Peeling skin syndromes

INTRODUCTION — 

Peeling skin syndromes (PSS) are a heterogeneous group of rare autosomal recessive disorders characterized by superficial, painless peeling and blistering of the skin without mucosal fragility [1-3]. The two major forms are acral peeling skin syndrome (APSS; also called localized PSS) and generalized PSS [4-7]. The latter is subclassified into noninflammatory (type A) PSS and inflammatory (type B) PSS [8,9].

Although PSS was previously considered a subtype of epidermolysis bullosa simplex, it is now classified as a separate entity in the group of "other disorders with skin fragility."

This topic will review the pathogenesis, clinical features, and management of PSS. Congenital blistering diseases and keratinization disorders are discussed separately.

●(See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features".)

●(See "Diagnosis of epidermolysis bullosa".)

●(See "Overview of the management of epidermolysis bullosa".)

●(See "Overview and classification of the inherited ichthyoses".)

ACRAL PEELING SKIN SYNDROME — 

The localized form of PSS, called acral peeling skin syndrome (APSS) or PSS type 2 (MIM #609796), is a rare autosomal recessive disorder. It manifests at birth or in early infancy and is characterized by skin exfoliation limited to the hands and feet.

Pathogenesis — APSS is caused by variants in two genes: TGM5, implicated in the large majority of cases [4,10], and CSTA (PSS type 4, MIM #607936), encoding cystatin A, a cysteine protease inhibitor [11,12].

●TGM5 gene – TGM5, encoding transglutaminase 5, is located on 15q15.2, spans 33.7 kb of genomic deoxyribonucleic acid (DNA), and contains 13 exons. The TGM5 protein has three domains (beta-sandwich, beta-barrel 1, and beta-barrel 2) and an additional highly conserved, functionally important domain called the central catalytic core [6,13]. Most variants affect amino acids located in the catalytic core and the beta-sandwich domains [6]. The most commonly reported pathogenic variant, p.Gly113Cys, is located within the beta-sandwich domain and has been found to abolish TGM5 activity [4].

Crucial for normal epidermal differentiation, transglutaminases are a family of enzymes involved in the cross-linking of cornified cell envelope proteins through the formation of gamma-glutamyl-lysine isodipeptide bonds between adjacent polypeptides [14-17]. Therefore, variants in TGM5 completely abolish cross-linking activity, leading to the detachment of the stratum corneum from the underlying stratum granulosum at the site of activity and expression of TGM5 (figure 1) [18].

●CSTA gene – Homozygous variants in the CSTA gene, encoding cystatin A, a member of a superfamily of protease inhibitors expressed in the cornified cell envelope, were reported in families with APSS in the absence of TGM5 variants [11,12,19]. Other variants in the same gene have been implicated in the pathogenesis of autosomal recessive exfoliative ichthyosis (MIM #607936), a rare type of congenital ichthyosis characterized by palmoplantar hyperkeratosis with extension to the dorsal aspects of the hands and feet and acral skin peeling [11,20-22]. (See 'Autosomal recessive exfoliative ichthyosis' below.)

●Genotype-phenotype correlations – There is no obvious phenotype-genotype correlation or variation in severity between homozygous and compound heterozygous patients. The phenotype can vary in severity both within and among families [6]. It has been shown that homozygous ALOXE3 variants resulting in a phenotype of autosomal recessive congenital ichthyosis rescue cell-cell adhesion defects due to homozygous TGM5 variants through corneodesmosin upregulation [23].

Acral peeling of the skin has been reported as a minor feature of cutaneous serpinopathies due to loss-of-function defects in serpins, another class of protease inhibitors [24,25]. (See "Palmoplantar keratoderma (PPK)", section on 'SERPINA12-associated PPK'.)

Moreover, a homozygous variant in SERPINB7, another member of the peptidase inhibitor family, results in the acral peeling phenotype in patients with palmoplantar keratoderma Nagashima type through reduced desmoglein 1 and desmocollin 1 expression [24,26]. (See "Palmoplantar keratoderma (PPK)", section on 'Nagashima type'.)

Epidemiology — The precise incidence and prevalence of APSS are unknown, likely due to underreporting because of its relatively mild nature and misdiagnosis as other skin fragility disorders (eg, localized forms of epidermolysis bullosa simplex). The vast majority of reported patients are from European countries, suggesting a founder effect, with only very few cases described outside of Europe. Sporadic cases from Africa [5,27,28] and Japan [26] have been reported.

In European populations, the estimated carrier frequency of the most common TGM5 variant, p.Gly113Cys, is approximately 3 percent, predicting a disease prevalence of up to 1 in 4500 [4,14]. More than 160 patients with APSS have been reported, with TGM5 variants found in over 90 percent of cases [6,10,29].

Clinical manifestations — Patients with APSS present with superficial peeling or blistering that includes the dorsal surfaces of the hands and feet in addition to the palms and soles and is often associated with erythema (picture 1A and picture 1B) [30-32]. When present, blisters are superficial and flaccid, have a clear content, and rupture easily, resulting in exfoliation. Lesions occasionally involve the limbs and may be associated with mild pruritus [11,20,33].

The onset of symptoms is shortly after birth or in early childhood. Some patients present with only mild, painless disease characterized by superficial peeling of the dorsal and plantar areas of the hands and feet. However, episodes of aggravation may follow exposure to heat, mechanical trauma (friction), humidity, and water [30].

There are no known systemic manifestations or abnormal laboratory findings.

Clinical course — Healing usually occurs spontaneously, sometimes with residual erythema, burning sensation, or pruritus but without scarring or atrophy. In most cases, skin peeling persists over time, though it may improve [26], whereas blistering tends to cease with age [33].

Pathology — Histologically, APSS is characterized by compact orthokeratosis and detachment of the stratum corneum from the underlying stratum granulosum (picture 2) [18]. Electron microscopy, although not required for diagnosis, may reveal more subtle morphologic changes, including cleavage between cornified cells and disrupted tonofilament bundles.

Diagnosis — The diagnosis of APSS is suspected in children or adults presenting with acral skin blistering and peeling, especially when dorsal hands and feet are also affected, in the absence of mucosal involvement and systemic manifestations. The definitive diagnosis is based upon (algorithm 1):

●Histopathologic analysis of a skin biopsy obtained from an area of skin peeling revealing separation between the stratum corneum and stratum granulosum. Electron microscopy analysis, although not required for diagnosis, may reveal more subtle morphologic changes, including cleavage between cornified cells with disrupted tonofilament bundles. (See 'Pathology' below.)

●Identification of causative variants in TGM5 (or CSTA) by variant analysis on DNA isolated from peripheral blood or other appropriate tissue.

Differential diagnosis — The differential diagnosis of APSS includes several inherited and acquired conditions (algorithm 2). Among these, APSS is most frequently confused with localized epidermolysis bullosa simplex.

Localized epidermolysis bullosa simplex — Localized epidermolysis bullosa simplex is an autosomal dominant disorder most often caused by variants in the genes KRT5 or KRT14, although several additional genes have been implicated (table 1) [34,35]. Epidermolysis bullosa simplex is characterized by blisters and erosions on the palms and soles following mechanical trauma (picture 3A-B).

Ultrastructurally, epidermolysis bullosa simplex blisters are located in the basal layer of the epidermis and not in the upper epidermis (as in APSS) [36,37]. Histopathologic and ultrastructural analysis of a skin biopsy and variant analysis can clarify the diagnosis [30,34]. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Epidermolysis bullosa simplex'.)

Erythrokeratolysis hiemalis (keratolytic winter erythema) — Erythrokeratolysis hiemalis is an autosomal dominant disorder characterized by recurrent episodes of palmoplantar erythema and epidermal peeling that exacerbate during the winter. A less common finding is a slowly migratory, annular erythema involving the extremities. Itching, hyperkeratosis, and hyperhidrosis are associated features. In contrast to APSS, keratolytic winter erythema features a more pronounced erythema and hyperkeratosis with normal-appearing skin between flares. The disease is caused by genomic changes affecting a regulatory region modulating the expression of the CTSB gene on chromosome 8p22-p23, encoding cathepsin B, a cysteine protease involved in keratinocyte differentiation and desquamation [38-40].

Keratolysis exfoliativa — Keratolysis exfoliativa (also known as "dyshidrosis lamellosa sicca") is a palmoplantar dermatosis characterized by annular erythema over the volar aspects of the hands and feet with air-filled blisters heralding lamellar peeling (picture 4A-B). In contrast to APSS, it is characterized mainly by small, annular collarettes of white scale involving only the palms (and, less commonly, the soles) with no involvement of the dorsal aspects of the hands and feet. In addition, no fluid-filled blisters are seen in this condition. Keratolysis exfoliativa worsens under warm weather and may be associated with hyperhidrosis. Friction and water contact may aggravate findings. This may be explained by damage to the stratum corneum in volar skin by mechanical forces or soaking. Histopathologic findings include cleavage within the stratum corneum without an inflammatory infiltrate [41].

Genetic counseling — All patients and their family members should be referred for genetic counseling. In patients of European ancestry suspected to have epidermolysis bullosa simplex but lacking variants in the keratin genes, screening for the recurrent TGM5 variant p.Gly113Cys is indicated. If not found, direct sequencing of all coding regions of the TGM5 gene is indicated.

GENERALIZED NONINFLAMMATORY (TYPE A) PEELING SKIN SYNDROME — 

Generalized noninflammatory PSS, also called type A PSS (MIM #270300), is a rare autosomal recessive disorder characterized by painless peeling of the skin that affects multiple body surface areas and starts at birth or in early infancy.

Classification — Generalized noninflammatory PSS encompasses three major groups:

●PSS type 3 (MIM #616265), characterized by asymptomatic, superficial, generalized peeling [8,42]

●PSS type 5 (MIM #617115), also called "exfoliative ichthyosis," manifesting with skin peeling on the hands, feet, and knees associated with palmoplantar keratoderma [43]

●PSS type 6 (MIM #618084), characterized by generalized, dry skin and peeling lesions on the trunk and limbs at sites of minor trauma [44-46]

Pathogenesis

●Peeling skin syndrome type 3 – The genetic basis of noninflammatory type 3 PSS is unknown. A study of a large consanguineous Pakistani family using a combination of autozygosity mapping and whole exome sequencing suggested a biallelic variant (c.229C>T) within exon 4 of CHST8 as the cause of type 3 PSS [8]. CHST8 encodes a carbohydrate sulfotransferase, N-acetylgalactosamine-4-O-sulfotransferase 1 (GalNAc4-ST1), which is a type II transmembrane protein that functions almost exclusively in the Golgi apparatus and transfers sulfate groups to the C4 hydroxyl group of terminal beta-1,4-linked N-acetylgalactosamine [47]. However, this association was questioned in a subsequent study based on the observation that CHST8 is not expressed in the skin; the mutated protein maintains normal catalytic activity; and the putative CHST8 variant is frequently found across different ethnic groups, suggesting that it represents a neutral nonpathogenic polymorphism [42].

●Peeling skin syndrome type 5 – Biallelic loss-of-function variants in SERPINB8, encoding a serine peptidase inhibitor, result in noninflammatory type 5 PSS (also referred to as "exfoliative ichthyosis"). SERPINB8 protein absence in patients' skin results in impaired cell-cell adhesion exacerbated by mechanical stress [43].

●Peeling skin syndrome type 6 – Biallelic loss-of-function variants in FLG2, encoding filaggrin 2, have been reported in three consanguineous families of Saudi, Moroccan, and Israeli origins with generalized noninflammatory PSS [44-46]. Reduced filaggrin expression in patients' epidermis resulted in impaired cell-cell adhesion through a reduction in corneodesmosin expression, a crucial component of corneodesmosomes (intercellular junctions located in the uppermost layers of the epidermis). This effect is enhanced by high temperatures, consistent with the observed clinical exacerbation of type 6 PSS by warm weather [46].

Pathology — On light microscopy, generalized noninflammatory PSS is characterized by slight hyperkeratosis, thinning of the granular layer, and separation of the stratum corneum from the underlying stratum granulosum or intracorneal split [8,44-46,48]. Type 5 PSS is characterized by cell-cell disadhesion within the Malpighian layer of the epidermis, which includes both the basal and spinous cells [43].

Electron microscopy shows intracellular cytoplasmic splitting in the lower stratum corneum and abnormal cribriform or reduced keratohyalin granules, which are indicative of disturbed keratinization [44-46]. In some patients, reduced desmosomal plaques or intracellular electron-dense globular deposits within the stratum corneum have also been observed [49-51].

Clinical manifestations — Generalized noninflammatory PSS presents at birth or in early childhood with diffuse, white or skin-colored scaling, most prominent over the upper and lower extremities (including areas of large joints) (picture 5) [43]. The stratum corneum of the skin can be easily and painlessly removed [52,53]. Exacerbations may occur following contact with water, dust, and sand. In addition, shear and friction forces may induce peeling [52].

Thickened skin with yellowish, hyperkeratotic plaques over the palms and soles, as well as hyperkeratosis over the knees and elbows, may be seen in generalized noninflammatory PSS type 5 [43-45]. Residual hyperpigmentation following the healing of denuded skin areas has been described in type 6 PSS [45].

Erythema and pruritus are usually absent [8]. No systemic symptoms or laboratory abnormalities have been reported.

Diagnosis — Similar to acral peeling skin syndrome (APSS), generalized noninflammatory (type A) PSS is suspected in a patient presenting with painless skin peeling since birth or early childhood. The diagnosis is often delayed in less severe cases due to late presentation and mild symptoms.

A skin biopsy from areas of skin peeling is necessary for the diagnosis (see 'Pathology' above). If available, ultrastructural analysis using electron microscopy may provide additional information, although this is not necessary for the diagnosis.

Molecular analysis for variants in SERPINB8 or FLG2 is indicated in patients and family members for definitive diagnosis (algorithm 1).

Differential diagnosis — The differential diagnosis of generalized noninflammatory PSS includes a number of genodermatoses characterized by scaly skin in the absence of erythema (algorithm 2).

Superficial epidermolytic ichthyosis — Superficial epidermolytic ichthyosis (formerly called "ichthyosis bullosa of Siemens"; MIM #146800) is a rare autosomal dominant genodermatosis caused by heterozygous variants in KRT2, encoding keratin 2. The disease is characterized by mild blistering in early infancy that usually subsides by early childhood when hyperkeratosis develops [54]. An additional characteristic feature is superficial peeling, described as the "mauserung (molting) phenomenon," secondary to superficial blistering and shedding of the stratum corneum [55]. Histopathology shows characteristic epidermolytic changes. (See "Keratinopathic ichthyoses", section on 'Superficial epidermolytic ichthyosis'.)

PLACK syndrome — PLACK (peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads) syndrome (MIM #616295) is a form of peeling skin caused by biallelic loss-of-function variants in CAST, encoding calpastatin, an inhibitor of the calcium-dependent cysteine protease calpain [56-64]. The reduced calpastatin expression and activity results in defective cell adhesion and increased epidermal desquamation. PLACK syndrome has been shown to be associated with low levels of vitamin A and essential fatty acids. In a single case report, treatment with intravenous infusions of lipid emulsions containing fat-soluble vitamins resulted in remarkable improvement in pruritus and skin lesions [65].

Autosomal recessive exfoliative ichthyosis — Autosomal recessive exfoliative ichthyosis (PSS type 4; MIM #607936) is an autosomal recessive disease caused by loss-of-function variants in CSTA, encoding cystatin A (see 'Acral peeling skin syndrome' above). Autosomal recessive exfoliative ichthyosis is characterized by circumscribed, nonerythematous peeling of the skin on the hands, feet, and neck and by generalized, white scaling. Histopathology shows abnormal cell-cell adhesion in the lower epidermal layers [21,22]. Ultrastructurally, autosomal recessive exfoliative ichthyosis is characterized by impaired desmosome morphology in the lower epidermal layers, reduced thickness of the cornified envelope, disturbed lamellar lipid bilayer, premature lamellar body secretion, and delayed processing of secreted lamellar body contents [21,22]. In contrast to PSS, the level of detachment by electron microscopy is in the basal and lower suprabasal layers of the epidermis [21].

GENERALIZED INFLAMMATORY (TYPE B) PEELING SKIN SYNDROME — 

Generalized inflammatory PSS, also called type B PSS or PPS 1 (MIM #270300), is a rare autosomal recessive genodermatosis characterized by widespread peeling of the skin associated with erythroderma, severe pruritus, and atopic manifestations.

Pathogenesis

●Genetics – Generalized inflammatory PSS is caused by loss-of-function variants in CDSN, encoding corneodesmosin, resulting in complete loss of protein expression in the epidermis [9,66-69]. Genomic deletion at the PSORS1 locus removing the entire CDSN gene and a large homozygous deletion of six genes, including CDSN, have also been reported as the cause of type B PSS [70,71]. This genomic deletion resulting from a founder variant has been identified in several Japanese patients with PSS [72].

●Protein function – Corneodesmosin is an extracellular 52 to 56 kDa glycoprotein that contributes to the formation of corneodesmosomes, critical intercellular junctions in the upper epidermal layers. This protein plays a role in reinforcing cell-cell adhesion in the upper epidermis, and its degradation by epidermal proteases is essential for normal desquamation [73,74]. The absence of corneodesmosin in patients with type B PSS results in impaired cell-cell coherence in the upper epidermis and defective skin barrier function, with increased permeability to allergens and microbes [75].

Pathology — On histology, generalized inflammatory PSS shows subcorneal separation with mild inflammatory infiltrate in the upper dermis. Electron microscopy shows evidence of split formation between the keratinocytes of the stratum granulosum and corneocytes of the stratum corneum and loss of corneodesmosomes [9]. The total absence of corneodesmosin expression in the epidermis, demonstrated by immunohistochemistry, can confirm the diagnosis.

Clinical manifestations — Generalized inflammatory PSS presents at birth or during early infancy with spontaneous and widespread skin peeling associated with erythroderma that persists into adulthood (picture 6). Additional major features are severe pruritus, food allergies, asthma, repeated episodes of angioedema, and urticaria. Patients may exhibit failure to thrive and recurrent skin infections, especially with Staphylococcus aureus [9,66,68]. The condition is usually not associated with any hair abnormalities. However, a single case associated with trichorrhexis invaginata, a typical manifestation of Netherton syndrome, has been reported [76]. (See "Netherton syndrome".)

Characteristic laboratory findings include elevated immunoglobulin E (IgE) levels and eosinophilia.

Diagnosis — The diagnosis of generalized inflammatory PSS is based on the combination of clinical and laboratory findings (algorithm 1):

●Widespread skin peeling associated with erythroderma, severe pruritus, and atopic manifestations, including food allergies and asthma

●Elevated levels of serum IgE and eosinophilia

●Histopathologic findings of subcorneal separation with mild inflammatory infiltrate in the upper dermis and absent corneodesmosin stain on immunohistochemistry

●Evidence of loss of corneodesmosomes on electron microscopy

Differential diagnosis — The differential diagnosis of type B PSS includes several acquired and inherited disorders. Due to considerable phenotypic overlap, the differentiation of type B PSS from Netherton syndrome and SAM (severe dermatitis, multiple allergies, and metabolic wasting) syndrome requires molecular analysis (algorithm 2) [49,75].

Netherton syndrome — Netherton syndrome (MIM #256500) is a rare, severe autosomal recessive disorder caused by loss-of-function variants in the serine protease inhibitor of Kazal type 5 (SPINK5) gene, encoding the serine protease inhibitor lymphoepithelial Kazal-type-related inhibitor type 5 (LEKTI) [77-79]. Netherton syndrome is characterized by the clinical triad of congenital ichthyosiform erythroderma in newborns and ichthyosis linearis circumflexa in older children and adults (picture 7); a specific hair shaft abnormality termed "trichorrhexis invaginata" resulting in short, lusterless hair; and atopic manifestations (eg, eczematous lesions, asthma, allergic rhinitis, food allergies) with elevated serum levels of IgE [80-82]. (See "Netherton syndrome".)

SAM syndrome — SAM (severe dermatitis, multiple allergies, and metabolic wasting) syndrome (MIM #615508) is a genodermatosis first described in 2013 caused by homozygous variants in DSG1, encoding desmoglein 1, a cadherin-like transmembrane glycoprotein that is an essential component of the desmosomes in the upper epidermal layers [83-89]. Isolated cases caused by a point variant in DSP, encoding desmoplakin, have been described [90-92]. Desmoplakin is an obligate component of functional desmosomes that anchors intermediate filaments to desmosomal plaques.

SAM syndrome is characterized by congenital erythroderma, striate palmoplantar keratoderma (yellowish papules and plaques at the periphery of the palms, along the fingers, and over weight-bearing areas of the feet), skin erosions, scaling, and hypotrichosis [75,83]. Additional features are severe food allergies, recurrent skin and respiratory infections, eosinophilic esophagitis, esophageal reflux, minor cardiac defects, failure to thrive, and growth retardation. Elevated IgE level is a common laboratory finding.

MANAGEMENT — 

There is no specific therapy for PSS. Patients should be educated about avoiding exacerbating factors, such as heat, humidity, excessive perspiration, friction, and mechanical trauma (eg, using padding or appropriate footwear). Daily topical application of emollients to the affected areas may be beneficial.

Evidence supporting medical treatments for PSS is limited to a few case reports and small case series. Agents that have been used with variable success include botulinum toxin type A for acral peeling skin syndrome (APSS) [32], oral retinoids [52,93], and topical calcipotriol [94].

In a single case report, treatment of generalized inflammatory PSS with dupilumab reduced IgE levels but did not improve the skin manifestations or quality of life [95].

A preclinical in vitro study with liposomal-encapsulated recombinant human corneodesmosin demonstrated promising results in primary keratinocytes and human epidermal equivalents [96].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ichthyosis".)

SUMMARY AND RECOMMENDATIONS

●Definition and classification – Peeling skin syndromes (PSS) encompass a heterogeneous group of rare autosomal recessive disorders characterized by superficial peeling and blistering of the skin without mucosal fragility. The two major forms of PSS are localized/acral peeling skin syndrome (APSS) and generalized PSS. The latter is subclassified into noninflammatory (type A) PSS and inflammatory (type B) PSS. (See 'Introduction' above.)

●Acral peeling skin syndrome – In most cases, APSS is caused by variants in TGM5, encoding transglutaminase 5, involved in the cross-linking of cornified cell envelope proteins. APSS manifests at birth or in early infancy and is characterized by skin exfoliation limited to the hands and feet (picture 1A-B). Rare cases may result from variants in CSTA, encoding cystatin A, a cysteine protease inhibitor. (See 'Acral peeling skin syndrome' above.)

●Generalized noninflammatory peeling skin syndrome – Generalized noninflammatory PSS, or type A PSS, results from biallelic variants in SERPINB8 or FLG2, encoding serpin peptidase inhibitor, clade B, member 8, and filaggrin 2, respectively. In most cases, it presents at birth or early childhood with generalized, white or skin-colored scaling that is most prominent over the upper and lower extremities (picture 5), with painless and easy removal of the skin. (See 'Generalized noninflammatory (type A) peeling skin syndrome' above.)

●Generalized inflammatory peeling skin syndrome – Generalized inflammatory PSS, or type B PSS, is caused by loss-of-function variants in the CDSN gene, encoding corneodesmosin. Type B PSS presents at birth or in early childhood with widespread peeling of the skin associated with erythroderma (picture 6), severe pruritus, and atopic manifestations. (See 'Generalized inflammatory (type B) peeling skin syndrome' above.)

●Diagnosis – The diagnosis and differential diagnosis of PSS are based on the combination of clinical features, histopathologic and ultrastructural analysis of a skin biopsy, and molecular analysis (algorithm 1 and algorithm 2).

●Management – There are no specific therapies for PSS. Improvement of scaling and blistering may be observed with avoidance of exacerbating factors, such as heat, friction, humidity, mechanical trauma (eg, using padding or appropriate footwear), and excessive perspiration, as well as daily topical application of emollients to affected areas. (See 'Management' above.)