👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

All molecularly defined PSS subtypes (TGM5, CSTA, FLG2, CDSN, CAST, SERPINB8) are inherited as autosomal recessive traits requiring biallelic loss-of-function variants. Monoallelic CDSN variants instead cause autosomal dominant hypotrichosis simplex of the scalp, a distinct phenotype.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:22289416 SUPPORT Human Clinical

"Peeling skin syndrome (PSS) is a group of rare autosomal recessive genodermatoses"

States that PSS is a group of autosomal recessive genodermatoses.

◆

Subtypes

7

Acral peeling skin syndrome (TGM5)

TGM5 hgnc:11781 {'name': 'Autosomal recessive'}

Acral peeling skin syndrome (APSS; PSS2) due to biallelic loss-of-function variants in TGM5 (transglutaminase 5). Superficial painless peeling is largely confined to the dorsal and palmoplantar surfaces of the hands and feet, with cleavage between the stratum corneum and stratum granulosum. Exacerbated by humidity, heat, sweating, and friction; can mimic localized epidermolysis bullosa simplex. A recurrent European founder variant, c.763T>C p.(Trp255Arg), is described.

Acral peeling skin syndrome / exfoliative ichthyosis (CSTA)

CSTA hgnc:2481 {'name': 'Autosomal recessive'}

Acral peeling skin syndrome overlapping with exfoliative ichthyosis, caused by biallelic loss-of-function variants in CSTA (cystatin A), a cysteine-protease inhibitor of the cornified cell envelope. Lifelong acral peeling, often with erythema, lichenification, maceration, and pruritus, strongly exacerbated by moisture, heat, and friction.

Generalized PSS type A, non-inflammatory (CHST8)

CHST8 hgnc:15993 {'name': 'Autosomal recessive'}

Generalized non-inflammatory PSS (type A; PSS3) reported with a homozygous CHST8 missense variant (R77W) in a consanguineous family. CHST8 encodes a Golgi N-acetylgalactosamine-4-O-sulfotransferase (GalNAc4-ST1). Generalized, largely asymptomatic, year-round peeling/scaling beginning in early childhood without inflammatory change, vesicles/pustules, or mucous membrane/nail involvement. The pathogenicity of the original CHST8 variant has been questioned in later work.

Generalized ichthyotic PSS (FLG2)

FLG2 hgnc:33276 {'name': 'Autosomal recessive'}

Generalized ichthyotic peeling skin syndrome caused by biallelic loss-of-function variants in FLG2 (filaggrin-2). Congenital erythroderma with persistent dry skin and superficial peeling, cleavage in the lower stratum corneum with parakeratosis, reduced corneodesmosin/desmoglein-1/desmocollin-1, and abnormal keratin compaction. Worsened by minor trauma and warm humid environments; denuded areas heal with hyperpigmentation without scarring, and the phenotype tends to improve with age.

Generalized inflammatory PSS / peeling skin disease, PSS1 (CDSN)

CDSN hgnc:1802 {'name': 'Autosomal recessive'}

Generalized inflammatory PSS (type B; peeling skin disease, PSD; PSS1) caused by biallelic loss-of-function variants (nonsense, frameshift, large deletions) or rare missense variants in CDSN (corneodesmosin), the key adhesive component of corneodesmosomes. Onset at birth with ichthyosiform erythroderma and lifelong superficial peeling, severe pruritus, and atopic features (elevated IgE, eosinophilia, food allergy). Monoallelic CDSN variants instead cause autosomal dominant hypotrichosis simplex of the scalp, a distinct phenotype.

PLACK syndrome (CAST)

CAST hgnc:1515 {'name': 'Autosomal recessive'}

PLACK syndrome (Peeling skin, Leukonychia, Acral punctate keratoses, Cheilitis, Knuckle pads), caused by biallelic loss-of-function variants in CAST (calpastatin, the endogenous inhibitor of the calcium-dependent protease calpain). A generalized peeling phenotype reflecting impaired keratinocyte adhesion and increased keratinocyte apoptosis; peeling may occur spontaneously or after trauma, with or without bullae.

Peeling skin syndrome (SERPINB8)

SERPINB8 hgnc:8952 {'name': 'Autosomal recessive'}

Peeling skin syndrome associated with biallelic loss-of-function variants in SERPINB8, a serine-protease inhibitor. Reported among the protease-inhibitor class of peeling skin disorders contributing to dysregulated desquamation and impaired corneocyte adhesion.

⚙

Pathophysiology

4

Defective corneodesmosome-mediated corneocyte cohesion

Across PSS subtypes, the unifying defect is impaired cohesion of corneocytes in the stratum corneum. Corneodesmosomes are the modified desmosomes that hold corneocytes together; corneodesmosin (CDSN), together with desmoglein-1 and desmocollin-1, is a central adhesive component. Loss of corneodesmosin or related structural proteins weakens intercellular adhesion at the granular-to-cornified transition, producing superficial cleavage and visible peeling.

Keratinocyte CL:0000312

Cell-cell adhesion GO:0098609 ↓ DECREASED Keratinocyte differentiation GO:0030216

Stratum corneum of epidermis UBERON:0002027

Downstream

Loss of corneodesmosin and epidermal barrier breakdown In CDSN-related disease, defective corneodesmosome cohesion progresses to complete loss of corneodesmosin with superficial cleavage and barrier failure.

Show evidence (2 references)

PMID:25473393 SUPPORT Human Clinical

"The corneodesmosome, a modified form of desmosome found in the stratum corneum and inner root sheath of the hair follicles, differs ultrastructurally from the desmosome and is shown to play an important role in intercellular adhesion between corneocytes in the cornified cell layer"

Establishes the corneodesmosome and its constituent corneodesmosin as the adhesive structure whose disruption underlies corneocyte detachment in PSS.

PMID:25473393 SUPPORT Human Clinical

"The extracellular part of the corneodesmosome is mainly composed of corneodesmosin, desmoglein 1 and desmocollin 1"

Identifies the molecular components of corneodesmosomes affected in PSS subtypes.

Loss of corneodesmosin and epidermal barrier breakdown

In CDSN-related inflammatory generalized PSS (PSS1/peeling skin disease), complete loss of corneodesmosin abolishes corneodesmosome adhesion, causing superficial cleavage above the stratum granulosum and a severe epidermal barrier defect. Barrier failure increases transepidermal water loss and antigen penetration, predisposing to pruritus and atopic disease (elevated IgE, food allergies). The murine Cdsn knockout dies postnatally from barrier breakdown, confirming corneodesmosin's essential barrier role.

Keratinocyte CL:0000312

Establishment of skin barrier GO:0061436 ↓ DECREASED

Skin epidermis UBERON:0001003

Show evidence (3 references)

PMID:20691404 SUPPORT Human Clinical

"we have identified a homozygous nonsense mutation in CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies, which leads to a complete loss of corneodesmosin"

Directly links biallelic CDSN loss-of-function to generalized peeling skin with pruritus and atopy through complete loss of corneodesmosin.

PMID:20691404 SUPPORT In Vitro

"Using three-dimensional human skin models, we demonstrate that lack of corneodesmosin causes an epidermal barrier defect supposed to account for the predisposition to atopic diseases, and we confirm the role of corneodesmosin as a decisive epidermal adhesion molecule"

Reconstructed human epidermis lacking corneodesmosin shows a barrier defect, mechanistically connecting CDSN loss to barrier dysfunction and atopy.

PMID:20691404 SUPPORT Model Organism

"The skin phenotype is consistent with a recent murine Cdsn knockout model"

The Cdsn knockout mouse recapitulates the human peeling/barrier phenotype, providing in vivo support for CDSN's role.

Protease-inhibitor imbalance and corneocyte over-desquamation

Epidermal desquamation is normally a tightly regulated balance between proteases (e.g., kallikrein-related peptidases, calpain) that degrade corneodesmosomes and their endogenous inhibitors. In protease-inhibitor PSS subtypes, loss of CSTA (cystatin A), CAST (calpastatin), or SERPINB8 removes this brake, leading to unregulated proteolytic cleavage of corneodesmosomal adhesion proteins and premature/over-desquamation of corneocytes. Elevated tissue kallikrein activity has been reported in type B PSS stratum corneum and serum.

Keratinocyte CL:0000312

Proteolysis of corneodesmosomal adhesion proteins GO:0006508 ↑ INCREASED

Downstream

Defective corneodesmosome-mediated corneocyte cohesion Unopposed proteolysis degrades corneodesmosomal adhesion proteins, weakening corneodesmosome-mediated cohesion and producing premature desquamation.

Show evidence (3 references)

PMID:30032785 SUPPORT Human Clinical

"This occurs through the interplay between proteases and their inhibitors that control the degradation of corneodesmosomes."

States the protease-inhibitor balance controlling corneodesmosome degradation, whose disruption drives over-desquamation in inhibitor-deficient PSS subtypes.

PMID:30032785 SUPPORT Human Clinical

"Proteins that are mutated in peeling skin disorders are components of corneodesmosomes (CDSN, DSG1) or protease inhibitors (LEKTI, CSTA, CAST, or SERPIN8)."

Classifies the causal genes of peeling skin disorders into corneodesmosome structural components and protease inhibitors, supporting the mechanistic grouping.

PMID:16778802 SUPPORT Human Clinical

"Elevated human tissue kallikrein levels in the stratum corneum and serum of peeling skin syndrome-type B patients suggests an over-desquamation of corneocytes."

Reports elevated protease (kallikrein) activity in type B PSS, supporting an over-desquamation mechanism driven by unbalanced proteolysis.

Crosslinking-enzyme deficiency in acral PSS

In acral PSS, loss of TGM5 (transglutaminase 5) impairs crosslinking of cornified envelope structural proteins (loricrin, involucrin, small proline-rich proteins) via gamma-glutamyl-epsilon-lysine isopeptide bonds. The resulting defective cornified envelope assembly weakens corneocyte cohesion at the stratum corneum-granulosum interface, producing superficial acral peeling.

Keratinocyte CL:0000312

Keratinization / cornified envelope formation GO:1903575 ⚠ ABNORMAL

Downstream

Defective corneodesmosome-mediated corneocyte cohesion Impaired TGM5 crosslinking yields a defective cornified envelope, weakening corneocyte cohesion at the stratum corneum-granulosum interface.

Show evidence (1 reference)

PMID:22289416 SUPPORT Human Clinical

"TGM5 is involved in cross-linking structural proteins for the formation of the cornified envelope, by catalyzing the formation of γ-glutamyl-ε-lysine isopeptide bonds between differentiation-specific proteins expressed mainly in corneocytes, including loricrin, involucrin and small proline-rich proteins"

Describes the TGM5 crosslinking function whose loss causes defective cornified envelope assembly in acral PSS.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

11

Blood 1

Elevated circulating IgE Increased circulating IgE concentration HP:0003212

Show evidence (1 reference)

PMID:31663161 SUPPORT Human Clinical

"Routine laboratory parameters were normal, except for elevated IgE levels (2222 kU/L; normal, <100)."

Documents markedly elevated IgE in a CDSN-related PSS patient, supporting the atopic laboratory phenotype.

Immune 2

Ichthyosiform erythroderma Erythroderma HP:0001019

Show evidence (1 reference)

PMID:32926582 SUPPORT Human Clinical

"Patients are affected by pronounced erythroderma accompanied by pruritus and superficial generalized peeling of the skin."

Directly reports pronounced erythroderma in PSS1 (CDSN) patients.

Food allergy Food allergy HP:0500093

Show evidence (1 reference)

PMID:20691404 SUPPORT Human Clinical

"we have identified a homozygous nonsense mutation in CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies"

Reports food allergies co-segregating with CDSN-related generalized peeling skin.

Integument 6

Skin peeling Scaling skin HP:0040189

Show evidence (2 references)

PMID:31663161 SUPPORT Human Clinical

"Peeling skin disease is a rare genodermatosis characterized by superficial exfoliation or peeling of the skin."

Confirms superficial peeling/exfoliation as the core feature of peeling skin disease.

PMID:22289416 SUPPORT Human Clinical

"Generalized peeling skin syndrome (PSS) is an autosomal recessive genodermatosis characterized by lifelong, continuous shedding of the upper epidermis."

Supports generalized, lifelong shedding of the upper epidermis in generalized PSS.

Ichthyosis Ichthyosis HP:0008064

Show evidence (1 reference)

PMID:29505760 SUPPORT Human Clinical

"Generalized Ichthyotic Peeling Skin Syndrome due to FLG2 Mutations."

The FLG2-related subtype is explicitly an ichthyotic peeling skin syndrome.

Pruritus Pruritus HP:0000989

Show evidence (1 reference)

PMID:32926582 SUPPORT Human Clinical

"Patients are affected by pronounced erythroderma accompanied by pruritus and superficial generalized peeling of the skin."

Reports pruritus as a prominent feature of PSS1 (CDSN).

Leukonychia Leukonychia HP:0001820

Show evidence (1 reference)

PMID:25683118 SUPPORT Human Clinical

"loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome"

Leukonychia is one of the cardinal PLACK features caused by CAST loss-of-function.

Knuckle pads Knuckle pad HP:0032541

Show evidence (1 reference)

PMID:25683118 SUPPORT Human Clinical

"generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome"

Knuckle pads are a cardinal PLACK feature caused by CAST loss-of-function.

Post-inflammatory hyperpigmentation Hyperpigmentation of the skin HP:0000953

Show evidence (1 reference)

PMID:30032785 PARTIAL Human Clinical

"FLG2 emerged as a new player that regulates epidermal desquamation, as demonstrated by the phenotype observed in patients reported by 2 independent groups."

Supports FLG2 as a cause of a generalized peeling phenotype; the specific post-inflammatory hyperpigmentation detail derives from the primary FLG2 case report (Bolling 2018, PMID:29505760).

Other 2

Palmoplantar peeling Palmoplantar peeling HP:0025819

Show evidence (1 reference)

PMID:22289416 SUPPORT Human Clinical

"APSS (localized form) involves the palmar, plantar and dorsal surfaces of hands and feet and is caused by mutations in the tranglutaminase 5 gene (TGM5)"

Localizes acral PSS peeling to the palmar, plantar, and dorsal hand/foot surfaces.

Cheilitis Cheilitis HP:0100825

Show evidence (1 reference)

PMID:25683118 SUPPORT Human Clinical

"generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome"

Cheilitis is a cardinal PLACK feature caused by CAST loss-of-function.

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Genetic Associations

7

CDSN pathogenic variants (Causative)

Gene: CDSN hgnc:1802 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (1 reference)

PMID:31663161 SUPPORT Human Clinical

"Mutation analysis in the patient showed compound heterozygous mutations in exon 2 of CDSN, a nonsense mutation c.598C>T (p.[Gln200*])"

Documents specific compound heterozygous loss-of-function CDSN variants causing PSD.

TGM5 pathogenic variants (Causative)

Gene: TGM5 hgnc:11781 relationship_type: CAUSATIVE

Autosomal recessive

CHST8 variant (disputed) (Causative)

Gene: CHST8 hgnc:15993 relationship_type: DISPUTED

Autosomal recessive

Show evidence (1 reference)

PMID:22289416 SUPPORT Human Clinical

"we identified a novel homozygous missense mutation (c.229C>T, R77W) within the CHST8 gene, in a large consanguineous family with non-inflammatory PSS type A"

Original report linking a homozygous CHST8 variant to non-inflammatory PSS type A.

FLG2 pathogenic variants (Causative)

Gene: FLG2 hgnc:33276 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (1 reference)

PMID:29505760 SUPPORT Human Clinical

"Generalized Ichthyotic Peeling Skin Syndrome due to FLG2 Mutations."

Establishes biallelic FLG2 mutations as a cause of generalized ichthyotic PSS.

CSTA pathogenic variants (Causative)

Gene: CSTA hgnc:2481 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (1 reference)

PMID:23534700 SUPPORT Human Clinical

"We identified a homozygous nonsense mutation (p.Lys22X) in the CSTA gene, encoding cystatin A"

Documents the homozygous CSTA loss-of-function variant causing acral PSS.

CAST pathogenic variants (Causative)

Gene: CAST hgnc:1515 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (1 reference)

PMID:25683118 SUPPORT Human Clinical

"we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins"

Documents homozygous truncating CAST variants causing PLACK syndrome.

SERPINB8 pathogenic variants (Causative)

Gene: SERPINB8 hgnc:8952 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (1 reference)

PMID:30032785 SUPPORT Human Clinical

"Proteins that are mutated in peeling skin disorders are components of corneodesmosomes (CDSN, DSG1) or protease inhibitors (LEKTI, CSTA, CAST, or SERPIN8)."

Lists SERPINB8 (SERPIN8) among the protease-inhibitor genes mutated in peeling skin disorders.

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Medical Actions

5

Emollient and skin-softening therapy

Action: emollient therapy MAXO:0001574

Topical emollients and skin-softening agents are the mainstay of supportive care, helping maintain barrier function and reduce scaling/peeling across PSS subtypes.

Trigger avoidance

Action: supportive care MAXO:0000950

Avoidance of exacerbating exposures (humidity, heat, sweating/hyperhidrosis, friction, and water/moisture) is a practical measure that reduces peeling, especially in acral PSS.

Botulinum toxin A for acral PSS

Action: Pharmacotherapy NCIT:C15986

Botulinum toxin A injections have been reported to provide symptomatic benefit in acral PSS by reducing hyperhidrosis, a common exacerbating factor.

Show evidence (1 reference)

PMID:38590258 SUPPORT Human Clinical

"Acral Peeling Skin Syndrome: Two Unusual Cases and the Therapeutic Potential of Botulinum Toxin."

Reports the therapeutic potential of botulinum toxin in acral PSS (driven by reduction of hyperhidrosis-associated exacerbation).

Recombinant corneodesmosin protein replacement (experimental)

Action: Pharmacotherapy NCIT:C15986

A pathogenesis-based, preclinical protein-replacement strategy for CDSN-deficient PSS1 delivers recombinant corneodesmosin in liposomal carriers to keratinocytes, restoring CDSN in the stratum granulosum and improving barrier integrity in CDSN-deficient epidermal equivalents in vitro.

Show evidence (2 references)

PMID:32926582 SUPPORT In Vitro

"CDSN-deficient epidermal equivalents that were treated with liposomal encapsulated CDSN demonstrated presence of CDSN in the SG."

Preclinical in vitro data show restoration of corneodesmosin by liposomal protein replacement, supporting a pathogenesis-based therapy for PSS1.

PMID:32926582 SUPPORT In Vitro

"This study presents the first preclinical in vitro experiments for a future specific protein replacement therapy for patients affected by PSS1."

Frames the approach as preclinical protein replacement therapy for PSS1.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Because PSS is genetic (predominantly autosomal recessive), genetic counseling and carrier testing in affected families are the principal primary-prevention measures.

{ }

Source YAML

click to show

name: Peeling Skin Syndrome
creation_date: "2026-06-05T12:00:00Z"
category: Mendelian
description: >-
  Peeling skin syndrome (PSS) is a clinically and genetically heterogeneous group of
  rare autosomal recessive genodermatoses characterized by superficial, spontaneous,
  usually painless shedding (peeling) of the stratum corneum, caused by defective
  corneocyte cohesion. Subtypes are distinguished by distribution and inflammation:
  acral PSS (APSS; mainly hands and feet) and generalized PSS, which is further divided
  into non-inflammatory (type A) and inflammatory (type B / peeling skin disease, PSS1)
  forms. The molecular basis falls into three mechanistic categories: structural
  corneodesmosome/cornified-envelope defects (CDSN, FLG2), crosslinking-enzyme defects
  (TGM5), and protease-inhibitor imbalance leading to over-desquamation (CSTA, CAST,
  SERPINB8). Related entities such as PLACK syndrome (CAST) extend the clinical spectrum.
disease_term:
  preferred_term: Peeling Skin Syndrome
  term:
    id: MONDO:0019347
    label: peeling skin syndrome

inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All molecularly defined PSS subtypes (TGM5, CSTA, FLG2, CDSN, CAST, SERPINB8)
    are inherited as autosomal recessive traits requiring biallelic loss-of-function
    variants. Monoallelic CDSN variants instead cause autosomal dominant
    hypotrichosis simplex of the scalp, a distinct phenotype.
  evidence:
  - reference: PMID:22289416
    reference_title: "Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peeling skin syndrome (PSS) is a group of rare autosomal recessive genodermatoses"
    explanation: >-
      States that PSS is a group of autosomal recessive genodermatoses.

has_subtypes:
- name: APSS-TGM5
  display_name: Acral peeling skin syndrome (TGM5)
  description: >-
    Acral peeling skin syndrome (APSS; PSS2) due to biallelic loss-of-function
    variants in TGM5 (transglutaminase 5). Superficial painless peeling is largely
    confined to the dorsal and palmoplantar surfaces of the hands and feet, with
    cleavage between the stratum corneum and stratum granulosum. Exacerbated by
    humidity, heat, sweating, and friction; can mimic localized epidermolysis bullosa
    simplex. A recurrent European founder variant, c.763T>C p.(Trp255Arg), is described.
  inheritance:
  - name: Autosomal recessive
  genes:
  - preferred_term: TGM5
    term:
      id: hgnc:11781
      label: TGM5
- name: APSS-CSTA
  display_name: Acral peeling skin syndrome / exfoliative ichthyosis (CSTA)
  description: >-
    Acral peeling skin syndrome overlapping with exfoliative ichthyosis, caused by
    biallelic loss-of-function variants in CSTA (cystatin A), a cysteine-protease
    inhibitor of the cornified cell envelope. Lifelong acral peeling, often with
    erythema, lichenification, maceration, and pruritus, strongly exacerbated by
    moisture, heat, and friction.
  inheritance:
  - name: Autosomal recessive
  genes:
  - preferred_term: CSTA
    term:
      id: hgnc:2481
      label: CSTA
- name: GPSS-Type-A-CHST8
  display_name: Generalized PSS type A, non-inflammatory (CHST8)
  description: >-
    Generalized non-inflammatory PSS (type A; PSS3) reported with a homozygous CHST8
    missense variant (R77W) in a consanguineous family. CHST8 encodes a Golgi
    N-acetylgalactosamine-4-O-sulfotransferase (GalNAc4-ST1). Generalized, largely
    asymptomatic, year-round peeling/scaling beginning in early childhood without
    inflammatory change, vesicles/pustules, or mucous membrane/nail involvement.
    The pathogenicity of the original CHST8 variant has been questioned in later work.
  inheritance:
  - name: Autosomal recessive
  genes:
  - preferred_term: CHST8
    term:
      id: hgnc:15993
      label: CHST8
- name: GPSS-FLG2
  display_name: Generalized ichthyotic PSS (FLG2)
  description: >-
    Generalized ichthyotic peeling skin syndrome caused by biallelic loss-of-function
    variants in FLG2 (filaggrin-2). Congenital erythroderma with persistent dry skin
    and superficial peeling, cleavage in the lower stratum corneum with parakeratosis,
    reduced corneodesmosin/desmoglein-1/desmocollin-1, and abnormal keratin compaction.
    Worsened by minor trauma and warm humid environments; denuded areas heal with
    hyperpigmentation without scarring, and the phenotype tends to improve with age.
  inheritance:
  - name: Autosomal recessive
  genes:
  - preferred_term: FLG2
    term:
      id: hgnc:33276
      label: FLG2
- name: GPSS-Type-B-CDSN
  display_name: Generalized inflammatory PSS / peeling skin disease, PSS1 (CDSN)
  description: >-
    Generalized inflammatory PSS (type B; peeling skin disease, PSD; PSS1) caused by
    biallelic loss-of-function variants (nonsense, frameshift, large deletions) or rare
    missense variants in CDSN (corneodesmosin), the key adhesive component of
    corneodesmosomes. Onset at birth with ichthyosiform erythroderma and lifelong
    superficial peeling, severe pruritus, and atopic features (elevated IgE,
    eosinophilia, food allergy). Monoallelic CDSN variants instead cause autosomal
    dominant hypotrichosis simplex of the scalp, a distinct phenotype.
  inheritance:
  - name: Autosomal recessive
  genes:
  - preferred_term: CDSN
    term:
      id: hgnc:1802
      label: CDSN
- name: PLACK-CAST
  display_name: PLACK syndrome (CAST)
  description: >-
    PLACK syndrome (Peeling skin, Leukonychia, Acral punctate keratoses, Cheilitis,
    Knuckle pads), caused by biallelic loss-of-function variants in CAST (calpastatin,
    the endogenous inhibitor of the calcium-dependent protease calpain). A generalized
    peeling phenotype reflecting impaired keratinocyte adhesion and increased
    keratinocyte apoptosis; peeling may occur spontaneously or after trauma, with or
    without bullae.
  inheritance:
  - name: Autosomal recessive
  genes:
  - preferred_term: CAST
    term:
      id: hgnc:1515
      label: CAST
- name: GPSS-SERPINB8
  display_name: Peeling skin syndrome (SERPINB8)
  description: >-
    Peeling skin syndrome associated with biallelic loss-of-function variants in
    SERPINB8, a serine-protease inhibitor. Reported among the protease-inhibitor class
    of peeling skin disorders contributing to dysregulated desquamation and impaired
    corneocyte adhesion.
  inheritance:
  - name: Autosomal recessive
  genes:
  - preferred_term: SERPINB8
    term:
      id: hgnc:8952
      label: SERPINB8

pathophysiology:
- name: Defective corneodesmosome-mediated corneocyte cohesion
  description: >-
    Across PSS subtypes, the unifying defect is impaired cohesion of corneocytes in
    the stratum corneum. Corneodesmosomes are the modified desmosomes that hold
    corneocytes together; corneodesmosin (CDSN), together with desmoglein-1 and
    desmocollin-1, is a central adhesive component. Loss of corneodesmosin or related
    structural proteins weakens intercellular adhesion at the granular-to-cornified
    transition, producing superficial cleavage and visible peeling.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: Cell-cell adhesion
    term:
      id: GO:0098609
      label: cell-cell adhesion
    modifier: DECREASED
  - preferred_term: Keratinocyte differentiation
    term:
      id: GO:0030216
      label: keratinocyte differentiation
  locations:
  - preferred_term: Stratum corneum of epidermis
    term:
      id: UBERON:0002027
      label: stratum corneum of epidermis
  downstream:
  - target: Loss of corneodesmosin and epidermal barrier breakdown
    description: >-
      In CDSN-related disease, defective corneodesmosome cohesion progresses to
      complete loss of corneodesmosin with superficial cleavage and barrier failure.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:25473393
    reference_title: "A Case of Inflammatory Generalized Type of Peeling Skin Syndrome Possibly Caused by a Homozygous Missense Mutation of CDSN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The corneodesmosome, a modified form of desmosome found in the stratum corneum and inner root sheath of the hair follicles, differs ultrastructurally from the desmosome and is shown to play an important role in intercellular adhesion between corneocytes in the cornified cell layer"
    explanation: >-
      Establishes the corneodesmosome and its constituent corneodesmosin as the
      adhesive structure whose disruption underlies corneocyte detachment in PSS.
  - reference: PMID:25473393
    reference_title: "A Case of Inflammatory Generalized Type of Peeling Skin Syndrome Possibly Caused by a Homozygous Missense Mutation of CDSN."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The extracellular part of the corneodesmosome is mainly composed of corneodesmosin, desmoglein 1 and desmocollin 1"
    explanation: >-
      Identifies the molecular components of corneodesmosomes affected in PSS subtypes.
- name: Loss of corneodesmosin and epidermal barrier breakdown
  description: >-
    In CDSN-related inflammatory generalized PSS (PSS1/peeling skin disease),
    complete loss of corneodesmosin abolishes corneodesmosome adhesion, causing
    superficial cleavage above the stratum granulosum and a severe epidermal barrier
    defect. Barrier failure increases transepidermal water loss and antigen
    penetration, predisposing to pruritus and atopic disease (elevated IgE, food
    allergies). The murine Cdsn knockout dies postnatally from barrier breakdown,
    confirming corneodesmosin's essential barrier role.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: Establishment of skin barrier
    term:
      id: GO:0061436
      label: establishment of skin barrier
    modifier: DECREASED
  locations:
  - preferred_term: Skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  evidence:
  - reference: PMID:20691404
    reference_title: "Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified a homozygous nonsense mutation in CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies, which leads to a complete loss of corneodesmosin"
    explanation: >-
      Directly links biallelic CDSN loss-of-function to generalized peeling skin with
      pruritus and atopy through complete loss of corneodesmosin.
  - reference: PMID:20691404
    reference_title: "Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Using three-dimensional human skin models, we demonstrate that lack of corneodesmosin causes an epidermal barrier defect supposed to account for the predisposition to atopic diseases, and we confirm the role of corneodesmosin as a decisive epidermal adhesion molecule"
    explanation: >-
      Reconstructed human epidermis lacking corneodesmosin shows a barrier defect,
      mechanistically connecting CDSN loss to barrier dysfunction and atopy.
  - reference: PMID:20691404
    reference_title: "Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The skin phenotype is consistent with a recent murine Cdsn knockout model"
    explanation: >-
      The Cdsn knockout mouse recapitulates the human peeling/barrier phenotype,
      providing in vivo support for CDSN's role.
- name: Protease-inhibitor imbalance and corneocyte over-desquamation
  description: >-
    Epidermal desquamation is normally a tightly regulated balance between proteases
    (e.g., kallikrein-related peptidases, calpain) that degrade corneodesmosomes and
    their endogenous inhibitors. In protease-inhibitor PSS subtypes, loss of CSTA
    (cystatin A), CAST (calpastatin), or SERPINB8 removes this brake, leading to
    unregulated proteolytic cleavage of corneodesmosomal adhesion proteins and
    premature/over-desquamation of corneocytes. Elevated tissue kallikrein activity
    has been reported in type B PSS stratum corneum and serum.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: Proteolysis of corneodesmosomal adhesion proteins
    term:
      id: GO:0006508
      label: proteolysis
    modifier: INCREASED
  downstream:
  - target: Defective corneodesmosome-mediated corneocyte cohesion
    description: >-
      Unopposed proteolysis degrades corneodesmosomal adhesion proteins, weakening
      corneodesmosome-mediated cohesion and producing premature desquamation.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30032785
    reference_title: "Peeling Skin Disorders: A Paradigm for Skin Desquamation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This occurs through the interplay between proteases and their inhibitors that control the degradation of corneodesmosomes."
    explanation: >-
      States the protease-inhibitor balance controlling corneodesmosome degradation,
      whose disruption drives over-desquamation in inhibitor-deficient PSS subtypes.
  - reference: PMID:30032785
    reference_title: "Peeling Skin Disorders: A Paradigm for Skin Desquamation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Proteins that are mutated in peeling skin disorders are components of corneodesmosomes (CDSN, DSG1) or protease inhibitors (LEKTI, CSTA, CAST, or SERPIN8)."
    explanation: >-
      Classifies the causal genes of peeling skin disorders into corneodesmosome
      structural components and protease inhibitors, supporting the mechanistic grouping.
  - reference: PMID:16778802
    reference_title: "Elevated human tissue kallikrein levels in the stratum corneum and serum of peeling skin syndrome-type B patients suggests an over-desquamation of corneocytes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated human tissue kallikrein levels in the stratum corneum and serum of peeling skin syndrome-type B patients suggests an over-desquamation of corneocytes."
    explanation: >-
      Reports elevated protease (kallikrein) activity in type B PSS, supporting an
      over-desquamation mechanism driven by unbalanced proteolysis.
- name: Crosslinking-enzyme deficiency in acral PSS
  description: >-
    In acral PSS, loss of TGM5 (transglutaminase 5) impairs crosslinking of cornified
    envelope structural proteins (loricrin, involucrin, small proline-rich proteins)
    via gamma-glutamyl-epsilon-lysine isopeptide bonds. The resulting defective
    cornified envelope assembly weakens corneocyte cohesion at the stratum
    corneum-granulosum interface, producing superficial acral peeling.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: Keratinization / cornified envelope formation
    term:
      id: GO:1903575
      label: cornified envelope assembly
    modifier: ABNORMAL
  downstream:
  - target: Defective corneodesmosome-mediated corneocyte cohesion
    description: >-
      Impaired TGM5 crosslinking yields a defective cornified envelope, weakening
      corneocyte cohesion at the stratum corneum-granulosum interface.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22289416
    reference_title: "Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TGM5 is involved in cross-linking structural proteins for the formation of the cornified envelope, by catalyzing the formation of γ-glutamyl-ε-lysine isopeptide bonds between differentiation-specific proteins expressed mainly in corneocytes, including loricrin, involucrin and small proline-rich proteins"
    explanation: >-
      Describes the TGM5 crosslinking function whose loss causes defective cornified
      envelope assembly in acral PSS.

phenotypes:
- name: Skin peeling
  description: >-
    Superficial, usually painless, spontaneous peeling/shedding of the stratum
    corneum, the defining feature of all PSS subtypes; acral in APSS and generalized
    in the generalized subtypes.
  phenotype_term:
    preferred_term: Superficial skin peeling
    term:
      id: HP:0040189
      label: Scaling skin
  evidence:
  - reference: PMID:31663161
    reference_title: "Mutations in the CDSN gene cause peeling skin disease and hypotrichosis simplex of the scalp."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peeling skin disease is a rare genodermatosis characterized by superficial exfoliation or peeling of the skin."
    explanation: >-
      Confirms superficial peeling/exfoliation as the core feature of peeling skin disease.
  - reference: PMID:22289416
    reference_title: "Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generalized peeling skin syndrome (PSS) is an autosomal recessive genodermatosis characterized by lifelong, continuous shedding of the upper epidermis."
    explanation: >-
      Supports generalized, lifelong shedding of the upper epidermis in generalized PSS.
- name: Palmoplantar peeling
  description: >-
    In acral PSS, peeling predominantly affects the palms, soles, and dorsal aspects
    of the hands and feet, often exacerbated by friction, humidity, and sweating.
  phenotype_term:
    preferred_term: Palmoplantar peeling
    term:
      id: HP:0025819
      label: Palmoplantar peeling
  subtype: APSS-TGM5
  evidence:
  - reference: PMID:22289416
    reference_title: "Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APSS (localized form) involves the palmar, plantar and dorsal surfaces of hands and feet and is caused by mutations in the tranglutaminase 5 gene (TGM5)"
    explanation: >-
      Localizes acral PSS peeling to the palmar, plantar, and dorsal hand/foot surfaces.
- name: Ichthyosiform erythroderma
  description: >-
    Congenital ichthyosiform erythroderma with generalized scaling and redness,
    characteristic of CDSN-related inflammatory generalized PSS (PSS1).
  phenotype_term:
    preferred_term: Erythroderma
    term:
      id: HP:0001019
      label: Erythroderma
  subtype: GPSS-Type-B-CDSN
  evidence:
  - reference: PMID:32926582
    reference_title: "Development of a pathogenesis-based therapy for peeling skin syndrome type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients are affected by pronounced erythroderma accompanied by pruritus and superficial generalized peeling of the skin."
    explanation: >-
      Directly reports pronounced erythroderma in PSS1 (CDSN) patients.
- name: Ichthyosis
  description: >-
    Ichthyotic scaling is a feature of generalized PSS subtypes, including
    FLG2-related generalized ichthyotic PSS and CDSN-related inflammatory PSS.
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:29505760
    reference_title: "Generalized Ichthyotic Peeling Skin Syndrome due to FLG2 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generalized Ichthyotic Peeling Skin Syndrome due to FLG2 Mutations."
    explanation: >-
      The FLG2-related subtype is explicitly an ichthyotic peeling skin syndrome.
- name: Pruritus
  description: >-
    Itch, often severe, accompanies the inflammatory generalized (CDSN) subtype and
    is also reported in acral and other generalized forms.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  subtype: GPSS-Type-B-CDSN
  evidence:
  - reference: PMID:32926582
    reference_title: "Development of a pathogenesis-based therapy for peeling skin syndrome type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients are affected by pronounced erythroderma accompanied by pruritus and superficial generalized peeling of the skin."
    explanation: >-
      Reports pruritus as a prominent feature of PSS1 (CDSN).
- name: Elevated circulating IgE
  description: >-
    Markedly elevated serum IgE is characteristic of the atopic phenotype seen in
    CDSN-related inflammatory generalized PSS; one patient had IgE of 2222 kU/L.
  phenotype_term:
    preferred_term: Increased circulating IgE concentration
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  subtype: GPSS-Type-B-CDSN
  evidence:
  - reference: PMID:31663161
    reference_title: "Mutations in the CDSN gene cause peeling skin disease and hypotrichosis simplex of the scalp."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Routine laboratory parameters were normal, except for elevated IgE levels (2222 kU/L; normal, <100)."
    explanation: >-
      Documents markedly elevated IgE in a CDSN-related PSS patient, supporting the
      atopic laboratory phenotype.
- name: Food allergy
  description: >-
    Food allergies are part of the atopic spectrum associated with CDSN-related
    inflammatory generalized PSS, reflecting barrier failure and antigen sensitization.
  phenotype_term:
    preferred_term: Food allergy
    term:
      id: HP:0500093
      label: Food allergy
  subtype: GPSS-Type-B-CDSN
  evidence:
  - reference: PMID:20691404
    reference_title: "Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified a homozygous nonsense mutation in CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies"
    explanation: >-
      Reports food allergies co-segregating with CDSN-related generalized peeling skin.
- name: Leukonychia
  description: >-
    White discoloration of the nails, a defining component of PLACK syndrome (CAST).
  phenotype_term:
    preferred_term: Leukonychia
    term:
      id: HP:0001820
      label: Leukonychia
  subtype: PLACK-CAST
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome"
    explanation: >-
      Leukonychia is one of the cardinal PLACK features caused by CAST loss-of-function.
- name: Cheilitis
  description: >-
    Inflammation of the lips, a component of PLACK syndrome (CAST).
  phenotype_term:
    preferred_term: Cheilitis
    term:
      id: HP:0100825
      label: Cheilitis
  subtype: PLACK-CAST
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome"
    explanation: >-
      Cheilitis is a cardinal PLACK feature caused by CAST loss-of-function.
- name: Knuckle pads
  description: >-
    Thickened skin over the finger joints, a component of PLACK syndrome (CAST).
  phenotype_term:
    preferred_term: Knuckle pad
    term:
      id: HP:0032541
      label: Knuckle pad
  subtype: PLACK-CAST
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome"
    explanation: >-
      Knuckle pads are a cardinal PLACK feature caused by CAST loss-of-function.
- name: Post-inflammatory hyperpigmentation
  description: >-
    In FLG2-related generalized ichthyotic PSS, denuded areas heal with
    hyperpigmentation without scarring.
  phenotype_term:
    preferred_term: Hyperpigmentation of the skin
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  subtype: GPSS-FLG2
  evidence:
  - reference: PMID:30032785
    reference_title: "Peeling Skin Disorders: A Paradigm for Skin Desquamation."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "FLG2 emerged as a new player that regulates epidermal desquamation, as demonstrated by the phenotype observed in patients reported by 2 independent groups."
    explanation: >-
      Supports FLG2 as a cause of a generalized peeling phenotype; the specific
      post-inflammatory hyperpigmentation detail derives from the primary FLG2 case
      report (Bolling 2018, PMID:29505760).

genetic:
- name: CDSN pathogenic variants
  gene_term:
    preferred_term: CDSN
    term:
      id: hgnc:1802
      label: CDSN
  association: Causative
  relationship_type: CAUSATIVE
  subtype: GPSS-Type-B-CDSN
  inheritance:
  - name: Autosomal recessive
    description: >-
      Inflammatory generalized PSS / peeling skin disease (PSS1) results from biallelic
      (homozygous or compound heterozygous) loss-of-function CDSN variants. Monoallelic
      CDSN variants instead cause autosomal dominant hypotrichosis simplex of the scalp.
    evidence:
    - reference: PMID:31663161
      reference_title: "Mutations in the CDSN gene cause peeling skin disease and hypotrichosis simplex of the scalp."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Peeling skin disease is caused by biallelic mutations in CDSN as an autosomal recessive trait."
      explanation: >-
        States the autosomal recessive, biallelic CDSN basis of peeling skin disease.
  notes: >-
    Reported variants include nonsense c.598C>T p.(Gln200*), frameshift c.164_167dup
    p.(Thr57Profs*6), large 6p21.3 deletions encompassing CDSN, and a missense
    c.1358G>A p.(Ser453Asn).
  evidence:
  - reference: PMID:31663161
    reference_title: "Mutations in the CDSN gene cause peeling skin disease and hypotrichosis simplex of the scalp."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analysis in the patient showed compound heterozygous mutations in exon 2 of CDSN, a nonsense mutation c.598C>T (p.[Gln200*])"
    explanation: >-
      Documents specific compound heterozygous loss-of-function CDSN variants causing PSD.
- name: TGM5 pathogenic variants
  gene_term:
    preferred_term: TGM5
    term:
      id: hgnc:11781
      label: TGM5
  association: Causative
  relationship_type: CAUSATIVE
  subtype: APSS-TGM5
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:22289416
      reference_title: "Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "APSS (localized form) involves the palmar, plantar and dorsal surfaces of hands and feet and is caused by mutations in the tranglutaminase 5 gene (TGM5)"
      explanation: >-
        Identifies TGM5 as the cause of the localized acral PSS form.
- name: CHST8 variant (disputed)
  gene_term:
    preferred_term: CHST8
    term:
      id: hgnc:15993
      label: CHST8
  association: Causative
  relationship_type: DISPUTED
  subtype: GPSS-Type-A-CHST8
  inheritance:
  - name: Autosomal recessive
  notes: >-
    A homozygous CHST8 missense variant (c.229C>T, R77W) was proposed for
    non-inflammatory generalized PSS type A, but its pathogenicity has been questioned
    in later work.
  evidence:
  - reference: PMID:22289416
    reference_title: "Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a novel homozygous missense mutation (c.229C>T, R77W) within the CHST8 gene, in a large consanguineous family with non-inflammatory PSS type A"
    explanation: >-
      Original report linking a homozygous CHST8 variant to non-inflammatory PSS type A.
- name: FLG2 pathogenic variants
  gene_term:
    preferred_term: FLG2
    term:
      id: hgnc:33276
      label: FLG2
  association: Causative
  relationship_type: CAUSATIVE
  subtype: GPSS-FLG2
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:30032785
      reference_title: "Peeling Skin Disorders: A Paradigm for Skin Desquamation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "FLG2 emerged as a new player that regulates epidermal desquamation, as demonstrated by the phenotype observed in patients reported by 2 independent groups."
      explanation: >-
        Supports FLG2 as a recessive cause of generalized peeling skin disorder.
  evidence:
  - reference: PMID:29505760
    reference_title: "Generalized Ichthyotic Peeling Skin Syndrome due to FLG2 Mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generalized Ichthyotic Peeling Skin Syndrome due to FLG2 Mutations."
    explanation: >-
      Establishes biallelic FLG2 mutations as a cause of generalized ichthyotic PSS.
- name: CSTA pathogenic variants
  gene_term:
    preferred_term: CSTA
    term:
      id: hgnc:2481
      label: CSTA
  association: Causative
  relationship_type: CAUSATIVE
  subtype: APSS-CSTA
  inheritance:
  - name: Autosomal recessive
  notes: >-
    A homozygous nonsense variant p.Lys22X (p.Lys22Ter) in CSTA was identified in a
    consanguineous pedigree with acral PSS / exfoliative ichthyosis overlap.
  evidence:
  - reference: PMID:23534700
    reference_title: "Acral peeling skin syndrome resulting from a homozygous nonsense mutation in the CSTA gene encoding cystatin A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous nonsense mutation (p.Lys22X) in the CSTA gene, encoding cystatin A"
    explanation: >-
      Documents the homozygous CSTA loss-of-function variant causing acral PSS.
- name: CAST pathogenic variants
  gene_term:
    preferred_term: CAST
    term:
      id: hgnc:1515
      label: CAST
  association: Causative
  relationship_type: CAUSATIVE
  subtype: PLACK-CAST
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:25683118
      reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin"
      explanation: >-
        States the autosomal recessive basis of CAST-related PLACK syndrome.
  notes: >-
    Homozygous truncating CAST variants (e.g., c.607dup, c.424A>T, c.1750delG) cause
    PLACK syndrome.
  evidence:
  - reference: PMID:25683118
    reference_title: "Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins"
    explanation: >-
      Documents homozygous truncating CAST variants causing PLACK syndrome.
- name: SERPINB8 pathogenic variants
  gene_term:
    preferred_term: SERPINB8
    term:
      id: hgnc:8952
      label: SERPINB8
  association: Causative
  relationship_type: CAUSATIVE
  subtype: GPSS-SERPINB8
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: PMID:30032785
    reference_title: "Peeling Skin Disorders: A Paradigm for Skin Desquamation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Proteins that are mutated in peeling skin disorders are components of corneodesmosomes (CDSN, DSG1) or protease inhibitors (LEKTI, CSTA, CAST, or SERPIN8)."
    explanation: >-
      Lists SERPINB8 (SERPIN8) among the protease-inhibitor genes mutated in peeling
      skin disorders.

treatments:
- name: Emollient and skin-softening therapy
  description: >-
    Topical emollients and skin-softening agents are the mainstay of supportive care,
    helping maintain barrier function and reduce scaling/peeling across PSS subtypes.
  treatment_term:
    preferred_term: emollient therapy
    term:
      id: MAXO:0001574
      label: emollient therapy
- name: Trigger avoidance
  description: >-
    Avoidance of exacerbating exposures (humidity, heat, sweating/hyperhidrosis,
    friction, and water/moisture) is a practical measure that reduces peeling,
    especially in acral PSS.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Botulinum toxin A for acral PSS
  description: >-
    Botulinum toxin A injections have been reported to provide symptomatic benefit in
    acral PSS by reducing hyperhidrosis, a common exacerbating factor.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:38590258
    reference_title: "Acral Peeling Skin Syndrome: Two Unusual Cases and the Therapeutic Potential of Botulinum Toxin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acral Peeling Skin Syndrome: Two Unusual Cases and the Therapeutic Potential of Botulinum Toxin."
    explanation: >-
      Reports the therapeutic potential of botulinum toxin in acral PSS (driven by
      reduction of hyperhidrosis-associated exacerbation).
- name: Recombinant corneodesmosin protein replacement (experimental)
  description: >-
    A pathogenesis-based, preclinical protein-replacement strategy for CDSN-deficient
    PSS1 delivers recombinant corneodesmosin in liposomal carriers to keratinocytes,
    restoring CDSN in the stratum granulosum and improving barrier integrity in
    CDSN-deficient epidermal equivalents in vitro.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:32926582
    reference_title: "Development of a pathogenesis-based therapy for peeling skin syndrome type 1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CDSN-deficient epidermal equivalents that were treated with liposomal encapsulated CDSN demonstrated presence of CDSN in the SG."
    explanation: >-
      Preclinical in vitro data show restoration of corneodesmosin by liposomal protein
      replacement, supporting a pathogenesis-based therapy for PSS1.
  - reference: PMID:32926582
    reference_title: "Development of a pathogenesis-based therapy for peeling skin syndrome type 1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This study presents the first preclinical in vitro experiments for a future specific protein replacement therapy for patients affected by PSS1."
    explanation: >-
      Frames the approach as preclinical protein replacement therapy for PSS1.
- name: Genetic counseling
  description: >-
    Because PSS is genetic (predominantly autosomal recessive), genetic counseling and
    carrier testing in affected families are the principal primary-prevention measures.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling

datasets: []

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 35 citations 2026-06-05T14:02:57.801981

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Peeling Skin Syndrome
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Peeling Skin Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Peeling Skin Syndrome (PSS) — Comprehensive Disease Characteristics Report (Mendelian)

Target disease

Disease name: Peeling Skin Syndrome (PSS) (umbrella term covering acral and generalized genetic peeling disorders). (metze2026desmosomaltypeacantholysis—anew pages 10-12, velden2020mutationsinthe pages 1-2)

Definition / overview: PSS is characterized by superficial, often painless “spontaneous peeling of the stratum corneum without bleeding or pain.” (metze2026desmosomaltypeacantholysis—anew pages 10-12)

Key concept (current understanding): PSS represents a heterogeneous set of Mendelian disorders of cornification/skin fragility in which defective stratum corneum cohesion (often via corneodesmosome dysfunction or dysregulated desquamation proteolysis) causes superficial epidermal detachment/peeling. (has2018peelingskindisorders pages 1-2, komatsu2006elevatedhumantissue pages 1-2)

Key identifiers (available from retrieved sources)

OMIM/MIM:
Acral Peeling Skin Syndrome (APSS): MIM 609796. (stjernbrandt2024acralpeelingskin pages 1-2)
Peeling skin disease / inflammatory generalized PSS (often called PSS type B / PSS1): MIM 270300. (metze2026desmosomaltypeacantholysis—anew pages 10-12)
MONDO / ICD-10 / ICD-11 / MeSH: Not available in the retrieved evidence set; should be added via dedicated ontology lookup (e.g., MONDO/Orphanet/MeSH portals).

Synonyms and alternative names

Acral peeling skin syndrome (APSS) (localized/acral form). (stjernbrandt2024acralpeelingskin pages 1-2)
Generalized peeling skin syndrome (GPSS); subdivided into non-inflammatory (type A) and inflammatory (type B). (kawakami2014acaseof pages 1-2, velden2020mutationsinthe pages 1-2)
Peeling skin disease (PSD) is frequently used for the inflammatory generalized CDSN-related form. (velden2020mutationsinthe pages 1-2, oji2010lossofcorneodesmosin pages 6-7)
PLACK syndrome (CAST-related: Peeling skin, Leukonychia, Acral punctate keratoses, Cheilitis, Knuckle pads). (vidya2023placksyndromeassociated pages 1-3, lin2015lossoffunctionmutationsin pages 1-2)

Evidence source type

The information in this report is derived primarily from aggregated disease-level resources (reviews/commentaries) and primary human case reports/series with supporting in vitro and animal model data for specific genes (notably CDSN and FLG2). (has2018peelingskindisorders pages 1-2, bolling2018generalizedichthyoticpeeling pages 1-6, oji2010lossofcorneodesmosin pages 6-7)

1. Disease information (classification)

Clinical classification used in the literature

A commonly used clinical framework divides PSS into: 1) Acral PSS (APSS) — predominant involvement of hands/feet. (kawakami2014acaseof pages 1-2, stjernbrandt2024acralpeelingskin pages 1-2) 2) Generalized PSS — widespread peeling/scaling. (kawakami2014acaseof pages 1-2, velden2020mutationsinthe pages 1-2)

Generalized PSS is further divided into: * Type A (non-inflammatory) — associated with CHST8 in some families. (kawakami2014acaseof pages 1-2, cabral2012wholeexomesequencingin pages 4-5) * Type B (inflammatory) — associated with CDSN (corneodesmosin) and often includes pruritus and atopic features. (velden2020mutationsinthe pages 1-2, oji2010lossofcorneodesmosin pages 6-7)

A complementary gene/pathway framing is that peeling skin disorders arise from (i) structural corneodesmosome/cornified envelope defects, (ii) crosslinking enzyme defects (transglutaminases), or (iii) protease–inhibitor imbalance leading to premature corneodesmosome cleavage and over-desquamation. (has2018peelingskindisorders pages 1-2, komatsu2006elevatedhumantissue pages 1-2)

2. Etiology

Primary causal factors (genetic)

PSS is predominantly genetic (Mendelian), most often autosomal recessive across major subtypes. (velden2020mutationsinthe pages 1-2, bolling2018generalizedichthyoticpeeling pages 1-6)

Key genes and gene→phenotype links supported by primary literature in this evidence set:

TGM5 (transglutaminase 5): causes APSS (autosomal recessive). (stjernbrandt2024acralpeelingskin pages 1-2, velden2020mutationsinthe pages 1-2)
Examples of pathogenic variants reported in recent APSS series include c.337G>T p.(Gly113Cys) and c.763T>C p.(Trp255Arg). (stjernbrandt2024acralpeelingskin pages 1-2)
CSTA (cystatin A; protease inhibitor in cornified envelope): causes APSS / exfoliative ichthyosis overlap; typically autosomal recessive loss-of-function. (krunic2013acralpeelingskin pages 1-2, lin2015lossoffunctionmutationsin pages 1-2)
Example: c.64A>T p.Lys22X segregating in a large consanguineous pedigree. (krunic2013acralpeelingskin pages 1-2)
CDSN (corneodesmosin): causes inflammatory generalized PSS / peeling skin disease (often PSS1/PSS-B/PSD), typically autosomal recessive biallelic LOF; monoallelic CDSN variants can cause autosomal dominant hypotrichosis simplex of the scalp (distinct phenotype). (velden2020mutationsinthe pages 1-2)
CHST8: implicated in type A (non-inflammatory) generalized PSS in some families. (kawakami2014acaseof pages 1-2, cabral2012wholeexomesequencingin pages 4-5)
FLG2 (filaggrin-2): biallelic loss-of-function causes generalized ichthyotic peeling skin syndrome with improvement by age in reported siblings. (bolling2018generalizedichthyoticpeeling pages 1-6)
CAST (calpastatin; endogenous protease inhibitor): biallelic LOF causes PLACK syndrome, a generalized peeling phenotype with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads. (lin2015lossoffunctionmutationsin pages 1-2, vidya2023placksyndromeassociated pages 1-3)

Risk factors (genetic and environmental)

Because PSS is Mendelian, the dominant risk factor is having biallelic pathogenic variants in the relevant causal gene (subtype-dependent). (velden2020mutationsinthe pages 1-2, bolling2018generalizedichthyoticpeeling pages 1-6)

Environmental exacerbating factors (disease modifiers) are well described for APSS and some generalized forms: * Humidity, heat, moisture/water exposure, friction/trauma, perspiration/hyperhidrosis commonly worsen acral peeling. (gierach2023acralpeelingskin pages 1-3, krunic2013acralpeelingskin pages 1-2, stjernbrandt2024acralpeelingskin pages 1-2) * For FLG2-related generalized peeling, warm humid environments and minor trauma can exacerbate peeling. (bolling2018generalizedichthyoticpeeling pages 1-6)

Protective factors / gene–environment interactions

No specific protective factors or formal gene–environment interaction models were identified in the retrieved evidence set.

3. Phenotypes (clinical spectrum) with ontology suggestions

Core phenotype across PSS

Superficial skin peeling/desquamation (stratum corneum detachment) that is often painless and non-bleeding. (metze2026desmosomaltypeacantholysis—anew pages 10-12)
Suggested HPO: HP:0001053 (Abnormality of the skin); HP:0000964 (Erythema) when present; HP:0000982 (Skin erosion) in denuded areas.

Acral peeling skin syndrome (APSS; often TGM5 or CSTA)

Typical features: * Painless peeling affecting hands and feet; may include erythema, itching, erosions, and sometimes blisters. (stjernbrandt2024acralpeelingskin pages 1-2) * Onset often from birth, but later onset can occur. (stjernbrandt2024acralpeelingskin pages 1-2) * Exacerbations with humidity, friction, and hyperhidrosis are common. (stjernbrandt2024acralpeelingskin pages 1-2) * CSTA pedigree: lifelong hand/foot peeling with erythema, lichenification, maceration, pruritus, and strong moisture/heat/friction sensitivity. (krunic2013acralpeelingskin pages 1-2)

Suggested HPO terms (examples): * HP:0030050 (Skin peeling) [term commonly used in HPO; verify exact ID in HPO browser] * HP:0000972 (Palmoplantar hyperkeratosis) (if punctate keratoses/keratoderma) * HP:0000989 (Pruritus) * HP:0012471 (Blistering of the skin) (when blisters occur)

Generalized non-inflammatory PSS (Type A; CHST8)

Reported phenotype characteristics in the Cabral et al. CHST8 study include an otherwise asymptomatic generalized peeling phenotype with occasional pruritus and without vesicles/pustules or mucous membrane/nail involvement; histology shows mild hyperkeratosis and splitting around the SG/SC interface. (cabral2012wholeexomesequencingin pages 4-5)

Suggested HPO: * Skin peeling; pruritus (as above) * HP:0000958 (Dry skin)

Inflammatory generalized PSS / peeling skin disease (Type B / PSS1; CDSN)

Hallmark features: * Onset at birth with ichthyosiform erythroderma and lifelong patchy superficial peeling, often with severe pruritus. (metze2026desmosomaltypeacantholysis—anew pages 10-12, valentin2021developmentofa pages 1-5) * Systemic/atopic complications reported include urticaria, angioedema, food allergies, asthma, and lab findings of elevated IgE and eosinophilia. (metze2026desmosomaltypeacantholysis—anew pages 10-12) * PSS1 causes major quality-of-life burden including impaired sleep and recurrent superinfections. (valentin2021developmentofa pages 1-5)

Quantitative examples from the evidence set: * One CDSN-related patient had IgE 2222 kU/L (markedly elevated). (velden2020mutationsinthe pages 1-2) * Corneodesmosome ultrastructure in one CDSN missense case showed reduced length and density vs control (length 386.2±149.5 nm vs 446.3±185.8 nm; density 0.860±0.233 μm−1 vs 1.309±0.413 μm−1, p<0.05). (kawakami2014acaseof pages 4-5)

Suggested HPO: * HP:0001041 (Ichthyosis) / ichthyosiform erythroderma * HP:0000989 (Pruritus) * HP:0002721 (Eosinophilia) * HP:0003212 (Elevated circulating IgE) * HP:0001022 (Food allergy) [verify exact ID]

FLG2-related generalized ichthyotic peeling skin syndrome

Phenotype from affected siblings: * Erythroderma at birth, persistent dry skin and superficial peeling, worsened by minor trauma and warm humid environments; denuded areas heal with hyperpigmentation without scarring; hair/nails/mucosa unaffected; clinical improvement with age. (bolling2018generalizedichthyoticpeeling pages 1-6)

Suggested HPO: * Ichthyosis/erythroderma; skin peeling; post-inflammatory hyperpigmentation (ontology mapping may vary).

PLACK syndrome (CAST)

Core phenotype: * “Generalised peeling, leukonychia, acral punctate keratoses, cheilitis, knuckle pads.” (vidya2023placksyndromeassociated pages 1-3) * Peeling may occur spontaneously or after trauma and may occur with or without bullae. (vidya2023placksyndromeassociated pages 1-3)

Suggested HPO: * Leukonychia (HP term exists) * Cheilitis (HP term exists) * Knuckle pads (HP term exists) * Punctate palmoplantar keratoderma (HP term exists)

4. Genetic / molecular information

Causal genes (supported in this evidence set)

TGM5 (APSS) (stjernbrandt2024acralpeelingskin pages 1-2)
CSTA (APSS / exfoliative ichthyosis overlap) (krunic2013acralpeelingskin pages 1-2)
CHST8 (generalized PSS-A) (cabral2012wholeexomesequencingin pages 4-5)
CDSN (PSS-B/PSS1/PSD) (velden2020mutationsinthe pages 1-2, oji2010lossofcorneodesmosin pages 6-7)
FLG2 (generalized ichthyotic peeling) (bolling2018generalizedichthyoticpeeling pages 1-6)
CAST (PLACK) (lin2015lossoffunctionmutationsin pages 1-2)

Variant classes and functional consequences

Across PSS genes, disease is frequently caused by loss-of-function variants (nonsense, frameshift, splice, deletions) consistent with reduced/absent protein affecting stratum corneum cohesion or protease regulation. (velden2020mutationsinthe pages 1-2, lin2015lossoffunctionmutationsin pages 1-2, krunic2013acralpeelingskin pages 1-2)

Examples: * CSTA p.Lys22X (nonsense) in APSS pedigree. (krunic2013acralpeelingskin pages 1-2) * FLG2 p.Ser211* (nonsense) in generalized ichthyotic peeling. (bolling2018generalizedichthyoticpeeling pages 1-6) * CDSN LOF (nonsense/deletions) in PSS1; CDSN protein absence contributes to subcorneal splitting and barrier failure. (valentin2021developmentofa pages 1-5, oji2010lossofcorneodesmosin pages 6-7)

Modifier genes / epigenetics / chromosomal abnormalities

No robust modifier genes, epigenetic signatures, or chromosomal abnormalities were identified in the retrieved evidence set beyond copy-number/deletion events encompassing CDSN in some cases (reviewed). (pan2022atopicdermatitislikegenodermatosis pages 33-33)

5. Environmental information

PSS is not infectious; environmental factors are primarily exacerbating triggers: * Moisture/water exposure, humidity, heat, friction/trauma, sweating/hyperhidrosis worsen APSS and some generalized forms. (krunic2013acralpeelingskin pages 1-2, stjernbrandt2024acralpeelingskin pages 1-2, bolling2018generalizedichthyoticpeeling pages 1-6)

6. Mechanism / pathophysiology

Mechanistic causal chain (high-level)

Gene LOF → impaired stratum corneum cohesion and/or dysregulated desquamation proteolysis → superficial cleavage at/within the stratum corneum → recurrent peeling/erosions → barrier dysfunction and (in inflammatory forms) itch/atopy/infection risk. (has2018peelingskindisorders pages 1-2, oji2010lossofcorneodesmosin pages 6-7, komatsu2006elevatedhumantissue pages 1-2)

Corneodesmosome and barrier defect axis (CDSN; inflammatory generalized PSS)

CDSN encodes corneodesmosin, a key adhesion component in corneodesmosomes; loss causes severe barrier breakdown. (oji2010lossofcorneodesmosin pages 6-7)
Functional/model evidence: murine Cdsn knockout results in early postnatal death from barrier breakdown and ~10-fold increase in transepidermal water loss, supporting CDSN’s essential barrier role. (oji2010lossofcorneodesmosin pages 6-7)
Human reconstructed epidermis from patient keratinocytes shows absent CDSN staining and increased permeability (e.g., increased testosterone permeation) consistent with barrier defect. (oji2010lossofcorneodesmosin pages 6-7)

Suggested GO biological process terms: * GO:0030216 (Keratinocyte differentiation) * GO:0061436 (Establishment of skin barrier) (or related epidermal barrier GO term) * GO:0007155 (Cell adhesion)

Suggested CL (cell types): * Keratinocyte (CL:0000312)

Suggested UBERON (anatomy): * Epidermis, stratum corneum, stratum granulosum.

Protease–inhibitor imbalance / over-desquamation axis

In PSS-type B patients, kallikrein (hK) levels and multiple serine protease activities were reported as elevated in stratum corneum and serum, supporting an “over-desquamation” mechanism via proteolytic cleavage of adhesion proteins. (komatsu2006elevatedhumantissue pages 1-2)
CAST (calpastatin) and CSTA (cystatin A) are protease inhibitors; CAST LOF (PLACK) and CSTA LOF (APSS/exfoliative ichthyosis overlap) implicate dysregulated proteolysis and impaired adhesion. (lin2015lossoffunctionmutationsin pages 1-2, krunic2013acralpeelingskin pages 1-2)

Cornified envelope / keratin compaction axis (FLG2)

FLG2 deficiency leads to abnormal cornification: patient tissue shows parakeratosis, altered keratin/corneodesmosome-associated proteins (reduced corneodesmosin; altered desmoglein/desmocollin), and abnormal stratum corneum ultrastructure; an in vitro FLG2 knockdown model reproduces parakeratosis/loricrin downregulation/abnormal SC vesicles. (bolling2018generalizedichthyoticpeeling pages 1-6)

7. Anatomical structures affected

Primary: skin epidermis, especially stratum corneum (and SG/SC interface depending on subtype). (gierach2023acralpeelingskin pages 1-3, bolling2018generalizedichthyoticpeeling pages 1-6)
APSS: predominant involvement of hands and feet (acral skin; palms/soles and sometimes dorsal aspects). (stjernbrandt2024acralpeelingskin pages 1-2)
CDSN-related inflammatory generalized PSS: generalized involvement; also hair follicle biology can be affected (CDSN expression in hair structures and AD hypotrichosis phenotype with monoallelic variants). (velden2020mutationsinthe pages 1-2, metze2026desmosomaltypeacantholysis—anew pages 10-12)

8. Temporal development

APSS: often evident from birth but can present later; course is typically chronic with flares triggered by friction/humidity/sweating. (stjernbrandt2024acralpeelingskin pages 1-2)
CDSN-related inflammatory generalized PSS: onset at birth with lifelong disease. (valentin2021developmentofa pages 1-5, metze2026desmosomaltypeacantholysis—anew pages 10-12)
FLG2-related generalized peeling: congenital onset with improvement by age in a reported family. (bolling2018generalizedichthyoticpeeling pages 1-6)

9. Inheritance and population

Inheritance patterns

Predominantly autosomal recessive across PSS subtypes (TGM5, CSTA, CDSN (biallelic), CHST8, FLG2, CAST). (velden2020mutationsinthe pages 1-2, bolling2018generalizedichthyoticpeeling pages 1-6, lin2015lossoffunctionmutationsin pages 1-2)

Notable exception: * Monoallelic CDSN variants can cause autosomal dominant hypotrichosis simplex of the scalp, distinct from the recessive peeling phenotype. (velden2020mutationsinthe pages 1-2)

Epidemiology / prevalence

Robust population prevalence is generally not provided in primary PSS reports within this evidence set. A specific prevalence estimate is reported for PLACK syndrome: * PLACK syndrome prevalence stated as 1:10,00,000 (as written in the case report). (vidya2023placksyndromeassociated pages 1-3)

Population genetics / founder effects

A recurrent APSS variant TGM5 c.763T>C p.(Trp255Arg) is described as a European founder variant, with reported gnomAD counts 78 occurrences overall and 49 in the Swedish ancestry group (as reported by the authors). (stjernbrandt2024acralpeelingskin pages 1-2)

10. Diagnostics

Clinical presentation and differential diagnosis

APSS can be difficult to distinguish clinically from localized epidermolysis bullosa simplex (EBS), and can also resemble keratosis palmaris et plantaris and allergic contact dermatitis. (stjernbrandt2024acralpeelingskin pages 1-2, gierach2023acralpeelingskin pages 1-3)
Inflammatory generalized CDSN-related PSS can overlap with eczema/atopic presentations and has been confused with Netherton syndrome. (komatsu2006elevatedhumantissue pages 1-2, valentin2021developmentofa pages 1-5)

Histopathology / ultrastructure

APSS (reviewed): cleavage between stratum corneum and stratum granulosum is typical. (gierach2023acralpeelingskin pages 1-3)
FLG2-related generalized peeling: separation in the lower stratum corneum with parakeratosis and ultrastructural corneocyte abnormalities. (bolling2018generalizedichthyoticpeeling pages 1-6)
CDSN-related inflammatory generalized PSS: reduced corneodesmosome length/density has been quantified in at least one case; abnormal corneodesmosome biology is central. (kawakami2014acaseof pages 4-5)

Genetic testing strategy (practical approach)

Because APSS may mimic EBS, authors recommend gene testing panels that include TGM5 and CSTA and localized EBS genes, with sequence + copy-number analysis. (stjernbrandt2024acralpeelingskin pages 2-2, stjernbrandt2024acralpeelingskin pages 1-2)
For generalized/inflammatory phenotypes, testing should include CDSN and should consider large deletions/CNVs (CDSN deletions have been reported). (pan2022atopicdermatitislikegenodermatosis pages 33-33)
Whole-exome sequencing has been useful in genetically heterogeneous pedigrees (e.g., identifying CSTA p.Lys22X when linkage was uninformative). (krunic2013acralpeelingskin pages 1-2)

11. Outcome / prognosis

APSS is generally described as relatively mild with recurrent peeling that heals without scarring and without systemic involvement in many cases, though symptoms may be burdensome and recurrent. (gierach2023acralpeelingskin pages 1-3, stjernbrandt2024acralpeelingskin pages 1-2)
CDSN-related PSS1 is described as severe, with pronounced pruritus, sleep impairment, recurrent infections, and major quality-of-life impact; current therapies are unsatisfactory. (valentin2021developmentofa pages 1-5)
FLG2-related generalized peeling in one family showed marked improvement with age and no scarring, although hyperpigmentation could follow denudation. (bolling2018generalizedichthyoticpeeling pages 1-6)

12. Treatment (current applications and real-world implementations)

Current standard management (symptomatic/supportive)

Friction reduction / avoidance of triggers (humidity, sweating, friction) and skin softening/emollient-based care are common practical measures. (stjernbrandt2024acralpeelingskin pages 1-2)
In severe CDSN-related PSS1, symptomatic measures such as balneotherapy and bland topical ointments are used but are often inadequate. (valentin2021developmentofa pages 1-5)

Suggested MAXO terms (examples): * Topical emollient therapy (MAXO term for emollient/moisturizer treatment) * Avoidance of triggering environmental exposure

Recent (2023–2024) treatment development: botulinum toxin for APSS

A 2024 report describes symptomatic benefit from botulinum toxin A injections in APSS, motivated by reduction of hyperhidrosis (a common exacerbating factor). (stjernbrandt2024acralpeelingskin pages 1-2)

Suggested MAXO: * Botulinum toxin therapy (for hyperhidrosis-associated exacerbation)

Pathogenesis-based / experimental therapies (preclinical)

A 2021 British Journal of Dermatology study developed a protein-replacement approach for CDSN-deficient PSS1 using recombinant CDSN in targeted liposomes, restoring CDSN staining and improving barrier function in CDSN-deficient epidermal equivalents in vitro. (valentin2021developmentofa pages 9-12, valentin2021developmentofa pages 1-5)

Suggested MAXO: * Protein replacement therapy

Topical calcipotriol (limited evidence)

A review of eczema-like genodermatoses notes a reported case of PSS treated successfully with topical calcipotriol (details not present in retrieved snippet). (pan2022atopicdermatitislikegenodermatosis pages 33-33)

Clinical trials

No PSS-specific interventional trials were identified in the ClinicalTrials.gov search results retrieved during this run.

13. Prevention

Because PSS is genetic, primary prevention largely involves genetic counseling, carrier testing in affected families, and reproductive options when desired.

Tertiary prevention includes trigger avoidance (humidity, friction, sweating) and measures to reduce barrier breakdown/infections in severe forms. (valentin2021developmentofa pages 1-5, stjernbrandt2024acralpeelingskin pages 1-2)

14. Other species / natural disease

No naturally occurring veterinary PSS analogs were identified in the retrieved evidence set.

15. Model organisms and experimental systems

CDSN (in vivo and human skin models)

Murine Cdsn knockout causes lethal barrier breakdown and dramatic TEWL increase, supporting causality and providing a strong in vivo model for CDSN-related PSS. (oji2010lossofcorneodesmosin pages 6-7)
Patient-derived reconstructed human epidermis lacking CDSN shows defective barrier function and altered differentiation. (oji2010lossofcorneodesmosin pages 6-7)

FLG2 (in vitro models)

FLG2 knockdown models reproduce parakeratosis and other disease-relevant features, supporting a mechanistic link between FLG2 deficiency and impaired cornification/adhesion. (bolling2018generalizedichthyoticpeeling pages 1-6)

CAST (human tissue + in vitro)

CAST LOF shows reduced calpastatin staining in patient tissue and CAST knockdown impairs keratinocyte adhesion in vitro. (lin2015lossoffunctionmutationsin pages 1-2)

Recent developments and latest research (prioritizing 2023–2024)

1) Improved APSS clinical characterization and genetics in recent clinical reports (2023–2024): 2023 and 2024 reports emphasize APSS triggers (humidity/friction/hyperhidrosis), genetic heterogeneity (TGM5 vs CSTA), and diagnostic confusion with localized EBS—supporting broader adoption of gene testing in recurrent acral blistering/peeling. (gierach2023acralpeelingskin pages 1-3, stjernbrandt2024acralpeelingskin pages 1-2)

2) Therapeutic repurposing at the symptom-modifier level: botulinum toxin A is reported as potentially beneficial for APSS by reducing sweating/hyperhidrosis-driven exacerbations. (stjernbrandt2024acralpeelingskin pages 1-2)

3) Expansion of CAST-related PLACK phenotypes with new variants (2023): a 2023 case report identifies a novel homozygous CAST frameshift leading to truncation and reiterates the PLACK phenotype (peeling + leukonychia + keratoses + cheilitis + knuckle pads), contributing to genotype expansion. (vidya2023placksyndromeassociated pages 1-3)

Subtype crosswalk (summary table)

Clinical entity/subtype	Key features	Causal gene(s)	Inheritance	Example variant(s) mentioned in evidence	Key triggers/exacerbating factors	Key references (PMID/DOI)
Acral peeling skin syndrome (APSS)	Painless superficial peeling/exfoliation mainly of hands and feet; may include erythema, itching, erosions, flaccid blisters; histologic cleavage between stratum corneum and granular layer; can mimic localized epidermolysis bullosa simplex (gierach2023acralpeelingskin pages 1-3, stjernbrandt2024acralpeelingskin pages 1-2)	TGM5	Autosomal recessive (stjernbrandt2024acralpeelingskin pages 1-2, velden2020mutationsinthe pages 1-2)	p.Gly113Cys / c.337G>T; p.Trp255Arg / c.763T>C; c.2T>C p.M1T; c.1037G>A; c.684+1G>A (stjernbrandt2024acralpeelingskin pages 2-2, stjernbrandt2024acralpeelingskin pages 1-2, krunic2013acralpeelingskin pages 1-2)	Humidity, friction/trauma, perspiration/hyperhidrosis, heat, water/moisture (gierach2023acralpeelingskin pages 1-3, stjernbrandt2024acralpeelingskin pages 1-2, krunic2013acralpeelingskin pages 1-2)	DOI: 10.5114/dr.2023.131389; 10.2340/actadv.v104.24305; 10.1159/000354572; 10.1111/1346-8138.17422
Acral peeling skin syndrome due to CSTA	Lifelong acral peeling; some reports note overlap with exfoliative ichthyosis/fine scaling; skin fragility related to impaired adhesion/protease inhibition (stjernbrandt2024acralpeelingskin pages 1-2, krunic2013acralpeelingskin pages 1-2)	CSTA (cystatin A)	Autosomal recessive (consanguineous pedigree; homozygous LOF) (krunic2013acralpeelingskin pages 1-2)	p.Lys22Ter / p.Lys22X nonsense mutation (krunic2013acralpeelingskin pages 1-2)	Heat, friction, perspiration, excessive moisture, exposure to water (krunic2013acralpeelingskin pages 1-2)	DOI: 10.1111/pde.12092
Generalized PSS type A / non-inflammatory generalized PSS	Generalized superficial peeling/scaling beginning in early childhood; non-inflammatory generalized form (gierach2023acralpeelingskin pages 1-3, kawakami2014acaseof pages 1-2, velden2020mutationsinthe pages 1-2)	CHST8	Autosomal recessive (kawakami2014acaseof pages 1-2, velden2020mutationsinthe pages 1-2)	R77W was historically proposed, but causality has been questioned in later work; no firmly validated pathogenic example variant was provided in gathered evidence (kawakami2014acaseof pages 1-2)	Mechanical friction reported to exacerbate generalized non-inflammatory PSS in a quiz/case context (bolling2018generalizedichthyoticpeeling pages 1-6)	DOI: 10.1016/j.ygeno.2012.01.005
Generalized inflammatory peeling skin syndrome / PSS type B / PSS1 / peeling skin disease (PSD)	Congenital ichthyosiform erythroderma with lifelong patchy/superficial peeling, severe pruritus, burning red denuded patches with collarette; may show urticaria, angioedema, food allergies, asthma, elevated IgE/eosinophilia; due to corneodesmosomal dysfunction/barrier defect (metze2026desmosomaltypeacantholysis—anew pages 10-12, kawakami2014acaseof pages 3-4, velden2020mutationsinthe pages 1-2, kawakami2014acaseof pages 4-5)	CDSN (corneodesmosin)	Autosomal recessive for peeling skin disease; monoallelic CDSN variants instead can cause autosomal dominant hypotrichosis simplex of the scalp (velden2020mutationsinthe pages 1-2)	c.598C>T p.Gln200; c.164_167dup p.Thr57Profs6; c.1358G>A missense (velden2020mutationsinthe pages 1-2, kawakami2014acaseof pages 1-2)	Summer worsening reported; inflammatory/barrier-driven phenotype rather than classic friction-limited acral disease (kawakami2014acaseof pages 1-2, kawakami2014acaseof pages 4-5)	DOI: 10.1016/j.ajhg.2010.07.005; 10.1038/jid.2010.363; 10.1111/1346-8138.15136; 10.1159/000368823
Generalized ichthyotic peeling skin syndrome due to FLG2	Recessive generalized skin-fragility/peeling with ichthyotic features; cleavage in lower stratum corneum, parakeratosis, reduced keratin 2/corneodesmosin/desmocollin-1/desmoglein-1, abnormal keratin compaction (bolling2018generalizedichthyoticpeeling pages 1-6, has2018peelingskindisorders pages 1-2)	FLG2	Recessive / biallelic loss-of-function (has2018peelingskindisorders pages 1-2, bolling2018generalizedichthyoticpeeling pages 1-6)	c.632C>G, p.Ser211; p.Tyr355 also cited in commentary evidence (bolling2018generalizedichthyoticpeeling pages 1-6, has2018peelingskindisorders pages 1-2)	Not specifically stated in gathered evidence	DOI: 10.1016/j.jid.2018.01.038
PLACK syndrome (related PSS phenotype)	Generalized peeling, leukonychia, acral punctate keratoses, cheilitis, knuckle pads; may also show xerosis, palmoplantar keratoderma, hyperkeratotic papules; distinct generalized AR peeling phenotype with impaired keratinocyte adhesion/apoptosis (vidya2023placksyndromeassociated pages 1-3, lin2015lossoffunctionmutationsin pages 1-2)	CAST (calpastatin)	Autosomal recessive (vidya2023placksyndromeassociated pages 1-3, lin2015lossoffunctionmutationsin pages 1-2)	p.Glu441Ter; homozygous exon 18 insertion causing frameshift/premature truncation (vidya2023placksyndromeassociated pages 1-3)	Spontaneous or trauma-associated peeling; bullae may follow trauma (vidya2023placksyndromeassociated pages 1-3)	PMID: 37317743; DOI: 10.25259/ijdvl_1138_2021; 10.1016/j.ajhg.2014.12.026

Table: This table summarizes the main Peeling Skin Syndrome subtypes and closely related peeling disorders supported by the gathered evidence, including genes, inheritance, representative variants, triggers, and key references. It is useful as a compact crosswalk between clinical classification and molecular etiology.

Direct abstract quotations (as available in retrieved snippets)

PSS definition (review excerpt): “spontaneous peeling of the stratum corneum without bleeding or pain.” (metze2026desmosomaltypeacantholysis—anew pages 10-12)
Komatsu et al. 2006 (title reflects core mechanistic claim): “Elevated human tissue kallikrein levels in the stratum corneum and serum of peeling skin syndrome-type B patients suggests an over-desquamation of corneocytes.” (komatsu2006elevatedhumantissue pages 1-2)

Notes on evidence limitations

Several requested identifier fields (MONDO, MeSH, ICD-10/11, Orphanet IDs) were not retrievable from the current tool-based literature corpus; they should be populated by direct ontology/database queries.
Some therapy claims (e.g., topical calcipotriol) are referenced secondarily in reviews without full primary-case detail in retrieved snippets; additional primary retrieval is recommended before encoding as high-confidence treatment evidence. (pan2022atopicdermatitislikegenodermatosis pages 33-33)

References

(metze2026desmosomaltypeacantholysis—anew pages 10-12): Dieter Metze, Kira Süßmuth, Clemens Metze, Vinzenz Oji, and Heiko Traupe. Desmosomal-type acantholysis—a new histologic pattern related to mutations of genes for desmosomal proteins. Dermatopathology, 13(2):17, Apr 2026. URL: https://doi.org/10.3390/dermatopathology13020017, doi:10.3390/dermatopathology13020017. This article has 0 citations.
(velden2020mutationsinthe pages 1-2): Jaap J. A. J. van der Velden, Michel van Geel, Jans J. Engelhart, Marcel F. Jonkman, and Peter M. Steijlen. Mutations in the cdsn gene cause peeling skin disease and hypotrichosis simplex of the scalp. The Journal of Dermatology, 47:3-7, Oct 2020. URL: https://doi.org/10.1111/1346-8138.15136, doi:10.1111/1346-8138.15136. This article has 15 citations.
(has2018peelingskindisorders pages 1-2): Cristina Has. Peeling skin disorders: a paradigm for skin desquamation. The Journal of investigative dermatology, 138 8:1689-1691, Aug 2018. URL: https://doi.org/10.1016/j.jid.2018.05.020, doi:10.1016/j.jid.2018.05.020. This article has 51 citations.
(komatsu2006elevatedhumantissue pages 1-2): Nahoko Komatsu, Yasushi Suga, Kiyofumi Saijoh, Amber C. Liu, Saba Khan, Yuki Mizuno, Shigaku Ikeda, Hua-Kang Wu, Arumugam Jayakumar, Gary L. Clayman, Fumiaki Shirasaki, Kazuhiko Takehara, and Eleftherios P. Diamandis. Elevated human tissue kallikrein levels in the stratum corneum and serum of peeling skin syndrome-type b patients suggests an over-desquamation of corneocytes. The Journal of investigative dermatology, 126 10:2338-42, Oct 2006. URL: https://doi.org/10.1038/sj.jid.5700379, doi:10.1038/sj.jid.5700379. This article has 84 citations.
(stjernbrandt2024acralpeelingskin pages 1-2): Anna-Lotta Stjernbrandt, Magnus Burstedt, Emma Holmbom, and Alexander Shayesteh. Acral peeling skin syndrome: two unusual cases and the therapeutic potential of botulinum toxin. Acta Dermato-Venereologica, 104:adv24305, Apr 2024. URL: https://doi.org/10.2340/actadv.v104.24305, doi:10.2340/actadv.v104.24305. This article has 2 citations and is from a domain leading peer-reviewed journal.
(kawakami2014acaseof pages 1-2): Hiroshi Kawakami, Masaki Uchiyama, Tatsuo Maeda, Takahiko Tsunoda, Yoshihiko Mitsuhashi, and Ryoji Tsuboi. A case of inflammatory generalized type of peeling skin syndrome possibly caused by a homozygous missense mutation of cdsn. Case Reports in Dermatology, 6:232-238, Oct 2014. URL: https://doi.org/10.1159/000368823, doi:10.1159/000368823. This article has 4 citations.
(oji2010lossofcorneodesmosin pages 6-7): Vinzenz Oji, Katja-Martina Eckl, Karin Aufenvenne, Marc Nätebus, Tatjana Tarinski, Katharina Ackermann, Natalia Seller, Dieter Metze, Gudrun Nürnberg, Regina Fölster-Holst, Monika Schäfer-Korting, Ingrid Hausser, Heiko Traupe, and Hans Christian Hennies. Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease. American journal of human genetics, 87 2:274-81, Aug 2010. URL: https://doi.org/10.1016/j.ajhg.2010.07.005, doi:10.1016/j.ajhg.2010.07.005. This article has 291 citations and is from a highest quality peer-reviewed journal.
(vidya2023placksyndromeassociated pages 1-3): Aparna S. Vidya, Anza Khader, Keerankulangara Devi, Geetha Anandkumar Archana, Jose Reeshma, and Neerackal J. Reshma. Plack syndrome associated with alopecia areata and a novel homozygous base pair insertion in exon 18 of cast gene. Indian journal of dermatology, venereology and leprology, 90:1-4, May 2023. URL: https://doi.org/10.25259/ijdvl_1138_2021, doi:10.25259/ijdvl_1138_2021. This article has 6 citations.
(lin2015lossoffunctionmutationsin pages 1-2): Zhimiao Lin, Jiahui Zhao, Daniela Nitoiu, Claire A. Scott, Vincent Plagnol, Frances J.D. Smith, Neil J. Wilson, Christian Cole, Mary E. Schwartz, W.H. Irwin McLean, Huijun Wang, Cheng Feng, Lina Duo, Eray Yihui Zhou, Yali Ren, Lanlan Dai, Yulan Chen, Jianguo Zhang, Xun Xu, Edel A. O’Toole, David P. Kelsell, and Yong Yang. Loss-of-function mutations in cast cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads. American journal of human genetics, 96 3:440-7, Mar 2015. URL: https://doi.org/10.1016/j.ajhg.2014.12.026, doi:10.1016/j.ajhg.2014.12.026. This article has 63 citations and is from a highest quality peer-reviewed journal.
(bolling2018generalizedichthyoticpeeling pages 1-6): Maria C. Bolling, Sabrina Z. Jan, Anna M.G. Pasmooij, Henny H. Lemmink, Lude H. Franke, Vamsi K. Yenamandra, Richard J. Sinke, Peter C. van den Akker, and Marcel F. Jonkman. Generalized ichthyotic peeling skin syndrome due to flg2 mutations. Journal of Investigative Dermatology, 138:1881-1884, Aug 2018. URL: https://doi.org/10.1016/j.jid.2018.01.038, doi:10.1016/j.jid.2018.01.038. This article has 26 citations and is from a highest quality peer-reviewed journal.
(cabral2012wholeexomesequencingin pages 4-5): Rita M. Cabral, Mazen Kurban, Muhammad Wajid, Yutaka Shimomura, Lynn Petukhova, and Angela M. Christiano. Whole-exome sequencing in a single proband reveals a mutation in the chst8 gene in autosomal recessive peeling skin syndrome. Genomics, 99 4:202-8, Apr 2012. URL: https://doi.org/10.1016/j.ygeno.2012.01.005, doi:10.1016/j.ygeno.2012.01.005. This article has 74 citations and is from a peer-reviewed journal.
(krunic2013acralpeelingskin pages 1-2): Aleksandar L. Krunic, Kristina L. Stone, Michael A. Simpson, and John A. McGrath. Acral peeling skin syndrome resulting from a homozygous nonsense mutation in the csta gene encoding cystatin a. Pediatric Dermatology, Sep 2013. URL: https://doi.org/10.1111/pde.12092, doi:10.1111/pde.12092. This article has 56 citations and is from a peer-reviewed journal.
(gierach2023acralpeelingskin pages 1-3): Daria Gierach and Łukasz Kępczyński. Acral peeling skin syndrome. Dermatology Review, 110:567-573, Jan 2023. URL: https://doi.org/10.5114/dr.2023.131389, doi:10.5114/dr.2023.131389. This article has 2 citations.
(valentin2021developmentofa pages 1-5): F. Valentin, H. Wiegmann, T. Tarinski, H. Nikolenko, H. Traupe, E. Liebau, M. Dathe, and V. Oji. Development of a pathogenesis‐based therapy for peeling skin syndrome type 1*. British Journal of Dermatology, 184:1123-1131, Nov 2021. URL: https://doi.org/10.1111/bjd.19546, doi:10.1111/bjd.19546. This article has 21 citations and is from a highest quality peer-reviewed journal.
(kawakami2014acaseof pages 4-5): Hiroshi Kawakami, Masaki Uchiyama, Tatsuo Maeda, Takahiko Tsunoda, Yoshihiko Mitsuhashi, and Ryoji Tsuboi. A case of inflammatory generalized type of peeling skin syndrome possibly caused by a homozygous missense mutation of cdsn. Case Reports in Dermatology, 6:232-238, Oct 2014. URL: https://doi.org/10.1159/000368823, doi:10.1159/000368823. This article has 4 citations.
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(stjernbrandt2024acralpeelingskin pages 2-2): Anna-Lotta Stjernbrandt, Magnus Burstedt, Emma Holmbom, and Alexander Shayesteh. Acral peeling skin syndrome: two unusual cases and the therapeutic potential of botulinum toxin. Acta Dermato-Venereologica, 104:adv24305, Apr 2024. URL: https://doi.org/10.2340/actadv.v104.24305, doi:10.2340/actadv.v104.24305. This article has 2 citations and is from a domain leading peer-reviewed journal.
(valentin2021developmentofa pages 9-12): F. Valentin, H. Wiegmann, T. Tarinski, H. Nikolenko, H. Traupe, E. Liebau, M. Dathe, and V. Oji. Development of a pathogenesis‐based therapy for peeling skin syndrome type 1*. British Journal of Dermatology, 184:1123-1131, Nov 2021. URL: https://doi.org/10.1111/bjd.19546, doi:10.1111/bjd.19546. This article has 21 citations and is from a highest quality peer-reviewed journal.
(kawakami2014acaseof pages 3-4): Hiroshi Kawakami, Masaki Uchiyama, Tatsuo Maeda, Takahiko Tsunoda, Yoshihiko Mitsuhashi, and Ryoji Tsuboi. A case of inflammatory generalized type of peeling skin syndrome possibly caused by a homozygous missense mutation of cdsn. Case Reports in Dermatology, 6:232-238, Oct 2014. URL: https://doi.org/10.1159/000368823, doi:10.1159/000368823. This article has 4 citations.

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OpenScientist Report

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Source YAML

References & Deep Research

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Peeling Skin Syndrome (PSS) — Comprehensive Disease Characteristics Report (Mendelian)

Target disease

Key identifiers (available from retrieved sources)

Synonyms and alternative names

Evidence source type

1. Disease information (classification)

Clinical classification used in the literature

2. Etiology

Primary causal factors (genetic)

Risk factors (genetic and environmental)

Protective factors / gene–environment interactions

3. Phenotypes (clinical spectrum) with ontology suggestions

Core phenotype across PSS

Acral peeling skin syndrome (APSS; often TGM5 or CSTA)

Generalized non-inflammatory PSS (Type A; CHST8)

Inflammatory generalized PSS / peeling skin disease (Type B / PSS1; CDSN)

FLG2-related generalized ichthyotic peeling skin syndrome

PLACK syndrome (CAST)

4. Genetic / molecular information

Causal genes (supported in this evidence set)

Variant classes and functional consequences

Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

Mechanistic causal chain (high-level)

Corneodesmosome and barrier defect axis (CDSN; inflammatory generalized PSS)

Protease–inhibitor imbalance / over-desquamation axis

Cornified envelope / keratin compaction axis (FLG2)

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

Inheritance patterns

Epidemiology / prevalence

Population genetics / founder effects

10. Diagnostics

Clinical presentation and differential diagnosis

Histopathology / ultrastructure

Genetic testing strategy (practical approach)

11. Outcome / prognosis

12. Treatment (current applications and real-world implementations)

Current standard management (symptomatic/supportive)

Recent (2023–2024) treatment development: botulinum toxin for APSS

Pathogenesis-based / experimental therapies (preclinical)

Topical calcipotriol (limited evidence)

Clinical trials

13. Prevention

14. Other species / natural disease

15. Model organisms and experimental systems