Cutaneous Manifestations of Internal Disease

1
Cutaneous Manifestations of Internal Disease

• Residents Conference
• Hallie McDonald, MD
• August 16, 2005

2
Diabetes Mellitus

• According to Perez et al (3) ,approximately 30
  of patients with DM develop skin lesions at some
  point
• Overall prevalence of cutaneous disorders does
  not differ between type I and type II diabetics
• Type I patients get more autoimmune-type lesions
• Type II patients get more cutaneous infections

3
Diabetes Mellitus

• Cutaneous lesions usually appear after the
  development of DM, but may be the first
  presenting sign
• Four major groups of skin findings
• Skin diseases associated with DM (necrobiosis
  lipoidica and diabetic bullae)
• Cutaneous infections
• Cutaneous manifestions of diabetic complications
  (neuropathic ulcers)
• Skin reactions to diabetic treatment

4
Necrobiosis Lipoidica (NL)

• NL appears in 0.3-1.6 of diabetics (2,4)
• Anywhere from 11-65 of patients with NL have DM
  at the time of skin dx (2,7,8)
• If they do not have DM at time of dx, about 90
  will develop diabetes, have abnormal glucose
  tolerance, or report parents with DM (2, 4)
• Diabetic control has no effect on the course of
  NL.

5
Necrobiosis Lipoidica (NL)

• NL is 3x more common in women.
• According to Jelinek, (9) NL appears earlier
  (mean age 22) in Type I diabetics than Type II
  (mean age 49.)
• Appearance
• Begins as an oval, violaceous patch and expands
  slowly.
• Advancing border is red.
• Central area turns yellowish brown.
• Central area atrophies and telangiectasia become
  evident.
• 13 of cases progress to ulceration

6
Necrobiosis Lipoidica (NL)

• Classically, NL occurs bilaterally on the
  pretibial or medial malleolar areas.
• Not painful.
• Spontaneous resolution occurs in 13-19 with
  residual scarring.
• Treatment potent topical steroids, intralesional
  steroids at the active border, or rarely systemic
  steroids

7
Necrobiosis Lipoidica (NL)
8
Necrobiosis Lipoidica (NL)
9
Necrobiosis Lipoidica (NL)
10
Necrobiosis Lipoidica (NL)
11
Necrobiosis Lipoidica (NL)
12
Granuloma Annulare (GA)

• Controversy surrounds the association between GA
  and DM.
• A case-control study by Nebesio et al. (5)
  failed to reveal a statistically significant
  correlation between the two.
• A retrospective study by Studer et al. (6)
  suggested that up to 12 of patients presenting
  with GA had DM.
• Despite conflicting studies, it is reasonable to
  screen patients presenting with GA for DM.

13
Granuloma Annulare (GA)

• Appearance
• Ring of small, firm, flesh-colored or red papules
• If localized, most frequently found on lateral
  and dorsal surfaces of hands and feet
• Disease begins with an asymptomatic,
  flesh-colored papule that undergoes central
  involution
• Over months, a ring of papules grows
• Can spontaneously regress without scarring
• Histology
• Focal degeneration of collagen in the upper and
  mid-dermis, palisaded histiocytes around collagen
  bundles, and abundant dermal mucin
• Pathogenesis unknown

14
Granuloma Annulare (GA)

• Treatment
• If localized, best left untreated.
• Can treat with intralesional steroids, if needed
• If generalized, can also use dapsone,
  isotretinoin, freezing, cyclosporin, or PUVA.

15
Granuloma Annulare (GA)
16
Granuloma Annulare (GA)
17
Granuloma Annulare (GA)
18
Granuloma Annulare (GA)
19
Granuloma Annulare (GA)
20
Granuloma Annulare (GA)
21
Granuloma Annulare (GA)
Histology showing focal degeneration of collagen
in the upper and mid-dermis, palisaded
histiocytes around collagen bundles, and abundant
dermal mucin
22
Diabetic Bullae

• Approximately 0.5 of diabetics (2)
• More common in men with long-standing DM and
  neuropathy
• Two types have been described
• More frequent, non-scarring lesions with a
  histologic intraepidermal split without
  acantholysis
• Less common, occasionally hemorrhagic bullae that
  heal with scarring, slight atrophy, and have a
  histologic subepidermal split
• Pathogenesis not well-understood
• Could be related to trauma with reduced threshold
  for blister formation
• Other theories include immunologic factors,
  disturbed catabolism of calcium, magnesium, or
  carbohydrates, microangiopathy, and vascular
  insufficiency
• Appearance
• Painless bullae on non-inflamed base that appear
  suddenly
• Most common on the dorsa and sides of lower legs
  and feet, sometimes with similar lesions on the
  hands and forearms
• Bullae contain clear, sterile fluid

23
Diabetic Bullae

• Bullae tend to heal spontaneously in 2-5 weeks
• Bullosis diabeticorum remains a diagnosis of
  exclusion with negative immunofluorescence
  studies, porphyrin levels, and cultures
• DDx bullous pemphigoid, epidermolysis bullosa
  acquisita, porphyria cutanea tarda, bullous
  impetigo, erythema multiforme, and coma blisters
• May recur in the same or new locations
• If large and symptomatic, can aspirate the fluid
  leaving an intact blister roof as a wound covering

24
Diabetic Bullae
25
Diabetic Bullae
26
Diabetic Bullae

• Histology showing a noninflammatory blister with
  a subepidermal and focally intraepidermal
  separation

27
Acanthosis Nigricans

• Seen in situations of insulin resistance
• Besides in DM, also seen in the following
• Carcinomas, especially of the stomach
• Secondary to meds (nicotinic acid, estrogen, or
  corticosteroids)
• Pineal tumors
• Other endocrine syndromes (PCOS, acromegaly,
  Cushings disease, hypothyroidism)
• Obesity
• Pathogenesis
• According to Cruz (12) , it may be related to
  insulin binding insulin-like growth factor
  receptors on keratinocytes and dermal
  fibroblasts, thus stimulating growth.

28
Acanthosis Nigricans

• Appearance
• Hyperpigmented, velvety plaques in body folds,
  mostly axillae and neck
• Can also present on groin, umbilicus, areolae,
  submammary areas, and on the hands (tripe hands)
• Treatment- usually asymptomatic
• Weight loss
• Retinoic acid and salicylic acid

29
Acanthosis Nigricans
30
Acanthosis Nigricans
31
Acanthosis Nigricans
32
Skin Infections in DM

• Occur in 20-50 of poorly controlled diabetics
  (2, 4)
• More common in Type II
• May be related to abnormal microcirculation,
  hypohidrosis, PVD, neuropathy, decreased
  phagocytosis and killing activity, impaired
  leukocyte adherence, and delayed chemotaxis all
  seen in diabetics (2, 9, 10, 11)

33
Skin Infections in DM

• Fungal infections- most common
• Candida
• Candidal paronychia
• Inframammary candida
• Genital candida
• Psedudohyphae and spores on KOH prep support dx
  of Candida
• Purulent drainage may indicate secondary
  bacterial infection
• Because maceration and skin breaks can serve as
  portals of infection, tinea pedis should be
  treated aggressively in diabetics
• Treatment includes drainage of any abscesses,
  keeping the digits dry, and topical antifungals
  (clotrimazole)

34
Candidiasis in Diabetics

• White, curdlike material adherent to
  erythematous, fissured oral commisure angular
  stomatitis

35
Candidiasis in Diabetics

• Initial pustules on erythematous base that become
  eroded and confluent

36
Candidiasis in Diabetics
37
Candidiasis in Diabetics
38
Candidiasis in Diabetics
39
Candidiasis in Diabetics
KOH prep showing pseudohyphae and budding yeast
forms
40
Skin Infections in DM

• Bacterial Infections- can be more severe and
  widespread in diabetics
• Malignant otitis externa
• Pseudomonas aeruginosa
• Fatal in over 50 patients (13)
• Can progress to chondritis, osteomyelitis, and
  bacterial meningitis
• Treat up to 3 months with oral quinolones but may
  need IV antibiotics

41
Malignant Otitis Externa in Diabetics
42
Skin Infections in DM

• Bacterial infections in DM
• Erythrasma
• Reddish tan scaling patches of the upper inner
  thighs, axillae, toe web spaces, and inframammary
  creases
• Gram positive Corynebacterium minutissimum
• Identified with Woods light coral fluorescence
• Treat with oral erythromycin for 5 days

43
Erythrasma in Diabetics

• Reddish tan scaling patches of the upper inner
  thighs, axillae, toe web spaces, and inframammary
  creases

44
Erythrasma in Diabetics
45
Erythrasma in Diabetics
46
Woods Lamp in the Diagnosis of Erythrasma
47
Cutaneous Manifestations of Diabetic
Complications Foot Ulcers

• Responsible for 70 of annual lower limb
  amputations in the U.S.(2)
• Large economic impact from medical and surgical
  therapy, rehab, loss of work, and mortality
• Prevention is key
• Daily foot inspections, appropriate footwear
• Causes for ulcer formation
• Peripheral neuropathy (60-70)
• Treatment aggressive debridement and offloading
  or with a contact cast
• Vascular disease (15-20)
• Treatment surgical re-vascularization
• Combination of peripheral neuropathy and vascular
  disease (15-20)

48
Cutaneous Reactions to Diabetic Treatment

• Insulin
• Allergy may be local or systemic and usually
  occurs within the first month of therapy
• Erythematous or urticarial pruritic nodules at
  the site of injection
• Lipoatrophy can also occur
• Circumscribed depressed areas of skin at the
  insulin injection site 6-24 months after starting
  insulin
• More common in women and children
• Pathogenesis unknown but may be related to
  lipolytic components of the insulin preparation,
  an immune complex-mediated inflammatory process
  with lysosomal enzyme release, cryotrauma from
  refrigerated insulin, or mechanical trauma from
  injection
• Lipohypertrophy can also occur
• Soft dermal nodules that resemble lipomas at
  sites of frequent injection
• May be a response to the lipogenic action of
  insulin
• Treat and prevent by rotating sites of injection

49
Cutaneous Reactions to Diabetic Treatment
Lipoatrophy
50
Cutaneous Reactions to Diabetic Treatment- Insulin

• Highly purified or recombinant insulins have a
  reduced allergy prevalence (0.1-0.2) (4)
• Observe the patients technique to make sure it
  isnt intradermal
• Treatment includes substitution of a more
  purified insulin, discontinuation or
  desensitization for severe systemic rxns

51
Cutaneous Reactions to Diabetic Treatment-Oral
Hypoglycemics

• Most rxns are associated with the
  first-generation sulfonylureas (chlorpropamide
  and tolbutamide)
• 1-5 of patients on these drugs will develop skin
  rxns during the first 2 months of treatment (2,4)
• Most commonly, they present with maculopapular
  eruptions that resolve despite continuation of
  the drug
• For patients of chlorpropamide, 10-30 will
  develop a disulfiram-like rxn of flushing,
  headache, tachycardia, and shortness of break
  after ingesting alcohol. This seems to be
  autosomal dominant. (2,3)
• Second-generation sulfonylureas can also be
  associated with cutaneous rxns.

52
Hyperthyroidism and the Skin

• Thyroid hormone plays a pivotal role in the
  growth and formation of hair and sebum
  production.
• Thyroid hormone stimulates epidermal oxygen
  consumption, protein synthesis, mitosis, and
  determination of epidermal thickness.
• There is increased cutaneous blood flow and
  peripheral vasodilation.

53
Hyperthyroidism and the Skin

• Skin is usually warm, moist, and smooth
• Facial flushing
• Palmar erythema
• Hyperpigmentation, esp. creases of palms and
  soles, gingiva, and buccal mucosa
• Hyperhydrosis, particularly of palms and soles
• Scalp hair can be soft, fine and sometimes
  accompanied by non-scarring alopecia
• 5 of patients with hyperthyroidism have nail
  findings (14)

54
Plummers Nail in Hyperthyroidism
Plummers nail concave contour and distal
onycholysis, esp. the ring finger (not specific-
also seen in hypothyroidism, psoriasis, after
trauma, or in allergic contact dermatitis)
55
Scleromyxedema in Hyperthyroidism

• Numerous firm white, yellow, or pink papules on
  face, trunk, axillae, and extremities
• Lesions result from accumulation of hyaluronic
  acid in the dermis, accompanied by large
  fibrocytes (14, 15)
• Can be accompanied by weight loss, esophageal
  dysmotility, vascular dz, Raynauds phenomenon,
  monoclonal gammopathy, neurologic manifestations,
  joint dz, and myopathy (14)
• Treatment of hyperthyroid state with radioactive
  iodine does not improve skin findings (14, 16)

56
Scleromyxedema in Hyperthyroidism

• Firm white, yellow, or pink papules on face,
  trunk, axillae, and extremities

57
Scleromyxedema in Hyperthyroidism
58
Graves Disease

• These patients can have all of the other
  previously mentioned cutaneous manifestations of
  hyperthyroidism in addition to several unique
  entities
• Pretibial myxedema (0.5-4 of patients)
• Presentation varies from peau dorange
  appearance to extensive infiltration that mimics
  elephantitis vurrucosa nostra
• Most often, bilateral, asymmetric, raised, firm
  plaques or nodules varying from pink to brown,
  sometimes with woody induration
• Can appear anywhere (arms, shoulders, head)
• Can treat with topical steroids, intralesional
  steroids, IV pulse steroids, or IVIG
• Pathogenesis remains unknown, but one theory
  suggests pretibial fibroblasts are the target for
  antithyroid antibodies(14)
• In support of this theory, Wu et al. (16)
  reported the presence of TSH and TSH receptor
  antibody binding in fibroblasts as well as the
  presence of RNA encoding the extracellular domain
  of the TSH receptor.

59
Pretibial Myxedema in Graves Disease

• Bilateral, asymmetric, raised, firm plaques or
  nodules varying from pink to brown, sometimes
  with woody induration

60
Pretibial Myxedema in Graves Disease
61
Pretibial Myxedema in Graves Disease
62
Thyroid Acropachy in Graves Disease
Thyroid acropachy (1 of Graves patients) Triad
of digital clubbing, soft tissue swelling of
hands and feet, and periosteal new bone formation
63
Graves Disease and Thyroid Acropachy

• AP radiograph of the hand demonstrates feathery
  periosteal bone proliferation of the diaphyses of
  the metacarpals and proximal phalanges

64
Hypothyroidism and the Skin

• Skin changes in hypothyroidism reflect a
  hypometabolic state and subsequent reduced core
  body temperature results in cutaneous
  vasoconstriction. (14)
• Skin is cool, dry, and pale.
• Pallor results from cutaneous vasoconstriction
  and increased deposition of water and
  mucopolysaccharides in the dermis, which alter
  the refraction of light
• Hypohydrosis may lead to palmoplantar keratoderma
• Carotenemia (from decreased hepatic conversion of
  beta carotene to Vit A) gives skin yellowish hue
  (14, 17)
• Hair dry, brittle, coarse partial alopecia
• Loss of hair from lateral 1/3 of eyebrows

65
Hypothyroidism Facies with Generalized Myxedema

• Generalized myxedema
• Occurs as a result of deposition of dermal acid
  mucopolysaccharides (esp. hyaluronic acid and
  chondroitin sulfate) in the skin
• Skin is non-pitting
• Face swollen lips, broad nose, macroglossia, and
  puffy eyelids

66
Thyroid Disease and Other Cutaneous Disease
Associations

• Autoimmune thyroid disease has been associated
  with other cutaneous diseases
• Alopecia areata (18)
• Bullous disorders
• Pemphigus foliaceus
• Pemphigus vulgaris (19)
• Vitiligo (20)
• Derived from the Greek vitelius, signifying a
  calf's white patches
• Fairly symmetric pattern of white macules with
  well-defined borders
• Connective tissue diseases
• Dermatomyositis (21) , SLE (22) , scleroderma(23)

67
Alopecia Areata Associated with Autoimmune
Thyroid Disease

• Rapid onset of total hair loss in a sharply
  defined, usually round, area
• Regrowth begins in 1 to 3 months and may be
  followed by loss in the same or other areas

68
Pemphigus foliaceus Associated with Autoimmune
Thyroid Disease

• Pemphigus foliaceus recurrent shallow erosions,
  erythema, scaling, and crusting

69
Pemphigus vulgaris Associated with Autoimmune
Thyroid Disease

• Painful oral erosions usually precede the onset
  of skin blisters by weeks or months

70
Pemphigus vulgaris Associated with Autoimmune
Thyroid Disease

• Nonpruritic flaccid blisters varying in size from
  1 to several cm appear gradually on normal or
  erythematous skin
• Invariably generalize if left untreated

71
Cutaneous Paraneoplastic Syndromes

• In 1976, Helen Ollendorff Curth set criteria that
  should be met before a skin disease can be called
  a paraneoplastic dermatosis (24,25)
• Both conditions start approximately the same time
• Both conditions follow a parallel course
• Neither the onset nor the course of either
  condition is dependent on the other
• A specific tumor occurs with a specific skin
  manifestation
• The dermatosis is not common in the general
  population
• A high percentage of association between the two
  conditions is noted
• Currently, only the first two criteria should be
  met to call a skin disease a paraneoplastic
  process (24, 25) .

72
Cutaneous Paraneoplastic Syndromes

• May be initial clue to underlying neoplasm
• Can herald the recurrence of a malignancy
• Examples
• Necrolytic migratory erythema
• Sign of Leser-Trelat
• Hypertichosis lanuginosa acquisita
• Bazexs syndrome
• Dermatomyositis
• Erythroderma

73
Necrolytic Migratory Erythema

• Glucagonoma syndrome includes glucose
  intolerance, weight loss, anemia, hair and nail
  changes, hypoaminoaciduria, psychiatric
  disturbances, and thromboembolic disease (24, 26)
• Skin manifestation of the glucagonoma syndrome
• Erythematous macules and papules, often annular
  or arciform, on central face, lower abdomen,
  perineum, groin, buttocks, and thighs
• Progress to erosions secondary to epidermal
  necrosis
• Skin disease has waxing and waning course that
  does not seem to follow the course of the
  glucagonoma
• Pathophysiology is not known, but it is probably
  related to catabolism from increased levels of
  glucagon
• When physician suspects this, be aggressive
• 75 glucagonomas are metastatic at time of
  diagnosis(27)
• Gold standard for treatment is surgery

74
Necrolytic migratory erythema

• Erythematous macules and papules, often annular
  or arciform than can progress to erosions

75
Sign of Leser-Trelat

• First described in 1890 as an increase in the
  number of cherry angiomas in patients with cancer
  (28)
• Now refers to an increase in number or size of
  seborrheic keratoses in patients with internal
  malignancy (24)
• Most often found in patients with adenocarcinoma
  of the stomach or colon (28) , but also reported
  with hematopoietic, breast, lung, ovarian, and
  uterine cancers (24, 29, 30)
• Can appear as early as 5 months before the dx of
  cancer or as late as 9.8 months after (29)

76
Sign of Leser-Trelat

• Pathogenesis could be due to elevated levels of
  growth factors, disrupted epidermal cell turnover
  regulation, and impeded host defense (30)
• Treatment of the underlying malignancy results in
  involution of the SKs in about ½ of cases
  (24,31)

77
Hypertrichosis lanuginosa acquisita

• Sudden appearance of downy, soft, nonpigmented
  hair on the body
• Most common associated malignancy is lung
  followed by colorectal cancer (32)
• Also has been associated with bladder, ovarian,
  uterine, and pancreatic cancer (24, 33)
• Typically occurs on face, but also on trunk,
  limbs, and ears
• Palms, soles, and genitals are spared
• Can be associated with other signs and symptoms,
  including glossitis, glossodynia, diarrhea,
  adeopathy, and acanthosis nigricans
• In some cases, the hypertrichosis resolves with
  treatment of the tumor (24)

78
Bazexs Syndrome

• Violaceous, symmetric papulosquamous plaques on
  the acral surfaces of ears, nose, hands, and feet
• 75 have nail changes including longitudinal or
  horizontal ridging, thickening, subungal debris,
  and discoloration (24)
• Mostly male (93 in one study) (34)
• Associated with squamous cell carcinoma of the
  oropharynx, larynx, lung, or esophagus
• In one review, cutaneous changes preceded the
  diagnosis of malignancy by an average of 11
  months in over 60 of patients with Bazexs
  syndrome (35)

79
Bazexs Syndrome

• Violaceous, symmetric papulosquamous plaques on
  the acral surfaces of ears, nose, hands, and feet
• The dermatosis improves with cancer treatment and
  worsens as the cancer progresses (24)
• Nail changes tend to persist after effective
  cancer treatment and resolution of other skin
  manifestations

80
Dermatomyositis

• Proximal muscle weakness, elevated CK and
  aldolase
• Heliotrope rash, Gottrons papules, and others
• Poikiloderma, periungual telangiectasia, scalp
  pruritis and erythema
• Some factors associated with higher incidence of
  paraneoplastic dermatomyositis
• Older age, male gender, patients that are
  difficult to control
• Perform age-appropriate cancer screening for
  dermatomyositis patients
• 25 will develop malignancy (24, 35) , most
  commonly
• Genital neoplasms in women (24, 36)
• Respiratory tract neoplasms in men (24, 36)

81
Heliotrope Rash in Dermatomyositis

• Heliotrope rash (violaceous erythema) of
  periorbital skin

82
Gottrons papules in Dermatomyositis

• Flat-topped, violaceous or erythematous papules
  on extensor surfaces

83
Erythroderma

• Exfoliative dermatitis with a dramatic
  presentation characterized by widespread erythema
  and scaling of skin
• Often have lymphadenopathy, headaches, malaise,
  photosensitivity, and chills
• Pathogenesis is unknown, but may have to do with
  elevated cytokines and adhesion molecules causing
  increased epidermal turnover and exfoliation
• Many potential causes, including pre-existing
  dermatoses, drug rxns, and malignancy.
• Skin changes most commonly present before the
  diagnosis of malignancy is made.
• According to a study by Nicolis (37) , 20 out of
  24 patients with erythroderma and mycosis
  fungoides, Hodgkins, or other lymphomas or
  leukemias had skin changes up to 25 years before
  the dx of cancer was made.
• Most often associated with lymphomas and
  leukemias (24, 37, 38, 39)
• Also been reported with liver, lung, thyroid, and
  prostate cancer (38)

84
Erythroderma

• May begin as scattered erythematous pruritic
  patches that generalize with time
• Palms and soles usually spared
• Treat the underlying malignancy and use topical
  steroids.

85
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