Skip to content
Download PDF

Skin Manifestations of Internal Disease

Part 2: Cardinal Manifestations and Presentation of Diseases · Part 2 – Cardinal Manifestations & Presentation · Chapter 61

Key Clinical Points

  1. Erythroderma (erythema covering the majority of the skin surface) can indicate primary cutaneous disease, drug reactions (DRESS), or systemic malignancy (e.g., CTCL).
  2. Figurate lesions provide critical clues: Erythema migrans (≥5 cm) suggests Lyme disease; Erythema gyratum repens is pathognomonic for underlying malignancy.
  3. Nailfold telangiectasias are pathognomonic for systemic sclerosis, dermatomyositis, and lupus erythematosus.
  4. Alopecia is categorized as nonscarring (hair follicles preserved) or scarring (fibrosis/loss of hair follicles).
  5. Purpura is differentiated by palpability: Nonpalpable often indicates clotting issues or vascular fragility; Palpable suggests vasculitis.
  6. Mucocutaneous ulcers can signal systemic diseases like Behçet’s, IBD, or infections (e.g., fungal, viral).
  7. Acneiform eruptions may be caused by systemic hyperandrogenism or medications like EGFR inhibitors.
  8. Hypopigmentation types vary: Vitiligo (autoimmune), Pityriasis versicolor (fungal; gold fluorescence), and Waardenburg syndrome (genetic).
  9. Hyperpigmentation can indicate endocrine disorders (Addison's, Nelson's) or metabolic issues (Hemochromatosis).
  10. Vesicles/Bullae may signify autoimmune diseases (Pemphigus, Bullous pemphigoid) or systemic conditions like Calciphylaxis.

DEFINITION & OVERVIEW

• General Concept: The skin serves as a window to internal disease; cutaneous signs often point to specific systemic disorders. • Clinical Challenge: Identifying these lesions is difficult for non-dermatologists due to the wide spectrum of presentations and lack of familiarity with cutaneous morphology. • Diagnostic Goal: Distinguish significant systemic diseases from common, benign cutaneous conditions. • Papulosquamous Lesions: Defined as elevated lesions (papules ≤1 cm) in association with scale. • Primary Cutaneous vs. Systemic: Most papulosquamous cases are primary (Tinea, Psoriasis, Pityriasis rosea, Lichen planus). • Systemic Indicators: ◦ Psoriasis + Arthritis → Psoriatic or Reactive arthritis. ◦ Reactive arthritis: Associated with history of oral ulcers, conjunctivitis, uveitis, and/or urethritis. ◦ Mycosis fungoides (MF): Early stages may mimic eczema/psoriasis; confirmed by biopsy showing atypical T lymphocytes in the epidermis and dermis.

Papulosquamous Overview

• Table 61-1 Reference: ◦ Primary cutaneous: Tinea (widespread may indicate immunosuppression), Psoriasis (widespread/resistant may indicate HIV), Pityriasis rosea, Lichen planus, Parapsoriasis, Bowen’s disease. ◦ Systemic diseases: Lupus erythematosus (subacute or chronic/discoid), Cutaneous T-cell lymphoma (mycosis fungoides), Secondary syphilis, Reactive arthritis, Sarcoidosis, Bazex syndrome (acrokeratosis paraneoplastica; associated with squamous cell carcinoma of the upper aerodigestive tract).

EPIDEMIOLOGY

• Psoriasis: Common primary cutaneous disorder. • Erythroderma: Rare condition. • Alopecia: Affects a significant portion of the population; androgenetic alopecia is the most common cause of nonscarring alopecia.

ETIOLOGY & PATHOPHYSIOLOGY

• Psoriasis: Driven by immune dysregulation (TNF, IL-17, IL-23 pathways). • Erythroderma: Causes include primary cutaneous (psoriasis, dermatitis), drugs (DRESS syndrome), systemic (CTCL), or idiopathic. • Alopecia: ◦ Nonscarring: Hair shafts are absent/minimized; follicles preserved → reversible. ◦ Scarring: Fibrosis and loss of hair follicles → irreversible. • Telangiectasias: Dilated blood vessels; morphology varies (linear, mat, spider). • Hypopigmentation: Result of impaired melanocyte migration or survival. • Figurate Lesions: ◦ Migratory: Erythema migrans, erythema gyratum repens, erythema marginatum. ◦ Nonmigratory: Subacute cutaneous LE, sarcoidosis.

CLINICAL FEATURES

• Erythroderma: ◦ Definition: Erythema covering the majority of the skin surface. ◦ Systemic Signs: Fever, chills, hypothermia, reactive lymphadenopathy, peripheral edema, hypoalbuminemia, and high-output cardiac failure. ◦ Table 61-3 Highlights: ◦ Psoriasis: Pink-red, silvery scale; common on elbows/knees; associated with nail dystrophy (pits, oil drop sign), arthritis, pustules, and SAPHO syndrome. ◦ Dermatitis: Acute (erythema, fine scale, crust, indistinct borders, excoriations) vs. Chronic (lichenification, excoriations). ◦ Contact: Irritant (onset within hours) vs. Allergic (delayed-type hypersensitivity; lag time of 48 h). ◦ Seborrheic: Greasy scale on scalp/nasolabial folds; associated with Parkinson’s disease. ◦ Stasis: Lower extremities; associated with varicosities, hemosiderin deposits, lipodermatosclerosis. (Exclude cellulitis and superimposed contact dermatitis). ◦ Pityriasis rubra pilaris: Orange-red (salmon-colored), perifollicular papules; "skip" areas of uninvolved skin; wax-like palmoplantar keratoderma. • Alopecia: ◦ Telogen effluvium: Diffuse shedding following stress or hormone changes. ◦ Androgenetic: Miniaturization along the midline of the scalp. ◦ Alopecia areata: Circular patches (2–5 cm) with T-lymphocyte infiltration; may have pitting/sandpaper appearance of nails. ◦ Tinea capitis: Scaly patches with "black dots" from Trichophyton tonsurans. • Figurate Lesions: ◦ Erythema migrans: Single annular lesion expanding to ≥10 cm; CDC definition is ≥5 cm. ◦ Erythrema marginatum: Pink-red, flat, transient lesions in rheumatic fever. ◦ Erythema gyratum repens: Concentric arcs resembling wood grain (malignancy indicator). • Telangiectasias: ◦ Linear/branching: Seen in rosacea, actinic damage, or venous hypertension. ◦ Mat: 2–7 mm; seen in systemic sclerosis. ◦ Spider: Central punctum with radiating legs; common in cirrhosis. ◦ Nailfold: Pathognomonic for systemic sclerosis, dermatomyositis, and lupus. • Hypopigmentation: ◦ Vitiligo: Chalk-white, symmetric areas of pigment loss. ◦ Pityriasis versicolor: Scaly macules on trunk/folds; "gold" fluorescence under Wood's lamp. ◦ Waardenburg syndrome: Associated with piebaldism and hearing loss. • Purpura: ◦ Nonpalpable: May indicate clotting defects (thrombocytopenia, Scurvy), or vascular fragility (Amyloidosis, Ehlers-Danlos). ◦ Palpable: Indicates vasculitis (e.g., small-vessel vasculitis). • Mucocutaneous Ulcers: ◦ Lower legs: Vasculitis, Hemoglobinopathies, Cryoglobulinemia, Calciphylaxis. ◦ Face/Anogenital: Chronic herpes simplex; Behçet's disease. ◦ Systemic: Pyoderma gangrenosum, Kaposi's sarcoma. • Additional Features (Tables 15-17): ◦ Papulonodular Lesions: White (Calcinosis cutis, Osteoma cutis); Yellow (Xanthomas, Tophi, Necrobiosis lipoidica); Red (Angiokeratomas [Fabry], Bacillary angiomatosis, Sweet syndrome); Red-brown (Sarcoidosis, Urticaria pigmentosa); Blue (Venous malformations, Venous lake); Violaceous (Lupus pernio, Lymphoma cutis). ◦ Acneiform Eruptions: Primary (Acne vulgaris, Rosacea); Drugs (Steroids, Lithium, EGFR inhibitors); Systemic (Hyperandrogenism [Cushing's, PCOS], Cryptococcosis, Dimorphous fungal infections, Behçet's). ◦ Hyperpigmentation: Localized (Seborrheic keratosis, Lentigo, Melasma); Systemic (Addison's, Hemochromatosis, Porphyria cutanea tarda, Melanoma-associated vitiligo-like leukoderma).

Additional Clinical Features (Tables 15-17)

• Papulonodular Lesions (Table 61-15): ◦ White: Calcinosis cutis, Osteoma cutis. ◦ Skin-colored: Rheumatoid nodules, Neurofibromas, Angiofibromas. ◦ Yellow: Xanthomas, Tophi, Necrobiosis lipoidica. ◦ Red: Angiokeratomas (Fabry), Bacillary angiomatosis, Sweet syndrome. ◦ Red-brown: Sarcoidosis, Urticaria pigmentosa. ◦ Blue: Venous malformations, Venous lake. ◦ Violaceous: Lupus pernio, Lymphoma cutis. ◦ Purple: Kaposi's sarcoma, Palpable purpura. • Acneiform Eruptions (Table 61-7): ◦ Primary: Acne vulgaris, Acne rosacea. ◦ Drugs: Steroids, Lithium, EGFR inhibitors. ◦ Systemic: Hyperandrogenism (Cushing's, PCOS), Cryptococcosis, Dimorphous fungal infections, Behçet's. • Hyperpigmentation (Table 61-11): ◦ Localized: Seborrheic keratosis, Lentigo, Melasma. ◦ Systemic: Addison's, Hemochromatosis, Porphyria cutanea tarda.

DIFFERENTIAL DIAGNOSIS

• Erythroderma: Differentiate between primary cutaneous (Psoriasis, Dermatitis), Drug-induced (DRESS), and Systemic (CTCL). • Alopecia: Distinguish Nonscarring (Telogen effluvium, Androgenetic) from Scarring (Lichen planus, Discoid lupus). • Figurate Lesions: Differentiate Migratory (E. migrans, E. gyratum repens) from Nonmigratory (Sarcoidosis, SLE). • Purpura: Distinguish Nonpalpable (Clotting issues/Vasculopathy) from Palpable (Vasculitis).

DIAGNOSTIC APPROACH

  1. Initial Clinical Assessment: Identify the primary morphology (e.g., Erythroderma, Alopecia, Figurate lesions).
  2. Specific Diagnostic Indicators: ◦ Erythema migrans ≥5 cm → Lyme disease. ◦ Erythema gyratum repens → Malignancy. ◦ Nailfold telangiectasias → Systemic sclerosis, dermatomyositis, or lupus.
  3. Diagnostic Aids (Table 61-3): ◦ Skin biopsy: Used for Psoriasis, Dermatitis, Seborrheic, Stasis, and PRP. ◦ Patch testing: Used to confirm allergic contact dermatitis. ◦ Wood's Lamp: Used to differentiate hypopigmentation types (e.g., Vitiligo vs. Pityriasis versicolor).
  4. Laboratory/Imaging: ◦ Evaluate for systemic markers in Erythroderma (Fever, eosinophilia, organ involvement [hepatitis, nephritis, myocarditis, thyroiditis]). ◦ Check for hyperandrogenism in acneiform eruptions.

MANAGEMENT & TREATMENT

  1. Erythroderma Management: ◦ Psoriasis: Topical glucocorticoids, vitamin D analogues, aryl hydrocarbon receptor agonist, PDE4 inhibitor; UV-B (narrowband) > PUVA; oral retinoids; MTX; anti-TNF agents, anti-IL-12/23 Ab, anti-IL-23 Ab, anti-IL-17A, anti-IL-17F, or anti-IL-17 receptor A Ab; TYK2 inhibitor; apremilast; cyclosporine; anti-IL-36 receptor Ab for generalized pustular psoriasis. ◦ Dermatitis: Topical glucocorticoids; open wet dressings; leg elevation; pressure stockings; pressure wraps if associated ulcers. (Seborrheic: add imidazoles). ◦ Contact: Remove irritant/allergen; topical glucocorticoids; oral antihistamines; oral/IM glucocorticoids (short-term). ◦ Stasis: Topical glucocorticoids; open wet dressings; leg elevation; pressure stockings; pressure wraps if associated ulcers. ◦ Pityriasis rubra pilaris: Isotretinoin or acitretin; MTX; anti-IL-12/23 Ab, anti-IL-23 Ab, anti-TNF agents, anti-IL-17A, anti-IL-17, or anti-IL-17 receptor A Ab.
  2. Alopecia Management: ◦ Telogen effluvium: Observation; discontinue drugs with alopecia side effects; exclude metabolic causes (hypothyroidism, hyperthyroidism). ◦ Androgenetic: If no hyperandrogenemia → topical minoxidil, low-dose oral minoxidil, finasteride, spironolactone, hair transplant. ◦ Alopecia areata: Intralesional glucocorticoids; topical anthralin or tazarotene; topical contact sensitizers; JAK inhibitors; pulse prednisone (e.g., 300 mg orally once a month for 4-6 doses). ◦ Tinea capitis: Oral griseofulvin or terbinafine plus 2.5% selenium sulfide or ketoconazole shampoo; examine family members. ◦ Traumatic: Discontinuation of offending hair style/chemicals; observation/biopsy/psychotherapy.

COMPLICATIONS & PROGNOSIS

• Erythroderma: Can lead to systemic complications including fever, hypothermia, and high-output cardiac failure. • Mycosis Fungoides (MF): Progression from early stages to cutaneous tumors and lymph node involvement. • Scarring Alopecia: Results in permanent loss of hair follicles due to fibrosis.

SPECIAL CONSIDERATIONS

• HIV Infection: Associated with widespread/resistant psoriasis, seborrheic dermatitis, and various infections (e.g., Tinea capitis). • Pregnancy: Mentioned in context of systemic conditions like Scurvy or other metabolic issues. • Pediatrics: Seborrheic dermatitis is primarily seen in infants; Pityriasis versicolor common in young adults.

KEY PEARLS & CLINICAL TRAPS

• Erythema migrans: CDC definition ≥5 cm. • Erythema gyratum repens: Pathognomonic for malignancy. • DRESS Syndrome: Characterized by fever, eosinophilia, and organ involvement (hepatitis, nephritis, myocarditis). • Nailfold Telangiectasias: High-yield finding for systemic sclerosis, dermatomyositis, and lupus. • Pityriasis Versicolor: Shows "gold" fluorescence under Wood's lamp. • Purpura Differentiation: Palpable = Vasculitis; Nonpalpable = Clotting/Vascular issues.

Reference Tables

TABLE 61-1 Selected Causes of Papulosquamous Skin Lesions 1. Primary cutaneous disorders

Harrison's 22e, p.392

1. Primary cutaneous disorders
a. Tineaa—widespread disease may be sign of immunosuppression
b. Psoriasisa—widespread or resistant disease may be sign of HIV infection
c. Pityriasis roseaa
d. Lichen planusa
e. Parapsoriasis, small plaque and large plaqueb
f. Bowen’s disease (squamous cell carcinoma in situ)c
2. Drugs
3. Systemic diseases
a. Lupus erythematosus, primarily subacute or chronic (discoid) lesionsd
b. Cutaneous T-cell lymphoma, in particular, mycosis fungoidese
c. Secondary syphilis
d. Reactive arthritis
e. Sarcoidosisf—with scale less common than without scale
f. Bazex syndrome (acrokeratosis paraneoplastica)g
61 Skin Manifestations of
Internal Disease
Jean L. Bolognia, Jonathan S. Leventhal,
Irwin M. Braverman

TABLE 61-2 Causes of Erythroderma 1. Primary cutaneous disorders

Harrison's 22e, p.393

    1. Primary cutaneous disorders
      a. Psoriasisa
      b. Dermatitis (atopic > contact >> stasis [with autosensitization] or
      seborrheic [primarily infants])a
      c. Pityriasis rubra pilaris
      2. Drugs
      3. Systemic diseases
      a. Cutaneous T-cell lymphoma (Sézary syndrome, erythrodermic mycosis
      fungoides)
      b. Other lymphomas
      c. Rarely, late-stage solid tumors, autoimmune bullous diseases
      4. Idiopathic (usually older men)

TABLE 61-3 Erythroderma (Primary Cutaneous Disorders) Psoriasis a

Harrison's 22e, p.393

INITIAL LESIONS LOCATION OF
INITIAL LESIONS		 OTHER FINDINGS DIAGNOSTIC AIDS TREATMENT
Psoriasisa Pink-red, silvery
scale, sharply
demarcated		 Elbows, knees, scalp,
presacral area,
intergluteal fold		 Nail dystrophy (e.g., pits, oil drop
sign), arthritis, pustules, SAPHO
syndromeb		 Skin biopsy Topical glucocorticoids, vitamin D analogues,
aryl hydrocarbon receptor agonist, PDE4
inhibitor; UV-B (narrowband) > PUVA;
oral retinoids; MTX; anti-TNF agents,
anti-IL-12/23 Ab, anti-IL-23 Ab, anti-IL-17A,
anti-IL-17F, or anti-IL-17 receptor A Ab;
TYK2 inhibitor; apremilast; cyclosporine;
anti-IL-36 receptor Ab for generalized
pustular psoriasis
Dermatitisa
Acute:
Erythema, fine scale,
crust, indistinct
borders, excoriations
Chronic:
Lichenification
(increased
skin markings),
excoriations		 Antecubital and
popliteal fossae,
neck, hands, eyelids		 Pruritus
Personal and/or family history of
atopy, including asthma, allergic
rhinitis or conjunctivitis, and
atopic dermatitis
Exclude secondary infection with
Staphylococcus aureus or HSV
Exclude superimposed irritant or
allergic contact dermatitis		 Skin biopsy
Contact Local:
Erythema, crusting,
vesicles, and bullae
Systemic: Erythema,
fine scale, crust		 Depends on
offending agent
Generalized vs major
intertriginous zones
(especially groin)		 Irritant—onset often within hours
Allergic—delayed-type
hypersensitivity; lag time of 48 h
with rechallenge
Patient has history of allergic
contact dermatitis to topical
agent and then receives systemic
medication that is structurally
related, e.g., formaldehyde (skin),
aspartame (oral)		 Patch testing;
repeat open
application test
Patch testing		 Remove irritant or allergen; topical
glucocorticoids; oral antihistamines; oral/
IM glucocorticoids (short-term)
Same as local
Pink-red to pink-
orange, greasy scale		 Scalp, nasolabial
folds, eyebrows,
intertriginous zones		 Flares with stress, HIV infection
Associated with Parkinson’s
disease		 Skin biopsy
Stasis (with
autosensitization)		 Erythema, crusting,
excoriations		 Lower extremities Pruritus, lower extremity edema,
varicosities, hemosiderin deposits,
lipodermatosclerosis
History of venous ulcers,
thrombophlebitis, and/or cellulitis
Exclude cellulitis
Exclude superimposed contact
dermatitis, e.g., topical neomycin		 Skin biopsy Topical glucocorticoids; open wet
dressings; leg elevation; pressure
stockings; pressure wraps if associated
ulcers
Orange-red
(salmon-colored),
perifollicular papules		 Scalp
When generalized,
characteristic “skip”
areas of uninvolved
skin		 Wax-like palmoplantar
keratoderma
Exclude cutaneous T-cell
lymphoma		 Skin biopsy

TABLE 61-4 Causes of Alopecia I. Nonscarring alopecia

Harrison's 22e, p.394

  • I. Nonscarring alopecia
    A. Primary cutaneous disorders
    1. Androgenetic alopecia (female pattern, male pattern)
    2. Telogen effluvium
    3. Alopecia areata
    4. Tinea capitis
    5. Traumatic alopeciaa
    6. Psoriasiform alopecia, including tumor necrosis factor (TNF)
    inhibitor–induced
    B. Drugs
    1. Telogen effluvium—see text for most common causes
    2. Anagen effluvium—chemotherapeutic agents (e.g., anthracyclines)
    C. Systemic diseases
    1. Systemic lupus erythematosus
    2. Secondary syphilis
    3. Hypothyroidism
    4. Hyperthyroidism
    5. Hypopituitarism
    6. Deficiencies of protein, biotin, zinc, and perhaps iron
    II. Scarring alopecia
    A. Primary cutaneous disorders
    1. Cutaneous lupus (chronic discoid lesions)b
    2. Lichen planus, including frontal fibrosing alopecia
    3. Central centrifugal cicatricial alopecia
    4. Folliculitis decalvans
    5. Dissecting cellulitis
    6. Linear morphea (linear scleroderma)c
    B. Drugs
    1. Chemotherapeutic agents (e.g., taxanes, busulfan)
    C. Systemic diseases
    1. Discoid lesions in the setting of systemic lupus erythematosusb
    2. Sarcoidosis
    3. Cutaneous metastases

TABLE 61-5 Nonscarring Alopecia (Primary Cutaneous Disorders) Telogen effluvium

Harrison's 22e, p.395

CLINICAL CHARACTERISTICS PATHOGENESIS TREATMENT
Telogen effluvium Diffuse shedding of normal hairs
Follows major stress (high fever, severe
infection) or change in hormone levels
(postpartum)
Reversible without treatment		 Stress causes more of the asynchronous growth
cycles of individual hairs to become synchronous;
therefore, larger numbers of growing (anagen) hairs
simultaneously enter the dying (telogen) phase		 Observation; discontinue any drugs that
have alopecia as a side effect; must
exclude underlying metabolic causes,
e.g., hypothyroidism, hyperthyroidism
Miniaturization of hairs along the midline of
the scalp
Recession of the anterior scalp line in men
and some women		 Increased sensitivity of affected hairs to the effects
of androgens—most common
Increased levels of circulating androgens (ovarian or
adrenal source in women)—less common
Alopecia areata Well-circumscribed, circular areas of hair
loss, 2–5 cm in diameter
In extensive cases, coalescence of lesions
and/or involvement of other hair-bearing
surfaces of the body
Pitting or sandpapered appearance of the
nails		 The germinative zones of the hair follicles are
surrounded by T lymphocytes
Occasional associated diseases: hyperthyroidism,
hypothyroidism, vitiligo, Down syndrome		 Intralesional glucocorticoids; topical
anthralin or tazarotene; topical contact
sensitizers; JAK inhibitors; pulse
prednisone (e.g., 300 mg orally once a
month for 4–6 doses)
Varies from scaling with minimal hair loss to
discrete patches with “black dots” (sites of
broken infected hairs) to boggy plaque with
pustules (kerion)b		 Invasion of hairs by dermatophytes, most commonly
Trichophyton tonsurans
Traumatic alopeciac Broken hairs, often of varying lengths
Irregular outline in trichotillomania and
traction alopecia
Fringe sign in traction alopecia		 Traction with curlers, rubber bands, tight braiding
Exposure to heat or chemicals (e.g., hair
straighteners)
Mechanical pulling (trichotillomania)		 Discontinuation of offending hair style
or chemical treatments; diagnosis of
trichotillomania may require observation
of shaved hairs (for growth) or biopsy,
possibly followed by psychotherapy

TABLE 61-6 Causes of Figurate Skin Lesions I. Primary cutaneous disorders

Harrison's 22e, p.395

  • I. Primary cutaneous disorders
    A. Tinea
    B. Urticaria (primary in ≥90% of patients)
    C. Granuloma annulare
    D. Erythema annulare centrifugum
    E. Psoriasis, annular pustular psoriasis
    F. Reactive granulomatous dermatitis, which includes interstitial
    granulomatous drug reaction
    II. Systemic diseases
    A. Migratory
    1. Erythema migrans (CDC case definition is ≥5 cm in diameter)
    2. Urticaria (≤10% of patients)
    3. Erythema gyratum repens
    4. Erythema marginatum
    5. Pustular psoriasis (generalized and annular forms)
    6. Necrolytic migratory erythema (glucagonoma syndrome)a
    B. Nonmigratory (may slowly expand)
    1. Subacute cutaneous LE, LE tumidus
    2. Sarcoidosis
    3. Leprosy (borderline, tuberculoid)
    4. Secondary syphilis (especially the face)
    5. Cutaneous T-cell lymphoma (especially mycosis fungoides)
    6. Interstitial granulomatous dermatitisb
    7. Annular erythema of Sjögren’s syndrome

TABLE 61-7 Causes of Acneiform Eruptions I. Primary cutaneous disorders

Harrison's 22e, p.395

  • I. Primary cutaneous disorders
    A. Acne vulgaris
    B. Acne rosacea
    II. Drugs, e.g., anabolic steroids, glucocorticoids, lithium, EGFR inhibitors, HER2
    inhibitors, MEK inhibitors, iodides
    III. Systemic diseases
    A. Increased androgen production
    1. Adrenal origin, e.g., Cushing’s disease, 21-hydroxylase deficiency
    2. Ovarian origin, e.g., polycystic ovary syndrome, ovarian hyperthecosis
    B. Cryptococcosis, disseminated
    C. Dimorphic fungal infections
    D. Behçet’s disease

TABLE 61-8 Causes of Telangiectasias I. Primary cutaneous disorders

Harrison's 22e, p.396

  • I. Primary cutaneous disorders
    A. Linear/branching
    1. Acne rosacea (face)
    2. Actinically damaged skin (face, neck, V of chest)
    3. Venous hypertension (legs)
    4. Generalized essential telangiectasia
    5. Cutaneous collagenous vasculopathy
    6. Within basal cell carcinomas or cutaneous lymphoma
    B. Poikiloderma
    1. Ionizing radiationa
    C. Spider angioma
    1. Idiopathic
    2. Pregnancy
    II. Systemic diseases
    A. Linear/branching
    1. Carcinoid (head, neck, upper trunk)
    2. Ataxia-telangiectasia (bulbar conjunctivae, head and neck)
    3. Mastocytosis (within lesions)
    B. Poikiloderma
    1. Dermatomyositis, lupus erythematosus
    2. Mycosis fungoides, patch stage
    3. Genodermatoses, e.g., xeroderma pigmentosum, Kindler syndrome
    C. Mat
    1. Systemic sclerosis (scleroderma)
    D. Nailfold
    1. Lupus erythematosus
    2. Systemic sclerosis (scleroderma)
    3. Dermatomyositis
    4. Hereditary hemorrhagic telangiectasia
    E. Papular
    1. Hereditary hemorrhagic telangiectasia
    F. Spider angioma
    1. Cirrhosisb
    2. Trastuzumab emtansine (may also involve mucosae)

TABLE 61-9 Causes of Hypopigmentation I. Primary cutaneous disorders

Harrison's 22e, p.397

  • I. Primary cutaneous disorders
    A. Diffuse
    1. Generalized vitiligoa
    B. Localized
    1. Postinflammatory
    2. Idiopathic guttate hypomelanosis
    3. Pityriasis (tinea) versicolor
    4. Vitiligoa
    5. Chemical- or drug-induced leukoderma, e.g., topical imiquimod, oral
    imatinib
    6. Nevus depigmentosus and Blaschko-linear hypopigmentation
    (pigmentary mosaicism)b
    7. Progressive macular hypomelanosis
    8. Piebaldisma
    II. Systemic diseases
    A. Diffuse
    1. Oculocutaneous albinismb
    2. Hermansky-Pudlak syndromeb,c
    3. Chédiak-Higashi syndromeb,d
    4. Phenylketonuria
    B. Localized
    1. Systemic sclerosis (scleroderma)e
    2. Melanoma-associated vitiligo-like leukoderma, immunotherapy-
    induced or spontaneouse
    3. Sarcoidosis
    4. Cutaneous T-cell lymphoma (especially mycosis fungoides)
    5. Tuberculoid and indeterminate leprosy
    6. Onchocerciasise
    7. Blaschko-linear hypopigmentation (pigmentary mosaicism)b,f
    8. Incontinentia pigmenti (stage IV)
    9. Tuberous sclerosis
    10. Waardenburg syndrome and Shah-Waardenburg syndrome
    11. Vogt-Koyanagi-Harada syndromee

TABLE 61-10 Hypopigmentation (Primary Cutaneous Disorders, Localized) Postinflammatory hypopigmentation

Harrison's 22e, p.398

CLINICAL CHARACTERISTICS WOOD’S LAMP
EXAMINATION (UV-A;
PEAK = 365 NM)		 SKIN BIOPSY SPECIMEN PATHOGENESIS TREATMENT
Postinflammatory
hypopigmentation		 Can develop within active
lesions, as in subacute
cutaneous lupus, or after
the lesion fades, as in atopic
dermatitis		 Depends on particular
disease
Usually less
enhancement than in
vitiligo		 Type of inflammatory
infiltrate depends on
specific disease		 Block in transfer of melanin
from melanocytes to
keratinocytes could be
secondary to edema or
decrease in contact time
Destruction of melanocytes
if inflammatory cells attack
basal layer of epidermis		 Treat underlying
inflammatory disease
Common; acquired; usually
2–4 mm in diameter
Shins and extensor forearms		 Less enhancement
than vitiligo		 Abrupt decrease in
epidermal melanin
content		 Possible somatic mutations
as a reflection of aging or UV
exposure
Pityriasis (tinea)
versicolora		 Common disorder
Upper trunk and neck (shawl-like
distribution), body folds
Young adults
Macules have fine white scale
when scratched		 Golden fluorescence Hyphal forms and budding
yeast in stratum corneum		 Invasion of stratum corneum
by the yeast Malassezia
Yeast is lipophilic and
produces C and C
9 11
dicarboxylic acids, which
in vitro inhibit tyrosinase		 Selenium sulfide 2.5%
shampoo; topical
imidazoles; oral
fluconazole
Acquired; progressive
Symmetric areas of complete
pigment loss
Periorificial—around mouth,
nose, eyes, nipples, umbilicus,
anus
Other areas—flexor wrists,
extensor distal extremities
Segmental form is less
common—unilateral,
dermatomal-like		 More apparent
Chalk-white		 Absence of melanocytes
in well-developed lesions
Mild inflammation		 Autoimmune phenomenon
that results in destruction
of melanocytes—primarily
cellular (circulating skin-
homing autoreactive T cells)
Chemical- or
drug-induced
leukoderma		 Similar appearance to vitiligo
Often begins on hands when
associated with chemical
exposure
Satellite lesions in areas not
exposed to chemicals		 More apparent
Chalk-white		 Decreased number or
absence of melanocytes		 Exposure to chemicals
that selectively destroy
melanocytes, in particular
phenols and catechols
(germicides; rubber
products) or ingestion of
drugs such as imatinib
Release of cellular antigens
and activation of circulating
lymphocytes may explain
satellite phenomenon
Possible inhibition of KIT
receptor		 Avoid exposure to
offending agent, then
treat as vitiligo
Drug-induced variant may
undergo repigmentation
when medication is
discontinued
Autosomal dominant
Congenital, stable
White forelock
Areas of amelanosis contain
normally pigmented and
hyperpigmented macules of
various sizes
Symmetric involvement of central
forehead, ventral trunk, and
mid regions of upper and lower
extremities		 Enhancement of
leukoderma and
hyperpigmented
macules		 Amelanotic areas—few
to no melanocytes		 Defect in migration of
melanoblasts from neural
crest to involved skin or
failure of melanoblasts to
survive or differentiate in
these areas
Mutations within the KIT
protooncogene that encodes
the tyrosine kinase receptor
for stem cell growth factor
(kit ligand)

TABLE 61-11 Causes of Hyperpigmentation I. Primary cutaneous disorders

Harrison's 22e, p.399

  • I. Primary cutaneous disorders
    A. Localized
    1. Epidermal alteration
    a. Seborrheic keratosis
    b. Pigmented actinic keratosis
    2. Proliferation of melanocytes
    a. Lentigo
    b. Melanocytic nevus (mole)
    c. Melanoma
    3. Increased pigment production
    a. Ephelide (freckle)
    b. Café au lait macule
    c. Postinflammatory hyperpigmentation (also dermal)
    d. Melasma (also dermal)
    4. Dermal pigmentation
    a. Fixed drug eruption
    B. Localized and diffuse
    1. Drugs (e.g., minocycline, hydroxychloroquine, bleomycin)
    II. Systemic diseases
    A. Localized
    1. Epidermal alteration
    a. Acanthosis nigricans (insulin resistance > other endocrine
    disorders, paraneoplastic)
    b. Seborrheic keratoses (sign of Leser-Trélat)
    2. Proliferation of melanocytes
    a. Lentigines (Peutz-Jeghers and LEOPARD/Noonan with multiple
    lentigines syndromes; xeroderma pigmentosum)
    b. Melanocytic nevi (Carney complex [LAMB and NAME syndromes])a
    3. Increased pigment production
    a. Café au lait macules (neurofibromatosis, Legius syndrome,
    McCune-Albright syndromeb)
    b. Urticaria pigmentosac
    4. Dermal pigmentation
    a. Incontinentia pigmenti (stage III)
    b. Dyskeratosis congenita
    5. Dermal deposits
    a. Exogenous ochronosis
    b. Localized argyria
    B. Diffuse
    1. Endocrinopathies
    a. Addison’s disease
    b. Nelson’s syndrome
    c. Ectopic ACTH syndrome
    d. Hyperthyroidism
    2. Metabolic
    a. Porphyria cutanea tarda
    b. Hemochromatosis
    c. Vitamin B , folate deficiency
    12
    d. Pellagra
    e. Malabsorption, including Whipple’s disease
    3. Melanosis secondary to metastatic melanoma
    4. Autoimmune
    a. Primary biliary cholangitis
    b. Systemic sclerosis (scleroderma)
    c. POEMS syndrome
    d. Eosinophilia-myalgia syndromed
    5. Drugs (e.g., cyclophosphamide) and metals (e.g., silver)

TABLE 61-12 Causes of Vesicles/Bullae I. Primary mucocutaneous diseases

Harrison's 22e, p.400

  • I. Primary mucocutaneous diseases
    A. Primary blistering diseases (autoimmune)
    1. Pemphigus, foliaceus and vulgarisa
    2. Bullous pemphigoidb
    3. Gestational pemphigoidb
    4. Cicatricial pemphigoidb
    5. Dermatitis herpetiformisb,c
    6. Linear IgA bullous dermatosisb
    7. Epidermolysis bullosa acquisitab,d
    B. Secondary blistering diseases
    1. Contact dermatitisa,b
    2. Erythema multiformee
    3. Stevens-Johnson syndromee
    4. Toxic epidermal necrolysise
    5. Bullous fixed drug eruption, including generalized variante
    6. Pseudoporphyria, drug- or tanning booth–induced
    C. Infections
    1. Varicella-zoster virusa,f
    2. Herpes simplex virusa,f
    3. Enteroviruses, e.g., hand-foot-and-mouth diseasef
    4. SARS-CoV-2
    5. Staphylococcal scalded-skin syndromea,g
    6. Bullous impetigoa
    7. Bullous tinea
    II. Systemic diseases
    A. Autoimmune
    1. Paraneoplastic pemphigusa (bronchiolitis obliterans)
    2. Bullous systemic lupus erythematosus
    B. Infections
    1. Cutaneous embolib
    C. Metabolic
    1. Diabetic bullaea,b
    2. Porphyria cutanea tardab
    3. Porphyria variegatab
    4. Bullous dermatosis of hemodialysisb (less often associated with
    peritoneal dialysis and also referred to as pseudoporphyria)
    D. Ischemia
    1. Coma bullae
    E. Secondary blistering diseases
    1. Toxic epidermal necrolysise (respiratory and gastrointestinal tracts
    can be involved)
    2. Edema bullae (venous hypertension, congestive heart failure)

TABLE 61-13 Causes of Exanthems I. Morbilliform

Harrison's 22e, p.401

  • I. Morbilliform
    A. Drugs
    B. Viral
    1. Rubeola (measles)
    2. Rubella
    3. Erythema infectiosum (erythema of cheeks; reticulated on extremities)
    4. Epstein-Barr virus, echovirus, coxsackievirus, CMV, adenovirus,
    HHV-6/HHV-7a, SARS-CoV-2, dengue, chikungunya, and West Nile
    virus infections
    5. HIV seroconversion exanthem (plus mucosal ulcerations)
    C. Bacterial
    1. Typhoid fever
    2. Early secondary syphilis
    3. Early Rickettsia infections
    4. Early meningococcemia
    5. Ehrlichiosis
    D. Acute graft-versus-host disease
    E. Kawasaki disease
    II. Scarlatiniform
    A. Scarlet fever
    B. Toxic shock syndrome
    C. Kawasaki disease
    D. Early staphylococcal scalded-skin syndrome

TABLE 61-14 Causes of Urticaria and Angioedema I. Primary cutaneous disorders

Harrison's 22e, p.402

  • I. Primary cutaneous disorders
    A. Acute and chronic urticariaa
    B. Physical urticaria
    1. Dermographism
    2. Solar urticariab
    3. Cold urticariab
    4. Cholinergic urticariab
    C. Angioedema (hereditary and acquired)b,c
    II. Systemic diseases
    A. Urticarial vasculitis
    B. Hepatitis B or C viral infection, SARS-CoV-2 infection
    C. Serum sickness
    D. Angioedema (hereditary and acquired)

TABLE 61-15 Papulonodular Skin Lesions According to Color Groups III. Pink/translucent b

Harrison's 22e, p.403

  • I. White
    A. Calcinosis cutis
    B. Osteoma cutis (also skin-colored or blue)
    II. Skin-colored
    A. Rheumatoid nodules
    B. Neurofibromas (von Recklinghausen’s disease [NF1])
    C. Angiofibromas (tuberous sclerosis, MEN syndrome, type 1; also pink-red)
    D. Neuromas (MEN syndrome, type 2b)
    E. Adnexal tumors
    1. Basal cell carcinomas (basal cell nevus syndrome)
    2. Tricholemmomas (Cowden disease)
    3. Fibrofolliculomas (Birt-Hogg-Dubé syndrome)
    F. Osteomas (arise in skull and jaw in Gardner syndrome)
    G. Primary cutaneous disorders
    1. Epidermal inclusion cystsa
    2. Lipomas
    III. Pink/translucentb
    A. Amyloidosis, primary systemic
    B. Papular mucinosis/scleromyxedema
    C. Multicentric reticulohistiocytosis
    IV. Yellow
    A. Xanthomas
    B. Tophi
    C. Necrobiosis lipoidica
    D. Pseudoxanthoma elasticum
    E. Sebaceous adenomas (Muir-Torre syndrome)
    V. Redb
    A. Papules
    1. Angiokeratomas (Fabry disease and related lysosomal storage
    diseases)c
    2. Bacillary angiomatosis (primarily in AIDS)
    B. Papules/plaques
    1. Cutaneous lupus erythematosus
    2. Lymphoma cutis
    3. Leukemia cutis
    4. Sweet syndrome
    C. Nodules
    1. Panniculitis
    2. Medium-sized vessel vasculitis (e.g., cutaneous polyarteritis
    nodosa/cutaneous arteritis)
    D. Primary cutaneous disorders
    1. Arthropod bites
    2. Cherry hemangiomas
    3. Infections, e.g., streptococcal cellulitis, sporotrichosis
    4. Polymorphous light eruption
    5. Cutaneous lymphoid hyperplasia (lymphocytoma cutis, pseudolymphoma)
    VI. Red-brownb
    A. Sarcoidosis
    B. Urticaria pigmentosa
    C. Erythema elevatum diutinum (chronic leukocytoclastic vasculitis)
    D. Lupus vulgaris
    VII. Blueb
    A. Venous malformations (e.g., blue rubber bleb syndrome)
    B. Primary cutaneous disorders
    1. Venous lake
    2. Blue nevus
    VIII. Violaceous
    A. Lupus pernio (sarcoidosis)
    B. Lymphoma cutis
    C. Cutaneous lupus erythematosus
    IX. Purple
    A. Kaposi’s sarcoma, acral angiodermatitis (pseudo-Kaposi’s sarcoma)
    B. Angiosarcoma
    C. Palpable purpura (see Table 61-16)
    D. Primary cutaneous disorders
    1. Angiokeratomas of the scrotum and vulva
    X. Brown-blackd
    XI. Any color
    A. Metastases

TABLE 61-16 Causes of Purpura I. Primary cutaneous disorders

Harrison's 22e, p.407

  • I. Primary cutaneous disorders
    A. Nonpalpable
    1. Trauma
    2. Solar (actinic, senile) purpura
    3. Steroid purpura
    4. Stasis purpura due to venous hypertension
    5. Capillaritis
    6. Livedoid vasculopathy in the setting of venous hypertensiona
    II. Drugs (e.g., antiplatelet agents, anticoagulants)
    III. Systemic diseases
    A. Nonpalpable
    1. Clotting disturbances
    a. Thrombocytopenia (including ITP)
    b. Abnormal platelet function
    c. Clotting factor defects
    2. Vascular fragility
    a. Amyloidosis (within normal-appearing skin)
    b. Ehlers-Danlos syndrome
    c. Scurvy
    3. Thrombi
    a. Disseminated intravascular coagulation, purpura fulminans
    b. Warfarin (Coumadin)-induced necrosis
    c. Heparin-induced thrombocytopenia and thrombosis
    d. Antiphospholipid antibody syndrome
    e. Monoclonal cryoglobulinemia
    f. Vasculopathy induced by levamisole-adulterated cocaineb
    g. SARS-CoV-2 infection
    h. Thrombotic thrombocytopenic purpura
    i. Thrombocytosis
    j. Homozygous protein C or protein S deficiency
    4. Emboli
    a. Cholesterol
    b. Fat
    5. Possible immune complex
    a. Gardner-Diamond syndrome (autoerythrocyte sensitivity)
    b. Waldenström’s hypergammaglobulinemic purpura
    6. Calciphylaxis
    B. Palpable
    1. Vasculitis
    a. Cutaneous small-vessel vasculitis, including in the setting of
    systemic vasculitides
    2. Embolic
    a. Acute meningococcemia
    b. Disseminated gonococcal infection
    c. Rocky Mountain spotted fever
    d. Ecthyma gangrenosum

TABLE 61-17 Causes of Mucocutaneous Ulcers I. Primary cutaneous disorders

Harrison's 22e, p.408

  • I. Primary cutaneous disorders
    A. Peripheral vascular disease (Chap. 292)
    1. Venous
    2. Arteriala
    B. Livedoid vasculopathy in the setting of venous hypertensionb
    C. Squamous cell carcinoma (e.g., within scars), basal cell carcinomas
    D. Infections, e.g., ecthyma caused by Streptococcus (Chap. 153)
    E. Physical, e.g., trauma, pressure
    F. Drugs, e.g., hydroxyurea
    II. Systemic diseases
    A. Lower legs
    1. Small-vessel and medium-vessel vasculitisc
    2. Hemoglobinopathies (Chap. 103)
    3. Cryoglobulinemia,c cryofibrinogenemia
    4. Cholesterol embolia,c
    5. Necrobiosis lipoidicad
    6. Antiphospholipid syndrome (Chap. 121)
    7. Neuropathice (Chap. 415)
    8. Panniculitis
    9. Kaposi’s sarcoma, acral angiodermatitis (pseudo-Kaposi’s sarcoma)
    10. Diffuse dermal angiomatosis
    B. Hands and feet
    1. Raynaud’s phenomenon (Chap. 292)
    2. Buerger disease
    C. Generalized
    1. Pyoderma gangrenosum, but most commonly legs
    2. Calciphylaxis (Chap. 422)
    3. Infections, e.g., dimorphic fungi, leishmaniasis
    4. Lymphoma
    D. Face, especially perioral, and anogenital
    1. Chronic herpes simplexf
    III. Mucosal
    A. Aphthae
    B. Drug-induced mucositis
    C. Behçet’s disease (Chap. 376)
    D. Erythema multiforme major, Stevens-Johnson syndrome, TEN
    E. Primary blistering disorders (Chap. 62)
    F. Lupus erythematosus, lichen planus, lichenoid GVHD
    G. Inflammatory bowel disease
    H. Acute HIV infection
    I. Reactive arthritis