (type I), VLDL or pre-beta lipoproteins
lecular defect of various lipid disorders is now known; (type IV), “broad beta” disease (or type III hyperlipopro-
however, the classification and diagnosis are still based on teinemia), beta lipoproteins (LDL) (type II), and eleva-
history and clinical presentation (Table 26-1). tions of both chylomicrons and VLDL (type V). In addi-
tion, the combined elevations in pre-beta (VLDL) and
Pathophysiology. The liver secretes lipoproteins, which beta (LDL) lipoproteins were recognized as type IIb
are particles composed of various combinations of cho- hyperlipoproteinemia. This older classification still pro-
lesterol and triglycerides. These particles are made water vides a useful conceptual framework. It does not, however,
soluble to facilitate transport to peripheral tissues by po- include HDL cholesterol nor does it differentiate severe
lar phospholipids and 12 different specific proteins monogenic lipoprotein disorders from the more common
termed apolipoproteins. The apolipoproteins also serve polygenic disorders. The World Health Organization has
TABLE 26-1 Xanthomas

Type Clinical characteristics Associated lipid abnormality
Xanthelasma Inner or outer canthus; plane or papular No lipid abnormality; increased frequency of apo
E-ND phenotype and hyperapobetalipoprotein-
emia, type II*
Eruptive Crops of discrete yellow papules on an erythematous base Indicative of hypertriglyceridemia and seen with
on buttocks, extensor aspects of elbows and knees; le- types I, II, IV, and rarely III and diabetes mellitus
sions clear when triglycerides return to normal
Plane Palms and palmar creases, eyelids, face, neck, chest Biliary cirrhosis, type III; reported in types II, IV
Tuberous Lipid deposits in dermis and subcutaneous tissue; plaque- Hypertriglyceridemia (familial or acquired), types
like or nodular; frequently found on elbows or knees II and III; biliary cirrhosis
Tendinous Nodules involving elbows, knees, Achilles tendon, and dor- Indicates hypercholesterolemia, type II; occasion-
sum of hands and feet ally type III
*There are five types of familial hyperlipidemia.
TABLE 26-2 Primary Dyslipidemia (Genetic Dyslipidemias)

Lipoprotein at Cholesterol Triglyceride
Phenotype increased concentration concentration concentration Dermatologic lesion(s)
I Chylomicrons ! !!!! Eruptive xanthomas
IIa LDL !!!! ! Tendon, tuberous, and intertriginous xanthomas; xan-
thelasma, plane
IIb VLDL and LDL !!!! !! Tendon, tuberous, and intertriginous xanthomas; xan-
thelasma, plane
III IDL !!! !!! Tuberoeruptive, tuberous, plane (palmar creases)
IV VLDL ! !!! Eruptive xanthomas
V Chylomicrons and VLDL !! !!!! Eruptive xanthomas
classified lipoprotein disorders on the basis of arbitrary lesterol levels. Longevity studies have shown that xanthe-
cut-points, but the traditional classification will be used in lasma, with or without hypercholesterolemia, is a risk
this text. factor for death from atherosclerotic disease. Further
Secondary hyperlipoproteinemias occur as a result of study of these patients with normal levels of cholesterol
another disease process that can induce symptoms (Box and triglycerides often reveals elevated LDL and VLDL
26-3), lipoprotein changes, and xanthomas that mimic the levels and decreased HDL level. This profile is found for
primary syndromes. Diagnosis should be made as follows: patients who have a high risk of atherosclerotic cardiovas-
1. Determine the type of xanthoma. cular disease. Premature carotid atherosclerosis is ob-
2. Measure fasting blood levels of cholesterol, served in some patients with normolipidemic and hyper-
triglycerides, and HDL, VLDL, and LDL. lipidemic xanthelasma. Patients with xanthelasma should
3. Rule out secondary diseases (see Box 26-3). The be considered to have an increased risk of cardiovascular
diagnosis of primary hyperlipoproteinemia is one of disease independent to the level of plasma lipids. It may
exclusion. be that all patients with xanthelasma have an increased
a. Thyroid, liver, renal function tests risk for atherosclerosis.
b. Glucose tolerance tests Trichloroacetic acid (TCA) is commonly used for cos-
c. Complete blood count (CBC); serum and urine im- metic treatment. Papulonodular lesions required an aver-
munoelectrophoresis age of two applications with 100% TCA, three with 70%
d. Chest x-ray film, bone marrow aspiration TCA, and four with 50% TCA. Flat plaques responded to
e. Antinuclear antibodies (ANAs) testing an average of one, two, and three sittings with 100%,
70%, and 50% TCA, respectively. Macular lesions re-
Xanthelasma and Plane Xanthomas. Plane xanthomas sponded to only one application of all strengths of TCA
occur in several areas of the body and are flat or slightly applied. Hypopigmentation is the most common side ef-
elevated (Figures 26-7 and 26-8). Xanthelasma is the fect, followed by hyperpigmentation. Scarring is a minor
most common form (see Figure 26-7). Xanthelasma can problem. PMID: 16467024
be associated with familial hypercholesterolemia, pheno-
type IIa or IIb, but 50% of the patients have normal cho-
BOX 26-3 Acquired Disorders of Lipoprotein

Metabolism
HYPERCHOLESTEROLEMIA
Nephrotic syndrome
Hypothyroidism
Dysgammaglobulinemia
Acute intermittent porphyria
Obstructive liver disease
COMBINED HYPERLIPIDEMIA
Nephrotic syndrome
Hypothyroidism FIGURE 26-7 Xanthelasma. Lesions are usually located
Glucocorticoid excess/Cushing’s disease on the medial side of the lids.
Diuretics
Uncontrolled diabetes
Alcohol
Estrogens
Beta-adrenergic blocking agents
Isotretinoin (13-cis-retinoic acid)
HYPERTRIGLYCERIDEMIA
Diabetes mellitus
Uremia
Sepsis
Obesity
Systemic lupus erythematosus
Dysgammaglobulinemia
Glycogen storage disease, type I
Lipodystrophy
Drugs
Alcohol
Estrogens
Beta-adrenergic blocking agents
Isotretinoin (13-cis-retinoic acid) FIGURE 26-8 Plane xanthomas (macular) of the palms
are characteristic of type III dysbetalipoproteinemia.
FIGURE 26-9 Eruptive xanthomas are found on the buttocks, shoulders, and the ex-
tensor surfaces of the extremities. The red-yellow papules erupt abruptly and may
resolve in a few weeks. Pruritus is common. They are a sign of hypertriglyceridemia
and appear in secondary hyperlipidemias (e.g., diabetes).
Eruptive Xanthomas. These are yellow, 1- to 4-mm

papules with a red halo around the base. They appear
suddenly in crops on extensor surfaces of the arms, legs,
and buttocks and over pressure points (Figure 26-9). Le-
sions clear rapidly when serum lipid levels are lowered.
Tuberous Xanthomas. These are slowly evolving yellow

papules, nodules, or tumors that occur on the knees, el-
bows, and extensor surfaces of the body and the palms
(Figure 26-10).
Tendinous Xanthomas. These smooth, deeply situated

nodules are attached to tendons, ligaments, and fascia.
They are most often found on the Achilles tendons and
the dorsal aspects of the fingers.
Regression of Xanthomas. Certain xanthomas disap-

pear with treatment. The eruptive and palmar xanthomas
can regress rapidly. The eruptive type of tuberous xan-
thomas can disappear. Tendinous xanthomatous lesions
tend to persist.
FIGURE 26-10 Tuberous xanthomas are painless, red-

yellow nodules that develop in pressure areas.
Clinical Manifestations
NEUROFIBROMATOSIS
Café-au-Lait Spots. Café-au-lait spots are light-colored
The neurofibromatoses comprise at least two autosomal to brown macules (see Chapter 19). The criteria for es-
dominant disorders with an incidence of approximately 1 tablishing the diagnosis with reference to the number and
in 3000. These diseases have tumors surrounding nerves. size of café-au-lait spots are listed in Box 26-4. The spots
Riccardi (1982) classified NF into eight types. Neurofi- are present in virtually every patient with neurofibroma-
bromatosis 1 (NF1) is the most common and is character- tosis, usually at birth, but they may not appear for months.
ized by congenital lesions of the skin, central nervous Their size and number increase with age (Figure 26-11,
system, bone, and endocrine glands. The cardinal features A). Intertriginous freckling, a pathognomonic sign, may
of the disorder are café-au-lait spots, axillary freckling, occur in the axillae, inframammary region, and groin
cutaneous neurofibromas, and iris hamartomas (Lisch (Figure 26-11, B). Café-au-lait macules alone are not ab-
nodules). Common complications include learning dis- solutely diagnostic of NF1, regardless of their size and
ability, scoliosis, and optic gliomas. Neurofibromatosis 2 number.
(NF2) is characterized by bilateral acoustic neuromas and
other nerve tumors. Skin and other systemic manifesta-
Presumptive Evidence of Neurofibromatosis
tions are minimal or absent. Café-au-lait macules, freck-
ling, and neurofibromas localized to a segment of the • Six or more café-au-lait macules more than 5 mm in
body are called segmental neurofibromatosis (NF5). The greatest diameter if prepubertal
NF1 gene is located on chromosome 17 and the NF2 • Six or more café-au-lait macules larger than 15 mm
gene is found on chromosome 22. in greatest diameter if postpubertal
Neurofibromatosis 1
NF1 is a disorder of neural crest–derived cells character- BOX 26-4 Diagnostic Criteria for
ized by the presence of café-au-lait spots, multiple neuro- Neurofibromatosis 1 (NF1)
fibromas, and Lisch nodules (pigmented iris hamarto-
mas); there are several other less common features. There Six or more café-au-lait macules
1.5 cm in postpubertal individuals
is considerable variation of manifestations within the
0.5 cm in prepubertal individuals
same family. It occurs in approximately 1 of every 3500 Two or more neurofibromas of any type or
births and affects both genders with equal frequency and One or more plexiform neurofibromas
severity. Neurofibromatosis is one of the most common Freckling of axillae or inguinal area
mutations in humans; at least half of the cases represent Bilateral optic gliomas
new mutations. Two or more Lisch nodules
Sphenoid wing dysplasia or
Congenital bowing or
Thinning of the long bone cortex (with or without pseudo-
arthrosis)
First-degree relative with NF1 by these criteria
NF1 diagnosis: Two or more features
Adapted from National Institutes of Health Consensus Development

Conference: Neurofibromatosis. Conference statement, Arch Neurol
45:576, 1988.
A B
FIGURE 26-11 von Recklinghausen’s neurofibromatosis. A, Café-au-lait spots vary in size and have a
smooth border. B, Axillary freckling (Crowe’s sign) is a pathognomonic sign.
Neurofibromas. Tumors are usually not present in child- Lisch Nodules. Lisch nodules (LNs) are pigmented, me-
hood, but they begin to appear at puberty. Tumors in- lanocytic, iris hamartomas (Figure 26-13). They increase
crease in both number and size as the patient ages. Some in number with age and are asymptomatic. The preva-
patients have only a few small tumors, whereas others de- lence of LNs and neurofibromas according to age is
velop hundreds over the entire body surface, including shown in Figure 26-14. All adults with neurofibromatosis
the palms and soles (Figure 26-12). who are 21 years of age or older have LNs. LNs have
There are three different types of cutaneous tumors. never been seen in the absence of neurofibromatosis.
The most common is sessile or pedunculated. Early tu- They are never the only clinical sign of NF1. They are
mors are soft, dome-shaped papules or nodules that have more likely to be present in younger patients than are
a distinctive violaceous hue. Digital pressure on the soft neurofibromas (see Figure 26-14) and therefore help to
tumor causes invagination or “button-holing.” When the make the diagnosis in younger patients. No association
soft tumors attain a certain size, they bend and hang or has been found between LNs and overall clinical severity.
become pendulous. The plexiform neuroma is an elon- They are markers for the von Recklinghausen’s neurofi-
gated tumor that occurs along the course of peripheral bromatosis gene; they may be present in immediate rela-
nerves. Elephantiasis neuromatosa is a term used to de- tives who have no cutaneous or other specific signs of the
scribe a diffuse tumor of nerve trunks that extends into disease. LNs may be seen without the aid of instruments,
surrounding tissues, causing gross deformity. This form but slit-lamp examination is essential for differentiation
of neuroma produced the facial deformity in Joseph from iris freckles or nevi. Iris freckles are flat and have a
Merrick of London, England, the man who was described lacework structure, whereas LNs are raised, round, dome-
in the play and movie The Elephant Man. Most tumors are shaped, brown papules that are present in both eyes.
benign, but malignant degeneration to a neurofibrosar-
coma or malignant schwannoma has been reported in ap- Systemic Manifestations. Neurofibromatosis has a
proximately 2% of cases; it rarely occurs before age 40. broad spectrum of systemic manifestations; the most im-
portant are listed in Box 26-5.
FIGURE 26-12 von Recklinghausen’s neurofibro-

matosis. A-B, Adult patient with hundreds of
neurofibromas.
A B
Natural History. Survival rates are significantly impaired Diagnosis. NF1 is considered to be present in an indi-
for relatives with neurofibromatosis, are worse in pro- vidual with two of the criteria listed in Box 26-4, provided
bands, and are worst in female probands. Malignant neo- no other disease accounts for the findings.
plasms or benign central nervous system tumors occur in NF1 should be suspected in children with a large head
45% of probands. Compared with the general popula- circumference (above the 97th percentile for age) and one
tion, male relatives with neurofibromatosis have the same of the following: a mild cognitive impairment, a learning
rate of neoplasms, whereas female relatives have a nearly disability, or a selective visual-spatial impairment.
twofold higher rate. Nervous system tumors are dispro-
portionately represented.
100
80
Prevalence (%)
60
40
20
0
≤2 3-4 5-6 7-8 9-14 15-20 ≥21
Age (years)
FIGURE 26-14 Prevalence of Lisch nodules (dark blue
bars) and neurofibromas (light blue bars) in 167 patients
with neurofibromatosis type 1, according to age. (Modi-
fied from Lubs ML et al: New Engl J Med 324:1264,
1991.) PMID: 1901624
BOX 26-5 Systemic Manifestations

of Neurofibromatosis
Central nervous system tumors
Optic gliomas
Astrocytomas, acoustic neuromas, meningiomas, neuri-
lemmomas
Constipation
Headache
Intellectual handicap
Kyphoscoliosis
Macrocephaly
Malignant disease
Neurofibrosarcoma
Malignant schwannoma
Neuroblastoma
B Wilms’ tumors
Rhabdomyosarcoma
FIGURE 26-13 von Recklinghausen’s neurofibromatosis. Leukemia
A, Pigmented iris hamartomas are present in more than Pheochromocytomas
Premature or delayed puberty
60% of patients with neurofibromatosis who are 7 years
Pseudoarthrosis (tibia, radius)
of age or older. B, Slit-lamp examination is essential for Seizures
differentiation from iris freckles. Iris freckles are flat and Speech impediment
have a lace-work structure; Lisch nodules are raised, Short stature
round, fluffy, and light brown. (Courtesy Lucian Szmyd,
MD.) From Riccardi VM: New Engl J Med 305:1617, 1981. PMID: 6796886
Segmental Neurofibromatosis (NF5). Segmental neu- Genetic Counseling. The patient’s offspring, both male
rofibromatosis (neurofibromatosis type 5) is a rare disor- and female, have a 50% chance of inheriting this autoso-
der characterized by café-au-lait macules and neurofibro- mal dominant disease. The penetrance is virtually 100%,
mas, or only neurofibromas, limited to one region of the but the expressivity is extremely variable. The severity of
body (Figure 26-15). Segmental neurofibromatosis has the disease is highest in those born to an affected mother.
only been described in about 100 patients. The median Fifty percent of cases are new mutations in which the par-
age at onset is 28 years. The neurofibromas most com- ents are unaffected. All family members and relatives
monly occupied either a cervical or a thoracic dermatome should be examined for the triad of Lisch iris nodules,
and were unilateral. Café-au-lait macules were present in solitary neurofibromas, and café-au-lait spots.
26% of patients. Axillary freckling occurs in only 10% of The LN is a reliable indicator of NF1; slit-lamp ex-
patients. Most patients with segmental neurofibromatosis amination is important to establish the diagnosis. All peo-
(93%) do not have a family history of neurofibromatosis. ple older than 20 years who have NF1 also have LNs.
The lesions are strictly unilateral and noninherited in Therefore minimally affected and unaffected parents and
most cases; however, in a few patients, the disease be- adult siblings can be identified. If the diagnosis is in doubt
comes generalized. These patients should be examined and a child has no LNs, the examination should be re-
for LNs and other signs of neurofibromatosis. peated periodically. LNs often appear before neurofibro-
mas. Adult siblings and adult children of affected persons
can be counseled that their risk of having affected chil-
dren is the same (approximately 1 in 3500) as that of the
parents of patients with sporadic cases if all three ele-
ments of the triad are absent. Patients who have a seg-
mental pattern of neurofibromatosis should be counseled
that genetic transmission of their trait, though rare, is
possible.
Management. There are more than 60 neurofibromato-

sis clinics in the United States. These clinics are usually
based at teaching centers where a group of specialists
provides a team approach to management. Internet re-
sources are available.
Cutaneous tumors may be excised. The patient must
be followed closely to detect malignant degeneration of
neurofibromas. Genetic counseling is of utmost impor-
tance. Periodic complete evaluations are required to de-
tect the numerous possible internal manifestations. Mag-
netic resonance imaging with gadolinium enhancement is
the primary neuroimaging modality used for diagnosis,
management, and screening of family members.
FIGURE 26-15 Segmental neurofibromatosis (NF5). Tu-

mors are restricted to a segment of skin.
TUBEROUS SCLEROSIS Adenoma Sebaceum. Adenoma sebaceum is the most

common cutaneous manifestation of tuberous sclerosis.
Tuberous sclerosis (epiloia) is an autosomal dominant The lesions consist of smooth, firm, 1- to 5-mm, yellow-
disease of variable penetrance that is characterized by pink papules with fine telangiectasia (Figures 26-17 and
multiple hamartomas of the skin, central nervous system, 26-18). Their color and location suggest an origin from
kidneys, heart, retina, and other organs. The skin lesions sebaceous glands, but these growths are benign hamarto-
(adenoma sebaceum, shagreen patch, white macules, or mas composed of fibrous and vascular tissue (angiofibro-
periungual fibromas) are reliable markers of the disease. mas). The angiofibromas are located on the nasolabial
Tuberous sclerosis (TS) affects at least 1 in 6000 people; folds, cheeks, and chin, and, occasionally, on the forehead,
two thirds of cases occur sporadically; one third of cases scalp, and ears. The number varies from a few inconspicu-
are familial. Mildly affected individuals may be undiag- ous lesions to dense clusters of papules. They are rare at
nosed. The triad of epilepsy, angiofibromas (adenoma se-
baceum), and intellectual disability (the Vogt triad) that is
typically associated with tuberous sclerosis is present in BOX 26-6 Updated Diagnostic Criteria for
only 25% of patients. Intellectual disability may be pres- Tuberous Sclerosis Complex 2012
ent in less than 50% of patients.
A. GENETIC DIAGNOSTIC CRITERIA
Diagnostic Criteria. Updated diagnostic criteria were The identification of either a TSC1 or a TSC2 pathogenic
mutation in DNA from normal tissue is sufficient to make a
published in 2012 (Box 26-6).
definite diagnosis of tuberous sclerosis complex (TSC). A
pathogenic mutation is defined as a mutation that clearly
Clinical Manifestations. The time course of tuberous inactivates the function of the TSC1 or TSC2 proteins
sclerosis lesions is illustrated in Figure 26-16. The fre- (e.g., out-of-frame indel or nonsense mutation), prevents
quency of cutaneous manifestations is listed in Table protein synthesis (e.g., large genomic deletion), or is a mis-
26-3. sense mutation whose effect on protein function has been
established by functional assessment (www.lovd.nl/TSC1,
www.lovd/TSC2, and Hoogeveen-Westerveld et al., 2012,
2013). Other TSC1 or TSC2 variants whose effect on func-
tion is less certain do not meet these criteria, and are not
sufficient to make a definite diagnosis of TSC. Note that
10% to 25% of TSC patients have no mutation identified
Cortical Subependymal Renal cysts, Maximum by conventional genetic testing, and a normal result does
tubers nodules angiomyolipoma expression not exclude TSC, or have any effect on the use of clinical
diagnostic criteria to diagnose TSC.
Relative level of
Subungual B. CLINICAL DIAGNOSTIC CRITERIA

expression
Facial
fibromas
lesions Cardiac Major features
rhabdo- 1. Hypomelanotic macules ("3, at least 5-mm diameter)
myomas 2. Angiofibromas ("3) or fibrous cephalic plaque
3. Ungual fibromas ("2)
0 10 20 30 40 50 60 4. Shagreen patch
Age (years) 5. Multiple retinal hamartomas
6. Cortical dysplasias*
FIGURE 26-16 Time course of TS lesions.
7. Subependymal nodules
8. Subependymal giant cell astrocytoma
9. Cardiac rhabdomyoma
10. Lymphangioleiomyomatosis (LAM)†
11. Angiomyolipomas ("2)†
Minor features
TABLE 26-3 Cutaneous Manifestations in 1. “Confetti” skin lesions
Children with Tuberous Sclerosis 2. Dental enamel pits ("3)
Complex 3. Intraoral fibromas ("2)
4. Retinal achromic patch
Skin features Frequency 5. Multiple renal cysts
6. Nonrenal hamartomas
Hypomelanotic macules 15/20, 75.0% Definite diagnosis: Two major features or one major fea-
Facial angiofibromas 9/20, 45.0% ture with "2 minor features
Possible diagnosis: Either one major feature or "2 minor
Fibrous forehead plaques 5/20, 25.0%
features
Shagreen patches 5/20, 25.0%
Ungual fibromas 2/20, 10.0% From Northrup H et al: Pediatr Neurol 49(4):243-254, 2013. PMID:
24053982
Café-au-lait macules 2/20, 10.0% *Includes tubers and cerebral white matter radial migration lines.
†A combination of the two major clinical features (LAM and angio-
From Mettin RR et al: Brain Dev 36(4):306-314, 2014. PMID: myolipomas) without other features does not meet criteria for a defi-
23751858 nite diagnosis.
birth but may begin to appear by ages 2 to 3 years and or yellow retinal plaques occur in 25% of cases. The inci-
proliferate during puberty. They may be mistaken for dence of enamel pitting in the adult is 100%. A dental
multiple trichoepitheliomas, an autosomal dominant disclosing solution swabbed on dry teeth exposes the pits.
condition that appears on the central face. A secondary
feature, the “forehead plaque,” is a large angiofibroma. Genetic Counseling. TS belongs to the family of tumor
Patients with the autosomal dominant disorder multiple suppressor gene syndromes. These genes normally func-
endocrine neoplasia type 1 (MEN1) can develop multiple tion as cellular “brakes.” When they lose their function
angiofibromas and several other types of cutaneous tu- (as a result of mutations), uncontrolled proliferation and
mors in addition to tumors of pituitary, parathyroid, and tumor formation occur. Affected patients typically have
enteropancreatic endocrine tissues. one inactivating mutation in either the TSC1 or the TSC2
Shagreen Patch. The shagreen patch is highly charac- gene in all germ-line and somatic cells. The patient’s off-
teristic of tuberous sclerosis and occurs in as many as spring, both male and female, have a 50% chance of in-
80% of patients; it occurs in early childhood and may be heriting this autosomal dominant disease. The penetrance
the first sign of disease. The lesion varies in size from 1 to is high, but expressivity is variable. Patients with normal
10 cm. There is usually one lesion, but several may be parents acquire the disease from a new mutation.
present. They are soft, flesh-colored to yellow plaques Approximately 50% of tuberous sclerosis complex
with an irregular surface that has been likened to pigskin (TSC) families show genetic linkage to TSC1 and 50% to
(Figure 26-19). The lesion consists of dermal connective TSC2. Among sporadic TSC cases, mutations in TSC2
tissue and appears most commonly in the lumbosacral re- are more frequent and often accompanied by more severe
gion. neurologic deficits. Intellectual disability is significantly
Whitish Macules and White Tufts of Hair. Hypomela- more frequent in TSC2 sporadic cases than in TSC1 spo-
notic macules (oval, ash-leaf shaped, stippled, or “confetti radic cases. The TSC1 (chromosome 9) and TSC2 (chro-
shaped”) are randomly distributed with a concentration mosome 16) genes encode distinct proteins, hamartin and
on the arms, legs, and trunk. They are the earliest sign of tuberin, respectively, that are widely expressed in the
tuberous sclerosis (Figure 26-20). They are present in brain. Mosaicism is the phenomenon in which a fraction
40% to 90% of patients with the disease and number of, rather than all, germ-line and somatic cells contain a
from 1 to 32 in affected individuals. The white macules mutation of chromosomal abnormality. It occurs in all ge-
are present at birth and increase in number and size netic disorders in which spontaneous mutations occur.
throughout life. They vary from 0.5 to 12 cm in diameter. Because of this phenomenon, some patients’ mutation
The “confetti” macules are the rarest of the three types may not be detected with present methods of testing. The
and consist of numerous 1- to 3-mm macules. Wood’s failure to detect mosaicism has important implications
light examination can be used to accentuate the white for genetic counseling.
macules and is particularly useful for examining patients The Tuberous Sclerosis Alliance provides information
with light skin. A biopsy shows melanocytes, thus exclud- and support for physicians, patients, and families (www.
ing the diagnosis of vitiligo. Hypopigmented macules, tsalliance.org).
present at birth, are not invariably associated with tuber-
ous sclerosis, but their presence is an indication for fur- Diagnosis and Management. The diagnosis of tuberous
ther study. It is essential that the diagnosis be established sclerosis must be sought in infants with white macules,
as soon as possible so that parents can obtain genetic white hair tufts, or other cutaneous signs. The diagnosis
counseling. A tuft of white hair with no depigmentation may be established by demonstrating brain calcifications
of the scalp skin underlying the white tuft has been re- that may occur in early infancy. Brain lesions in tuberous
ported as an early sign of tuberous sclerosis. sclerosis are of three kinds: cortical tubers, white matter
Periungual Fibromas. Periungual fibromas appear at abnormalities, and subependymal nodules. CT imaging
or after puberty in approximately 50% of cases. They are demonstrates calcified subependymal nodules. MR imag-
smooth, flesh-colored, conical projections that emerge ing demonstrates more clearly cortical and white matter
from the nailfolds of the toenails and fingernails (Figure lesions than CT imaging. A positive scan result is often
26-21). obtainable before the calcifications are present on skull
x-ray films and even before the pathognomonic cutane-
Systemic Manifestations. Intellectual disability occurs ous findings appear.
in less than 50% of cases. Subependymal nodules and Facial angiofibromas may be surgically removed for
cortical and white matter tubers are characteristic of tu- cosmetic purposes by electrosurgery, cryosurgery, derm-
berous sclerosis. Sclerotic patches (tubers) consisting of abrasion, or lasers.
astrocytes and giant cells are scattered throughout the
cortical gray matter. Calcium is deposited in tubers and Diagnostic Studies. In newly diagnosed patients, testing
may be detected shortly after birth by computed tomog- helps to confirm the diagnosis and to identify complica-
raphy (CT) scan, magnetic resonance imaging (MRI), or tions. For patients with an established diagnosis, studies
x-ray films and is found in 90% of affected children. Brain can identify treatable complications. Tests sometimes
lesions cause seizures in more than 90% of patients. Be- provide evidence of disease in asymptomatic relatives of
nign tumors consisting of vascular fibrous tissue and fat children with tuberous sclerosis complex. Affected rela-
and smooth muscle are found in numerous organs, in- tives who have abnormal tests usually have at least subtle
cluding the kidneys, liver, and gastrointestinal tract. Gray findings.
TUBEROUS SCLEROSIS
FIGURE 26-19 Tuberous sclerosis. Shagreen patch is

most commonly found in the lumbosacral region. The
patch appears in childhood or early adolescence.
FIGURE 26-17 Tuberous sclerosis. Adenoma sebaceum

appears during childhood or early adolescence. These
angiofibromas first appear as flat, pink macules and
later become papular. Lesions may bleed easily.
FIGURE 26-20 Tuberous sclerosis. Ash-leaf macules

(hypomelanotic macules) are often present at birth.
FIGURE 26-18 Tuberous sclerosis. Adenoma sebaceum.

A florid presentation.
FIGURE 26-21 Tuberous sclerosis. Periungual fibromas.
INTERNAL CANCER AND SKIN DISEASE FAMILIAL CANCER SYNDROMES

The skin can be associated with internal malignancy in a Many familial cancer syndromes have cutaneous signs
variety of ways. The skin lesions may be a marker for an that can help make a diagnosis. An overview of some of
inherited syndrome (i.e., the genodermatoses), may rep- the familial cancer syndromes with cutaneous findings
resent a reaction to the tumor (the paraneoplastic syn- appears in Figure 26-23.
dromes) (Figure 26-22), may be caused by a carcinogen, Oncologists or dermatologists may be the first to sus-
may occur as a result of treatment, or may represent di- pect a familial cancer syndrome when high-risk features
rect tumor extension or metastasis to the skin. are noted. These include a cluster of relatives within the
patient’s family who have the same or similar cancers, the
development of cancer at a young age, or the presentation
CUTANEOUS PARANEOPLASTIC of more than one tumor or a second primary tumor. Many
SYNDROMES familial cancer syndromes have skin signs. These syn-
dromes may occur as the result of a new mutation and
Paraneoplastic syndromes (PNSs) are diseases that ap- present without a family history. The most common are
pear before or concurrently with an internal malignancy. hereditary breast and ovarian cancers, hereditary nonpol-
They represent a remote or systemic effect of a neoplasm. yposis colon cancer, and familial adenomatous polyposis.
There is a wide range of categories of PNSs, including There are many other familial cancer syndromes, many
endocrine, neurologic, hematologic, rheumatic, renal, of which have cutaneous signs. Patients suspected of hav-
and cutaneous. They may be the initial clue to the pres- ing a familial cancer syndrome are referred to a genetic
ence of an underlying neoplasm. The activity of a PNS counselor or a clinical geneticist. Visit Mendelian Inheri-
can parallel the course of the tumor and thus be used as a tance in Man (www.ncbi.nlm.nih.gov/omim/) for details
marker of remission or recurrence. PNSs are estimated to of all familial syndromes.
occur in 7% to 15% of patients with cancer.
The cutaneous changes are thought to result from the
production of biologically active hormones or growth COWDEN DISEASE (MULTIPLE
factors, or antigen-antibody interactions induced by or HAMARTOMA SYNDROME)
produced by the tumor. Many of these syndromes, such as
acanthosis nigricans, are proliferative skin disorders. Cowden disease (multiple hamartoma syndrome) is a
Products secreted by the tumor, such as transforming multisystem disease inherited as an autosomal dominant
growth factor alpha, may stimulate keratinocytes to pro- trait with incomplete penetrance and variable expression.
liferate. The incidence is estimated to be 1 in 200,000. It is
characterized by multiple hamartomas of ectodermal, en-
dodermal, and mesodermal origin and a high incidence of
malignant tumors of the breast and/or thyroid gland. The
mucocutaneous manifestations are the most characteris-
tic feature and are the key to diagnosis. The diagnostic
criteria for Cowden disease are listed in Box 26-7.
Mucocutaneous Lesions. Facial papules and oral muco-

sal papillomatosis are the most sensitive indicators of the
disease. The asymptomatic cutaneous lesions are usually
noticed at age 20, and no further progression of lesions is
seen after the age of 30. The principal cutaneous lesion is
a papule that may be smooth or keratotic. Cutaneous fa-
cial papules are of two types: lichenoid, flesh-colored,
flat-topped papules are found in the centrofacial and peri-
orificial areas; and flesh-colored, elongated, verrucoid,
papillomatous lesions are found clustered around the
mouth (Figures 26-23 and 26-24), nose, eyes, and on the
ears. The majority of these lesions are trichilemmomas.
The differential diagnosis of these facial papules includes
Darier’s disease and adenoma sebaceum found in tuber-
ous sclerosis. Acral keratoses are located primarily on the
dorsum of the hands and feet. They resemble flat warts
(i.e., they are flesh-colored, flat-topped papules 1 to 4 mm
in diameter). Palmoplantar keratoses are isolated, pin-
point to pea-sized, translucent, hard papules that may
FIGURE 26-22 A paraneoplastic syndrome; the Leser- show a central depression.
Trélat sign. The rapid onset of numerous seborrheic ker- The oral lesions are white, smooth-surfaced papules, 1
atoses can be associated with an internal malignancy. to 3 mm in diameter, that often coalesce, giving a cobble-
FAMILIAL MULTIPLE CANCER SYNDROMES

AUTOSOMAL DOMINANT ‘CANCER FAMILY SYNDROMES’
Cowden disease Muir-Torre syndrome Gardner’s syndrome
Females Males = females Males = females
Mucocutaneous lesions Skin tumors Skin signs

Facial papules Sebaceous gland Epidermal cysts
Oral papules (at least 1)
Hand keratosis Osteomas (palpable)
Keratoacanthomas Skull
Breast lesions Jaw
Cancer Internal tumors
Fibrocystic Colorectal Pigmented ocular
Genitourinary fundus lesions
Thyroid Breast
Goiter Colon
Carcinoma Polyps > 100
Adenocarcinoma
Solid tumors
Thyroid carcinoma
A B C
FIGURE 26-23 Familial multiple cancer syndromes: autosomal dominant cancer

family syndromes: A, Cowden disease. Trichilemmomas. Multiple 2- to 3-mm small
papules on the nose and cheek. B, Muir-Torre syndrome. Sebaceous tumors.
C, Gardner’s syndrome. Multiple epidermoid cysts on the chest. (A, Courtesy of Cary
Chrisholm and Clay Cockerell, MD. From J Am Acad Dermatol 68:189, 2013; PMID:
23317980. C, From Lebwohl MG: The skin and systemic disease: a color atlas, ed 2,
Churchill Livingstone, New York, © Elsevier 2004.)
stone appearance. They are located primarily on the gin-

BOX 26-7 Cowden Disease Diagnostic
gival, labial, and palatal surfaces.
Criteria
PATHOGNOMONIC CRITERIA Breast Lesions. Breast lesions are the most important
Mucocutaneous lesions
and potentially serious abnormality of Cowden disease.
• Multiple facial trichilemmomas Ductal adenocarcinoma occurs in 25% to 36% and fibro-
• Mucosal lesions cystic disease occurs in 60% of patients. The median age
• Acral keratosis of diagnosis of breast cancer is 41 years. All women with
Cowden disease should be considered for prophylactic
MAJOR CRITERIA bilateral total mastectomy by their third decade of life.
Breast cancer
Thyroid cancer, especially follicular thyroid carcinoma Thyroid Gland Lesions. Palpable enlargement (goiter
Macroencephaly and adenoma) is the most frequently reported internal
Hamartomatous outgrowths of cerebellum (Lhermitte- abnormality of Cowden disease. Cowden syndrome car-
Duclos disease)
ries a 10% risk for thyroid cancer.
MINOR CRITERIA A wide variety of other abnormalities and malignan-
Thyroid lesions (e.g., adenoma or goiter) cies have been reported, but the incidence is low.
Intellectual disability (IQ #75)
Hamartomatous intestinal polyps
Fibrocystic disease of the breast MUIR-TORRE SYNDROME
Lipomas
Fibromas Muir-Torre syndrome (MTS) is a rare autosomal domi-
Genitourinary tumors or malformations nant genodermatosis characterized by at least one seba-
OPERATIONAL DIAGNOSIS FOR INDIVIDUAL ceous gland tumor and a minimum of one internal malig-
1. Mucocutaneous lesions alone if
nancy. The common presentation is the presence of
a. Six facial papules with three trichilemmomas sebaceous tumors along with a low-grade visceral malig-
b. Cutaneous facial papules and oral mucosal papillo- nancy. The presence of sebaceous tumors warrants a
matosis search for an internal malignancy. This syndrome is now
c. Oral mucosal papillomatosis and acral keratoses considered a subtype of the more common hereditary
d. Six or more palmar/plantar keratoses or nonpolyposis colorectal cancer (HNPCC) syndrome.
2. Two major criteria, but one must include macrocephaly MTS and HNPCC syndrome are associated with hMSH2
or Lhermitte-Duclos disease or gene mutations.
3. One major and three minor criteria or
4. Four minor criteria Skin Tumors. Sebaceous tumors appear before the inter-
Adapted from Lindor NM, Greene MH: J Natl Cancer Inst 90:1059,
nal malignancy in 22% of patients, concurrently in 6% of
1998; Tsao H: J Am Acad Dermatol 42:939, 2000. PMID: 10827397 patients, and after the internal malignancy in 56% of pa-
tients. The sebaceous gland tumors (adenoma, seba-
ceoma, epithelioma, or carcinoma) usually occur on the
trunk, face, and scalp (Figures 26-23, B and 26-25). They
vary from small, asymptomatic papules or nodules that
resemble cysts or benign tumors to waxy papules. The
syndrome may occur in individuals with a single seba-
FIGURE 26-24 Cowden disease. White oral papules often FIGURE 26-25 Muir-Torre syndrome. A sebaceous ade-
coalesce. noma is the most characteristic marker of the disease.
ceous gland tumor. Some benign sebaceous neoplasms in GARDNER’S SYNDROME

MTS might have a high potential for malignant transfor-
mation or may be well-differentiated sebaceous carcino- Gardner’s syndrome (familial adenomatous polyposis
mas with low-grade malignancy, mimicking sebaceous with extraintestinal manifestations) is an autosomal dom-
adenoma/sebaceoma. inantly transmitted disease with a similar penetrance in
Single or multiple keratoacanthomas occur in approxi- both genders of nearly 100% (see Figure 26-23, C ). It
mately 20% of patients. The median age for the appear- consists of intestinal polyposis, epidermal cysts, multiple
ance of the skin lesions is 53 years (range, 23 to 89 years). osteomas, mesenteric fibromas, desmoid tumors, pig-
Sebaceous gland tumors in the general population are mented ocular fundus lesions, unerupted teeth, and odon-
rare. A tumor diagnosed as a sebaceous adenoma, seba- tomas. The incidence is approximately 1 of 8300 to 1 of
ceous epithelioma, or sebaceous carcinoma should alert 16,000 births. The adenomatous polyposis coli (APC)
the clinician to the possibility of visceral cancer both in gene on chromosome 5q21 is altered by point mutations
the patient and in family members. Sebaceous hyperplasia in the germ line of Gardner’s syndrome patients. The
commonly seen on the face is not associated with malig- identification of these genes should aid in the counseling
nancy. of patients with genetic predispositions to colorectal
cancer.
Internal Tumors. The most commonly associated neo-
plasms are colorectal (47%); 58% of these tumors occur Cutaneous Signs. Polyposis is a nearly constant feature,
proximal to or at the splenic flexure. but epidermal cysts occur in approximately 35% of cases.
MTS patients have a genetic predilection to hereditary Epidermal cysts are frequently the presenting complaint
nonpolyposis colorectal cancer (HNPCC). There are at and appear most often on the head and neck, but they
least eight other major cancer susceptibility syndromes frequently also occur in areas such as the legs, where epi-
that infer an increased risk for colorectal cancer and/or dermal cysts are rarely found. Gardner’s syndrome should
colorectal polyposis. Therefore the differential diagnosis be considered in patients with epidermal cysts in unusual
of hereditary colorectal cancer can be complex. Genito- areas. The cysts can occur in childhood, but the average
urinary tumors (21%), breast carcinomas (12%), and he- age at onset is 13 years. They range from a few to many
matologic disorders (9%) are also common. Fifty-three lesions and can be small or large enough to distort normal
percent of patients develop one cancer, 37% develop two structures. Osteomas can be recognized clinically and ra-
to three cancers, and 10% develop four to nine cancers. diographically in childhood. They most commonly ap-
Cutaneous lesions occur before or concurrent with the pear on the head and neck and can be seen and felt.
diagnosis of the initial cancer in 63% of patients. The me- Osteomas. Multiple osteomas, especially of the skull
dian age for the detection of the initial visceral neoplasm and jaws, are found in a number of affected and at-risk
is 53 years (range, 23 to 89 years). A few cases have been relatives. In some, these “markers” are found early in life,
associated with polyps in the colon, but widespread gas- before the appearance of colonic polyps. Radiography of
trointestinal polyposis is rare. There is a relatively low the jaws may serve as a valuable tool for the early detec-
potential for malignancy in both cutaneous and internal tion of carriers of Gardner’s syndrome.
tumors, but metastasis from internal malignancies does Pigmented Ocular Fundus Lesions. Pigmented ocular
occur, particularly from colon cancer. fundus lesions are a reliable clinical marker for the disease
and are found in 90% of patients and 47% of relatives
Epidemiology. Muir-Torre syndrome may appear de who are at a 50% risk for Gardner’s syndrome. The pres-
novo, but there is often a variable family history of cuta- ence of bilateral lesions, multiple lesions (more than
neous and/or internal tumors. Males and females are four), or both is a specific and sensitive clinical marker for
equally affected. This may be one of the four subtypes of the syndrome. The lesions are discrete, darkly pigmented,
cancer family syndrome characterized by a genetically and round, oval, or kidney shaped; they range in size from
determined (autosomal dominant) predisposition to mul- 0.1 to 1 (or more) optic-disc diameters. A total of 1 to 30
tiple visceral malignancies that arise at an early age and lesions may be present.
pursue a relatively benign course. As in cancer family syn- Thyroid Carcinoma. Carcinoma of the thyroid gland
drome, colon cancers in Muir-Torre syndrome are often is frequently reported in these patients. It has the follow-
more proximal to the splenic flexure than in the general ing characteristics: female predominance (89%), youth
populace. (average 23.6 years; range, 16 to 40 years), papillary form
(88%), and multicentricity (70%).
Management. Regular follow-up and searches for new Colonic Polyps and Cancer. Colonic polyps can be de-
malignancy and also evaluation and monitoring of family tected before the patient reaches puberty. They are usu-
members are necessary. Patients and their families should ally asymptomatic, number greater than 100, and invari-
be counseled about genetic predisposition. ably progress to adenocarcinoma. Sulindac reduces the
number and size of colorectal adenomas in patients with
Treatment. The combination of interferon with isotreti- familial adenomatous polyposis, but its effect is incom-
noin or use of isotretinoin alone may prevent tumor de- plete, and it is unlikely to replace colectomy as primary
velopment. therapy. Gardner’s syndrome patients who undergo ag-
gressive bowel surgery when polyps are detected can have
a normal life span. All family members should be exam-
ined. Genetic counseling is essential for this autosomal
dominantly inherited disease.
BIRT-HOGG-DUBÉ SYNDROME Chronic Itch

AND RENAL CARCINOMA Pruritus is defined as an unpleasant sensation of the skin
leading to the desire to scratch. Pruritus can be distin-
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dom- guished as acute or chronic. Chronic itch is defined as
inant genodermatosis of unknown incidence character- pruritus lasting 6 or more weeks. Chronic pruritus is also
ized by skin fibrofolliculomas, an increased risk of spon- discussed in Chapter 6, p. 215.
taneous pneumothorax, and renal and possibly other Diseases with and without primary or secondary skin
tumors. The fibrofolliculomas tend to appear in the third lesions cause chronic pruritus. Three groups of condi-
or fourth decade of life. Trichodiscomas and other cuta- tions occur (Tables 26-4 to 26-7). PMID: 17598029
neous tumors (angiofibromas) have been reported. Clini- Chronic pruritus frequently leads to scratching, rub-
cal features are variable. Some patients have numerous bing, or pinching. Scratching may induce variable dam-
papules and others have none (Figure 26-26). age of the skin, presenting as excoriations, crusts, licheni-
Fibrofolliculomas and trichodiscomas are benign hair fication, papules, and nodules. These lesions may resolve,
follicle hamartomas, which usually present as many small leaving hyper- or hypopigmentation and atrophic scars of
asymptomatic skin-colored papules on the face, neck, the skin.
scalp, and upper trunk. Approach to the Evaluation and Treatment of Pruri-
The prevalence of spontaneous pneumothorax and re- tus. The approach to treating patients with pruritus starts
nal tumors is low. Various other extracutaneous tumors with a history and physical examination. Any dermato-
are reported. Colorectal cancer is not part of this syn- logic condition is treated. If none is apparent, order a
drome. BHD should be suspected in patients with few or complete blood cell count, chemistry profile for liver and
even without fibrofolliculomas and/or trichodiscomas renal function, thyroid function studies, and a fasting glu-
who may present with (familial) renal tumors (hybrid on- cose level. Consider a chest x-ray, stool for ova and para-
cocytic tumor, chromophobe renal cell carcinoma, clear sites, and imaging studies to rule out a lymphoma. A par-
cell tumors, oncocytoma) and/or spontaneous pneumo- tial list of topical treatments includes menthol and phenol,
thorax. Older age and male gender increase the risk for calamine, antihistamines, local anesthetics, and capsaicin.
renal tumors. Chromophobe renal cell carcinomas are Systemic drugs include histamine-1 (H1) receptor antag-
locally invasive but rarely metastasize. Tumors less than onists, H2-receptor antagonists, doxepin, ondansetron,
3 cm are observed, whereas tumors larger than 3 cm are paroxetine, and opiate antagonists. Consider prescribing
treated with nephron-sparing procedures including par- mirtazapine (Remeron), especially for patients with noc-
tial nephrectomy. The risk of spontaneous pneumothorax turnal itch. PMID: 16546594
is inversely associated with age. Between 15% and 30% of
BHD-affected patients develop renal cancers. Patients
develop renal tumors in their twenties or thirties and of-
Central Neuropathic Itch
ten present with multiple, bilateral renal cancers. Central neuropathic itch results from lesions in the cen-
tral nervous system. Various causes include cerebral vas-
cular accidents, demyelinating disorders, tumors, and ab-
scesses. This type of itch is hypothesized to be associated
with central hypersensitivity of nerve fibers. Treatments
include neuroleptics, antidepressants, anesthetics, and
topical capsaicin. Healing touch, a holistically based
treatment modality, has been used with success as an ad-
junct to therapy (Box 26-8 and Table 26-8).
BOX 26-8 Causes of Central Neuropathic

Itch
Demyelinating disorders
Multiple sclerosis
Vascular injury
Cerebral vascular accidents
Wallenberg syndrome
Tumors
Brain tumors
Nasal glioma
Spinal origin
Spinal-cord cavernous hemangioma
Ependymoma
Brain or spinal abscess
Creutzfeldt-Jakob disease (“prion pruritus”)
Phantom itch
FIGURE 26-26 Birt-Hogg-Dubé syndrome. Multiple,
small, skin-colored, dome-shaped papules distributed From Curtis AR et al: J Am Acad Dermatol 64:955-999, 2011. PMID:
over the face, neck, and upper trunk. 21292347
TABLE 26-4 Clinical Classification of Chronic

Pruritus According to Skin Changes
Clinical
Group presentation Diagnostics
Pruritus on diseased, Skin disease Skin biopsy, labora-
inflamed skin etiology tory investigation
Pruritus on normal, Normal skin Laboratory and
non-inflamed skin etiology radiological
investigation
Pruritus with chronic Chronic Skin biopsy, labora-
secondary scratch secondary tory and radiologi-
lesions scratch cal investigations
lesions
Adapted from Ständer S et al: Acta Derm Venereol 87:291-294.

2007; PMID: 17598029
TABLE 26-5 Skin Diseases Accompanied by Pruritus

Dermatologic diseases Examples of diagnoses
Inflammatory dermatoses Atopic dermatitis, psoriasis, contact dermatitis, dry skin, drug reactions, scars, “invisible
dermatoses”
Infectious dermatoses Mycotic, bacterial, and viral infections; folliculitis; scabies; pediculosis; arthropod reactions; insect
bites
Autoimmune dermatoses Bullous dermatoses, especially dermatitis herpetiformis Duhring, bullous pemphigoid,
dermatomyositis
Genodermatoses Darier’s disease, Hailey-Hailey disease, ichthyoses, Sjögren-Larsson syndrome, EB pruriginosa
Dermatoses of pregnancy Polymorphic eruption of pregnancy, pemphigoid gestationis, prurigo gestationis
Neoplasms Cutaneous T-cell lymphoma (especially erythrodermic variants), cutaneous B-cell lymphoma,
leukemic infiltrates of the skin
Adapted from Ständer S et al: Acta Derm Venereol 87:291-294, 2007. PMID: 17598029
EB, Epidermolysis bullosa.
TABLE 26-6 Systemic Origin of Chronic Pruritus without Skin Disease

Systemic diseases Examples of diagnoses
Endocrine and metabolic Chronic renal failure, liver diseases with or without cholestasis, hyperthyroidism, malabsorption,
diseases perimenopausal pruritus
Infectious diseases HIV infection, helminthiasis, parasitosis
Hematologic and lympho- Iron deficiency, polycythemia vera, Hodgkin’s disease, non-Hodgkin’s lymphoma, plasmocytoma
proliferative diseases
Visceral neoplasms Solid tumors of the cervix, prostate, or colon; carcinoid syndrome
Pregnancy Pruritus gravidarum with and without cholestasis
Drug-induced pruritus Opioids, ACE inhibitors, amiodarone, hydrochlorothiazide, estrogens, simvastatin, hydroxyethyl
(selection) starch, allopurinol
ACE, Angiotensin-converting enzyme; HIV, human immunodeficiency virus.
TABLE 26-7 Neurologic and Psychiatric/Psychosomatic Origin of Chronic Pruritus

without Skin Disease
Diseases Examples of diagnoses
Neurogenic origin (with- Few clinical examples yet, potentially hepatic itch with increased endogenous m-opioids (disinhibi-
out neuronal damage) tion of itch)
Neuropathic diseases Multiple sclerosis, neoplasms, abscesses, cerebral or spinal infarcts, brachioradial pruritus, notalgia
(neuronal damage paresthetica, postherpetic neuralgia, vulvodynia, small fiber neuropathy
causes itch)
Somatoform pruritus Psychiatric/psychosomatic diseases, depression, anxiety disorders, obsessive-compulsive disor-
ders, schizophrenia, tactile hallucinosis, fatigue
TABLE 26-8 Pharmacologic Treatments of Central Neuropathic Pruritus

ORAL TREATMENT
Gabapentin 300 mg daily titrated up to 3600 mg daily Weight gain, increased appetite, sedation, peripheral edema
Pregabalin 75 mg twice daily titrated up to 400 mg daily Dizziness, weight gain, peripheral edema, sedation
Mirtazapine 7.5 mg nightly increasing to 15 mg nightly Sedation, weight gain
Doxepin 25-100 mg daily Sedation, dry mouth; abrupt cessation may cause confusion; should
not administer with other antidepressants
Mexiletine 150 mg daily titrating up to 600 mg daily Clearance by cardiology before initiation; ECG monitoring
Butorphanol (intranasal) 1-4 mg inhaled daily Sedation, dizziness, nausea
Naltrexone 12.5-250 mg daily Hepatotoxicity, nausea, insomnia; contraindicated in patients with
liver disease
Naloxone 0.002 mcg/kg/min titrated gradually up to Hepatotoxicity, nausea, insomnia
0.2 mcg/kg/min over 24 hr
Carbamazepine 200 mg twice daily increasing up to Blood dyscrasias, Stevens-Johnson syndrome/TEN
1200 mg daily
TCAs (amitriptyline 12.5-75 mg daily) Sedation, anticholinergic effects (constipation, xerostomia, blurred
vision, urinary retention)
SSRIs (paroxetine 20 mg daily) Sedation, nausea, weight gain, impotence
Thalidomide 100-200 mg daily Peripheral neuropathy; teratogenic—federally regulated (STEPS
program)
TOPICAL TREATMENT
Capsaicin 0.075-0.1% cream 3 times per day Possible poor compliance secondary to initial burning sensation
EMLA cream twice daily
5% lidocaine patch daily
Crotamiton 10% lotion twice daily
Menthol 1% cream Skin irritation
Pramoxine 1-2.5% lotion 3 times per day Particularly effective for pruritus of the face
From Curtis AR et al: J Am Acad Dermatol 64:955-999, 2011. PMID: 21292347

ECG, Electrocardiogram; EMLA, lidocaine/prilocaine 2.5%; TCAs, tricyclic antidepressants; TEN, toxic epidermal necrolysis; SSRIs, selective
serotonin reuptake inhibitors; STEPS, system for thalidomide education and prescribing safety.

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CHAPTER 26

CUTANEOUS MANIFESTATIONS OF DIABETES CUTANEOUS PARANEOPLASTIC SYNDROMES

Certain cutaneous diseases are frequently associated with • Perforating disorders

FIGURE 26-1 Necrobiosis lipoidica. A, Erythematous violaceous plaques on the ante-

ACANTHOSIS NIGRICANS tance. There is a high prevalence of AN in obese adults.

Treatment. Lesions are usually asymptomatic and do

Malignant Acanthosis Nigricans. The cases of greatest

FIGURE 26-4 Acanthosis nigricans. The axilla is the most

as cofactors for plasma enzymes and interact with cell

TABLE 26-1 Xanthomas

*There are five types of familial hyperlipidemia.

TABLE 26-2 Primary Dyslipidemia (Genetic Dyslipidemias)

BOX 26-3 Acquired Disorders of Lipoprotein

Eruptive Xanthomas. These are yellow, 1- to 4-mm

Tuberous Xanthomas. These are slowly evolving yellow

Tendinous Xanthomas. These smooth, deeply situated

Regression of Xanthomas. Certain xanthomas disap-

FIGURE 26-10 Tuberous xanthomas are painless, red-

Adapted from National Institutes of Health Consensus Development

FIGURE 26-12 von Recklinghausen’s neurofibro-

BOX 26-5 Systemic Manifestations

Management. There are more than 60 neurofibromato-

FIGURE 26-15 Segmental neurofibromatosis (NF5). Tu-

TUBEROUS SCLEROSIS Adenoma Sebaceum. Adenoma sebaceum is the most

Subungual B. CLINICAL DIAGNOSTIC CRITERIA

FIGURE 26-19 Tuberous sclerosis. Shagreen patch is

FIGURE 26-17 Tuberous sclerosis. Adenoma sebaceum

FIGURE 26-20 Tuberous sclerosis. Ash-leaf macules

FIGURE 26-18 Tuberous sclerosis. Adenoma sebaceum.

FIGURE 26-21 Tuberous sclerosis. Periungual fibromas.

INTERNAL CANCER AND SKIN DISEASE FAMILIAL CANCER SYNDROMES

Mucocutaneous Lesions. Facial papules and oral muco-

FAMILIAL MULTIPLE CANCER SYNDROMES

Females Males = females Males = females

Mucocutaneous lesions Skin tumors Skin signs

FIGURE 26-23 Familial multiple cancer syndromes: autosomal dominant cancer

stone appearance. They are located primarily on the gin-

ceous gland tumor. Some benign sebaceous neoplasms in GARDNER’S SYNDROME

BIRT-HOGG-DUBÉ SYNDROME Chronic Itch

BOX 26-8 Causes of Central Neuropathic

TABLE 26-4 Clinical Classification of Chronic

Adapted from Ständer S et al: Acta Derm Venereol 87:291-294.

TABLE 26-5 Skin Diseases Accompanied by Pruritus

TABLE 26-6 Systemic Origin of Chronic Pruritus without Skin Disease

TABLE 26-7 Neurologic and Psychiatric/Psychosomatic Origin of Chronic Pruritus

TABLE 26-8 Pharmacologic Treatments of Central Neuropathic Pruritus

From Curtis AR et al: J Am Acad Dermatol 64:955-999, 2011. PMID: 21292347

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