Papulosquamous disorders are characterized by scaling papules and plaques.
Palmoplantar keratodermas (PPKs) are disorders of cornification characterized by hyperkeratosis of the palms and soles.
 PSORIASIS → Diagnosis Group 1 |
Psoriasis is a papulosquamous disorder caused by a complex interplay of genetic and environmental factors. The pathogenesis of psoriasis (Figure 2.1) is primarily mediated by T cells.
Psoriasis affects ˜2% of the world’s population. The age of onset is bimodal, occurring in peaks from 20 to 30 years and 50 to 60 years.
Associations include cardiovascular disease, inflammatory bowel disease (IBD), metabolic syndrome, psoriatic arthritis, and depression/anxiety.
Drug associations include tumor necrosis factor alpha (TNFα) inhibitors, dupilumab, IFNs, ICIs, imiquimod, β-blockers, and lithium. Rapid tapering of systemic corticosteroids may trigger generalized pustular psoriasis (GPP).
Dupilumab can swing the pendulum from eczema to psoriasis (“Th2 to Th1 shift”).
The leading HLA association is -Cw6 within psoriasis susceptibility region 1 (PSORS1), which accounts for ˜50% of psoriasis risk. Specific HLA associations include:
Early-onset psoriasis: -B13, -B17, -Cw6, -DR7.
Guttate psoriasis: -B17, -Cw6.
Psoriatic arthritis (spondylitis and sacroiliitis variant): -B27.
Pustular psoriasis: -B27.
PSORS1 is #1. HLA-B17 association is easy to recall because psoriasis is a Th17 disease.
Psoriasis vulgaris classically presents with sharply demarcated, scaly, erythematous plaques favoring the scalp, intergluteal fold, elbows, and knees. Pruritus is common.
In infants, psoriasis is in the differential diagnosis for diaper dermatitis. In contrast to contact dermatitis, psoriasis classically presents with sharply demarcated psoriasiform plaques involving the inguinal creases, and often involves the umbilicus.
Diaper-area psoriasis is also known as “napkin psoriasis.”
The Auspitz sign refers to pinpoint bleeding after scraping psoriatic lesions.
Thin suprapapillary plates and tortuous blood vessels in dermal papillae on histopathology are responsible for the Auspitz sign.
Woronoff ring refers to blanching around psoriatic lesions due to decreased prostaglandin E2.
Psoriasiform alopecia classically presents with nonscarring circumscribed hair loss. Involvement of the nail unit occurs in 10% to 80% of patients and may be the sole manifestation of psoriasis. Nail psoriasis is a strong predictor of psoriatic arthritis.
Psoriasis variants are summarized in Table 2.1.
Guttate psoriasis is the most common variant in children and adolescents.
The Koebner phenomenon (isomorphic response) describes the appearance of new psoriatic lesions at sites of cutaneous trauma.
Psoriasis Vulgaris Honestly Loves Koebnerizing like Vitiligo, Halo nevus, Lichen planus (LP), Kyrle disease, and Keratoacanthoma (KA), while warts and molluscum contagiosum pseudo-Koebnerize.
Table 2.1. PSORIASIS VARIANTS
Varianta
Subvariant
Classic Description
Notes
Guttate
N/A
Numerous, small, widely disseminated psoriasiform papules and plaques.
Associations include streptococcal pharyngitis. Tonsillectomy may help prevent recurrence. Drug associations include β-blockers.
The appearance of guttate psoriasis is often compared to “rain drops.”
Erythrodermic
N/A
Erythema and scaling > 80%-90% BSA ± PPK and ectropion; alopecia; onychodystrophy. Lymphadenopathy is the leading systemic feature.
Erythroderma may by complicated by hypothermia, peripheral edema, and fluid/electrolyte/albumin loss leading to tachycardia and high-output cardiac failure.
Location-specific
Scalp
Psoriatic lesions on the scalp ± periphery of the face, retroauricular areas, and posterior upper neck.
Scalp psoriasis is the leading cause of pityriasis amiantacea.
Inverse
Psoriatic lesions on flexural sites and/or genitalia.
Palmoplantar
Psoriatic lesions on palms and/or soles.
Nail
N/A
Irregular pitting, the “oil drop” sign (salmon patch), and onycholysis with an erythematous border > onychauxis, paronychia, splinter hemorrhages (distal), and subungual hyperkeratosis.
Nail psoriasis is a strong predictor of psoriatic arthritis.
Pustular
GPP (von Zumbusch)
Primary, relapsing (>1 episode) or persistent (>3 months), sterile pustules on nonacral skin ± psoriasis vulgaris. Patterns include annular and exanthematic. Annulus migrans resembling geographic tongue may occur. Patients may exhibit fever and other constitutional symptoms.
Triggers include rapid tapering of systemic corticosteroids, hypocalcemia, and infection.
PPP
Primary, persistent (>3 months), sterile pustules on palms and/or soles ± psoriasis vulgaris.
Associations include SAPHO syndrome. Triggers include stress, local infections, and smoking.
Acrodermatitis continua of Hallopeau
Primary, persistent (>3 months), sterile pustules affecting the nail apparatus. Annulus migrans may occur. Nail bed involvement may result in onycholysis.
Acrodermatitis continua of Hallopeau is often described as “lakes of pus.”
Pustular psoriasis of pregnancy (impetigo herpetiformis)
Presents in late pregnancy or postpartum with GPP favoring flexural sites.
Increases risk of maternal hypocalcemia and placental insufficiency leading to stillbirth and neonatal demise.
Pustular psoriasis of pregnancy harms the placenta.
BSA, body surface area; GPP, generalized pustular psoriasis; N/A, not applicable; PPK, palmoplantar keratoderma; PPP, palmoplantar pustulosis; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis.
a Illustrative examples provided. Since pustular psoriasis of pregnancy is a GPP variant, some authors do not classify it as a pregnancy dermatosis.
The Renbök phenomenon (reverse Koebner phenomenon) describes one skin condition inhibiting another (eg, regression of a psoriatic plaque on the scalp coinciding with appearance of a patch of AA).
In German, Renbök is a reversal of the letters of Köbner.
Other psoriasis triggers relate to infection (eg, human immunodeficiency virus [HIV], streptococcal pharyngitis), stress, weight gain, alcohol consumption, smoking, and associated drugs.
Psoriatic arthritis occurs in 5% to 30% of patients and may be the initial manifestation of psoriasis. Clinical features include tendonitis (inflammation of juxta-articular tendons), enthesitis (inflammation of sites where tendons insert into bones), and dactylitis (swelling of the fingers). Morning stiffness is common. Psoriatic arthritis variants are summarized in Table 2.2.
Psoriasis may overlap with seborrheic dermatitis (sebopsoriasis).
Psoriasis may overlap with lichen simplex chronicus (LSC).
Table 2.2. PSORIATIC ARTHRITIS VARIANTS | ||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||
 Figure 2.1. PATHOGENESIS OF PSORIASIS. CD, cluster of differentiation; dDCs, dermal dendritic cells; DEJ, dermalepidermal junction; DNA, deoxyribonucleic acid; IFN, interferon; IL, interleukin; K, keratin; pDCs, plasmacytoid dendritic cells; RNA, ribonucleic acid; SKALP, skin-derived antileukoproteinase; SLPI, secretory leukocyte protease inhibitor; STAT, signal transducer and activator of transcription; Th, T helper; TNFα, tumor necrosis factor α. |
 Figure 2.2. PITTING. (Psoriatic pitting image reprinted with permission from Goodheart HP. Goodheart’s Photoguide of Common Skin Disorders: Diagnosis and Management. 2nd ed. Lippincott Williams & Wilkins; 2003.) AA, alopecia areata. Psoriasis and AA are associated with punctate depressions in the nail plate surface; however, these pits have subtle distinguishing features. • Pits in psoriasis are large and irregularly distributed within the nail plate. • Pits in AA are small and geometrically distributed within the nail plate. Pits derive from the proximal matrix, while the “oil drop” sign (salmon patches) and onycholysis in psoriasis derive from the nail bed. |
 Figure 2.3. CLINICOPATHOLOGICAL CORRELATION: PSORIASIS. Characteristic features are alternating neutrophils and parakeratosis, hypogranulosis, regular acanthosis with thin suprapapillary plates, neutrophilic spongiform pustules in the stratum corneum (Munro microabscesses) and stratum spinosum (spongiform pustules of Kogoj) with variable spongiosis, and tortuous vessels in the dermal papillae. A, Early psoriasis. B, Late psoriasis. C, Munro microabscess. D, Spongiform pustule of Kogoj. E, Pustular psoriasis. PR, pityriasis rosea. (Histology images reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.) • Guttate variant: neutrophils above mounded parakeratosis. • Pustular variant: exaggerated neutrophilic spongiform pustules in the stratum corneum (Munro microabscesses) and stratum spinosum (spongiform pustules of Kogoj). Regular acanthosis may be described as “club shaped.” Remember Munro microabscesses are in the stratum corneum because Marilyn Monro was on top of Hollywood, while spongiform pustules of Kogoj are deeper in the stratum spinosum. Mounded parakeratosis is a shared feature between guttate psoriasis and PR. On high-power, psoriasis can NOT be distinguished from clear cell acanthoma on histopathology. |
The differential diagnosis of psoriasis includes other papulosquamous disorders, eczematous dermatoses, lichenoid dermatoses, dermatomyositis (DM), secondary syphilis, dermatophytosis, and cutaneous T-cell lymphoma (CTCL). Lichenoid keratosis (LK), superficial BCC, and squamous cell carcinoma in situ (SCCis) are important mimickers of isolated plaque psoriasis. Acrokeratosis paraneoplastica (Bazex sign) is characterized by psoriasiform lesions on the nose, ear helices, palms, and soles ± onychodystrophy in association with malignancy of the upper aerodigestive tract.
Do NOT confuse Bazex sign with Bazex-Dupré-Christol syndrome.
The differential diagnosis of erythroderma includes erythrodermic psoriasis, pityriasis rubra pilaris (PRP), eczematous dermatoses (especially AD, seborrheic dermatitis, contact dermatitis, and chronic actinic dermatitis [CAD]), morbilliform drug eruption/drug reaction with eosinophilia and systemic symptoms (DRESS), papuloerythroderma of Ofuji, CTCL, and paraneoplastic erythroderma (eg, lymphoma). Preexisting dermatoses are the leading cause of erythroderma
overall, while drug eruption (eg, allopurinol) is the leading cause of erythroderma in HIV-infected patients. Idiopathic erythroderma (“red man syndrome”) occurs in ˜25% of patients.
Do NOT get confused! “Red man syndrome” is used to refer to idiopathic erythroderma OR a rate-dependent infusion reaction to vancomycin.
In infants, the differential diagnosis of erythroderma additionally includes ichthyoses (eg, epidermolytic ichthyosis [EI]), immunodeficiencies (eg, SCID [Omenn syndrome]), and infections (eg, staphylococcal scalded skin syndrome [SSSS]).
The differential diagnosis of pustulosis includes pustular psoriasis, acute generalized exanthematous pustulosis (AGEP), pemphigus foliaceus (PF)/pemphigus erythematosus, IgA pemphigus (subcorneal pustular dermatosis [SPD] type), SPD (Sneddon-Wilkinson disease), amicrobial pustulosis of the folds, impetigo, superficial folliculitis, superficial candidiasis, and dermatophytosis.
In infants, the differential diagnosis of pustulosis additionally includes transient neonatal pustular melanosis, erythema toxicum neonatorum, autoinflammatory syndromes (eg, deficiency of the interleukin-1 receptor antagonist [DIRA], deficiency of the interleukin-36 receptor antagonist [DITRA], CARD14-mediated pustular psoriasis, ADAM17 deletion), and acropustulosis of infancy.
Dermoscopy features include white superficial scales and dotted vessels in a uniform distribution against a light red background ± red globular rings.
Psoriasis is primarily a clinical diagnosis, but skin scraping and/or biopsy may be helpful.
In patients with guttate psoriasis, antistreptolysin O (ASO) and anti-DNase B or streptozyme titer may be considered to identify streptococcal pharyngitis.
In patients with erythroderma, longitudinal evaluation (eg, repeated skin biopsies, peripheral blood flow cytometry, and high-throughput sequencing [HTS]) may be required to rule out CTCL.
There is no specific serologic test that establishes the diagnosis of psoriatic arthritis, and most patients are seronegative for rheumatoid factor (RF). Radiographic changes include joint erosions, joint-space narrowing, bony proliferation, osteolysis, ankylosis, spur formation, and spondylitis.
Osteolysis results in a “pencil in cup deformity.”
Psoriasis is a chronic relapsing disorder that requires a longterm treatment strategy (clearing phase followed by maintenance phase).
Recommendations from the Joint AAD/NPF (National Psoriasis Foundation) Guidelines of Care for the Management of Psoriasis include:
Awareness and attention to comorbidities: Patients should receive screening and education regarding cardiovascular disease, IBD, metabolic syndrome, psoriatic arthritis, and depression/anxiety, including advice on how to practice a healthy lifestyle.
Topical therapies: Corticosteroids play a key role, especially for localized disease. Steroid-sparing agents include vitamin D analogues (eg, calcipotriene), retinoids (eg, tazarotene), and calcineurin inhibitors (eg, pimecrolimus, tacrolimus). “Proactive treatment” to reduce frequency of flares typically involves twice-weekly treatment of clinically quiescent at-risk areas. Other recommended topical therapies are emollients, salicylic acid, anthralin, and coal tar preparations. Roflumilast was subsequently approved.
Phototherapy: Narrowband ultraviolet B (nbUVB) is recommended over broadband ultraviolet B (bbUVB) for generalized plaque psoriasis. Options for localized psoriasis include targeted UVB (eg, excimer laser) and topical psoralen ultraviolet A (PUVA), especially for palmoplantar disease. Bath and oral PUVA are also available. Though less effective, nbUVB is preferred to PUVA because of enhanced safety, convenience, and cost savings. Goeckerman therapy involves application of coal tar followed by nbUVB.
Systemic nonbiological therapies: Acitretin is recommended for plaque, erythrodermic, and pustular psoriasis. Apremilast and methotrexate are recommended for moderate to severe psoriasis, while cyclosporine is recommended for severe, recalcitrant psoriasis.
Biologics: TNFα inhibitors (adalimumab, certolizumab, etanercept, golimumab, infliximab), the IL-12/IL-23 inhibitor (ustekinumab), IL-17 inhibitors (brodalumab, ixekizumab, secukinumab), and IL-23 inhibitors (guselkumab, risankizumab, tildrakizumab) are recommended for moderate to severe psoriasis.
The TNFα inhibitor etanercept (age ≥ 4 years) and the IL-12/IL-23 inhibitor ustekinumab (age ≥ 6 years) are recommended for moderate to severe psoriasis in pediatric patients.
Body surface area (BSA) of involved skin is an important measure of psoriasis severity to risk stratify patients for future comorbidities and to assess response to treatment (Figure 2.4). The Psoriasis Area and Severity Index (PASI) measures average erythema, induration, and scaling of psoriatic lesions on a scale of 0 to 4 and is weighted by area of involvement. A common outcome measure in clinical trials, the PASI is seldom used in clinical practice.
It is important to recognize the negative impact of psoriasis on quality of life and psychosocial well-being, which is comparable to other chronic diseases such as type 2 diabetes mellitus.
Cost-effectiveness is an important consideration when treating patients. In a prior study, methotrexate was found to be the least costly systemic psoriasis therapy.
Acitretin is not immunosuppressive and is therefore beneficial for immunosuppressed patients (eg, HIV).
Early diagnosis of psoriatic arthritis is critical to prevent disease progression resulting in irreversible joint destruction and loss of function. In these patients, remember to select a therapy efficacious for both skin and joint disease (eg, biologics are preferred to phototherapy).
 Figure 2.4. BODY SURFACE AREA. (Illustration by Caroline A. Nelson, MD.) |
 REACTIVE ARTHRITIS Balanitis circinata reprinted with permission from Reprinted with permission from Edwards L, Lynch P. Genital Dermatology Atlas and Manual. 3rd ed. Wolters Kluwer; 2017. |
Reactive arthritis is a psoriasiform disorder. It occurs most often in men. The leading association is urethritis (eg, Chlamydia trachomatis) followed by enteritis (eg, Shigella flexneri). HIV-infected patients may develop severe disease. The leading HLA association is -B27.
The historical name for reactive arthritis, Reiter disease, is no longer in use due to Reiter’s activities during the German Nazi regime.
Reactive arthritis presents in ˜5% of patients with psoriasiform skin lesions favoring the scalp, genitalia, and acral areas. Balanitis circinata refers to involvement of the penis, while keratoderma blennorrhagicum refers to involvement of the palms and soles, often with pustules. Other mucocutaneous findings include oral ulcers and psoriasiform onychodystrophy. Patients may exhibit fever and other constitutional symptoms. Arthritis (polyarthritis/sacroiliitis ≥ 1 month) occurs in ˜20% of patients. Morning stiffness is common. Other systemic features include ocular findings (eg, conjunctivitis) and urethritis (±cystitis, cervicitis, salpingitis).
The “classic triad” of reactive arthritis—conjunctivitis, urethritis, arthritis—may be remembered with the popular saying, “can’t see, can’t pee, can’t climb a tree.”
Reactive arthritis exhibits psoriasiform dermatitis.
NSAIDs are first line for acute disease, which typically self-resolves within 6 to 12 months but may flare. For ˜25% of patients who develop chronic disease, biologics (eg, TNFα inhibitors) are increasingly popular.
 GEOGRAPHIC TONGUE → Diagnosis Group 2 Synonym: benign migratory glossitis Reprinted with permission from Goodheart HP. Goodheart’s Photoguide of Common Skin Disorders: Diagnosis and Management. 2nd ed. Lippincott Williams & Wilkins; 2003. |
Geographic tongue is a common psoriasiform disorder (1%-3% of the general population).
The incidence of geographic tongue may be increased in patients with psoriasis.
Geographic tongue classically presents with asymptomatic sharply demarcated erythematous patches with yellowwhite serpiginous borders favoring the lateral and dorsal tongue.
Geographic tongue exhibits psoriasiform mucositis and atrophy of filiform papillae.
The differential diagnosis of geographic tongue includes LP, candidiasis, and leukoplakia.
No evaluation is typically indicated for geographic tongue.
No treatment is typically indicated for geographic tongue. A topical corticosteroid gel may be helpful in some patients with burning or sensitivity to hot or spicy foods.
Given the striking appearance of geographic tongue, reassurance regarding its benign nature is important.
 PARAPSORIASIS → Diagnosis Group 2 Reprinted with permission from Shaw KN, Bachur RG, Chamberlain JM, et al. Fleisher & Ludwig’s Textbook of Pediatric Emergency Medicine. 7th ed. Wolters Kluwer; 2015. |
Parapsoriasis is an umbrella term for two distinct papulosquamous disorders: small plaque parapsoriasis and large plaque parapsoriasis.
Parapsoriasis, pityriasis lichenoides (PL), and lymphomatoid papulosis (LyP) are overlapping clonal T cell-related dermatoses associated with CTCL.
Parapsoriasis classically presents with asymptomatic round-oval scaly erythematous patches. Small plaque parapsoriasis lesions are <5 cm, while large plaque parapsoriasis lesions are >5 cm. Lesions may wax and wane but ultimately become persistent.
Beware the misnomer! Lesions of small and large “plaque” parapsoriasis are patches.
The digitate dermatosis variant of small plaque parapsoriasis is characterized by elongated patches symmetrically distributed on the flanks.
Digitate dermatosis lesions are elongated like fingers.
Parapsoriasis exhibits parakeratosis and spongiotic dermatitis. Large plaque parapsoriasis may exhibit a lichenoid interface dermatitis. There is a predominance of CD4+ T cells. TCR gene rearrangement may detect T-cell clonality. For discussion of risk of progression to CTCL, see below.
The differential diagnosis of parapsoriasis includes other papulosquamous disorders and mycosis fungoides (MF). Nummular dermatitis and secondary syphilis are important mimickers of small plaque parapsoriasis, while poikiloderma and chronic radiation dermatitis are important mimickers of large plaque parapsoriasis.
Treatments for parapsoriasis include topical corticosteroids, coal tar preparations, and phototherapy.
The risk of progression from large plaque parapsoriasis to CTCL is well established (10%-35% over 6-10 years), leading some to consider it the earliest stage of MF. In contrast, the risk of progression from small plaque parapsoriasis to CTCL remains controversial. Some consider small plaque parapsoriasis a forme fruste of MF, while others recommend reassurance.
Topical calcineurin inhibitors carry a boxed warning for lymphoma and other malignancies. Although a causal relationship has not been established, exercise caution in parapsoriasis.
PITYRIASIS LICHENOIDES
Pityriasis lichenoides et varioliformis acuta (left) courtesy of Sa Rang Kim, MD. Pityriasis lichenoides chronica (right).
PL is a papulosquamous disorder. Pityriasis lichenoides et varioliformis acuta (PLEVA) is at the acute end of the spectrum, while pityriasis lichenoides chronica (PLC) is at the chronic end of the spectrum. Parapsoriasis, PL, and LyP are overlapping clonal T cell-related dermatoses associated with CTCL.
PL classically presents with recurrent crops of asymptomatic erythematous papules that involute spontaneously. PLEVA lesions are crusty or vesiculopustular and heal with varioliform scars, while PLC lesions are scaly and heal with hypopigmentation. Patients with the febrile ulceronecrotic Mucha-Habermann disease variant of PLEVA may exhibit mucosal involvement, fever, and other constitutional symptoms, along with gastrointestinal and pulmonary involvement.
Varicella is an important mimicker of PLEVA, while secondary syphilis is an important mimicker of PLC.
The prognosis of PL depends on its distribution, as patients with diffuse lesions have the shortest average disease course (11 vs 33 months). Treatments for PL are similar to parapsoriasis with the addition of systemic antiinflammatory antibacterials (eg, doxycycline, erythromycin) and immunosuppressants (eg, methotrexate).
 PITYRIASIS ROSEA → Diagnosis Group 1 |
Pityriasis rosea (PR) is a papulosquamous disorder. A role for human herpes virus (HHV)-7 > HHV-6 in PR has been hypothesized but remains unproven.
HHV-6 and HHV-7 have been implicated in PR, DRESS, and roseola infantum.
PR most commonly occurs in healthy young adults with a seasonal predilection for spring and fall.
The peak incidence of PR is during adolescence.
PR may increase the risk of spontaneous abortion, particularly during the first 15 weeks of pregnancy (controversial).
PR classically presents with a scaling erythematous plaque on the trunk. Within hours to days, scaly erythematous
papules with long axes along Langer lines erupt on the trunk and proximal extremities. Lesions are characterized by a subtle advancing border and collarette of scale. Follicular prominence and hyperpigmentation are often observed in darkly pigmented skin. Pruritus is common.
Figure 2.5. CLINICOPATHOLOGICAL CORRELATION: PITYRIASIS LICHENOIDES. Characteristic features are a perivascular interface dermatitis and erythrocyte extravasation extending to the epidermis. There is a predominance of CD8+ T cells in PLEVA versus CD4+ T cells in PLC. TCR gene rearrangement may detect T-cell clonality. CD, cluster of differentiation; PLC, pityriasis lichenoides chronica; PLEVA, pityriasis lichenoides et varioliformis acuta; TCR, T-cell receptor. A, PLEVA. B, PLC.
(Histology images reprinted with permission from Husain AN. Biopsy Interpretation of Pediatric Lesions. Wolters Kluwer; 2014.)
The histopathology of PLC is more subtle than PLEVA, the latter of which has a denser “V-shaped” infiltrate and variable epidermal changes (eg, parakeratosis, crust, ulceration, necrotic keratinocytes).
Pityriasis is derived from the Greek word pítouro meaning “bran.” Collectively, the pityriases are characterized by fine “branlike” scale.
In PR, the initial lesion is known as the “herald patch.” On the posterior trunk, lesions with long axes along Langer lines may create a “Christmas tree” pattern.
Patients may exhibit fever and other constitutional symptoms.
Rare variants include vesicular, pustular, erythema multi-forme (EM)-like, purpuric, and inverse PR.
The differential diagnosis of PR includes other papulosquamous disorders, nummular dermatitis, and secondary syphilis. The pityriases include:
Pityriasis amiantacea refers to thick scales, often adhering to hair shafts in clumps. It is not a specific disease, but rather a clinical finding associated with multiple dermatoses. Scalp psoriasis is the leading cause, followed by seborrheic dermatitis and Darier disease.
Amiantacea is derived from the French word amiante meaning “asbestos.”
PL (see above).
PR (see above).
Pityriasis rotunda refers to large sharply demarcated circular and polycyclic scaly hyperpigmented patches favoring the trunk and extremities. This disorder is hypothesized to arise from malnutrition in genetically susceptible individuals (eg, Far East, Mediterranean basin, African descent) with an underlying disorder (eg, gastric or hepatocellular carcinoma, hepatic cirrhosis, plasma cell dyscrasia, mycobacterial infection).
Figure 2.6. CLINICOPATHOLOGICAL CORRELATION: PITYRIASIS ROSEA. Characteristic features are mounded parakeratosis, spongiosis, a superficial perivascular and interstitial lymphohistiocytic infiltrate, and erythrocyte extravasation extending to the epidermis. Dashed arrow: erythrocyte extravasation. Solid arrow: mounded parakeratosis. PR, pityriasis rosea.
(Histology image reprinted with permission from Husain AN, Stocker JT, Dehner LP. Stocker and Dehner’s Pediatric Pathology. 5th ed. Wolters Kluwer; 2021.)
Mounded parakeratosis is a shared feature between guttate psoriasis and PR.
PRP (see below).
Drug-induced PR-like eruption such as angiotensinconverting enzyme inhibitors (ACEIs), β-blockers, and gold.
Serologic testing may be considered to rule out syphilis.
PR typically self-resolves within 6 to 8 weeks; therefore, observation is satisfactory.
Optional treatments for PR include topical corticosteroids, oral antihistamines, and phototherapy. Small studies have additionally reported the efficacy of oral acyclovir and erythromycin.
 PITYRIASIS RUBRA PILARIS → Diagnosis Group 2 Courtesy of Victoria Werth, MD. |
PRP is a disorder of follicular keratinization.
PRP classically presents with follicular hyperkeratosis on an erythematous base with follicular plugging. Lesions coalesce into orange-red (salmon) patches sparing discrete areas of skin. ± Waxy orange-red PPK. Psoriasiform onychodystrophy may occur (without pitting).
PRP, like lichen spinulosus, has a “nutmeg grater” texture. “Islands of sparing” is an important clue. The PPK is “sandal-like.”
PRP morphology and distribution vary based on type. PRP types in adults are summarized in Table 2.3.
PRP types in children are summarized in Table 2.4.
Generalization of PRP may lead to erythroderma.
The differential diagnosis of PRP includes other papulosquamous disorders, seborrheic dermatitis, PRP-like (Wong) type DM, and CTCL.
Biologics carry a boxed warning for lymphoma and other malignancies. Since CTCL may clinically mimic PRP, exercise caution.
Table 2.3. PITYRIASIS RUBRA PILARIS TYPES IN ADULTS | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||
Table 2.4. PITYRIASIS RUBRA PILARIS TYPES IN CHILDREN | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||
 Figure 2.7. CLINICOPATHOLOGICAL CORRELATION: PITYRIASIS RUBRA PILARIS. Characteristic features are alternating vertical and horizontal ortho- and parakeratosis, parakeratosis adjacent to follicles, follicular plugging, acanthosis, and acantholysis with thick suprapapillary plates. A, Low-power view. B, High-power view. Solid arrow: “checkerboard parakeratosis.” C, High-power view. Dashed arrows: “shoulder parakeratosis.” Dotted arrow: follicular plugging. DLE, discoid lupus erythematosus; LS, lichen sclerosus; PRP, pityriasis rubra pilaris. Alternating vertical and horizontal ortho- and parakeratosis is often called “checkerboard parakeratosis.” Parakeratosis adjacent to follicles is often called “shoulder parakeratosis.” “Shoulder parakeratosis” is a shared feature between PRP and seborrheic dermatitis. Follicular plugging is a shared feature between PRP, DLE, and LS. |
 SPOTLIGHT ON HEREDITARY PALMOPLANTAR KERATODERMAS Courtesy of Sara Berg, MD. |
Hereditary PPKs are disorders of cornification that may be nonsyndromic or syndromic. PPK classification is based on pattern:
Diffuse: involvement of the entire palmoplantar surface.
Focal: oval lesions over pressure points (areata) or linear lesions over flexor tendons (striate).
Punctate: multiple small keratotic papules or pits.
Hereditary PPKs are summarized in Table 2.5. Transgrediens refers to extension beyond volar skin. Pseudoainhum refers to keratotic constriction bands around digits that may lead to autoamputation.
Histopathological features depend on the hereditary PPK. Note that Vörner-Unna-Thost epidermolytic PPK demonstrates epidermolytic hyperkeratosis (EHK) (Figure 2.8).
Table 2.5. HEREDITARY PALMOPLANTAR KERATODERMAS
Diagnosisa
Inheritance pattern
Gene(s)
Classic Description
Notes
Nonsyndromic Diffuse PPKs
Vörner-Unna-Thost epidermolytic PPK
AD
K1 encoding K1 and
K9 encoding K9
Diffuse PPK with a smooth surface, sharply demarcated erythematous border, and pseudoainhum.
Remember K1 mutation in Vörner-Unna-Thost epidermolytic PPK by the card game UNO.
Nonepidermolytic PPK
AD, AR
Variable
Diffuse PPK similar to epidermolytic PPK with a less erythematous border.
Mal de Meleda nonepidermolytic PPK
AR
SLURP1 encoding SLURP1
Diffuse PPK, mutilating and transgradient, with pseudoainhum; angular cheilitis; hyperhidrosis with malodor; onychodystrophy (eg, koilonychia).
Increased risk of skin infections.
Mal de Meleda is malodorous.
Loricrin keratoderma
AD
LOR encoding loricrin
Diffuse PPK (Vohwinkel-like) and ichthyosis.
Variant Vohwinkel syndrome.
Nonsyndromic Focal PPKs
Striate PPK
AD
DSG1 encoding desmoglein 1, DSP encoding desmoplakin, and K1 encoding K1
Focal PPK (striate on the palms and areata on the soles).
Nonsyndromic Punctate PPKs
Punctate PPK
AD
Variable
Punctate PPK.
Spiny keratoderma variant: numerous tiny keratotic spines.
Marginal papular keratoderma variant: small, keratotic yellow (acrokeratoelastoidosis) or skin-colored (FAH) papules along the margins of the palms, soles, and digits.
Punctate PPK favors palmar creases in adults with African ancestry. Pits on palms and soles may also be identified in reticulate acropigmentation of Kitamura, Darier disease, PAON/PEODDN/porokeratosis punctata palmaris et plantaris, Gorlin syndrome, and Cowden syndrome.
Syndromic PPKs
Vohwinkel syndrome
AD
GJB2 encoding connexin 26
Diffuse PPK, mutilating, with pseudoainhum and stellate knuckle keratoses; alopecia; onycholysis; and subungual hyperkeratosis. Systemic features include congenital sensorineural hearing impairment.
Classic Vohwinkel syndrome.
PPK is “honeycomb-like,” knuckle keratoses are “starfish-like.”
Bart-Pumphrey syndrome
AD
GJB2 encoding connexin 26
Diffuse PPK (Vohwinkel-like) with knuckle pads; leukonychia (true). Extracutaneous features include congenital sensorineural hearing impairment.
Olmstead syndrome
AD > AR
TRPV3 encoding TRPV3
Diffuse PPK, mutilating, with pseudoainhum and periorificial and intertriginous keratotic plaques. Systemic features include visual and hearing impairment.
XLR
MBTPS2 encoding MBTPS2
Papillon-Lefèvre syndrome/Haim-Munk syndrome
AR
CTSC encoding cathepsin C
Diffuse PPK, mutilating and transgradient, with pseudoainhum and hyperkeratotic psoriasiform plaques on elbows and knees; periodontitis. Haim-Munk syndrome features onychodystrophy (eg, onychogryphosis).
Intracranial calcification of choroid plexus and tentorium on radiographic examination. Increased risk of skin infections.
Papillon is the French word for butterfly. The “butterfly-shaped” choroid plexus is calcified in Papillon-Lefèvre syndrome.
Naxos disease
AR
JUP encoding junction plakoglobin
Diffuse PPK. The characteristic hair shaft abnormality without increased fragility is woolly hair. Systemic features include right ventricular cardiomyopathy with arrhythmias.
Perform cardiac evaluation.
Carvajal syndrome
AR > AD
DSP encoding desmoplakin
Focal (areata and striate) PPK. The characteristic hair shaft abnormality without increased fragility is woolly hair. Systemic features include dilated, often left-sided, cardiomyopathy.
Perform cardiac evaluation.
To remember leftvs right-sided cardiomyopathy, align the “plaks”: desmoplakin-plakoglobin. Carvajal is on the left and Naxos is on the right.
Richner-Hanhart syndrome (oculocutaneous tyrosinemia)
AR
TAT encoding hepatic TAT
Focal (areata) PPK, painful. Systemic features include dendritic keratitis with corneal ulcers and intellectual disability.
Treat with a tyrosine and phenylalanine-restricted diet.
In Richner-Hanhart syndrome, tyrosine- and phenylalanine-rich foods make hands hurt.
Howel-Evans syndrome (TOC)
AD
RHBDF2 encoding RhBDF2
Focal (areata) PPK; premalignant leukoplakia. Systemic features include esophageal leukokeratosis.
Increased risk of esophageal cancer. Perform serial endoscopy.
Miscellaneous
Aquagenic PPK
AD, AR
Variable
Transient translucent to white papules on the palms shortly after water immersion.
Associations include CF and marasmus. Drug associations include COX-2 inhibitors.
Aquagenic PPK has a “pebbly” appearance.
AD, autosomal dominant; AR, autosomal recessive; CF, cystic fibrosis; COX, cyclooxygenase; EB, epidermolysis bullosa; FAH, focal acral hyperkeratosis; K, keratin; MBTPS2, membrane-bound transcription factor peptidase, site 2; PAON, porokeratotic adnexal ostial nevus; PC, pachyonychia congenita; PEODDN, porokeratotic eccrine ostial and dermal duct nevus; PPK, palmoplantar keratoderma; RHBDF2, rhomboid 5 homolog 2; SLURP1, secreted LY6/PLAUR domain containing 1; TAT, tyrosine aminotransferase; TOC, tylosis with esophageal cancer; TRPV3, transient receptor potential vanilloid 3; XLR, X-linked recessive.
a Illustrative examples provided. Other hereditary disorders that feature PPK (eg, selected ichthyoses, erythrokeratodermas, EB, ectodermal dysplasias, PC) are discussed elsewhere.
Figure 2.8. CLINICOPATHOLOGICAL CORRELATION: EPIDERMOLYTIC HYPERKERATOSIS. Characteristic features are dense orthohyperkeratosis, acanthosis, hypergranulosis, vacuolar degeneration of the granular and suprabasal layers, and clumped keratin intermediate filaments. EHK, epidermolytic hyperkeratosis; EI, epidermolytic ichthyosis; PPK, palmoplantar keratoderma.
(Reprinted with permission from Elder DE, Elenitsas R, Rubin AI, et al. Atlas of Dermatopathology: Synopsis and Atlas of Lever’s Histopathology of the Skin. 4th ed. Wolters Kluwer; 2020.)
EHK may be identified in Vörner-Unna-Thost epidermolytic PPK, EI, epidermolytic acanthoma, and epidermolytic epidermal nevus. The granular layer appears “chewed up.”
Screen with hearing and sweat tests. Skin biopsy may be helpful to establish the diagnosis, along with genetic testing. Other diagnostic tests are highlighted in the table.
Topical therapies to reduce hyperkeratosis include emollients, humectants, and keratolytics. Oral retinoids may have a role in treatment of severe PPKs.
 GRANULAR PARAKERATOSIS Courtesy of Seth J. Orlow, MD, PhD. From Gru AA, Wick MR, Mir A, et al. Pediatric Dermatopathology and Dermatology. Wolters Kluwer; 2018. |
Granular parakeratosis is a papulosquamous disorder. The hypothesized pathogenesis is a defect in processing profilaggrin to filaggrin.
Granular parakeratosis classically presents with brownishred keratotic papules coalescing into plaques favoring flexural sites (especially the axillae). Pruritus is common.
In infants, granular parakeratosis is in the differential diagnosis for diaper dermatitis.
Treatments for granular parakeratosis include topical corticosteroids, vitamin D analogues, retinoids, ammonium lactate, and antifungals.
 ACANTHOSIS NIGRICANS → Diagnosis Group 1 Reprinted with permission from Berek JS. Berek & Novak’s Gynecology. 16th ed. Wolters Kluwer; 2019. |
 Figure 2.9. CLINICOPATHOLOGICAL CORRELATION: GRANULAR PARAKERATOSIS. Characteristic features are compact orthohyperkeratosis, parakeratosis, basophilic KHGs in the stratum corneum, acanthosis, and papillomatosis. A, Lowpower view. B, Medium-power view. C, High-power view. Solid arrow: granules in the stratum corneum. KHGs, keratohyalin granules. |
Acanthosis nigricans (AN) is an epidermal proliferation.
The leading association is insulin resistance (eg, diabetes mellitus, hyperandrogenism, insulin resistance, AN (HAIR-AN) syndrome). Malignancy-associated AN is most often due to gastric carcinoma, and this holds true when AN is accompanied by florid cutaneous papillomatosis and/or tripe palms syndrome. However, tripe palms syndrome in isolation is most often due to lung carcinoma.
Beare-Stevenson cutis gyrata syndrome, due to AD FGFR2 gene mutation encoding fibroblast growth factor receptor 2 (FGFR2), leads to cutis gyrata, AN, furrowed palms and soles, craniosynostosis, and anogenital anomalies.
Drug associations include corticosteroids, OCPs, and human growth hormone (HGH).
AN is characterized by velvety hyperpigmentation favoring flexural sites (eg, neck, axillae, groin).
Florid cutaneous papillomatosis is characterized by verrucous skin lesions favoring the dorsal wrists and hands.
Tripe palms syndrome is characterized by rigid velvety hyperpigmentation of the palms with pronounced dermatoglyphs.
 Figure 2.10. CLINICOPATHOLOGICAL CORRELATION: ACANTHOSIS NIGRICANS. Characteristic features are loose orthohyperkeratosis, acanthosis, papillomatosis, and pigment at the base of bulbous rete ridges. AN, acanthosis nigricans; CARP, confluent and reticulated papillomatosis. (Reprinted with permission from Elder DE, Elenitsas R, Rubin AI, et al. Atlas of Dermatopathology: Synopsis and Atlas of Lever’s Histopathology of the Skin. 4th ed. Wolters Kluwer; 2020.) |
Evaluation for insulin resistance is appropriate for patients who are overweight or obese.
Evaluation for hyperandrogenism is appropriate for patients with AGA, hirsutism, and/or hormonal acne.
Evaluation for malignancy is appropriate for patients with rapid onset AN, widespread distribution (eg, lips, oral mucosa, palms), weight loss, and/or other dermatologic signs (eg, florid cutaneous papillomatosis, tripe palms syndrome, sign of Leser-Trélat).
Classic morphology is helpful to distinguish AN from CARP and PC. In contrast to the velvety hyperpigmentation of AN, CARP demonstrates brown verrucous papules and plaques, while PC demonstrates brown atrophic macules. Some consider PC to be a variant of CARP.
CONFLUENT AND RETICULATED PAPILLOMATOSIS
Synonym: confluent and reticulated papillomatosis of Gougerot and Carteaud
Reprinted with permission from Craft N, Fox LP, Goldsmith LA, et al. VisualDx: Essential Adult Dermatology. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010
CARP is an epidermal proliferation. Onset is most common in individuals of color during puberty.
CARP classically presents with brown verrucous papules and plaques (confluent centrally, reticulated peripherally) that spread from the inframammary area to the upper trunk and other flexural sites.
CARP can NOT be distinguished from AN on histopathology.
Minocycline is first line.
Eczematous dermatoses arise due to a combination of skin barrier dysfunction leading to increased transepidermal water loss (TEWL) and immune dysregulation.
Related disorders include:
Ichthyoses: disorders of cornification characterized by generalized scaling ± erythema.
Erythrokeratodermas: disorders of cornification characterized by circumscribed erythema and hyperkeratosis.
Keratosis pilaris (KP): disorder of follicular keratinization characterized by prominent keratin plugs within follicular orifices.
 ATOPIC DERMATITIS → Diagnosis Group 1 |
AD is an eczematous dermatosis due to a complex interplay of genetic factors (eg, filaggrin deficiency) and environmental factors (eg, high income, urban areas). Acute AD involves upregulation of Th2 cytokines (eg, IL-4, IL-13, IL-31) and basophils. Over time, chronic AD reflects a “Th2 to Th1 shift.” Decreased expression of antimicrobial peptides (eg, cathelicidin, human β-defensins) contributes to Staphylococcus aureus colonization.
AD affects up to 20% to 30% of children. It typically presents during infancy or early childhood and follows a chronic or relapsing course.
While AD is more common in children, it affects 2% to 10% of adults. Age-associated skin barrier dysfunction may lead to senile-onset AD (>60 years).
Associations include allergic rhinoconjunctivitis, asthma, food allergies, and eosinophilic esophagitis. The “atopic march” refers to progression from AD and food allergies (infancy or early childhood) to asthma (late childhood) to allergic rhinoconjunctivitis (adolescence).
The “allergic salute” refers to nasal creases in patients with AD and allergic rhinoconjunctivitis caused by habitual upward rubbing to relieve congestion.
Stages of eczematous dermatitis:
Acute: papules and plaques with erythema and edema ± vesiculation, oozing, and crust.
Subacute: variably thick plaques with scale and subtle erythema and edema ± crust.
Chronic: thick plaques with scale.
Eczematous dermatitis often heals with pigmentary changes.
In AD, the classic morphology and distribution pattern shift with age:
Infants: acute eczematous dermatitis on the scalp, cheeks, and extensor extremities. The diaper area is typically spared; however, AD is in the differential diagnosis for diaper dermatitis.
Children: chronic eczematous dermatitis on flexural sites (eg, neck, antecubital/popliteal fossae, wrists/ankles).
Adults: chronic eczematous dermatitis on eyelids, flexural sites, and hands.
Papular eczema with a follicular predilection is more common in African and Asian populations.
Other mucocutaneous findings include madarosis (Hertoghe sign) and onychodystrophy (eg, large and irregular pitting, Beau lines).
Atypical vascular responses include delayed blanching, midface pallor, and white dermatographism (blanching due to capillary vasoconstriction after stroking the skin).
AD may be associated with peripheral hypereosinophilia and elevated IgE.
Ocular findings include infraorbital darkening and pleats, recurrent conjunctivitis, keratoconus (progressive corneal thinning), and anterior subcapsular cataracts.
“Allergic shiners” refer to infraorbital darkening, while “Dennie-Morgan lines” refer to infraorbital pleats. Anterior neck creases are also characteristic.
Regional AD variants affect specific sites (eg, head/neck, eyelids, lips, ears, nipples, anogenital area).
Generalization of AD may lead to erythroderma.
AD is accompanied by intense pruritus that is often worse in the evening. Unfortunately, rubbing or scratching can trigger or exacerbate AD.
AD is the “itch that rashes.”
Other AD triggers relate to climate (eg, extreme temperatures, low humidity, sunlight), environmental allergies (eg, contact allergens, dust mites, pollen), food allergies (eg, egg > milk, peanuts/tree nuts, shellfish/fish, soy, wheat), irritants (eg, wool), infections (eg, eczema herpeticum [Kaposi varicelliform eruption], molluscum contagiosum, eczema coxsackium, S. aureus).
AD may overlap with LSC. Other dermatologic disorders associated with AD include:
AA: see Chapter 2: Disorders of the Hair and Nails.
Atopic eruption of pregnancy (AEP): classically presents in early pregnancy in women with atopy and recurs in subsequent pregnancies.
Disseminate and recurrent infundibulofolliculitis: superficial folliculitis (more common in adults with darkly pigmented skin) characterized by numerous pruritic, uniform, skin-colored papules favoring the neck, trunk, and upper extremities.
Disseminate and recurrent infundibulofolliculitis resembles “goose bumps.”
Follicular mucinosis (secondary): see Chapter 2: Depositional Disorders, Porphyrias, and Nutritional Deficiencies.
Frictional lichenoid eruption: multiple small, flat-topped, pink to skin-colored papules on the elbows > knees and dorsal hands.
Ichthyosis vulgaris: see below.
Immunologic contact urticaria: see Chapter 2: Urticaria and Other Erythemas.
Juvenile plantar dermatosis: shiny red plaques with scale on the balls of the feet and toepads in prepubertal children due to friction.
The colloquial name for juvenile plantar dermatosis is “sweaty sock syndrome.”
KP: see below.
Periorificial dermatitis: see Chapter 2: Disorders of Sebaceous, Apocrine, and Eccrine Glands.
Pityriasis alba: hypopigmented patches with minimal scale.
Xerosis: see below.
The histopathological correlate to eczematous dermatitis is spongiotic dermatitis (Figure 2.11).
The differential diagnosis of eczematous dermatitis includes:
Nonneoplastic disorders such as eczematous dermatoses and related disorders, psoriasis, and nutritional deficiencies.
Hyper-IgE syndromes, Wiskott-Aldrich syndrome (WAS), and infections/infestations such as human T-lymphotropic virus (HTLV)-associated infective dermatitis, dermatophytosis, and scabies.
Figure 2.11. CLINICOPATHOLOGICAL CORRELATION: SPONGIOTIC DERMATITIS. Spongiosis refers to intercellular edema in the epidermis with stretching of cell-cell junctions. A, Acute spongiotic dermatitis. B, Subacute spongiotic dermatitis. LSC, lichen simplex chronicus.
(A, Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015. B, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.)
Stages of Spongiotic Dermatitis:
• Acute: spongiosis and exocytosis of inflammatory cells.
• Subacute: parakeratosis, acanthosis, spongiosis, and exocytosis of inflammatory cells.
• Chronic: hyperkeratosis, hypergranulosis, irregular acanthosis, and papillary dermal fibrosis with capillary proliferation (angiofibroplasia) and vertically oriented collagen.
In acute and subacute spongiotic dermatitis, fluid accumulates in the epidermis like a “sponge.” Chronic spongiotic dermatitis can NOT be distinguished from LSC on histopathology.
Neoplastic disorders such as CTCL.
Eczematous drug eruptions (eg, TNFα inhibitors, ICIs, calcium channel blockers [CCBs]).
LK, superficial BCC, and SCCis are important mimickers of isolated eczematous dermatitis.
Evaluation of eczematous dermatitis may include skin scraping and/or biopsy, patch testing, blood and skin prick testing for allergen-specific IgE.
The differential diagnosis of peripheral hypereosinophilia includes:
Nonneoplastic disorders such as atopy, bullous pemphigoid (BP), eosinophilic fasciitis (EF), urticaria, cholesterol emboli, eosinophilic granulomatosis with polyangiitis (EGPA), and eosinophilic dermatoses.
Hyper-IgE syndromes and infections/infestations such as parasites.
Neoplastic disorders such as systemic mastocytosis.
Drug eruptions such as morbilliform drug eruption/DRESS.
Evaluation of peripheral hypereosinophilia may include skin biopsy, complete blood count (CBC), peripheral smear, IgE, C-reactive protein (CRP)/erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), vitamin B12, HIV, stool ova and parasites, Strongyloides serology, flow cytometry, and tryptase.
AD remits in ˜60% of infants and children by 12 years of age. However, appropriate management is critical not only to provide symptomatic relief but also to prevent epicutaneous sensitization and cutaneous inflammation that drive the “atopic march.”
Strategies for the primary prevention of AD may involve emollient therapy from birth, exclusive breastfeeding for 3 to 4 months, and probiotics/prebiotics.
In general, patients with AD should bathe or shower for 5 to 10 minutes in warm (not hot) water daily, use a gentle fragrance-free cleanser, and apply an emollient shortly after.
AAD Guidelines of Care for the Management of AD include:
Topical corticosteroids and calcineurin inhibitors (first line). Techniques to enhance penetration are “soak and smear” (soaking in plain water for 20 minutes followed by application) and “wet wraps” (application followed by an inner wet layer and an outer dry layer of cotton gauze or garments, 8-24 hours/day, <2 weeks). Crisaborole was subsequently approved (age ≥ 3 months).
Phototherapy (second line).
Systemic immunomodulatory agents including cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, and IFN-γ (third line). Short-term corticosteroids may be used to control an acute flare as a bridge to steroidsparing therapy. Dupilumab was subsequently approved.
Trigger avoidance involves:
Short-term sedating antihistamines to reduce itch and sleep disturbance during an acute flare.
Climate control.
Allergen and irritant avoidance.
Strategies to reduce S. aureus colonization (eg, “bleach baths” with intranasal mupirocin). Bacteriotherapy (topical coagulase negative Staphylococcus strains with antimicrobial activity) is being explored as a potential strategy. Shortterm antimicrobials may be necessary for superinfection.
It is important to recognize the negative impact of AD on quality of life and psychosocial well-being.
Patch testing should be considered in case of refractory disease or an unusual distribution. Blood and skin prick testing for allergen-specific IgE has high NPV but low PPV. Clinical history ± provocation testing is required to conclude that an allergen is triggering AD. Food allergy testing should only be considered in case of refractory disease or immediate reliable reaction after ingestion of a specific food. Nutritional deficiencies may result from unnecessarily restrictive diets.
Patients often state that topical corticosteroids “do not work” for them. Before reaching that conclusion, it is important to assess for poor adherence and corticosteroid contact dermatitis.
Given the risk of adverse events (eg, skin atrophy, cataracts/glaucoma), low-potency topical corticosteroids or calcineurin inhibitors are preferred on the face, axillae, and groin.
Long-term systemic corticosteroids, antihistamines, and antimicrobials are not indicated for AD.
 ASTEATOTIC DERMATITIS Synonyms: desiccation dermatitis, eczema craquelé, winter eczema, winter itch |
Asteatotic dermatitis is an eczematous dermatosis due to xerosis. Stratum corneum dysfunction including decreased natural moisturizing factor (NMF) occurs with aging. Other associations include nutritional deficiencies and metabolic disorders (eg, hypothyroidism). Drug associations include retinoids, epidermal growth factor receptor (EGFR) inhibitors, mitogenactivated protein kinase (MEK) 1/2 inhibitors, and statins.
Asteatotic dermatitis classically presents with skin scaling, erythema, and cracking favoring the shins.
Skin cracks in asteatotic dermatitis may resemble a “dried riverbed.”
Asteatotic dermatitis exhibits spongiotic dermatitis.
Topical corticosteroids are first line, followed by emollient application to prevent relapse.
DYSHIDROTIC ECZEMA
Synonym: pompholyx
Dyshidrotic eczema is an eczematous dermatosis associated with AD > contact dermatitis. Drug associations include IVIG.
Dyshidrotic eczema is characterized by symmetric, firm, deep-seated vesicles on the palms and lateral/medial fingers > soles and toes. The mildest variant of dyshidrotic eczema is dyshidrosis lamellosa sicca (keratolysis
exfoliativa) with small annular collarettes of white scale in place of vesicles. Dyshidrotic eczema is accompanied by intense pruritus. Triggers include stress and hot climates.
Vesicles in dyshidrotic eczema may resemble “tapioca pudding.”
Dyshidrotic eczema exhibits spongiotic dermatitis with vesicles on palmoplantar skin.
Management of dyshidrotic eczema is similar to AD (see above).
 NUMMULAR DERMATITIS → Diagnosis Group 1 |
Nummular dermatitis is an uncommon eczematous dermatosis.
Nummular dermatitis is characterized by round eczematous lesions favoring the extremities.
Nummular is derived from the Latin word nummus meaning “coin.”
Nummular dermatitis exhibits spongiotic dermatitis.
For the differential diagnosis of eczematous dermatitis, see above. SCCis is an important mimicker of isolated nummular dermatitis.
Round eczematous lesions may occur in other eczematous dermatoses; therefore, the existence of nummular dermatitis as an independent clinical entity is controversial.
 SEBORRHEIC DERMATITIS → Diagnosis Group 1 Reprinted with permission from Goodheart HP. Goodheart’s Same-Site Differential Diagnosis: A Rapid Method of Diagnosing and Treating Common Skin Disorders. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011. |
Seborrheic dermatitis is an eczematous dermatosis due to colonization with Malassezia species (yeasts that are part of normal resident skin flora) in areas with active sebaceous glands.
In adults, seborrheic dermatitis peaks in the fourth to sixth decades and follows a chronic course.
In infants, seborrheic dermatitis typically presents ˜1 week after birth and self-resolves within 3 months.
Associations include seborrhea, acne, hirsutism, and androgenetic alopecia (SAHA) syndrome. Severe seborrheic dermatitis may signal HIV infection or a neuropsychiatric disorder (eg, Parkinson disease).
A seborrheic dermatitis-like reaction has been reported to BRAF inhibitors.
Seborrheic dermatitis is characterized by pink-yellow to red-brown patches or thin plaques with scale in a seborrheic distribution (scalp, face, ears, presternal > flexural sites, anogenital area).
The scale in seborrheic dermatitis is often described as “greasy.” Chest lesions may have a “petaloid” appearance.
In infants, seborrheic dermatitis typically involves the scalp (cradle cap) ± diaper area. As such, seborrheic dermatitis is in the differential diagnosis for diaper dermatitis.
The mildest variant of seborrheic dermatitis is pityriasis simplex capillitii (dandruff). Thick scaling may result in pityriasis amiantacea.
Generalization of seborrheic dermatitis may lead to erythroderma.
Seborrheic dermatitis may overlap with psoriasis (sebopsoriasis).
 Figure 2.12. CLINICOPATHOLOGICAL CORRELATION: SEBORRHEIC DERMATITIS. Chronic seborrheic dermatitis. Acute seborrheic dermatitis exhibits spongiotic dermatitis. Chronic seborrheic dermatitis exhibits psoriasiform dermatitis with neutrophilic parakeratosis adjacent to follicles. Solid arrows: “shoulder parakeratosis.” PRP, pityriasis rubra pilaris. (Histology image reprinted with permission from Husain AN. Biopsy Interpretation of Pediatric Lesions. Wolters Kluwer; 2014.) “Shoulder parakeratosis” is a shared feature between PRP and seborrheic dermatitis. |
For the differential diagnosis of eczematous dermatitis, see above. Langerhans cell histiocytosis (LCH) is a rare but important mimicker of seborrheic dermatitis in flexural sites.
In adults, antifungal therapy with topical ketoconazole or ciclopirox (cream or shampoo) ± short-term low-potency topical corticosteroid therapy is first line. Second-line therapies include tar, selenium sulfide, or zinc pyrithione shampoos and topical calcineurin inhibitors.
In infants, bathing followed by emollient application (eg, mineral oil) is typically sufficient to control seborrheic dermatitis. Topical antifungal ± short-term low-potency topical corticosteroid therapy can be considered for refractory disease.
Understanding differing hair care practices between racial and ethnic groups is important. For example, a study assessing hair care practices among African American girls determined that hair extensions, chemical relaxers, and use of hair oil every 2 weeks versus daily were significantly associated with seborrheic dermatitis, while hair washing every 1 to 2 weeks was not. A recommendation to shampoo with ketoconazole or ciclopirox twice weekly may not be feasible in this patient population.
 STASIS DERMATITIS → Diagnosis Group 1 |
Stasis dermatitis is an eczematous dermatosis due to venous insufficiency/hypertension.
Risk factors include age, family history, female gender, height, obesity, pregnancy, and prolonged standing.
Stasis dermatitis is characterized by scaling and erythema of the distal lower extremities.
Contact dermatitis is often present. Disseminated eczema (autoeczematization, autosensitization, id reaction) refers to development of secondary lesions distant from the primary site. This phenomenon occurs most often in ACD and stasis dermatitis, along with other eczematous disorders and tinea pedis.
For the differential diagnosis of eczematous dermatitis, see above.
Treatment should be directed at the underlying venous insufficiency/hypertension including leg elevation and compression.
Topical corticosteroids and emollients are first line.
Other cutaneous signs of venous insufficiency/hypertension may provide helpful clues to the diagnosis of stasis dermatitis: acroangiodermatitis, edema, lipodermatosclerosis, livedoid vasculopathy, petechiae superimposed on yellow-brown discoloration (hemosiderin), varicosities, venous ulcers.
 Figure 2.13. CLINICOPATHOLOGICAL CORRELATION: STASIS DERMATITIS. Stasis dermatitis demonstrates spongiotic dermatitis with superficial vascular ectasia, nodular angioplasia, erythrocyte extravasation, and hemosiderin deposition in the superficial dermis. A, Low-power view. Solid arrow: nodular “cannonball-like” angioplasia. B, High-power view. Nodular angioplasia is “cannonball-like.” Hemosiderin is refractile, while melanin is not. |
 CONTACT DERMATITIS → Diagnosis Group 1 Courtesy of Ari Goldminz, MD. |
Contact dermatitis is an eczematous dermatosis that occurs in two forms: ACD (20%) and irritant contact dermatitis (ICD) (80%). The pathogenesis is illustrated in Figure 2.14.
In ACD, polysensitization is subcategorized into co-reactivity (concurrent, immunologically distinct chemicals) and crossreactivity (immunologically indistinct chemicals).
Plant recognition skills, while of uncertain relevance to examinations, may prevent a raging case of poison ivy dermatitis (Figure 2.15).
Contact dermatitis classically presents with eczematous dermatitis localized to the site of allergen or irritant exposure. Linear configuration is common when a plant brushes against the skin. ACD occurs within hours to days after exposure, while ICD occurs within minutes to hours after exposure.
In contact dermatitis, the distribution pattern depends on allergen or irritant exposure. Patterns include:
Airborne: ACD due to an aerosolized allergen (eg, sesquiterpene lactones, usnic acid) or ICD due to an aerosolized irritant (eg, fiberglass, solvents).
Photoinduced: photoallergic contact dermatitis (eg, benzophenones, musk ambrette) or phototoxic contact dermatitis (eg, furocoumarins).
Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE): see Chapter 2: Interface Dermatoses and Other Connective Tissue Disorders.
 Figure 2.14. PATHOGENESIS OF CONTACT DERMATITIS. ACD is a delayed-type, cell-mediated (type IV) reaction. Sensitization versus tolerance is determined by the balance of CD8+ T cells and Tregs. Similar reactions may not occur in other exposed individuals. ICD is dose dependent. Sensitization is not required. Similar reactions occur in other exposed individuals. ACD, allergic contact dermatitis; APCs, antigen-presenting cells; CD, cluster of differentiation; ICD, irritant contact dermatitis; IL, interleukin; TNF, tumor necrosis factor; Tregs, T-regulatory cells. |
Table 2.6. CONTACT ALLERGENS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Table 2.7. CONTACT IRRITANTS | ||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||
Table 2.8. PLANT ALLERGENS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Table 2.9. PLANT IRRITANTS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Generalization of contact dermatitis may lead to erythroderma.
Disseminated eczema may occur in ACD, most often in the setting of stasis dermatitis.
Other mucocutaneous findings include cheilitis, stomatitis, and balanitis/vulvovaginitis; onychodystrophy (eg, chronic paronychia, hapalonychia, onycholysis).
In infants, contact dermatitis (ICD > ACD) is in the differential diagnosis for diaper dermatitis. In contrast to psoriasis, contact dermatitis classically presents with poorly demarcated eczematous patches sparing the inguinal creases. Severe anogenital ICD is called Jacquet erosive diaper dermatitis. Granuloma gluteale infantum/adultorum is a reactive condition that exists on a spectrum with perianal pseudoverrucous papules/nodules. In addition to chronic irritation (eg, diarrhea), predisposing factors include topical corticosteroid use, occlusion, and candidal infection.
For the differential diagnosis of eczematous dermatitis, see above. Other rare but important mimickers of contact dermatitis include:
Autoimmune progesterone dermatitis: progesterone sensitization (eg, during pregnancy or postpartum) leads to cyclic eczematous dermatitis during the luteal phase of the menstrual cycle (ovulation to menses). A majority of patients react to intradermal injection of progesterone. Combined OCPs are first line.
Contact urticaria/protein contact dermatitis: see Chapter 2: Urticaria and Other Erythemas.
Infectious eczematous dermatitis: sensitization to bacterial antigens (eg, Staphylococcus or Streptococcus species).
Patch testing is often required to differentiate ACD from ICD. Patients should avoid corticosteroids for ≥1 week
beforehand (<20 mg prednisone equivalent daily if necessary) but may continue antihistamines. The upper back is the most common site of patch application. While the TRUE TEST is convenient, expanded testing improves diagnostic accuracy. Testing unknown personal care products is dangerous due to risk of “chemical burn.” As a general rule of thumb, “leave-on” products can be tested, while “rinse-off ” products require dilution. The first reading occurs at 48 hours (when patches are removed) and the second reading occurs between 72 hours and 1 week. The second reading is required to detect delayed reactions (eg, corticosteroids, gold, neomycin). The International Grading System for Patch Tests is:
Figure 2.15. MATCHING EXERCISE: PLANT ALLERGENS AND IRRITANTS. A, Primrose. Family Primulaceae. Allergen: primin. B, Peruvian lily. Family Alstroemeriaceae. Allergen: tuliposide. C, Poison oak (left), poison sumac (center), poison ivy (right). Family Anacardiaceae genus Toxicodendron (Rhus). Allergen: urushiol. D, Celery. Family Apiaceae (Umbelliferae). Photoirritant: furocoumarins. E, Daffodil. Family Amaryllidaceae genus Narcissus. Irritant: calcium oxalate. F, Chrysanthemum. Family Asteraceae (Compositae). Allergen: sesquiterpene lactone.
(Illustration by Caroline A. Nelson, MD.)
± doubtful reaction, faint macular erythema.
+ weak, nonvesicular reaction with erythema, infiltration, and papules.
++ strong, vesicular reaction with erythema, infiltration, and papules.
+++ spreading bullous reaction.
− negative reaction.
IR irritant reaction.
Ultimately, the diagnosis of ACD relies on finding a reaction of current relevance.
The open use test can be helpful to evaluate sensitivity to a product when patch testing is unavailable or to confirm a patch test reaction. The product is applied to a predetermined location (eg, antecubital fossa, flexor forearm) twice
daily for 1 to 2 weeks to determine whether dermatitis develops.
The open use test is sometimes called “the poor man’s patch test.”
Allergen avoidance is essential for the prevention of ACD (≥6 weeks may be required). Irritant avoidance is essential for the prevention of ICD. Barriers include emollient, clear nail polish over nickel, and personal protective equipment. In some patients, ICD may resolve spontaneously with continued exposure; however, this phenomenon (accommodation or hardening) is unpredictable.
Topical corticosteroids are first line. If corticosteroid contact dermatitis is suspected, prescribe ointment (to avoid preservatives) and switch to a Group 3 topical corticosteroid.
Group 1 corticosteroids are the #1 cause of corticosteroid contact dermatitis.
Severe ACD (eg, poison ivy dermatitis) may require prednisone 1 to 2 mg/kg/d tapered over 2 to 3 weeks.
It is important to counsel patients that the terms “clean beauty” or “natural skin care” do not mean “safe.” In fact, companies “greenwashing” products have often substituted low-risk chemicals for ACD (eg, parabens) for high-risk chemicals (eg, methylchloroisothiazolinone/methylisothiazolinone [MCI/MI]).
Poison ivy is “natural,” but that does not mean it should be included in a skin care line.
Patients with poison ivy dermatitis often state that prednisone “did not work” for them when, in fact, the duration was not sufficient.
In case of poison ivy reexposure, patients should immediately wash with water (soap may enhance oleoresin permeability).
 ICHTHYOSIS VULGARIS → Diagnosis Group 2 Reprinted with permission from Elder DE, Elenitsas R, Rubin AI, et al. Atlas of Dermatopathology: Synopsis and Atlas of Lever’s Histopathology of the Skin. 4th ed. Wolters Kluwer; 2020. |
Ichthyosis vulgaris is a disorder of cornification.
For hereditary ichthyosis vulgaris, see below.
Associations with acquired ichthyosis vulgaris include inflammatory disorders (eg, sarcoidosis), nutritional deficiencies (eg, marasmus, vitamin A deficiency), metabolic disorders (eg, hypothyroidism, end-stage renal disease [ESRD] ± uremic frost), infections (eg, HIV, HTLV-I/II), and malignancies (eg, Hodgkin lymphoma).
Drug associations with acquired ichthyosis vulgaris include cimetidine, clofazimine, and statins.
Ichthyosis vulgaris classically presents with fine, adherent scales on the trunk and extremities with flexural sparing, hyperlinear palms/soles, and furrowed heels.
Ichthyosis is derived from the Greek root ichthy in reference to “fish scales.”
The differential diagnosis of acquired ichthyosis vulgaris includes late-onset hereditary ichthyosis vulgaris and xerosis.
Terra firma-forme dermatosis is a disorder of cornification in children and adolescents. It classically presents with brown patches and plaques favoring the neck.
Figure 2.16. CLINICOPATHOLOGICAL CORRELATION: ICHTHYLOSIS VULGARIS. Characteristic features are compact orthohyperkeratosis and hypogranulosis. KP, keratosis pilaris; PXE, pseudoxanthoma elasticum.
(Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
At scanning power, the “normal skin” differential diagnosis includes guttate psoriasis, seborrheic dermatitis, ichthyosis vulgaris, KP atrophicans faciei, vitiligo, chrysiasis, argyria, PXE, urticaria, scleredema, macular amyloidosis, tinea, candidiasis, onchocerciasis, and mastocytosis. Diagnosis relies on systematic evaluation and clinicopathological correlation. Do NOT forget to search for organisms in the stratum corneum.
Although terra firma-forme does not relate to poor hygiene, the Latin words terra firma meaning “dry land” reference its “dirty” appearance.
If possible, treatment of acquired ichthyosis vulgaris should be directed at the underlying cause.
Topical therapies to reduce hyperkeratosis include emollients, humectants, and keratolytics. Topical retinoids cause skin irritation and oral retinoids are rarely indicated.
Patients with ichthyosis vulgaris should be carefully monitored for skin infection.
Application of salicylic acid over a large BSA may lead to salicylism.
 SPOTLIGHT ON HEREDITARY ICHTHYOSES AND ERYTHROKERATODERMAS Epidermolytic ichthyosis courtesy of Leslie Castelo-Soccio, MD, PhD and Douglas Pugliese, MD, MPH. |
Hereditary ichthyoses and erythrokeratodermas are disorders of cornification that may be nonsyndromic or syndromic. Ichthyosis classification is based on absence or presence of a collodion membrane at birth.
The collodion membrane is a taut, shiny, transparent membrane comprised of thickened stratum corneum that appears to wrap the neonate in “cellophane.”
Hereditary ichthyoses and erythrokeratodermas are summarized in Table 2.10.
Histopathological features depend on the hereditary ichthyosis or erythrokeratoderma. Note that epidermolytic ichthyosis (EI) demonstrates EHK. Note that neutral lipid storage disease with ichthyosis demonstrates oil stain positivity (eg, Oil Red O, Sudan Black) on frozen skin biopsy specimens.
Skin biopsy may be helpful to establish the diagnosis, along with genetic testing. Specific diagnostic tests are highlighted in the table.
Treatment of hereditary ichthyoses is similar to acquired ichthyosis vulgaris. Oral retinoids are indicated for some severe ichthyoses (eg, acitretin 1 mg/kg/d in Harlequin ichthyosis) but may enhance blistering in EI.
Harlequin ichthyosis was historically considered universally fatal; however, due to advances in postnatal care and oral retinoid therapy, that is no longer true.
KERATOSIS PILARIS
KP is a disorder of follicular keratinization. Filaggrin deficiency may be present. Associations include atopy, ichthyosis vulgaris, and Down syndrome. A KP-like reaction may occur in association with BRAF inhibitors.
KP classically presents with keratotic papules with a rim of erythema favoring the lateral cheeks, upper arms, and thighs. Background erythema is prominent in the widespread keratosis pilaris rubra (KPR) variant. The characteristic hair shaft abnormality without increased fragility is rolled hairs.
Beyond KP, other disorders of follicular keratinization include:
Erythromelanosis follicularis faciei et colli: multiple pinpoint follicular papules superimposed on a red-brown patch favoring the lateral cheeks/neck. May co-occur with KP.
FFA/LPP: see Chapter 2: Disorders of the Hair and Nails.
Table 2.10. HEREDITARY ICHTHYOSES AND ERYTHROKERATODERMAS
Diagnosisa
Inheritance Pattern
Gene(s)
Classic Description
Notes
Nonsyndromic Ichthyoses Without Collodion Membrane
Ichthyosis vulgaris
AD
FLG encoding filaggrin
See above.
Associations include atopy, KP, and multiple eruptive clear cell acanthoma.
Steroid sulfatase deficiency (XLR ichthyosis)
XLR
STS encoding steroid sulfatase
Fine to large dark adherent scales on lateral face, neck, trunk, and extremities with sparing of the skin folds. Systemic features include corneal opacities and cryptorchidism.
Increased plasma (hydroxy)cholesterol sulfate and decreased steroid sulfatase activity (eg, in leukocytes). Increased risk of hypogonadism and testicular cancer. Female carriers may have corneal opacities and prolonged labor.
Scales in steroid sulfatase deficiency have a “dirty” appearance.
EI (bullous CIE)
AD > AR
K1 encoding K1 and K10 encoding K10
Erythroderma, blistering, and erosions at birth evolving into hyperkeratosis overlying joints and flexural ridging. ± PPK with pseudoainhum (K1). Malodor. Systemic features include gait and posture abnormalities. EI is the leading cause of the ichthyosis hystrix phenotype (massive hyperkeratosis).
K1 is expressed in the suprabasal layers. K10 is expressed in the suprabasal layers excepting palms/soles. Lamellar granules are increased but abnormal. Monitor for sepsis and fluid and electrolyte imbalances. Mosaic EI, caused by a postzygotic mutation in K1 or K10 during embryogenesis, follows lines of Blaschko. If the mutation involves gonadal cells, it can be transmitted to the patient’s children, resulting in generalized EI.
Scales in EI have a “cobblestone” appearance. Flexural ridging may resemble “corrugated cardboard.” Ichthyosis hystrix may resemble a “porcupine.”
Superficial EI (ichthyosis bullosa of Siemens)
AD
K2 encoding K2
Similar to EI (without erythroderma or PPK). Skin molting.
K2 is expressed in the upper spinous and granular layers.
In ichthyosis bullosa of Siemens, the skin molts like the plumage of a seabird.
Ichthyosis with confetti
AD
K10 encoding K10 > K1 encoding K1
Ichthyosiform erythroderma with development of small islands of normal skin.
Revertant mosaicism.
Ichthyosis hystrix, Curth-Macklin
AD
K1 encoding K1
Similar to EI (without skin fragility). Severe mutilating PPK with digital contractures and pseudoainhum.
Nonsyndromic Ichthyoses With Collodion Membrane
LI/CIE (nonbullous CIE)
AR
LI: TGM1 encoding TG-1, ABCA12 encoding ABC lipid transporter
Desquamation of the collodion membrane leaves erythroderma in the neonate that evolves into large, thick, dark scales ± erythroderma (LI) or erythroderma and fine white scales (CIE). ± PPK with pseudoainhum. Ectropion > eclabium; scarring alopecia.
Collectively categorized as ARCI. Lamellar granules are decreased or absent. Premature delivery. Monitor for sepsis, fluid and electrolyte imbalances (eg, hypernatremic dehydration), and thermoinstability. Sepsis and respiratory insufficiency are the leading causes of mortality in Harlequin ichthyosis. To facilitate gradual desquamation of the collodion membrane, place the neonate in a humidified incubator and treat with wet compresses and emollients. Avoid manual removal (except if concern for autoamputation due to constricting skin bands) and topical keratolytics. Topical NAC has shown benefit.
Do NOT confuse TG-1 with TG-3, the targeted antigen in DH.
Scales in LI have a “plate-like” appearance. Scales in CIE have a “powdery” appearance.
Harlequin ichthyosis
AR
ABCA12 encoding ABC lipid transporter
Desquamation of large, very thick, dark scales with red fissuring leaves erythroderma in the neonate that evolves into a severe CIE phenotype.
Scales in Harlequin ichthyosis have an “armor-like” appearance. The hands and feet resemble “mittens.”
Self-improving collodion ichthyosis
AR
Variable
Desquamation of the collodion membrane may leave normal skin.
Syndromic Ichthyoses
Netherton syndrome
AR
SPINK5 encoding serineprotease inhibitor LEKT1
Eczematous dermatitis, ichthyosis (ichthyosis linearis circumflexa with double-edged scale or CIE-like), and pruritus. Characteristic hair shaft abnormalities with increased fragility are trichorrhexis invaginata (most specific, eyebrow) and trichorrhexis nodosa (most common).
Elevated IgE. Monitor for sepsis, fluid and electrolyte imbalances (eg, hypernatremic dehydration), and thermoinstability. Increased risk of skin infection and allergies. Exercise caution with topical corticosteroids and calcineurin inhibitors due to increased absorption.
Sjögren-Larsson syndrome
AR
ALDH3A2 encoding FALDH
Ichthyosis and pruritus. ± PPK. Systemic features include spastic diand tetraplegia, intellectual disability, and perifoveal glistening white dots.
Accumulation of leukotriene B4 is implicated in pruritus. Treat with 5-lipoxygenase inhibitors.
Spastic di- and tetraplegia leads to a “scissor gate.”
Neutral lipid storage disease with ichthyosis (Chanarin-Dorfman syndrome)
AR
ABHD5 encoding an activator ATGL
Ichthyosis (CIE-like). Systemic features include hepatomegaly.
Lipid vacuoles in circulating leukocytes on peripheral smear.
Trichothiodystrophy with ichthyosis
See Chapter 4: Photodermatoses.
Refsum disease (hereditary sensory motor neuropathy type IV)
AR
PHYH encoding phytanoyl-CoA hydroxylase and PEX7 encoding peroxisomal type 2 targeting signal receptor
Ichthyosis (ichthyosis vulgaris-like). Systemic features include cerebellar dysfunction, peripheral neuropathy, retinitis pigmentosa, and sensorineural hearing impairment.
Elevated plasma phytanic acid. Treat with dietary restriction of phytanic acid in dairy products and animal fats.
Refsum disease leads to retinitis pigmentosa.
Refsum disease patients should refuse the dairy products and fat of ruminants.
Erythrokeratodermas
EKV (Mendes da Costa disease)
AD > AR
GJB3 encoding connexin 31 and GJB4 encoding connexin 30.3a
Transient erythematous patches and stable hyperkeratotic plaques. ± PPK with pseudoainhum.
PSEK
AD, AR
Variable
Progressive erythematous hyperkeratotic plaques. ± PPK with pseudoainhum.
KID syndrome
AD
GJB2 encoding connexin 26
Erythematous hyperkeratotic plaques. PPK (Vohwinkel-like). Systemic features include keratitis and congenital sensorineural hearing impairment.
Erythrokeratoderma. Increased risk of skin infections and skin cancer.
KID syndrome in a kid is summarized by the name: keratitis-ichthyosis-deafness.
XLD Ichthyosiform Disorders
CHILD syndrome
XLD
NSDHL encoding 3β-hydroxysteroid dehydrogenase
Unilateral ichthyosiform erythroderma sparing the face at birth that evolves into verrucous hyperkeratosis. Verruciform xanthoma. Systemic features include ipsilateral organ hypoplasia and skeletal hemidysplasia.
XR demonstrates stippled epiphyses (chondrodysplasia punctata) during infancy. Treat with topical 2% lovastatin or simvastatin/2% cholesterol.
CHILD syndrome in a child is summarized by the name: congenital hemidysplasia with ichthyosiform erythroderma and limb defects.
Conradi-Hünermann-Happle syndrome (XLD chondrodysplasia punctata)c
XLD
EBP encoding EBP
Ichthyosiform erythroderma along lines of Blaschko that evolves into follicular atrophoderma and scarring alopecia. Systemic features include asymmetric skeletal abnormalities (eg, rhizomelia).
Accumulation of plasma 8(9) cholesterol. XR demonstrates stippled epiphyses (chondrodysplasia punctata) during infancy.
Miscellaneous
Flegeldisease (hyperkeratosis lenticularis perstans)
AD
Symmetric keratotic papules favoring the distal extremities and dorsal feet.
Lamellar granules are decreased or absent.
Keratotic papules in Flegel disease have a “disc-like” appearance.
AD, autosomal dominant; AR, autosomal recessive; ARCI, autosomal recessive congenital ichthyoses; ATGL, adipose triglyceride lipase; CIE, congenital ichthyosiform erythroderma; CHILD, congenital hemidysplasia with ichthyosiform erythroderma and limb defects; CoA, coenzyme A; DH, dermatitis herpetiformis; EBP, emopamil-binding protein; EI, epidermolytic ichthyosis; EKV, erythrokeratoderma variabilis; FALDH, fatty aldehyde dehydrogenase; Ig, immunoglobulin; K, keratin; KID, keratitis-ichthyosis-deafness; LEKT1, lymphoepithelial Kazal-type-related inhibitor; LI, lamellar ichthyosis; NAC, N-acetylcysteine; PPK, palmoplantar keratoderma; PSEK, progressive symmetric erythrokeratoderma; TG, transglutaminase; XLD, X-linked dominant; XLR, X-linked recessive; XR, x-ray.
a Illustrative examples provided.
b LI and CIE exist on a spectrum. Eleven genes that favor one phenotype have been identified.
c An AR variant (rhizomelic chondrodysplasia punctata) due to PEX7 mutation has been described.
Figure 2.17. CLINICOPATHOLOGICAL CORRELATION: KERATOSIS PILARIS. Characteristic features are an orthokeratotic keratin plug that dilates the follicular orifice, rolled hairs, and a mild perivascular lymphocytic infiltrate.
(Histology image reprinted with permission from Gru AA, Wick MR, Mir A, et al. Pediatric Dermatopathology and Dermatology. Wolters Kluwer; 2018.)
Lichen spinulosus: multiple skin-colored papules with keratotic spines.
Lichen spinulosus, like PRP, has a “nutmeg grater” texture.
Phrynoderma: see Chapter 2: Depositional Disorders, Porphyrias, and Nutritional Deficiencies.
PRP: see Chapter 2: Papulosquamous Disorders and Palmoplantar Keratodermas.
KP may improve after puberty. Keratolytics are first line. Topical retinoids cause skin irritation. Strategies to reduce erythema include topical corticosteroids and PDL.
Table 2.11. KERATOSIS PILARIS ATROPHICANS | |||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||||||||||||||
Hypopigmentation (leukoderma) results either from hypomelanosis or decreased cutaneous blood supply. Hypomelanosis is further classified into melanocytopenic (decreased melanocyte number) or melanopenic (decreased melanin synthesis or transfer to keratinocytes). Depigmentation results from amelanosis. The distribution pattern of hypopigmentation/depigmentation may be circumscribed, diffuse, guttate, or linear. Hair hypopigmentation/depigmentation may present as circumscribed poliosis (leukotrichia) or diffuse canities. Pigmentary dilution refers to diffuse hypopigmentation/depigmentation of the skin and hair ± eyes.
Hyperpigmentation may result from hypermelanosis or dermal deposition of exogenous substances. The distribution pattern of hyperpigmentation may be circumscribed, diffuse, linear, or reticulated.
Dyschromatoses are disorders characterized by both hypopigmentation and hyperpigmentation.
 VITILIGO → Diagnosis Group 1 Courtesy of Zelma Chiesa-Fuxench, MD, MSCE. |
Vitiligo results from autoimmune destruction of functional melanocytes.
Associations include AA, LE, lichen sclerosus (LS), halo nevi/melanoma, Addison disease, adult-onset insulin-dependent diabetes mellitus, autoimmune thyroid disease, pernicious anemia, and rheumatoid arthritis (RA).
Vitiligo is a characteristic feature of APECED/IPEX syndromes.
Drug associations include ICIs.
 Figure 2.18. CLINICOPATHOLOGICAL CORRELATION: VITILIGO. Vitiligo is characterized by absent or decreased melanocytes. Melanocyte stains include HMB-45, melan A (MART-1), MITF, S100, SOX10, while melanin stains include Fontana-Masson. A, H&E demonstrates total loss of melanocytes. B, S100 protein immunoperoxidase staining confirms the loss of melanocytes. H&E, hematoxylin and eosin; HMB, human melanoma black; MART, melanoma antigen recognized by T cells; MITF, microphthalmia-associated transcription factor; SOX10, sry-related HMg-Box gene 10. (Histology images reprinted with permission from Mills SE. Histology for Pathologists. 5th ed. Wolters Kluwer; 2019.) |
Generalized vitiligo may be classified as vulgaris, acrofacial, mixed, or universal. Localized vitiligo may be classified as focal, segmental, or mucosal.
While vitiligo vulgaris is the most common type in children, segmental vitiligo is relatively more common in children than adults.
Vitiligo vulgaris classically presents with circumscribed depigmented macules and patches favoring the face (periorificial), nipples, axillae, umbilical/sacral/inguinal/anogenital regions, and dorsal hands.
Poliosis may be observed.
Onset is typically insidious. Koebnerization is a known trigger.
Vitiligo variants include blue vitiligo (areas of postinflammatory hyperpigmentation), hypochromic vitiligo (hypopigmented macules in a seborrheic distribution), inflammatory vitiligo (erythematous border), trichrome/quadrichrome/pentachrome vitiligo (hypopigmented zone between normal and depigmented skin), and vitiligo ponctué (multiple discrete macules).
Vitiligo ponctué is also called “confetti-like” vitiligo.
Vitiligo syndromes include:
Alezzandrini syndrome: unilateral facial vitiligo and poliosis, ipsilateral ocular involvement (retinal pigment epithelial degeneration), and otic involvement (hypoacusis).
Kabuki syndrome: vitiligo, congenital heart defects, hemolytic anemia, idiopathic thrombocytopenic purpura, and thyroiditis.
Vogt-Koyanagi-Harada (VHK) syndrome: vitiligo and poliosis, alopecia, aseptic meningitis, ocular involvement (uveitis), and otic involvement (dysacusis/tinnitus).
The differential diagnosis of vitiligo includes:
Circumscribed (eg, vitiligo vulgaris): pityriasis alba, hypopigmented lesions of LS, sarcoidosis, halo nevi/melanoma-associated leukoderma, CTCL.
Diffuse (universal vitiligo): nutritional deficiencies (eg, copper deficiency/Menkes kinky hair disease, selenium deficiency).
Guttate (vitiligo ponctué): IGH characterized by guttate hypopigmentation favoring extensor forearms and shins, progressive macular hypomelanosis (PMH) characterized by guttate hypopigmentation in young women with darkly pigmented skin from the tropics, arsenic poisoning (see below).
Linear (segmental vitiligo): intralesional corticosteroids.
Hypopigmentation/depigmentation in multiple distribution patterns: postinflammatory (eg, LE), postinfectious (eg, treponematoses, leprosy, TV, onchocerciasis), posttraumatic (eg, cryotherapy), chemical (eg, phenols/catechols, sulfhydryls), and drug-induced (eg, topical corticosteroids, topical retinoids, kinase receptor/breakpoint cluster region-Abelson platelet-derived growth factor receptor [BCR-ABL/Kit/PDGFR] inhibitors, topical imiquimod).
The Wood’s lamp (nickel oxide-doped glass, peaks as 365 nm) can aid in the diagnosis of vitiligo by enhancing contrast between hypomelanosis and amelanosis.
Skin biopsies comparing melanocyte density in affected and unaffected skin may be helpful.
Mucosal involvement is associated with a poor prognosis.
Treatment options for vitiligo (in addition to psychological support) have differing goals:
Repigmentation: Topical corticosteroids, topical calcineurin inhibitors, and light devices (eg, phototherapy, excimer laser and lamp, helium-neon laser) are first line. Surgical options (eg, minigrafting of small punch biopsies from unaffected to affected skin) may be considered; however, risks include Koebnerization and keloiding. Emerging treatment options include afamelanotide and JAK inhibitors.
Camouflage: Permanent dermal micropigmentation utilizes a nonallergenic iron oxide pigment.
Depigmentation: Depigmentation (eg, with 20% monobenzyl ether of hydroquinone) may be considered for patients with widespread vitiligo who understand the significant impact depigmentation will have on their appearance and the need for lifelong strict photoprotection.
Vitiligo depigmentation and repigmentation each progress in a characteristic pattern. Peripheral hypopigmentation and poorly defined borders predict vitiligo activity. Repigmentation initially appears in a perifollicular pattern and/or at the periphery of vitiligo lesions.
Treatment options for vitiligo repigmentation are more effective in combination than as monotherapy.
ERYTHEMA DYSCHROMICUM PERSTANS
Synonyms: ashy dermatosis, dermatosis cenicienta
Reprinted with permission from Craft N, Fox LP, Goldsmith LA, et al. VisualDx: Essential Adult Dermatology. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010.
Erythema dyschromicum perstans (EDP) is an idiopathic disorder that most often occurs in adults from Latin America with skin phototypes III-IV.
EDP classically presents with symmetric gray-brown to blue-gray macules and patches favoring the neck, trunk, and proximal extremities.
The gray color of EDP lesions is reflected in its alternative names: ashy dermatosis and dermatosis cenicienta (Cinderella in Spanish).
Beyond EDP, disorders with circumscribed and diffuse hyperpigmentation include:
Melasma (circumscribed hyperpigmentation favoring the face and forearms, 90% in women with triggering factors including sun exposure, pregnancy, and OCPs).
Interface dermatoses and other CTDs (eg, LP pigmentosus, lichenoid drug eruption, fixed drug eruption [FDE], sclerodermoid disorders).
Metabolic disorders (eg, Addison disease, hyperthyroidism, primary biliary cirrhosis [PBC], and hemochromatosis), carotenemia (eg, diabetes mellitus, hypothyroidism), ectopic ACTH syndrome (eg, small-cell lung cancer).
Hemochromatosis is called “bronze diabetes” due to its association with diffuse hyperpigmentation and diabetes mellitus.
Depositional disorders, porphyrias, and nutritional deficiencies (eg, macular/lichen amyloidosis, porphyria cutanea tarda [PCT], vitamin B9 deficiency).
Postinflammatory hyperpigmentation (eg, acne vulgaris).
Postinfectious hyperpigmentation (eg, TV).
Posttraumatic hyperpigmentation (eg, cryotherapy).
Heavy metal and drug-induced hyperpigmentation or discoloration (Table 2.12).
Pregnancy (areolar hyperpigmentation, linea nigra, longitudinal melanonychia, melasma, darkening of preexisting nevi).
There is no consistently effective treatment for EDP. Treatments for hyperpigmentation include:
Photoprotection and camouflage facial foundations.
Topical hydroquinone (2%-4%, more effective if pigmentation is limited to the epidermis and in combination with a topical corticosteroid and a topical retinoid than as monotherapy).
Topical azelaic acid, α-hydroxy acids, β-hydroxy acids, kojic acid, and vitamin C.
Chemical peels (eg, glycolic acid, salicylic acid).
Lasers (eg, Q-switched ruby, alexandrite, and neodymium-doped yttrium aluminum garnet [Nd:YAG]) and intense pulsed light (IPL).
 Figure 2.19. CLINICOPATHOLOGICAL CORRELATION: ERYTHEMA DYSCHROMICUM PERSTANS. Active EDP is characterized by increased epidermal melanin, vacuolar degeneration of the basal cell layer, and a sparse perivascular lymphocytic infiltrate with melanophages. A, H&E. B, Fontana-Masson. EDP, erythema dyschromicum perstans; H&E, hematoxylin and eosin. |
Table 2.12. HEAVY METAL AND DRUG-INDUCED HYPERPIGMENTATION OR DISCOLORATION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 PIGMENTARY DEMARCATION LINES Synonyms: Ito lines, Futcher lines, Voight lines Reprinted with permission from Lugo-Somolinos A, McKinley-Grant L, Goldsmith LA, et al. VisualDx: Essential Dermatology in Pigmented Skin. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011 |
Pigmentary demarcation lines separate relatively hyperpigmented dorsal surfaces from ventral surfaces. They are more readily apparent in individuals with darkly pigmented skin.
Pigmentary demarcation lines may be classified into eight types:
A: Vertical line along anterolateral upper arm.
B: Curved line on the posteromedial thigh.
C: Vertical or curved hypopigmented band on the midchest.
D: Vertical pre- or paraspinal line.
E: Bilateral chest markings.
F, G: “V-” or “W”-shaped lines between lateral temple and malar prominence.
H: Diagonal line from oral commissure to lateral chin.
Pigmentary demarcation lines have normal histopathology.
Beyond pigmentary demarcation lines, other acquired disorders with linear hyperpigmentation include linea nigra (linear hyperpigmentation extending from the umbilicus to the pubis in pregnant women), linear postinflammatory hyperpigmentation (eg, linear LP, phytophotodermatitis), flagellate hyperpigmentation (eg, bleomycin, Shiitake mushrooms), and serpentine supravenous hyperpigmentation (eg, 5-fluorouracil [5-FU]). Wallace lines separate dorsal (hair bearing) skin from palmoplantar (glabrous) skin.
Pigmentary demarcation lines are normal. No treatment is indicated.
PRURIGO PIGMENTOSA
Courtesy of William James, MD.
Prurigo pigmentosa is an idiopathic disorder that most often occurs in young adults from Japan. Prurigo pigmentosa is associated with nutrition (eg, strict ketogenic diet).
Prurigo pigmentosa classically presents with recurrent crops of pruritic erythematous papules and papulovesicles favoring the neck, chest, and back. Lesions involute within a week, leaving behind macular reticulated hyperpigmentation.
Prurigo pigmentosa has three histopathologic stages: (1) neutrophilic exocytosis, spongiosis, papillary dermal edema, and a superficial perivascular neutrophilic infiltrate; (2) intra-/subepidermal vesiculation, necrotic keratinocytes, and a patchy lichenoid infiltrate of lymphocytes > eosinophils; and (3) variable parakeratosis, acanthosis, and hyperpigmentation of the epidermis with dermal melanophages.
Beyond prurigo pigmentosa, other acquired disorders with reticulated hyperpigmentation include CARP, atopic “dirty neck,” reticulated postinflammatory hyperpigmentation, erythema ab igne (EAI), and reticulated drug-induced hyperpigmentation.
Treatment options for prurigo pigmentosa include minocycline, doxycycline, and dapsone.
 SPOTLIGHT ON INCONTINENTIA PIGMENTI Synonym: Bloch-Sulzberger syndrome |
IP is a neurocutaneous disorder due to XLD mutation in NEMO, also known as IKBKG (inhibitor of κ light polypeptide gene enhancer in B cells, kinase γ). The gene product, NF-κB essential modulator, protects against apoptosis induced by the TNF cytokine family. IP is lethal in males (unless XXY or mosaic) and has a variable phenotype in females due to lyonization. Female carriers of hypohidrotic ectodermal dysplasia with immune deficiency due to X-linked recessive (XLR) NEMO mutation may have mild IP.
Skin lesions of IP follow lines of Blaschko and evolve through four classic stages: vesicular (birth-2 weeks), verrucous (2-6 weeks), hyperpigmented (3-6 months), and hypopigmented/atrophic (2nd-3rd decade). There is overlap (eg, older children can still have areas of blistering while developing hyperpigmentation). Patients may also develop periungual/subungual keratotic tumors and adnexal involvement (eg, anhidrosis, patchy scarring alopecia, onychodystrophy). Systemic features include dental (eg, hypodontia, conical teeth), neurologic (eg, seizures), and/or ophthalmologic (eg, retinal vascular abnormalities).
Remember that X-linked dominant (XLD) NEMO mutation in IP leads to striped skin lesions along lines of Blaschko by remembering that Nemo has become a popular name for striped clown fish.
IP must be distinguished from other hereditary pigmentary disorders (Table 2.13). Skin biopsy may be helpful to establish the diagnosis, along with genetic testing.
While skin lesions of IP do not require treatment, patients should be referred for dental, neurologic, and ophthalmologic evaluation.
 Figure 2.20. CLINICOPATHOLOGICAL CORRELATION: INCONTINENTIA PIGMENTI. The four classic stages of IP may overlap. Each of the four classic stages of IP is characterized by apoptotic keratinocytes. A, Vesicular stage. Solid arrow: eosinophilic spongiosis and vesiculation with eosinophils. B, Verrucous stage. Dashed arrow: dyskeratosis. IP, incontinentia pigmenti. (Histology images reprinted with permission from Husain AN. Biopsy Interpretation of Pediatric Lesions. Wolters Kluwer; 2014.) Stages: • Vesicular: eosinophilic spongiosis. • Verrucous: hyperkeratosis and papillomatosis with prominent dyskeratosis in whorls and clusters. • Hyperpigmented: pigment incontinence. • Hypopigmented: normal to decreased melanocytes ± dermal fibrosis. |
Table 2.13. HEREDITARY PIGMENTARY DISORDERS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Vesiculobullous disorders are often categorized according to the level at which the split occurs in the skin: subcorneal, intraepidermal, and/or subepidermal.
Pathogenetic mechanisms include autoimmune, druginduced, and genetic disorders. Edema (see Chapter 2: Livedo Reticularis, Purpura, and Other Vascular Disorders) and physical agents (see Chapter 4: Other Physical Agents) may also lead to blister formation.
A variety of techniques are available for the diagnosis of autoimmune blistering disorders. The optimal approach for obtaining biopsy specimens is as follows:
Biopsy a fresh vesicle or edematous papule. Otherwise, biopsy the edge of a fresh vesicle or bulla including the inflammatory rim. In pemphigus, a Tzanck smear may be helpful to reveal acantholytic epidermal cells within the blister cavity but cannot substitute for a biopsy.
Direct immunofluorescence (DIF) is the most reliable and sensitive diagnostic test. To avoid negative staining due to secondary degeneration of target antigens and immunoreactants, biopsy for DIF should be perilesional in pemphigus and pemphigoid and should sample adjacent normal skin in dermatitis herpetiformis (DH).
 ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS → Diagnosis Group 2 Synonym: pustular drug eruption |
AGEP may be classified as a delayed-type, cell-mediated (type IV) severe cutaneous adverse reaction (SCAR). The hypothesized mechanism is neutrophil and T-cell activation leading to release of chemokines such as CXC chemokine ligand 8 (CXCL8) and cytokines such as granulocyte-monocyte colony stimulating factor (GM-CSF).
Drug associations include β-lactams, macrolides, ICIs, and CCBs (eg, diltiazem). Other triggers include iodinated radiocontrast media, mercury, peritoneal dialysate, and enteroviral infection.
Urticaria after iodinated radiocontrast media is immediate, while reactions delayed 1 hour to 1 week include AGEP, SDRIFE, morbilliform drug eruption/DRESS, and iododerma.
AGEP characteristically presents with erythema studded with numerous, nonfollicular, sterile pustules that starts on the face and/or intertriginous zones. Edema of the face and hands may be present, and patients may exhibit fever, neutrophilia, and hypocalcemia. Pustules resolve with pinpoint desquamation.
The timing of AGEP relative to initial drug exposure is typically <4 days.
Acute generalized exanthematous pustulosis.
AGEP may present with multiorgan involvement (liver > kidney > lung) in a minority of patients.
The differential diagnosis for the pustules of AGEP is similar to pustular psoriasis.
In neonates, the differential diagnosis for sterile pustules includes transient neonatal pustular melanosis and erythema toxicum neonatorum (Table 2.14).
Transient neonatal pustular melanosis is characterized by subcorneal pustules with neutrophils > eosinophils.
Erythema toxicum neonatorum is characterized by intrafollicular, subcorneal, or intraepidermal pustules with eosinophils > neutrophils.
The differential diagnosis for the confluent erythema of AGEP includes other drug reactions, acute graftversus-host disease (GVHD), Kawasaki disease, and infections (eg, toxic shock syndrome).
The EuroSCAR validation score categorizes cases as definite, probable, possible, or no AGEP.
AGEP has a 1% to 2% reported mortality rate (controversial).
Discontinuation of the suspected drug along with all non-essential drugs is the first step. In-vitro assays to establish the culprit drug are under investigation. However, given uncertain sensitivity and specificity, their utility remains limited in clinical practice. 50% to 60% of patients are patch test positive. While AGEP is drug associated in 70% to 90% of cases, it is important to consider alternative etiologies.
Topical corticosteroids are first line.
 Figure 2.21. CLINICOPATHOLOGICAL CORRELATION: ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS. Characteristic features are subcorneal or superficial epidermal pustules, mild spongiosis, papillary dermal edema, and a superficial mixed infiltrate with neutrophils and eosinophils. AGEP, acute generalized exanthematous pustulosis. (Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.) (Illustration by Caroline A. Nelson, MD.) |
Table 2.14. TRANSIENT NEONATAL PUSTULAR MELANOSIS AND ERYTHEMA TOXICUM NEONATORUM | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Table 2.15. DIFFERENTIATING SELECTED DRUG REACTIONS | |||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||||||||||||||||||||||||
The presence of confluent pustules mimicking Nikolsky sign (see below) and desquamation in AGEP often prompts dermatology consultation to “rule out Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).” The key distinguishing feature is the superficial split in AGEP, which can be demonstrated by skin biopsy, if necessary.
Facial edema is a helpful diagnostic clue in both AGEP and DRESS.
PEMPHIGUS FOLIACEUS
PF is characterized by circulating autoantibodies to desmoglein 1. Jewish ancestry is a risk factor. Drug associations include ACEIs and D-penicillamine (PF > PV). Fogo selvagem is an endemic form of PF in rural Brazil that may be transmitted by the black fly (genus Simulium).
Mutation of desmoglein 1 leads to striate PPK and toxin-mediated cleavage of desmoglein 1 occurs in bullous impetigo and SSSS.
The classic presentation of PF is scaly crusted erosions favoring a seborrheic distribution. The lack of mucosal involvement in PF may be explained by the desmoglein compensation theory (Figure 2.22). Pemphigus erythematosus (Senear-Usher syndrome) is a localized PF variant, most notably on the malar region of the face that may overlap with LE. Pemphigus herpetiformis is a PF variant that classically presents with herpetiform erythematous urticarial plaques and tense vesicles.
Figure 2.22. THE DESMOGLEIN COMPENSATION THEORY. The desmoglein compensation theory holds that desmoglein 1 and 3 compensate for each other when coexpressed in the same cell. The distribution of desmoglein 1 (light blue) and desmoglein 3 (dark blue) in the skin and mucous membranes explains the distribution of pemphigus lesions. PF, pemphigus foliaceous; PV, pemphigus vulgaris.
The scaly crusted erosions of PF have been described as “corn flakes” pasted to the skin.
Obtain biopsies for hematoxylin and eosin (H&E) and perilesional DIF. To optimize sensitivity, indirect immunofluorescence (IIF) may be performed on human skin and guinea pig esophagus. Enzyme-linked immunosorbent assay (ELISA) can detect circulating autoantibodies to desmoglein 1.
 PEMPHIGUS VULGARIS → Diagnosis Group 2 Courtesy of Erin Wei, MD. |
 Figure 2.23. CLINICOPATHOLOGICAL CORRELATION: PEMPHIGUS FOLIACEUS. Characteristic features are a subcorneal split with acantholysis. Dyskeratosis may be present in the granular layer. Neutrophils and occasional eosinophils may be present in the blister cavity. DIF classically demonstrates intercellular deposition of IgG and C3 between keratinocytes in the upper epidermis. A, H&E. B, DIF (IgG). C, complement; DEJ, dermal-epidermal junction; DIF, direct immunofluorescence; GPCs, Gram-positive cocci; Ig, immunoglobulin; LE, lupus erythematosus; PF, pemphigus foliaceous; SSSS, staphylococcal scalded skin syndrome. (Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.) B, DIF (IgG) (Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.) Acantholytic cells on the blister roof (“cling ons”) provide a helpful diagnostic clue. The DIF pattern has been described as “chicken wire,” “lace-like,” or “net-like.” • Pemphigus erythematosus variant: resembles PF. When pemphigus erythematosus overlaps with LE, DIF classically demonstrates granular deposition of IgM, IgG, IgA, and C3 along the DEJ. • Pemphigus herpetiformis variant: eosinophilic spongiosis and subcorneal pustules with minimal to no acantholysis. |
PV is characterized by circulating autoantibodies to desmoglein 3 (mucosal dominant type, ˜50% of cases) or desmogleins 1 and 3 (mucocutaneous type, ˜50% of cases).
The desmoglein compensation theory explains why neonates manifest PV (30%-45%) but rarely manifest PF. Maternal IgG autoantibodies cross the placenta in both disorders; however, desmoglein 3 is distributed throughout neonatal skin (similar to the mucous membranes), compensating for desmoglein 1.
Jewish ancestry is a risk factor.
Drug associations include ACEIs and D-penicillamine (PF > PV).
HLA associations include -DR4 and -DR6.
PV presents on the oral mucosa in 70% to 90% of patients, with painful erosions that favor the buccal and palatine mucosa. When the gingiva is involved, patients present with desquamative gingivitis. The lack of skin involvement in mucosal-dominant PV may be explained by the desmoglein compensation theory.
PV on the skin is characterized by flaccid blisters that rupture to form painful crusted erosions that ooze and bleed. PV heals with pigmentary changes but not scarring.
Lack of cohesion within the epidermis may be demonstrated by the Nikolsky sign (lateral movement of the upper epidermis with slight pressure or rubbing) and the Asboe-Hansen sign (spread of fluid under the skin with gentle pressure on an intact bulla).
Pemphigus herpetiformis may rarely present as a PV variant.
Pemphigus vegetans is a PV variant that classically presents with flaccid pustules that become erosions and then form vegetating papillomatous plaques favoring intertriginous areas, the scalp, and the face. It is divided into the Neumann type (severe) and the Hallopeau type (mild).
The differential diagnosis for mucosal PV includes mucous membrane pemphigoid (MMP), LP, EM or SJS/TEN, SLE, aphthous stomatitis, and acute herpetic stomatitis. Desquamative gingivitis must be distinguished from necrotizing ulcerative gingivitis caused by bacteria belonging to the normal oral flora.
The differential diagnosis for cutaneous PV includes other forms of pemphigus, Hailey-Hailey disease, BP, linear IgA bullous dermatosis (LABD), EM or SJS/TEN, and Grover disease (GD).
Figure 2.24. CLINICOPATHOLOGICAL CORRELATION: PEMPHIGUS VULGARIS. Characteristic features are a suprabasal split with acantholysis tracking down adnexal structures. Eosinophils may be present in the blister cavity and the dermis alongside lymphocytes. DIF classically demonstrates intercellular deposition of IgG and C3 between keratinocytes in the lower epidermis. A, H&E. B, DIF (IgG). C, complement; DIF, direct immunofluorescence; H&E, hematoxylin & eosin; Ig, immunoglobulin; PEH, pseudoepitheliomatous hyperplasia.
(A, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD. B, Histology image courtesy of Kim B. Yancey, MD. From Gru AA, Wick MR, Mir A, et al. Pediatric Dermatopathology and Dermatology. Wolters Kluwer; 2018.)
The row of cells (“tombstones”) covering dermal papillae (“villi”) provides a helpful diagnostic clue.
The DIF pattern has been described as “chicken wire,” “lace-like,” or “net-like.”
• Pemphigus herpetiformis variant: eosinophilic spongiosis and subcorneal pustules with minimal to no acantholysis.
• Pemphigus vegetans variant: suprabasal acantholysis, acanthosis, papillomatosis, PEH with intraepidermal pustules, and an eosinophilrich inflammatory infiltrate.
Obtain biopsies for H&E and perilesional DIF. To optimize sensitivity, IIF may be performed on monkey esophagus. ELISA can detect circulating autoantibodies to desmogleins 1 and 3.
The monkey is vulgar (IIF on monkey esophagus in pemphigus vulgaris).
Untreated PV has a poor prognosis, resulting in death within 2 to 5 years due to loss of body fluids or to secondary bacterial infections.
Systemic corticosteroids are first line. Rituximab may be given 375 mg/m2 once weekly for 4 weeks (“lymphoma dosing”) or 1 g initially then at 2 weeks (“rheumatoid arthritis dosing”). Other steroid-sparing therapies include azathioprine, IVIG, methotrexate, mycophenolate mofetil, and plasmapheresis or extracorporeal photopheresis (ECP).
Pemphigus Disease Area Index (PDAI) and Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) are commonly used indices for disease activity. Autoantibody levels often correlate with disease activity and are therefore useful for assessing response to treatment and predicting flares or relapses before they are clinically evident.
Rituximab resistance can develop due to genetic polymorphisms (FCGR3A) or human antichimeric antibodies against its murine fragment that prevent binding to B cells. There are no commercially available tests; however, “lymphoma dosing” optimizes B-cell depletion by increasing serum levels.
Look out for novel therapies coming down the pipeline for PV, such as the use of chimeric autoantibody receptor (CAR) T cells to eliminate desmoglein-specific B cells.
IMMUNOGLOBULIN A PEMPHIGUS
Courtesy of Sotonye Imadojemu, MD, MBE.
IgA pemphigus typically occurs in middle-age or elderly persons. It may be divided into the SPD type and the intraepidermal neutrophilic (IEN) type. The SPD type is characterized by circulating autoantibodies to desmocollin 1, while the antigen in the IEN type has not been fully characterized. Associations include ulcerative colitis and IgA monoclonal gammopathy.
Figure 2.25. CLINICOPATHOLOGICAL CORRELATION: IgA PEMPHIGUS. IgA pemphigus is characterized by the formation of intraepidermal pustules. Acantholysis is rarely present. DIF classically demonstrates intercellular deposition of IgA between keratinocytes. A, Subcorneal pustular dermatosis subtype. B, Intraepidermal neutrophilic subtype. DIF, direct immunofluorescence; Ig, immunoglobulin.
(A, Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015. B, Histology image reprinted with permission from Gru AA, Wick MR, Mir A, et al. Pediatric Dermatopathology and Dermatology. Wolters Kluwer; 2018.)
• Subcorneal pustular dermatosis variant: pustules in the upper epidermis.
• Intraepidermal neutrophilic variant: pustules in the lower epidermis.
The classic presentation of IgA pemphigus is flaccid blisters or pustules in an annular or circinate pattern favoring intertriginous areas.
The configuration of the IEN type has been likened to a “sunflower.”
Immunofluorescence studies are required to distinguish the SPD type from classic SPD (Sneddon-Wilkinson disease).
Dapsone is first line.
PARANEOPLASTIC PEMPHIGUS
Courtesy of Sotonye Imadojemu, MD, MBE.
Paraneoplastic pemphigus (PNP) is characterized by circulating autoantibodies to desmoglein 1 and 3 along with a diverse array of antigens including desmocollins, members of the plakin family (BPAG1, desmoplakins I and II, envoplakin, epiplakin, periplakin, plectin), plakophilin, and the protease inhibitor alpha-2-macroglobulin-like 1. The pathogenesis of PNP involves both humoral autoimmunity and cell-mediated cytotoxicity, explaining its polymorphic and refractory presentation. In adults, the most common association is non-Hodgkin lymphoma (NHL). Other associations include Castleman disease, chronic lymphocytic leukemia (CLL), and thymoma. Drug associations include rituximab, bendamustine, and fludarabine.
Castleman disease is the most common association with PNP in children and adolescents.
The classic presentation of PNP is intractable stomatitis, often involving the entire oropharynx and extending on to the vermillion lip. Pseudomembranous conjunctivitis may lead to blindness, and all mucosal surfaces may be affected. Skin lesions are polymorphic (erythematous macules, flaccid blisters and erosions, tense blisters, EM-like lesions, and lichenoid eruptions). Bronchiolitis obliterans may lead to respiratory failure.
Obtain biopsies for H&E and perilesional DIF. To optimize sensitivity, IIF may be performed on guinea pig esophagus, monkey esophagus, and rat bladder (antiplakin). ELISA can detect circulating autoantibodies to desmogleins 1 and 3, BPAG1, envoplakin, and periplakin. To evaluate for bronchiolitis obliterans, it is important to obtain pulmonary function tests (PFTs), as chest x-ray (CXR) and computed tomography (CT) chest may be normal.
PNP has a 90% mortality rate. Unfortunately, PNP is often refractory to treatment of the associated neoplasm. Benign neoplasms such as localized Castleman disease or thymomas should be excised. Management of PNP is similar to PV with the addition of therapies directed against cellmediated cytotoxicity such as alemtuzumab.
 Figure 2.26. CLINICOPATHOLOGICAL CORRELATION: PARANEOPLASTIC PEMPHIGUS. PNP exhibits a combination of PV-like, LP-like, or EM-like patterns. DIF classically demonstrates intercellular deposition of IgG and C3 between keratinocytes, primarily in the lower epidermis, and linear deposition of IgG and C3 along the DEJ. A, H&E (lichen planus-like pattern). B, DIF (IgG). C, complement; DEJ, dermal-epidermal junction; DIF, direct immunofluorescence; EM, erythema multiforme; H&E, hematoxylin and eosin; Ig, immunoglobulin; LP, lichen planus; PNP, paraneoplastic pemphigus; PV, pemphigus vulgaris. (Histology images reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.) |
 SPOTLIGHT ON HAILEY-HAILEY DISEASE AND DARIER DISEASE Hailey-Hailey disease synonym: familial benign chronic pemphigus Darier disease synonym: keratosis follicularis Hailey-Hailey disease (left) courtesy of Victoria Werth, MD. Darier disease (right). |
Hailey-Hailey disease and Darier disease are AD genetic disorders due to mutations in genes encoding Ca2+ ATPase pumps. Abnormal intracellular Ca2+ signaling leads to impaired processing of junctional proteins, resulting in acantholytic dyskeratosis.
Do NOT confuse Darier disease with the “Darier sign” of mastocytosis.
Hailey-Hailey disease and Darier disease are compared and contrasted in Table 2.16.
Acrokeratosis verruciformis of Hopf may clinically mimic Darier disease, with warty papules favoring the dorsal hands and feet.
Common treatments include antimicrobial washes and ablative or surgical therapies. Additional treatments for Hailey-Hailey disease include local corticosteroids, naltrexone, and botulinum toxin, while additional treatments for Darier disease include keratolytic emollients and retinoids.
Table 2.16. HAILEY-HAILEY DISEASE AND DARIER DISEASE | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||
 Figure 2.27. CANDY CANE NAILS. Darier disease is characterized by longitudinal erythronychia and longitudinal leukonychia. These red and white bands are often referred to as “candy cane nails.” “V-shaped” nicking of the distal nail plate is pathognomonic. (Darier disease image reprinted with permission from Gru AA, Wick MR, Mir A, et al. Pediatric Dermatopathology and Dermatology. Wolters Kluwer; 2018.) |
 Figure 2.28. SIDE-BY-SIDE COMPARISON: HAILEY-HAILEY DISEASE AND DARIER DISEASE. Both Hailey-Hailey disease and Darier disease* are characterized by acantholytic dyskeratosis and a superficial perivascular lymphocytic infiltrate. Hailey-Hailey disease demonstrates acanthosis and acantholysis at all levels of the epidermis. Acantholysis in Darier disease is accentuated in the lower epidermis, forming suprabasal celfts. There is papillomatosis and hyperkeratosis. Grains classically occur in the stratum corneum and corps ronds classically occur in the stratum spinosum. A, Hailey-Hailey disease. B, Darier disease. Solid arrow: grain. Dashed arrow: corps rond. (Histology image A reprinted with permission from Husain AN, Stocker JT, Dehner LP. Stocker and Dehner’s Pediatric Pathology. 5th ed. Wolters Kluwer; 2021.) Acantholysis in Hailey-Hailey disease resembles a “dilapidated brick wall.” Acrokeratosis verruciformis of Hopf is warty due to “church spire” hyperkeratosis, papillomatosis, and acanthosis. |
 GROVER DISEASE Synonym: transient acantholytic dermatosis Reprinted with permission from Schalock PC, Hsu JTS, Arndt KA. Lippincott’s Primary Care Dermatology. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010. |
GD most often affects older White men with a peak onset in the winter. Triggers include heat, occlusion, sweating, UVR, and xerosis.
President Grover Cleveland was an older White man.
GD classically presents with an intensely pruritic papulovesicular eruption favoring the trunk.
Grover disease may exhibit a variety of patterns including PV-like, Hailey-Hailey disease-like, Darier disease-like, or spongiotic with minimal acantholysis.
GD is typically self-limited over weeks to months but may persist for years. First-line therapies include emollients, topical corticosteroids, topical vitamin D analogues, and oral antihistamines.
Transient acantholytic dermatosis.
 BULLOUS PEMPHIGOID → Diagnosis Group 2 |
BP is characterized by circulating autoantibodies to BPAG1 and BPAG2 (NC16A domain).
Advanced age (>60 years old) and male sex are risk factors: the relative risk of BP in patients over 90 years old is ˜300-fold higher than in patients 60 years old or younger.
BP is commonly associated with neurological disorders (eg, Parkinson disease).
While reported drug associations include β-lactams, ACEIs, and diuretics (eg, furosemide), the most compelling evidence exists for ICIs and dipeptidyl peptidase-4 (DPP-4) inhibitors.
BP is characterized by tense blisters on apparently normal or erythematous skin and annular or figurate urticarial and infiltrated papules and plaques favoring the flexural extremities and lower trunk. 10% to 30% of patients exhibit oral mucosal involvement. BP heals with pigmentary changes and occasionally milia.
Infantile and childhood BP classically presents with acral bullae.
BP may be associated with peripheral hypereosinophilia (˜50%) and elevated IgE.
Figure 2.29. CLINICOPATHOLOGICAL CORRELATION: BULLOUS PEMPHIGOID. Characteristic features are a subepidermal split and a predominantly eosinophilic infiltrate. DIF classically demonstrates linear deposition of IgG and C3 along the DEJ in an n-serrated pattern. A, H&E. B, DIF (IgG). BP, bullous pemphigoid; C, complement; DEJ, dermal-epidermal junction; DH, dermatitis herpetiformis; DIF, direct immunofluorescence; EBA, epidermolysis bullosa acquisita; H&E, hematoxylin and eosin; Ig, immunoglobulin; LABD, linear IgA bullous dermatosis; MMP, mucous membrane pemphigoid; PCT, porphyria cutanea tarda; SJS/TEN, Stevens-Johnson syndrome/toxic epidermal necrolysis; SLE, systemic lupus erythematosus.
(Histology images reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
• Nonbullous variant: eosinophilic spongiosis and/or dermal infiltrates.
• Pemphigoid vegetans variant: subepidermal split, epidermal hyperplasia, and an eosinophil-rich inflammatory infiltrate.
The intensity of inflammation can be a helpful clue to differentiate subepidermal blisters:
• Pauci-inflammatory: EBA (noninflammatory variant), SJS/TEN, PCT, pseudoporphyria In urticarial nonbullous BP, look for eosinophils “lined up” along the DEJ.
Nonbullous BP is a BP variant that classically presents with intractable pruritus ± eczematous and/or fixed urticarial lesions and often precedes the development of blisters (prodrome).
Pemphigoid vegetans is a BP variant that classically presents with blisters that form vegetating plaques favoring intertriginous areas.
Other clinical variants include dyshidrosiform pemphigoid, eczematous pemphigoid, erythrodermic pemphigoid, large erosive TEN-like lesions, papular pemphigoid, pemphigoid nodularis, and vesicular pemphigoid. Localized BP may also occur (eg, distal end of amputated limb, paralyzed limb, peristomal, pretibial, radiation therapy sites, umbilical, vulvar).
The differential diagnosis for nonbullous BP includes eczematous dermatoses, urticarial dermatoses, prurigo nodularis, arthropod assault, and drug reactions.
The differential diagnosis for bullous BP includes other subepidermal autoimmune blistering disorders (Table 2.17),
bullous eczematous dermatoses, SJS/TEN, PCT, pseudoporphyria, bullous diabeticorum (tense acral blisters), and bullous arthropod assault.
Obtain biopsies for H&E and perilesional DIF. To optimize sensitivity, IIF should be performed on salt-split human skin (epidermal ± dermal). ELISA can detect circulating autoantibodies to BPAG1 and BPAG2.
Systemic corticosteroids are first line. Potent topical corticosteroids have been shown to have equivalent efficacy, fewer adverse events, and reduced mortality. The next step on the therapeutic ladder for mild and/or localized BP is the combination of nicotinamide (500-2000 mg/d) with doxycycline, minocycline, or tetracycline. Steroid-sparing therapies are similar to PV, with additions including dapsone, dupilumab, and omalizumab.
Table 2.17. SUBEPIDERMAL AUTOIMMUNE BLISTERING DISORDERS
Diagnosisa
Classic Description
Notes
BPb
See above
Pemphigoid gestationis
Presents in late pregnancy or postpartum with BP-like skin lesions involving the umbilicus. Commonly recurs with menstruation, OCPs, and subsequent pregnancies.
Characterized by circulating autoantibodies to BPAG2 (NC16A domain) (epidermal staining on IIF of salt-split human skin). Associations in addition to pregnancy include trophoblastic tumors (eg, choriocarcinoma). HLA associations include -DR3 and -DR4. Increased risk of maternal Graves disease. Increased risk of prematurity, SGA, and mild and transient skin lesions (˜10%) in neonates. While antihistamines and topical corticosteroids are preferred, systemic corticosteroids (prednisolone) are often required.
Anti-p105 pemphigoid
Presents with extensive TEN or PV-like skin and mucosal lesions.
The antigen has not been fully characterized (dermal staining on IIF of salt-split human skin).
Anti-p200 pemphigoid
Presents with BP-like skin lesions but in a younger age group with significant acral and cephalic distribution and mucosal involvement.
Characterized by circulating autoantibodies to laminin γ1 (dermal staining on IIF of salt-split human skin).
LABD
See below.
MMP
See below.
EBA
See below.
Bullous SLE
See Chapter 2: Interface Dermatoses and Other Connective Tissue Disorders.
BP, bullous pemphigoid; BPAG2, bullous pemphigoid antigen 2; EBA, epidermolysis bullosa acquisita; HLA, human leukocyte antigen; IIF, indirect immunofluorescence; LABD, linear IgA bullous dermatosis; MMP; mucous membrane pemphigoid; OCP, oral contraceptive pill; PV, pemphigus vulgaris; SGA, small for gestational age; SLE, systemic lupus erythematosus; TEN, toxic epidermal necrolysis
a Illustrative examples provided.
b Four clinical criteria were reported to indicate a diagnosis of BP over other subepidermal autoimmune blistering disorders: (1) absence of skin atrophy; (2) absence of mucosal involvement; (3) absence of head and neck involvement; and (4) age greater than 70 years.
The BP Disease Area Index (BPDAI) and daily blister count are commonly used indices for disease activity. Autoanti-body levels may correlate with disease activity; however, this is not well established.
It is important to maintain a high level of suspicion for BP in older adults with unexplained generalized pruritus.
Pemphigoid incipiens refers to the presence of circulating autoantibodies to BPAG1 and/or BPAG2 without a confirmatory DIF or IIF. A subset of these patients will eventually develop BP.
Figure 2.30. THE SALT SPLIT-SKIN TECHNIQUE FOR DIFFERENTIATING SUBEPIDERMAL AUTOIMMUNE BLISTERING DISORDERS. Normal human skin is incubated in 1 M NaCl, resulting in a split in the lower portion of the lamina lucida. Using immunofluorescence to determine whether autoantibodies are bound to the epidermal side (roof) or dermal side (floor) helps to differentiate subepidermal autoimmune blistering disorders. A, Salt-split DIF of BP reveals IgG deposition on the epidermal side. B, Salt-split DIF of EBA reveals IgG deposition on the dermal side. BP, bullous pemphigoid; BPAG1, bullous pemphigoid antigen 1; BPAG2, bullous pemphigoid antigen 2; EBA, epidermolysis bullosa acquisita; Ig, immunoglobulin; LABD, linear IgA bullous dermatosis; MMP, mucous membrane pemphigoid; SLE, systemic lupus erythematosus.
(Histology images reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
LINEAR IMMUNOGLOBULIN A BULLOUS DERMATOSIS
LABD may be divided into a lamina lucida type (majority) and a sublamina densa type. The lamina lucida type is characterized by circulating IgA autoantibodies to BPAG1 and BPAG2, specifically a 120 kDa LAD antigen that corresponds to the cleaved shed extracellular domain of BPAG2 and a 97 kDa LAD antigen that results from further proteolytic degradation. The antigen in the sublamina densa type has not been fully characterized. Drug associations include vancomycin >>> β-lactams, ACEIs, NSAIDs, and vaccinations (eg, influenza).
LABD classically presents with herpetiform tense blisters with variable mucosal involvement.
The configuration of LABD is often described as a “crown of jewels.”
Pediatric LABD, chronic bullous disease of childhood, typically presents in preschool age children in flexural areas (eg, the lower trunk, thigh, groin) and remits in 2 to 4 years.
Figure 2.31. CLINICOPATHOLOGICAL CORRELATION: LINEAR IgA BULLOUS DERMATOSIS. Characteristic features are a subepidermal split and a predominantly neutrophilic infiltrate. DIF classically demonstrates linear deposition of IgA along the DEJ. A, H&E. B, DIF (IgA). DEJ, dermal-epidermal junction; DIF, direct immunofluorescence; H&E, hematoxylin and eosin; Ig, immunoglobulin.
(Histology images reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
Obtain biopsies for H&E and perilesional DIF. To optimize sensitivity, IIF should be performed on salt-split human skin (epidermal).
After discontinuation of the suspected drug, dapsone is first line.
MUCOUS MEMBRANE PEMPHIGOID
Synonym: cicatricial pemphigoid
Courtesy of Erin Wei, MD.
MMP constitutes a disease phenotype. The first subgroup is anti-laminin-332 MMP (anti-epiligrin MMP), associated with solid > liquid tumors (eg, gastrointestinal, lung). The second subgroup is ocular MMP in which integrin subunit β4 is the characteristic target antigen. The third subgroup is anti-BP antigen MMP in which BPAG2 (c-terminus) is the characteristic target antigen. The fourth subgroup is heterogeneous. Advanced age and female sex are risk factors for MMP.
To remember that integrin subunit β4 is a target antigen in ocular MMP, rotate β 90° clockwise to form eyeglasses.
The C-terminus extends into the lamina densa, which explains why the inflammation is cicatricial.
MMP classically presents with desquamative gingivitis. Conjunctival involvement in ˜40% of patients may lead to progressive scar tissue formation (eg, symblepharon, ankyloblepharon, trichiasis, entropion) and ultimately blindness. Cutaneous involvement in 25% to 40% of patients is characterized by erythematous plaques ± blisters that heal with scarring. Brunsting-Perry pemphigoid is a clinical MMP variant with skin lesions favoring the head and neck and minimal to absent mucosal involvement. Complications include scarring alopecia and dorsal pterygium.
Figure 2.32. CLINICOPATHOLOGICAL CORRELATION: MUCOUS MEMBRANE PEMPHIGOID. Characteristic features are a subepidermal split, a predominantly neutrophilic infiltrate, and scarring in the upper dermis. DIF classically demonstrates linear deposition of IgG and C3 along the DEJ. C, complement; DEJ, dermal-epidermal junction; DIF, direct immunofluorescence; H&E, hematoxylin and eosin; Ig, immunoglobulin.
(Histology image reprinted with permission from Stelow EB, Mills S. Biopsy Interpretation of the Head and Neck. 3rd ed. Wolters Kluwer; 2020.)
Obtain biopsies for H&E and perilesional DIF (ideally mucosal). To optimize sensitivity, IIF should be performed on salt-split human skin (epidermal with the exception of anti-laminin-332 MMP) and normal oral or genital mucosa or conjunctiva. ELISA can detect circulating autoantibodies to desmogleins 1 and 3, BPAG1, envoplakin, and periplakin.
Topical corticosteroids and dapsone are first line. Cyclophosphamide and rituximab are the treatments of choice for rapidly progressive or severe ocular MMP.
EPIDERMOLYSIS BULLOSA ACQUISITA
Reprinted with permission from Krakowski AC, Shumaker PR. The Scar Book: Formation, Mitigation, Rehabilitation and Prevention. Wolters Kluwer; 2017.
Epidermolysis bullosa acquisita (EBA) is characterized by circulating autoantibodies to collagen VII. The most common association is IBD.
Hereditary EB (Table 2.18) leads to mechanical fragility of the skin and other epithelial surfaces with formation of blisters that often heal with scarring and may result in alopecia and onychoatrophy. ± PPK with pseudoainhum. Since there is considerable overlap in clinical features, types can be distinguished based on immunofluorescence antigenic mapping, transmission electron microscopy, or genetic analysis. Current management primarily focuses on blister prevention, wound care, and treatment of systemic complications; however, gene therapy holds promise for the future.
EBA classically presents with acral blisters that heal with dyspigmentation, milia, and atrophic scarring that may result in alopecia and onychoatrophy, as well as pseudosyndactyly. EBA may be associated with verruciform xanthoma. Inflammatory EBA has also been described.
Pseudosyndactyly has been described as a “mitten” hand deformity.
Obtain biopsies for H&E and perilesional DIF. To optimize sensitivity, IIF should be performed on salt-split human skin (dermal). ELISA can detect circulating autoantibodies to collagen VII.
EBA is notoriously refractory to treatment. Management of EBA is similar to BP.
 DERMATITIS HERPETIFORMIS → Diagnosis Group 2 Synonym: Duhring disease |
DH is a cutaneous manifestation of gluten sensitivity characterized by circulating IgA autoantibodies to epidermal transglutaminase-3 (TG-3).
Do NOT confuse TG-3 with TG-1, an abnormal gene product in lamellar ichthyosis.
The mean age of onset is in the fourth decade. Male sex and Northern European ancestry are risk factors.
DH is associated with several autoimmune disorders, most commonly thyroid disease (eg, Hashimoto thyroiditis), insulin-dependent diabetes mellitus, and pernicious anemia. While only ˜20% of DH patients have intestinal symptoms of celiac disease, >90% have gluten-sensitive enteropathy. Long-standing enteropathy may lead to enteropathy-associated T-cell lymphoma.
Drug associations include ICIs.
The strongest HLA association is -DQ2. The pathogenesis of DH involves epitope spreading. Gluten digestion forms gliadin, which is absorbed via the lamina propria and deamidated by TG-2. Deamidated gliadin binds to HLA-DQ2 on APCs and is presented to sensitized helper T cells, which stimulate B cells. Differentiated plasma cells produce IgA antibodies to gliadin, gliadin-TG-2, TG-2, and epidermal TG-3. Deposition of IgA anti-TG-3 antibodies
within dermal papillae leads to neutrophil recruitment and degranulation.
Table 2.18. EPIDERMOLYSIS BULLOSA VARIANTS
Varianta
Inheritance Pattern
Gene Product(s)
Distinctive Clinical Features
Notes
EBS (Split: Intraepidermal)
EBS, generalized
AD
K5 and K14
Grouped or herpetiform blisters, sometimes in a figurate array, confluent palmoplantar keratoderma.
Formerly known as Dowling-Meara type. Keratin filaments coalesce into electron-dense clumps.
EBS, generalized intermediate
Formerly known as Koebner type.
EBS, localized
Primary palm and sole involvement.
Formerly known as Weber-Cockayne type.
EBS with mottled pigmentation
AD
K5 > K14
Reticulated hyperpigmented macules.
EBS with muscular dystrophy
AR
Plectin
Associated with muscular dystrophy.
Plectin is expressed in skeletal muscle.
JEB (Split: intralamina lucida)
JEB, generalized severe
AR
Laminin 332
Symmetric excessive granulation tissue favoring the periorificial area, nape of the neck, upper back, intertriginous areas, and periungual areas. Systemic complications in a majority of patients include oralb (enamel hypoplasia, excessive carries and premature loss of teeth, tracheolaryngeal stenosis), gastrointestinal (malnutrition/FTT), and hematologic (anemia).
Formerly known as Herlitz type. Often due to premature truncating mutations. May develop benign EB nevi that clinically resemble melanoma.
JEB, generalized intermediate
AR
Laminin 332, BPAG2
Formerly known as non-Herlitz type or GABEB.
JEB, localized
AR
BPAG2, α6β4 integrin
Primarily acral involvement.
JEB with pyloric atresia
AR
α6β4 integrin
Associated with pyloric atresia.
DEB (Split: sublamina densa)
DDEB, generalized
AD
Collagen VII
Formerly known as non-Hallopeau-Siemens type. DDEB Cockayne-Touraine (primarily acral involvement). DDEB Pasini (albopapuloid lesions).
RDEB, generalized severe
AR
Systemic complications in a majority of patients include ocular (corneal scarring), oral (enamel hypoplasia, excessive carries and premature loss of teeth, microstomia), gastrointestinalc (eg, esophageal strictures, GERD, malnutrition/FTT, severe constipation), musculoskeletal (eg, osteoporosis/osteopenia, pseudosyndactyly), and hematologic (eg, anemia).
Formerly known as Hallopeau-Siemens type. Often due to premature truncating mutations resulting in undetectable anchoring fibrils. SCC is a leading cause of death. Consider a systemic retinoid for prevention.
RDEB, generalized intermediate
RDEB, inversa
Primary axillae and groin involvement.
Kindler Syndrome (Split: Mixed)
Kindler syndrome
AR
Kindlin-1
Atrophy, photosensitivity/poikiloderma.
Disruption of actin assembly due to FERMT1 mutation results in basement membrane reduplication.
Kindle a match—photosensitivity.
AD, autosomal dominant; AR, autosomal recessive; DEB, dystrophic EB; DDEB, dominant dystrophic EB; EB, epidermolysis bullosa; EBS, EB simplex; FTT, failure to thrive; GABEB, generalized atrophic benign EB; GERD, gastroesophageal reflux disease; JEB; junctional EB; K, keratin; RDEB, recessive dystrophic EB; SCC, squamous cell carcinoma.
a Illustrative examples provided.
b Enamel hypoplasia occurs in a majority of patients with all JEB subtypes.
c Esophageal strictures also occur in a majority of patients with RDEB inversa and GERD occurs in a majority of patients with all RDEB subtypes.
Figure 2.33. SIDE-BY-SIDE COMPARISON: EPIDERMOLYSIS BULLOSA ACQUISITA AND BULLOUS SYSTEMIC LUPUS ERYTHEMATOSUS. Both EBA and bullous SLE are characterized by a subepidermal split with a variable inflammatory infiltrate. DIF classically demonstrates linear deposition along the DEJ in a u-serrated pattern: IgG in EBA and IgM, IgG, IgA, and C3 in bullous SLE. A and C, EBA (inflammatory type and noninflammatory type, respectively). B and D, Bullous SLE (neutrophilic type and mononuclear type, respectively). C, complement; DEJ, dermal-epidermal junction; DIF, direct immunofluorescence; EBA, epidermolysis bullosa acquisita; Ig, immunoglobulin; SLE, systemic lupus erythematosus.
(Histology images reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
EBA:
• Inflammatory variant: predominantly neutrophilic infiltrate.
• Noninflammatory variant: minimal to absent inflammatory infiltrate.
Bullous SLE:
• Noninflammatory variant: predominantly neutrophilic infiltrate.
• Mononuclear variant: predominantly mononuclear infiltrate.
HLA-DQ2 carriers should avoid the cones at Dairy Queen.
DH classically presents with urticarial plaques, papules, and vesicles symmetrically distributed on the back, buttocks, elbows, extensor forearms, and knees.
DH is associated with intense pruritus.
The differential diagnosis of DH includes subepidermal autoimmune blistering disorders, EM, arthropod assault, and drug reactions.
Obtain biopsies for H&E and sample adjacent normal skin for DIF. Test for IgA anti-TG-3 antibody (if available). Test total IgA and IgA anti-TG-2 antibodies. If positive, test for IgA antiendomysial antibody. If IgA is low, test for IgG anti-TG-2 antibody. If positive, test for IgG antiendomysial antibody.
Gluten avoidance is first line. IgA anti-TG-3 antibody may be helpful to assess compliance.
Figure 2.34. CLINICOPATHOLOGICAL CORRELATION: DERMATITIS HERPETIFORMIS. Characteristic features are a subepidermal split and dermal papillary neutrophilic microabscesses. DIF classically demonstrates granular deposition of IgA at the tips of the dermal papillae. A, H&E. B, DIF (IgA). DIF, direct immunofluorescence; H&E, hematoxylin and eosin; Ig, immunoglobulin.
(A, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD. B, Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
The DIF pattern has been described as a “picket fence” due to the granules.
Dapsone is highly efficacious for DH, relieving pruritus in 48 to 72 hours. Unfortunately, it has no effect on glutensensitive enteropathy.
Even though the hallmark lesion in DH is a papulovesicle, patients in practice often present with secondary changes from scratching. A high index of suspicion is required for diagnosis.
Gluten is found in wheat, rye, barley, and hybrids of these grains (eg, Kamut). Safe grains for patients with DH include corn, oats, and rice.
Connective tissue disorders (CTDs) affect tissues that support, ensheath, and bind tissues together.
Interface dermatoses are characterized by a predominantly lymphocytic infiltrate that abuts or obscures the DEJ on histopathology.
Interface dermatitis may be divided into lichenoid and vacuolar patterns (Figure 2.35).
 Figure 2.35. SIDE-BY-SIDE COMPARISON: LICHENOID AND VACUOLAR INTERFACE DERMATITIS. Both lichenoid and vacuolar interface dermatitis are characterized by a predominantly lymphocytic infiltrate that abuts or obscures the DEJ. Lichenoid interface dermatitis demonstrates destruction of the basal layer with apoptotic keratinocytes (colloid bodies) (PAS positive, diastase resistant) and conical rete. Vacuolar interface dermatitis demonstrates preservation of the basal layer with vacuoles and rounded rete. A, Lichenoid interface dermatitis: LP. B, Vacuolar interface dermatitis: SCLE. Colloid bodies are alternatively known as Civatte, cytoid, or hyaline bodies. DEJ, dermal-epidermal junction; LP, lichen planus; PAS, periodic acid-Schiff; SCLE, subacute cutaneous lupus erythematosus. (A, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.) Lymphocytes in lichenoid interface dermatitis are often described as “band-like.” Lymphocytes in vacuolar interface dermatitis tend to aggregate. |
 LICHEN PLANUS → Diagnosis Group 1 Reprinted with permission from Craft N, Fox LP, Goldsmith LA, et al. VisualDx: Essential Adult Dermatology. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010. |
LP is a T cell-mediated autoimmune reaction against keratinocyte epitopes modified by viral/drug antigens. IFN-γ is central to the pathogenesis.
The mean age of onset is 50 years.
Associations include viral infection (eg, hepatitis C virus [HCV] infection, especially oral LP), vaccinations (eg, influenza, hepatitis B virus [HBV]), drugs (see below), and dental restorative materials (eg, amalgam [mercury], copper, and gold).
HLA associations include -B8 (oral LP), -B35 (cutaneous LP), and -DR1 (cutaneous and oral LP).
Beatrice eight with her mouth open (HLA-B8 is associated with oral LP).
Cutaneous LP classically presents with pruritic, flattopped, polygonal, violaceous papules that favor the wrists, forearms, distal lower extremities, and presacral area.
Lichen is derived from the Greek word leichen meaning “tree moss.” In dermatology, “lichen” is used to describe an eruption of flat papules.
The five Ps of cutaneous LP: pruritic planar, polygonal, purple papules.
LP may involve the oral cavity and nail unit.
Koebnerization is common.
LP variants are summarized in Table 2.19.
20-nail dystrophy is more common in children than adults.
Some experts consider keratosis lichenoides chronica, which classically presents with symmetric keratotic
lichenoid papules arranged in a linear and reticulated pattern on the trunk and extremities and dorsal hands and feet, to be an LP variant.
Table 2.19. LICHEN PLANUS VARIANTS
Varianta
Classic Description
Notes
Actinic LP
Photodistribution of LP.
Majority of reported patients are from the Middle East.
Acute (exanthematous) LP
Rapid onset of LP over a wide distribution.
Annular LP
Annular LP favoring the axillae > penis, groin, and extremities.
Atrophic LP
LP with central atrophy and hyperpigmentation.
Bullous LP
Blisters within existing LP lesions.
Blisters in bullous LP are due to cytotoxic keratinocyte damage (expanded Max-Joseph spaces).
In contrast, blisters in LP pemphigoides may arise within existing LP lesions or on previously unaffected skin.
Hypertrophic LP
Hyperkeratotic LP favoring the lower extremities.
Increased risk of SCC.
Inverse LP
LP favoring flexural zones (especially the axillae).
LP pigmentosus
Gray-brown macules in sun-exposed areas > intertriginous zones.
Majority of reported patients are from South Asia, Latin America, and the Middle East.
Lichen planopilaris
See Chapter 2: Disorders of the Hair and Nails.
Linear LP
LP following the lines of Blaschko.
Nail LP
Onychoatrophy, onychorrhexis/trachyonychia, and onychoschizia may lead to scarring and dorsal pterygium formation. Red lunulae may also occur.
Trachyonychia is also referred to as “sandpapered nails.” Figure 2.36.
Oral LP
Desquamative gingivitis. Reticular (most common) oral LP classically presents with symmetric raised white linear lines or rings with short radiating spines favoring the buccal and gingival mucosa (Wickham striae).
Oral LP is present in 75% of patients, 10%-20% of whom develop cutaneous lesions. Increased risk of esophageal LP and SCC.
Reticular oral LP has been described as a “lace-like” pattern.
Ulcerative LP
Ulcerative LP favoring the palms/soles.
Increased risk of SCC.
Vulvovaginal LP
Erosive LP that may lead to scarring with dyspareunia and postcoital bleeding.
Often overlaps with oral LP (vulvovaginaldigital syndrome). Increased risk of SCC.
LP, lichen planus; SCC, squamous cell carcinoma.
a Illustrative examples provided.
LP may overlap with LE.
The differential diagnosis of cutaneous LP includes other lichenoid dermatoses and GVHD, papulosquamous dermatoses, CTDs, and secondary syphilis. LP pigmentosus should be differentiated from EDP and vulvovaginal LP should be differentiated from LS.
Dermoscopy features include white crossing streaks (Wickham striae) and dotted or linear vessels at the periphery.
There is no established guideline for the evaluation of LP. A skin biopsy may be helpful in case of diagnostic uncertainty, and some experts recommend HCV screening.
Patients with oral LP in apposition to dental restorative materials should undergo patch testing. Even if negative, removal may lead to improvement by reducing Koebnerization due to irritation.
Early detection of esophageal LP with endoscopy is important to avoid scarring stenosis.
It is important to monitor for the development of SCC in patients with LP, particularly in high-risk variants (hypertrophic, oral, ulcerative, and vulvovaginal).
 Figure 2.36. PTERYGIUM. By contrast, ventral pterygium (pterygium inversus unguis) results from adhesion of the distal nail plate to the hyponychium. It is associated with impaired peripheral perfusion in SSc. LP, lichen planus; MMP, mucous membrane pemphigoid; SSc, systemic sclerosis. (Dorsal pterygium image reprinted with permission from Craft N, Fox LP, Goldsmith LA, et al. VisualDx: Essential Adult Dermatology. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010. Illustration by Misha Rosenbach, MD.) |
 Figure 2.37. CLINICOPATHOLOGICAL CORRELATION: LICHEN PLANUS. Characteristic features are orthohyperkeratosis, “wedge-shaped” hypergranulosis, acanthosis, a lichenoid interface dermatitis, and dermal melanophages. Artifactual clefts between the epidermis and the dermis are called Max-Joseph spaces. DIF classically demonstrates shaggy deposition of fibrin and granular deposition of IgM, IgG, IgA, and C3 staining apoptotic keratinocytes at the DEJ. Oral LP is characterized by parakeratosis (not hyperkeratosis) and epidermal atrophy (not acanthosis). A, Low-power view. B, High-power view. Solid arrow: apoptotic keratinocyte (colloid body). C, complement; DEJ, dermal-epidermal junction; DIF, direct immunofluorescence; Ig, immunoglobulin; LP, lichen planus. (Histology images courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.) |
LP may resolve spontaneously (˜ 1 year for cutaneous LP vs ˜5 years for oral LP) or with treatment of an associated disease or discontinuation of an associated trigger; however, disease-targeted therapy is often required.
Oral LP is sustained, leading to strictures and squames.
High-potency topical corticosteroids are first line, but systemic corticosteroids may be required. Diverse steroid-sparing therapies have been reported, including topical calcineurin inhibitors, antimalarials, phototherapy, and retinoids.
Beware of pseudoepitheliomatous hyperplasia in hypertrophic LP masquerading as multiple SCCs.
 LICHENOID DRUG ERUPTION → Diagnosis Group 2 |
Lichenoid drug eruption may be classified as a delayedtype, cell-mediated (type IV) reaction. The mean age of onset is 65 years.
Drug associations include antimalarials, TNFα inhibitors, ICIs, anticonvulsants, anxiolytics, antidepressants, antipsychotics, anti-hypertensives (eg, ACEIs, diuretics), hypoglycemic agents, metals (eg, gold salts), NSAIDs, and D-penicillamine.
Clinical clues to differentiate lichenoid drug eruption from LP include older age at presentation, generalized or photodistributed lesions, and mucous membrane sparing.
Histopathological clues to differentiate lichenoid drug eruption from LP include parakeratosis and eosinophils.
The timing of lichenoid drug eruption relative to initial drug exposure ranges from months to years (˜12 months).
The differential diagnosis of lichenoid drug eruptions is similar to LP.
Discontinuation of the suspected drug along with all nonessential drugs is the first step. In vitro assays to establish the culprit drug are under investigation. However, given uncertain sensitivity and specificity, their utility remains limited in clinical practice. Patch testing has high false negative rates.
Treatment strategies for lichenoid drug eruptions mirror those for LP.
Lichenoid drug eruptions often resolve within weeks to months but may persist.
Beware of the long latency period. In a patient with a lichenoid eruption, it is important to perform a detailed medication history and not to disregard chronic medications.
 LICHEN STRIATUS → Diagnosis Group 2 Reprinted with permission from Schalock PC, Hsu JTS, Arndt KA. Lippincott’s Primary Care Dermatology. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010. |
Lichen striatus is a linear dermatosis that primarily affects preschool-age children.
Lichen striatus classically presents with flat-topped papules extending in a continuous or interrupted band along the lines of Blaschko down an extremity. Lichen striatus typically resolves with hypopigmentation. While lichen striatus is typically asymptomatic, intense pruritus may occur.
Nail involvement is common.
The differential diagnosis of lichen striatus includes other linear dermatoses (eg, blaschkitis, linear LP, GVHD, pigmented purpura) and neoplasms (eg, inflammatory linear verrucous epidermal nevus [ILVEN]).
Figure 2.38. CLINICOPATHOLOGICAL CORRELATION: LICHEN STRIATUS. Lichen striatus is characterized by lichenoid interface dermatitis with variable adnexal involvement. A, Low-power view. B, High-power view. Solid arrow: lymphoid aggregates in the eccrine coil. H&E, hematoxylin & eosin.
A striation is a line. Lichen striatus follows the lines of Blaschko. Under the microscope, lymphocytes follow adnexal structures, forming blue lines on H&E staining.
There is no established guideline for the evaluation of lichen striatus. Skin biopsy may be helpful.
Lichen striatus resolves spontaneously in a few months to a few years.
High-potency topical corticosteroids are first line; however, the efficacy of topical calcineurin inhibitors has also been reported.
Lichen striatus is self-limited; therefore, treatment is usually not needed.
LICHEN NITIDUS
Lichen nitidus is a rare disorder that is more prevalent in children and adolescents.
Lichen nitidus classically presents with multiple clusters of tiny, discrete, shiny papules that favor the anterior trunk, genitalia, and flexor aspects of the upper extremities.
Treatment includes topical corticosteroids and antihistamines.
 Figure 2.39. CLINICOPATHOLOGICAL CORRELATION: LICHEN NITIDUS. Characteristic features are parakeratosis, hypogranulosis, and epidermal atrophy with hyperplastic rete ridges surrounding a well-circumscribed lichenoid infiltrate. The infiltrate, spanning < 2-3 dermal papillae, is typically composed of lymphocytes, epithelioid cells, and occasionally Langhans giant cells. (Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.) The well-circumscribed infiltrate with surrounding hyperplastic rete ridges has been described as the “ball and claw” configuration. |
 ERYTHEMA MULTIFORME → Diagnosis Group 1 |
EM is an acute inflammatory disorder.
The EM spectrum is categorized into:
EM minor (EM von Hebra): absent or mild mucosal involvement.
EM major: severe mucosal involvement and systemic features.
The leading association is infection (˜90% of patients), most often herpes simplex virus (HSV). EM major may be associated with Mycoplasma pneumoniae (Mycoplasma pneumoniae-induced rash and mucositis [MIRM]). Less common associations include other infections (eg, Histoplasma capsulatum, particularly in patients with concomitant erythema nodosum [EN]) and exposures (eg, poison ivy).
Drugs associations (eg, NSAIDs) are rare.
Skin involvement in EM is characterized by abrupt onset of papular target lesions favoring the face and extremities (elbows, wrists, hands, knees). Target lesions may be typical (at least three different zones) or atypical (papular, only two different zones and/or a poorly defined border). Bullous lesions are occasionally present in EM major.
Target lesions may resemble a “bull’s eye.”
Mucosal involvement in EM major is characterized by vesiculobullous lesions that rapidly evolve into painful crusted erosions on the buccal mucosa and lips > ocular and anogenital mucosae.
Systemic features in EM major include fever and arthralgias.
EM may overlap with LE (Rowell syndrome).
 Figure 2.40. CLINICOPATHOLOGICAL CORRELATION: ERYTHEMA MULTIFORME. Characteristic features are an acute stratum corneum, individual necrotic keratinocytes that may progress to confluent epidermal necrosis, papillary dermal edema, and a dermal lymphocytic infiltrate. DIF may demonstrate granular deposition of IgM and C3 focally along the DEJ. Solid arrow: necrotic keratinocyte (present at all levels of the epidermis). (Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.) Cell death occurs out of proportion to inflammation. |
The differential diagnosis of EM includes SJS/TEN, generalized bullous fixed drug eruption (GBFDE), subacute cutaneous lupus erythematosus (SCLE), erythema annulare centrifugum (EAC), and CSVV.
In the pediatric population, urticaria multiforme and Kawasaki disease are often misdiagnosed as EM.
EM is self-limited. There is no risk of progression to TEN.
Oral corticosteroids and other systemic immunosuppressive therapies may be required.
For patients with HSV-associated EM with frequent recurrences, consider prophylaxis (eg, valacyclovir 500-1000 mg/d) for at least 6 months.
Distinguishing EM from SJS/TEN is challenging. Four clinical criteria are (1) type of elementary skin lesion, (2) distribution of skin lesions, (3) presence or absence of overt mucosal lesions, and (4) presence or absence of systemic symptoms.
Histopathological features that suggest EM over SJS/TEN are decreased cell death and increased inflammation.
Use of systemic corticosteroids is controversial in EM given concern for increased risk of infection.
 STEVENS-JOHNSON SYNDROME/TOXIC EPIDERMAL NECROLYSIS → Diagnosis Group 1 |
SJS/TEN may be classified as a delayed-type, cell-mediated (type IV) SCAR. The hypothesized mechanism is activation of CD4+ and CD8+ T cells leading to release of cytokines (eg, IFN-γ). Mediators of apoptosis include Fas-FasL interactions and granulysin.
The SJS/TEN spectrum is categorized according to BSA of detached (and detachable) epidermis into:
SJS: < 10% BSA.
SJS/TEN overlap: 10% to 30% BSA.
TEN (Lyell syndrome): >30% BSA.
Drug associations include dapsone, rituximab, nonnucleoside reverse transcriptase inhibitors (NNRTIs; eg, nevirapine), sulfonamides (eg, trimethoprim-sulfamethoxazole [TMP-SMX]), allopurinol, aromatic anticonvulsants (eg, carbamazepine, phenobarbital, phenytoin), lamotrigine, and NSAIDs. Additionally, SJS/TEN-like reactions have been reported to antineoplastics such as bortezomib and ICIs. Other SJS triggers include infection or vaccination.
HLA associations include -A3101 (carbamazepine in European populations), -B1502 (carbamazepine in Asian and East Indian populations; lamotrigine in Han Chinese population; phenytoin in Han Chinese population), and -B5801 (allopurinol in Han Chinese population). Other risk factors include slow acetylator genotype (eg, sulfonamides), immunosuppression (eg, HIV), and concomitant anticonvulsants or radiation therapy.
SJS/TEN classically presents with a prodrome of upper respiratory infection (URI) symptoms, fever, and skin pain.
Mucosal involvement (>90% of patients) is characterized by erythema and erosions of the buccal, ocular, and anogenital mucosae. TEN may involve the respiratory and gastrointestinal mucosa.
Skin involvement is characterized by dusky and/or dusky-red macules with epidermal detachment and erosions, macular atypical targets, and bullous lesions favoring the face and trunk.
Epidermal detachment may resemble “wet cigarette paper” peeling away from “scalded skin.”
The Nikolsky sign and the Asboe-Hansen sign are positive in SJS/TEN.Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
