Peeling Skin Syndrome

Are You Confident of the Diagnosis?

Peeling skin syndrome (PSS) refers to a rare group of heterogeneous autosomal recessive diseases that manifest as superficial skin peeling without mucosal peeling. Three types of PSS have been characterized based on the areas of skin affected, presence of systemic manifestations, and distinct genetic mutations. First, PSS can be categorized by the area of skin affected. Acral PSS is limited to the hands and feet, whereas generalized PSS results in widespread peeling. Generalized PSS is further subcategorized by the absence or presence of inflammation and includes generalized noninflammatory PSS (type A PSS) and generalized inflammatory PSS (type B PSS).

What you should be alert for in the history

Acral PSS: Onset of symptoms for acral PSS (APSS) occurs shortly after birth or in childhood; symptoms persist for the patient’s lifetime. Patients present with spontaneous or continuous peeling of skin on the hands and feet and sometimes on the lower extremities. Patients may complain of erythema, pruritus, or a burning sensation in the exposed denuded area. The history is not significant for systemic manifestations or atopy. Peeling may be induced by mechanical trauma, humidity, heat, perspiration, and exposure to water.

Generalized noninflammatory/Type A PSS: Onset of type A PSS also presents shortly after birth or in early childhood. Patients present with asymptomatic widespread white scaling of skin that is most prominent over upper and lower extremities and less prominent on the hands and feet. Patients may have occasional pruritus but do not show any evidence of atopy, fever, systemic manifestations, or nail, hair, or mucous membrane abnormalities. The fragile skin may be easily removed with water, wind, dust, sand, and friction.

Generalized inflammatory/Type B PSS: Also called peeling skin disease, presents shortly after birth or in early childhood with spontaneous, patchy peeling of the skin with erythema and pruritus. A review of the patient’s history will reveal atopy that can manifest as food allergies, severe pruritus, asthma, angioedema, and urticaria. Affected patients may present with failure to thrive and recurrent secondary infections (especially with Staphylococcus aureus).

Characteristic findings on physical examination

Acral PSS: Patients present with spontaneous or continuous superficial peeling and blistering on the volar and dorsal surfaces of hands and feet. Healing occurs spontaneously without scarring or atrophy but there may be erythema in the denuded area.

Expected results of diagnostic studies

Acral PSS: Patients with acral PSS have no associated laboratory abnormalities. Histopathologic examination of the skin shows cleavage at the junction between the stratum corneum and stratum granulosum. Compact orthokeratosis may also be present.

Noninflammatory/Type A PSS: Routine laboratory tests including serum IgE and a complete blood count are normal in type A PSS. Type A PSS is histologically characterized by hyperkeratosis, thinning of the granular layer, and a separation of the stratum corneum from the stratum granulosum or an intracorneal split. Cytoplasmic intracellular splitting in the lower stratum corneum has been observed on electron microscopy, as well as abnormal cribriform keratohyalin granules, which are indicative of disturbed keratinization.

Inflammatory/Type B PSS: Laboratory tests classically show evidence of atopy including eosinophilia and elevated IgE. Other diagnostic abnormalities that appear sporadically in case reports were abnormal tryptophan levels, aminoaciduria, elevated serum copper, elevated ceruloplasmin, increased iron and iron-binding capacity, and abnormal epidermal retinoid metabolism. Histologic changes in type B PSS show acanthosis and hypergranulosis. The stratum corneum appears stacked with hyperkeratosis and parakeratosis as well as detachment from the granular layer. Regular elongation of the rete ridges and dilation of capillaries can be observed. In contrast to acral PSS and type A PSS, a mild inflammatory infiltrate is present in the upper dermis. Electron microscopy shows intracellular and intercellular cleavage of corneocytes. It also shows intracellular cleavage of granulocytes with edema within and around spinous cells.

Diagnosis confirmation

Acral PSS: APSS is most frequently misdiagnosed as localized epidermolysis bullosa simplex. The two can be differentiated on biopsy since the cleavage is located between the corneal and granular layer of the epidermis in APSS, and located in the basal layer of the epidermis in localized epidermolysis bullosa simplex. Other differential diagnoses that clinically present in a similar way include keratolytic winter erythema, exfoliative ichthyosis, dermatophytosis, psoriasis, allergic contact dermatitis, and dyshidrotic eczema. These entities can be distinguished from APSS by history, physical exam, and histopathologic analysis of skin biopsies (See “Expected results of diagnostic studies” above).

The diagnosis of APSS is confirmed with identification of causative mutations in the TGM5 gene using mutation analysis from DNA derived from white blood cells. Screening for TGM5 is indicated for patients with European ancestry who are suspected of having epidermolysis bullosa simplex but do not have mutations in the associated keratin genes. For healthcare providers, laboratory testing sites can be found in the Genetic Testing Registry (GTR) through the National Council for Biotechnology Information (NCBI).

Generalized noninflammatory/type A PSS: Type A PSS presents with superficial peeling of skin shortly after birth or in early childhood. Differential diagnoses includes staphylococcal scalded skin syndrome, epidermolysis bullosa, subcorneal pustular dermatosis, superficial epidermolytic ichthyosis (a milder phenotype of epidermolytic ichthyosis), and other forms of PSS. Type A PSS can be distinguished from these diseases by history, physical exam, and histopathologic analysis of skin biopsies (See expected results of diagnostic studies). Molecular analysis for mutations in the CHST8 gene is indicated to confirm the diagnosis. For healthcare providers, laboratory testing sites can be found in the GTR through NCBI.

Inflammatory/Type B PSS: Type B PSS is characterized by superficial patchy peeling of the entire skin with underlying erythroderma and pruritus in the denuded areas. It is associated with atopic manifestations. Differential diagnoses include hyper-IgE syndrome, atopic dermatitis, and Netherton syndrome. There is considerable phenotypic overlap of Type B PSS with other atopic diseases, especially Netherton syndrome, although history, clinical findings, and ultrastructural or histopathologic analysis of skin biopsies can help make the diagnosis. The diagnosis of Type B PSS can be confirmed with immunohistochemistry showing absence of corneodesmosin in the epidermis or mutational analysis for loss of functions in CDSN gene. For healthcare providers, laboratory testing sites can be found in the GTR through NCBI.

Who is at risk for developing this disease?

The three identified forms of peeling skin syndrome are all rare autosomal recessive disorders. PSS, like other autosomal recessive diseases, shows greater incidence in progeny of consanguineous relationships. There is no male or female predominance. APSS shows a predominance in European populations, which is hypothesized to be due to a founder effect. Studies suggest that APSS is often misdiagnosed or underdiagnosed, and is more common than previously thought.

What is the Cause of the Disease?

Etiology

Acral PSS: APSS is most commonly due to a mutation in TGM5, which encodes for transglutaminase 5. TGM5 is an enzyme found in granular cells that crosslinks structural proteins during terminal differentiation of the epidermis to form the stratum corneum. A recessive mutation in the CSTA gene has also been identified in a few cases that do not have the TGM5 mutation. CSTA encodes for cystatin, a serine protease inhibitor that is expressed throughout the dermis. The same gene has been implicated in exfoliative ichthyosis.

Generalized noninflammatory/type A PSS: Type A PSS is due to a mutation in the CHST8 gene that encodes golgi transmembrane N-Acetylgalactosamine-4-O-sulfotransferase (GalNAc4ST1). This enzyme is expressed throughout the epidermis and is believed to be involved in sulfation of various substrates in the epidermis.

Generalized inflammatory/Type B PSS: Type B PSS is due to a mutation in the corneodesmosin gene (CDSN). Corneodesmosin is an adhesive glycoprotein located at the extracellular part of the desmosome and corneodesmosomes at the transition from the stratum granulosum to the stratum corneum and also in the inner root sheath of the hair follicles.

Pathogenesis

Acral PSS: Transglutaminase 5 is crucial for normal epidermal differentiation. This enzyme is localized between the stratum granulosum and the stratum corneum in the epidermis and introduces ƴ-glutamyl-ƹ-lysine isopeptide bonds between the structural proteins of the cornified cell envelope. The crosslinking of structural proteins between these two layers stabilizes their attachment and the loss of this enzyme leads to instability. This epidermal instability accounts for the superficial peeling on the acral surfaces that is seen in APSS.

Generalized noninflammatory/type A PSS: Less is known about CHST8, a gene that encodes a golgi transmembrane N-Acetylgalactosamine-4-O-sulfotransferase (GalNAc4-ST1). This syndrome is caused by a homozygous missense mutation in the CHST8 gene, leading to an amino acid substitution in the protein. Evidence shows this substitution results in decreased expression, increased degradation, and an alteration of the overall glycosylation state of GalNAc4-ST1, a sulfotransferase (transfers sulfur groups to biological molecules).

Sulfate groups on glycosaminoglycans and on oligosaccharides have been shown to play crucial roles in conferring highly specific function to molecules by signal transduction, cell-to-cell interaction and embryonic development throughout the body. The importance of sulphation of various substances in the epidermis has been appreciated as well. For example, cholesterol sulfate plays a crucial role for cohesion and desquamation of the stratum corneum in the epidermis. In normal subjects, substantial GalNAc4-ST1 protein is expressed in the upper spinous, granular, and cornified layers. Decreased amount of this protein is expressed in patients with type A PSS.

These findings has led to the hypothesis that GalNAc4-ST1 is responsible for normal epidermal cohesion in the upper epidermal layers, and loss of function leads to the clinical phenotype of increased and continual desquamation of the stratum corneum.

Generalized inflammatory/Type B PSS: A mutation in the CDSN leads to a loss of corneodesmosin, an adhesive glycoprotein that contributes to the formation of corneodesmosomes. Corneodesmosin is responsible for cell-to-cell adhesion in the upper dermis, and its degradation is essential for normal desquamation. The absence of corneodesmosin leads to impaired cell-to-cell adhesion in the upper dermis, resulting in desquamation of the stratum corneum. This impairment in cell-to-cell adhesion found on electron microscopy in the corneum and granular layers allows for increased permeation of reagents into the epidermis.

The penetration of allergens into the epidermis is thought to be a novel cause of atopic disease, with development of a hypersensitivity reactions to penetrating allergens. The local inflammatory reaction to the allergens in the upper dermis is portrayed histologically by an inflammatory infiltrate in the upper dermis, edema around the spinous cells, and capillary dilation. It is clinically manifested by erythema and pruritus due to release of histamine and other inflammatory mediators. The increased allergen penetration is thought to be the cause of the predisposition to develop allergic hypersensitivity reactions such as food allergies and asthma. The associated hypersensitivity reactions accounts for the diagnostic findings of eosinophilia and increased serum IgE.

Elevated kallikrein expression in the epidermis and serum results in has been implicated in the angioedema and urticaria that patients develop with this disease. Some studies have shown that elevated kallikrein and histamine levels also partially contribute to the increased turnover and desquamation of the stratum corneum found in this disease.

Systemic implications and complications

Acral PSS: Acral PSS is largely asymptomatic and the skin peeling does not lead to atrophy or scarring of that area. Patients may complain of pruritus in the denuded area. Injury, secondary infections, and scarring can arise with scratching of those areas.

Generalized noninflammatory/type A PSS: Acral PSS is largely asymptomatic and the skin peeling does not lead to atrophy or scarring of that area. Patients may complain of pruritus in the denuded area. Injury, secondary infections, and scarring can arise with scratching of those areas.

Generalized inflammatory/type B PSS: Complications of type B PSS include failure to thrive, atopy (asthma, food allergies, urticaria, angioedema), and secondary infections that are most commonly due to Staphylococcus aureus. There is also a single case report of a patient with type B PSS with recurrent infections and IgA nephropathy.

Treatment

Acral PSS: There is no specific treatment for APSS, and current treatment is aimed at symptomatic relief. Patients should be educated about how scratching can lead to scarring and secondary complications. They should also be educated about avoiding exacerbating triggers such as mechanical trauma, humidity, heat, perspiration, and exposure to water. Daily topical application of emollients to affected areas has been shown to be helpful. Absorbing powders or aluminum antiperspirant have been effective in controlling perspiration, which is an exacerbating factor in certain cases.

Generalized noninflammatory/Type A PSS: There is no specific treatment for type A PSS. Patients should be educated about how scratching can lead to scarring and secondary complications. They should also be educated about avoiding things that exacerbate the peeling such as water, wind, dust, sand, and friction. Daily topical application of emollients to affected areas has been shown to be helpful. Absorbing powders or aluminum antiperspirant have been effective in controlling perspiration, which can exacerbate this disease.

Generalized inflammatory/Type B PSS: Many therapies have been tried for treatment of type B PSS with limited success. Oral and topical methotrexate, oral and topical steroids, systemic isotretinoin, tar, and UVB phototherapy have been considered ineffective. Topical emollients may provide symptomatic relief.

Some researchers have hypothesized that antihistamines and kallikrein inhibitors may be helpful for this disease. Kallikrein and histamine are upregulated in the epidermis in patients with Type B PSS and studies suggest that these molecules disrupt epidermal barrier function leading to increased turnover and desquamation of the stratum corneum in these patients.

Histamine is implicated in the inflammatory aspect of this disease and kallikrein inhibitors may also be helpful in patients with type B PSS who develop angioedema. Although it is theorized that anti-histamines and kallikrein inhibitors could be a novel treatment for type B PSS, there have not been any clinical trials to support this due to the rarity of the disease. Antibiotic therapy that covers Staphylococcus aureus is recommended when secondary skin infections develop.

Optimal therapeutic approach

Optimal therapeutic approach for APSS and type A PSS involve avoiding exacerbating factors such as water, perspiration, humidity, heat, and friction. Absorbing powders or aluminum antiperspirants have been effective in controlling perspiration, which is known to exacerbate this disease. Applying topical emollients after bathing may offer some relief.

Treatment for type B or generalized inflammatory PSS is less straightforward and current research theorizes using antihistamines and kallikrein inhibitors, although these theories have not been proven. Avoiding scratching and other disease exacerbations is recommended. Topical emollients may be helpful for symptomatic relief and antibiotic therapy is recommended when skin infections develop.

Patient management

Patients are managed by long term care with a dermatologist who can monitor disease exacerbations, provide optimal therapeutic relief, and screen for secondary complications of these diseases.

Unusual clinical scenarios to consider in patient management

Aggressive clinical awareness is warranted as PSS is commonly misdiagnosed. APSS and type A PSS have commonly been misdiagnosed in the literature as epidermolysis bullosa (EB), a blistering skin disorder resulting from an anchoring defect between the epidermis and dermis. If a patient previously diagnosed with EB shows continuous superficial peeling, histological properties of cleavage between stratum corneum and stratum granulosum, and/or absence of associated desmin genes, screening for mutations of PSS may be warranted.

There is also significant overlap in the clinical presentation and pathogenesis of generalized inflammatory PSS and Netherton syndrome. The genetic defect in Netherton syndrome is in the Spink5 gene which encodes for LEKT1, a serine proteinase inhibitor. Loss of this serine proteinase inhibitor leads to increased activity of epidermal serine proteases including certain kallikreins. These serine proteases are responsible for desmosomal breakdown by premature proteolysis of corneodesmosomes, leading to epidermal instability. This is similar to type B PSS in which the defect is the absence of corneodesmosin, an integral part of corneodesmosomes. This pathogenic overlap elucidates why aspects of the Netherton syndrome phenotype is similar to Type B PSS, including skin peeling, erythroderma, secondary skin infections, and atopic manifestations.

They can be distinguished clinically with continuous peeling of the skin in type B PSS with absence of double-edged scales and trichorrhexis invaginata (bamboo hair), a clinical entity found in Netherton syndrome. A previously diagnosed case of Netherton syndrome with atypical clinical features and an absence of Spink5 mutations should be further worked up for type B PSS.

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Peeling Skin Syndrome