Olmsted Syndrome 2

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Classifications

Harrison's Part

Mechanistic Nosology

👪

Inheritance

1

Autosomal dominant HP:0000006

Heterozygous C-terminal PERP truncations cause the disease. In the founding series one allele arose de novo and one was transmitted from an affected father to his daughter. Heterozygous carriers of N-terminal PERP truncations are unaffected, so the dominant disease depends on the allele class rather than on a single dose of PERP.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:30321533 SUPPORT Human clinical

"Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds."

States that a single heterozygous allele is sufficient for Olmsted syndrome in several unrelated families.

PMID:30321533 SUPPORT Human clinical

"one which is de novo and one which is inherited from an affected parent, conclusively demonstrates that these mutations cause OS"

Documents both a de novo occurrence and parent-to-child transmission of the heterozygous allele.

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Pathophysiology

6

PERP Last-Exon Nonsense Variant

Heterozygous nonsense variants in the third and last exon of PERP, p.Trp151* (c.452G>A or c.453G>A) and p.Tyr153* (c.459C>G), lie within two residues of each other. Because they sit in the terminal exon the mutant transcript escapes nonsense-mediated decay, and patient keratinocytes make a C-terminally truncated protein. The authors argue against haploinsufficiency: obligate heterozygous carriers of an N-terminal truncation are unaffected, PERP truncating alleles occur in control databases, and Perp heterozygous mice have no phenotype. Their favored model is a combined dominant-negative and neomorphic effect, which remains untested.

keratinocyte CL:0000312

PERP hgnc:17637

Genetic context allele_type: nonsense variant in the terminal exon variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN

The functional class is recorded as unknown because the reporting authors propose, but do not demonstrate, a dominant-negative and neomorphic mechanism.

Downstream

Unstable Desmosomal Incorporation of Truncated PERP The truncated protein made from the mutant allele is the protein that fractionates as detergent-soluble.

Epidermal Hyperproliferation The founding study observes basal hyperproliferation in skin carrying the variant but does not establish whether it follows from the desmosomal defect or from another PERP function.

Altered Terminal Keratinocyte Differentiation Expanded filaggrin staining was observed in skin carrying the variant; no intermediate step between the variant and this change has been shown.

Show evidence (5 references)

PMID:30321533 SUPPORT Human clinical

"four OS subjects were found to be heterozygous for a nonsense mutation in the last exon of PERP (p.Trp151* or p.Tyr153*)"

Identifies the causal allele class and its position in the terminal exon.

PMID:30321533 SUPPORT In vitro / ex vivo

"qRT-PCR demonstrated no deficiency in PERP RNA, consistent with terminal exon mutations escaping nonsense-mediated decay"

Patient keratinocytes keep normal PERP mRNA levels, so the mutant transcript is not degraded.

PMID:30321533 SUPPORT In vitro / ex vivo

"Immunoblotting for PERP demonstrated lower molecular weight bands in Subject 1 keratinocyte lysates, consistent with expression of a truncated form"

Shows that the truncated protein is produced in patient keratinocytes.

+ 2 more references

Unstable Desmosomal Incorporation of Truncated PERP

In keratinocytes from a p.Tyr153* patient the truncated PERP reaches the plasma membrane normally but is enriched in the Triton X-100 soluble fraction, the behavior of a protein not stably held in desmosomes. Other desmosomal proteins, E-cadherin and claudin 1 keep normal solubility profiles, and their localization in skin is normal, which distinguishes this disease from desmosomal disorders in which other junction components are mislocalized.

keratinocyte CL:0000312

PERP hgnc:17637

desmosome GO:0030057

Downstream

Immature Desmosomes Lacking the Electron-Dense Midline Both observations are made in the same patient, but how PERP contributes to desmosome maturation is not known, so the intervening steps are unspecified.

Show evidence (2 references)

PMID:30321533 SUPPORT In vitro / ex vivo

"PERP immunostaining of keratinocytes from Subject 1 showed normal membrane localization"

The mutant protein is not mislocalized away from the membrane.

PMID:30321533 SUPPORT In vitro / ex vivo

"Other desmosomal proteins showed normal solubility profiles consistent with stable incorporation"

The solubility change is specific to PERP rather than shared by the other desmosomal proteins.

Immature Desmosomes Lacking the Electron-Dense Midline

Electron microscopy of skin from a p.Tyr153* patient shows desmosomes that lack the electron-dense midline of mature desmosomes, shorter outer plaques in the lower suprabasal layer and modestly fewer desmosomes in the upper suprabasal layer. Inner plaques and keratin filament attachments appear intact, so of the two defects named by the conformance target only the assembly arm is evidenced here; keratin filament anchorage is not shown to fail.

keratinocyte CL:0000312

desmosome organization GO:0002934 ⚠ ABNORMAL

desmosome GO:0030057

Animal models

Perp-null mouse Mouse partially recapitulates Perp-deficient skin carries numerous structural desmosome defects.

Downstream

Impaired Keratinocyte Adhesion Under Mechanical Stress The reporting authors interpret the adhesion defect through the missing midline, citing its role in desmosome adhesive strength.

Show evidence (4 references)

PMID:30321533 SUPPORT Human clinical

"In both subjects, desmosomes lack the electron-dense midline (EDM) normally present in mature desmosomes"

Ultrastructural evidence of immature desmosomes in the Olmsted syndrome subject's skin.

PMID:30321533 SUPPORT Human clinical

"In the lower suprabasal layer, morphometric analysis demonstrated shorter outer plaque length in Subject 1"

Morphometric evidence of abnormal desmosome structure in the Olmsted syndrome subject.

PMID:30321533 SUPPORT Human clinical

"In the upper suprabasal layer, desmosome frequency was modestly decreased in Subject 1"

Reduced desmosome number in the Olmsted syndrome subject.

+ 1 more reference

Impaired Keratinocyte Adhesion Under Mechanical Stress

Keratinocyte sheets cultured from a p.Tyr153* patient fragment more than control sheets in a dispase mechanical dissociation assay, a measure of desmosomal adhesive strength. Clinical blistering or acantholysis has not been reported in this disease.

keratinocyte CL:0000312

cell-cell adhesion GO:0098609 ↓ DECREASED

Animal models

Perp-null mouse Mouse partially recapitulates The null mouse blisters, a stronger adhesion failure than is seen clinically in OLMS2.

Downstream

Palmoplantar keratoderma The reporting authors read palmoplantar keratoderma and woolly hair as the hallmarks of desmosomal abnormality; the steps from reduced adhesion to keratoderma are not described for this disease.

Woolly hair Woolly hair is read by the reporting authors as a desmosomal hallmark; the hair shaft itself was not examined.

Show evidence (1 reference)

PMID:30321533 SUPPORT In vitro / ex vivo

"For both subjects increased fragmentation after mechanical stress was observed"

Patient keratinocyte sheets, including those from the Olmsted syndrome subject, show reduced intercellular adhesion.

Epidermal Hyperproliferation

Skin from the Olmsted syndrome subject has a higher proportion of Ki67 positive cells in the basal layer of the interfollicular epidermis and more dermal mast cells than control skin. Unlike TRPV3-related Olmsted syndrome, no apoptotic keratinocytes were detected by activated caspase 3 staining.

basal cell of epidermis CL:0002187

keratinocyte proliferation GO:0043616 ↑ INCREASED

Animal models

Stratified-epithelium Perp conditional knockout mouse Mouse partially recapitulates Loss of Perp in stratified epithelia makes the epithelium hyperproliferative.

Downstream

Epidermal acanthosis Increased basal proliferation thickens the viable epidermis; acanthosis is the histological reading of that thickening.

Show evidence (2 references)

PMID:30321533 SUPPORT Human clinical

"both probands exhibit significantly increased mast cell counts in the dermis, and greater percentages of proliferating cells in the basal layer of interfollicular epidermis"

Ki67 staining shows increased basal proliferation in the Olmsted syndrome subject's skin.

PMID:30321533 SUPPORT Human clinical

"Staining of skin from OS Subject 1 for activated caspase 3 revealed no detectable apoptotic cells"

Records that keratinocyte apoptosis, a feature reported in TRPV3-related Olmsted syndrome, was not found here.

Altered Terminal Keratinocyte Differentiation

Immunostaining of the Olmsted syndrome subject's skin shows expanded filaggrin with normal suprabasal keratin 1, which the reporting authors interpret as a possible defect in terminal differentiation. Unlike the recessive PERP erythrokeratoderma, keratin 14 is not expanded.

keratinocyte CL:0000312

keratinocyte differentiation GO:0030216 ⚠ ABNORMAL

Downstream

Hyperkeratosis A thickened stratum corneum is the histological endpoint of the altered terminal differentiation program; the connecting steps are not described for this disease.

Show evidence (2 references)

PMID:30321533 SUPPORT Human clinical

"Both OS Subject 1 and EK Subject 5 demonstrate expanded FLG but normal, suprabasal expression of KRT1."

Differentiation marker staining in the Olmsted syndrome subject's skin.

PMID:30321533 SUPPORT Human clinical

"Overall, these results suggest a potential defect in terminal differentiation in Subjects 1 and 5."

The authors' interpretation of the marker changes, stated as a possibility.

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Pathograph

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Phenotypes

12

Head and Neck 3

Cheilitis HP:0100825

Show evidence (1 reference)

PMID:30321533 SUPPORT Human clinical

"He has experienced chronic cheilitis with intermittent periorificial plaques."

Chronic cheilitis in the adult subject.

Sparse eyebrow HP:0045075

Show evidence (1 reference)

PMID:30321533 SUPPORT Human clinical

"Marked cheilitis, periorificial keratotic plaques, hyperkeratotic plaques on armpits, buttocks, abdomen, groin, and genitals, hyperkeratotic nails, scant eyebrows, and woolly yellow hair strikingly similar to that of Subject 1 are present."

Scant eyebrows in Subject 2.

Carious teeth HP:0000670

Show evidence (1 reference)

PMID:30321533 SUPPORT Human clinical

"While his primary teeth were normal he rapidly developed severe caries in his secondary teeth, necessitating extraction of all teeth at age 38."

Severe caries of the permanent teeth in Subject 4.

Integument 9

Palmoplantar keratoderma HP:0000982

Sequelae: Skin fissure

Show evidence (3 references)

PMID:30321533 SUPPORT Human clinical

"Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds."

Severe palmoplantar keratoderma is a defining feature of the PERP form.

PMID:30321533 SUPPORT Human clinical

"massive, transgrediens PPK extending to the dorsum of wrists and ankles"

Describes the transgrediens extent of the keratoderma in one subject.

PMID:34863005 SUPPORT BACKGROUND Human clinical

"Monoallelic nonsense mutations cause Olmsted syndrome with severe periorificial keratoderma and palmoplantar keratoderma (PPK)."

A later PERP study restating the dominant phenotype in its background.

Periorificial hyperkeratosis HP:0034521

Show evidence (2 references)

PMID:30321533 SUPPORT Human clinical

"Marked cheilitis, periorificial keratotic plaques, hyperkeratotic plaques on armpits, buttocks, abdomen, groin, and genitals, hyperkeratotic nails, scant eyebrows, and woolly yellow hair strikingly similar to that of Subject 1 are present."

Periorificial keratotic plaques in Subject 2.

PMID:34863005 SUPPORT BACKGROUND Human clinical

"Monoallelic nonsense mutations cause Olmsted syndrome with severe periorificial keratoderma and palmoplantar keratoderma (PPK)."

Restates periorificial keratoderma as part of the dominant PERP phenotype.

Hyperkeratotic plaques of the flexures and buttocks Skin plaque HP:0200035

Show evidence (1 reference)

PMID:30321533 SUPPORT Human clinical

"presented at age 5 months with cheilitis, periorificial keratotic plaques, keratotic papules on the ear at the junction of the lobule and tragus, hyperkeratotic plaques on the buttocks, transgrediens pink-red PPK which progressed over time to thick and fissured yellow plaques on the fingertips..."

Subject 1 has hyperkeratotic plaques on the buttocks and keratotic papules on the ear.

Skin fissure HP:0031057

Show evidence (1 reference)

PMID:30321533 SUPPORT Human clinical

"Subject 3 is age 4 and presented within the first month of life with pink-red thickening of the palms and soles, which has progressed to confluent palmoplantar keratoderma with thicker scale and fissures developing on pressure-bearing areas."

Fissures on pressure-bearing palmoplantar skin.

Hyperkeratotic nails Onychauxis HP:0012542

Show evidence (1 reference)

PMID:30321533 SUPPORT Human clinical

"Marked cheilitis, periorificial keratotic plaques, hyperkeratotic plaques on armpits, buttocks, abdomen, groin, and genitals, hyperkeratotic nails, scant eyebrows, and woolly yellow hair strikingly similar to that of Subject 1 are present."

Hyperkeratotic nails in Subject 2.

Woolly hair HP:0002224

Show evidence (1 reference)

PMID:30321533 SUPPORT Human clinical

"His hair was yellow, fine, and curly as a child, and became darker when he was a teen but remained woolly."

Woolly hair persisting into adulthood in Subject 4.

Yellow hair Fair hair HP:0002286

Show evidence (1 reference)

PMID:30321533 SUPPORT Human clinical

"Yellow hair is not a consistent feature of OS, and we know of no cases with both yellow hair and a pathogenic TRPV3 mutation."

Yellow hair is reported in the PERP subjects and is not known in TRPV3-related Olmsted syndrome.

Epidermal acanthosis HP:0025092

Show evidence (1 reference)

PMID:30321533 SUPPORT Human clinical

"Histology of affected skin from Subjects 1 and 5 showed thickening of the epidermis (acanthosis) and a thickened stratum corneum (hyperkeratosis), consistent with diagnoses of OS and EK"

Acanthosis on histology of the Olmsted syndrome subject's affected skin.

Hyperkeratosis HP:0000962

Show evidence (1 reference)

PMID:30321533 SUPPORT Human clinical

"Histology of affected skin from Subjects 1 and 5 showed thickening of the epidermis (acanthosis) and a thickened stratum corneum (hyperkeratosis), consistent with diagnoses of OS and EK"

Hyperkeratosis on histology of the Olmsted syndrome subject's affected skin.

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Genetic Associations

1

PERP (Causative)

Gene: PERP hgnc:17637 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:30321533 SUPPORT Human clinical

"Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma."

Establishes PERP as the causal gene for the dominant keratoderma.

PMID:37510397 SUPPORT BACKGROUND Human clinical

"Three of these variants have been linked to dominant inheritance, generally associated with more aggressive and severe phenotypes within Olmsted syndrome"

A later report's background summary of the dominant PERP variants and their Olmsted syndrome phenotype.

Variants (2)

PERP p.Trp151* Pathogenic

Gene: PERP hgnc:17637

Nonsense variant in the terminal exon, reported with two different nucleotide changes (c.452G>A and c.453G>A) in unrelated families, including one transmitted from an affected father to his daughter.

Show evidence (1 reference)

PMID:30321533 SUPPORT Human clinical

"one which is de novo and one which is inherited from an affected parent, conclusively demonstrates that these mutations cause OS"

Segregation and recurrence across unrelated probands establish pathogenicity of the clustered truncations.

PERP p.Tyr153* Pathogenic

Gene: PERP hgnc:17637

Nonsense variant in the terminal exon (c.459C>G in the founding report), two residues downstream of p.Trp151*.

Show evidence (1 reference)

PMID:30321533 SUPPORT Human clinical

"four OS subjects were found to be heterozygous for a nonsense mutation in the last exon of PERP (p.Trp151* or p.Tyr153*)"

Identifies p.Tyr153* as one of the two causal truncations.

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Progression

1

Onset

Age: First month of life to early childhood

In the founding series palmoplantar thickening began within the first month of life in one child, by 5 months in another, and in early childhood in an adult, with later progression to thick, fissured plaques at pressure sites.

Show evidence (2 references)

PMID:30321533 SUPPORT Human clinical

"Subject 3 is age 4 and presented within the first month of life with pink-red thickening of the palms and soles, which has progressed to confluent palmoplantar keratoderma with thicker scale and fissures developing on pressure-bearing areas."

Neonatal onset with progression in one subject.

PMID:30321533 SUPPORT Human clinical

"Subject 4 is age 40 and had onset of scaling of palms and soles in early childhood, with progression to thick, fissured, cobblestone-like hyperkeratosis on palms and soles which has slowly extended to the ankles, distal shins, and distal calves."

Early childhood onset and slow extension over decades in the adult subject.

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Animal Models

2

Perp-null mouse

Constitutive Perp knockout mice die postnatally with blistering of stratified epithelia and structural desmosome defects. The model is a null allele and so corresponds to the recessive loss-of-function PERP disease rather than to the dominant C-terminal truncation of this entry.

Species

Mouse

Genotype

Perp-/- (constitutive null)

Publication

PMID:15797384

Pathograph links

Immature Desmosomes Lacking the Electron-Dense Midline partially recapitulates fidelity: low observes: cellular Perp-deficient skin carries numerous structural desmosome defects.

Limitations: A null allele, not the dominant last-exon truncation; heterozygous Perp mice have no reported phenotype, so the dominant disease is not modeled.

Divergences from the human mechanism

cause unrepresented qualifying

The OLMS2 lesion is a truncated PERP protein made from one allele. The model removes PERP entirely from both alleles, so it shows what loss of PERP does to desmosomes, not what the truncated protein does.

species mismatch qualifying

The desmosome observations are made in mouse stratified epithelia, not in the human palmoplantar and periorificial skin affected in OLMS2.

Show evidence (1 reference)

PMID:15797384 SUPPORT Model organism

"Perp localizes specifically to desmosomes, adhesion junctions important for tissue integrity, and numerous structural defects in desmosomes are observed in Perp-deficient skin"

Desmosome defects in Perp-deficient mouse skin, the model counterpart of the immature desmosomes seen in patient skin.

Impaired Keratinocyte Adhesion Under Mechanical Stress partially recapitulates fidelity: low observes: tissue The null mouse blisters, a stronger adhesion failure than is seen clinically in OLMS2.

Limitations: Blistering is not reported in OLMS2 patients; the null allele produces a more severe adhesion failure than the dominant truncation.

Divergences from the human mechanism

cause unrepresented qualifying

Complete loss of PERP stands in for a truncated protein expressed from one allele, which changes the severity of the adhesion defect.

Show evidence (1 reference)

PMID:15797384 SUPPORT Model organism

"Perp-/- mice die postnatally, with dramatic blistering in stratified epithelia symptomatic of compromised adhesion."

Shows that loss of Perp compromises epithelial adhesion in vivo.

Show evidence (1 reference)

PMID:15797384 SUPPORT Model organism

"Perp-/- mice die postnatally, with dramatic blistering in stratified epithelia symptomatic of compromised adhesion."

Describes the adhesion phenotype of the null mouse.

Stratified-epithelium Perp conditional knockout mouse

Ablation of Perp in stratified epithelia reproduces the blistering, hyperproliferation and early postnatal death of the constitutive null, showing that these reflect a role of Perp within stratified epithelium.

Species

Mouse

Genotype

Perp conditional knockout with keratin 5 Cre

Publication

PMID:16417219

Pathograph links

Epidermal Hyperproliferation partially recapitulates fidelity: low observes: tissue Loss of Perp in stratified epithelia makes the epithelium hyperproliferative.

Limitations: A biallelic loss-of-function model with early lethality; the dominant truncation of OLMS2 is not modeled.

Divergences from the human mechanism

cause unrepresented qualifying

Hyperproliferation here follows complete loss of Perp, whereas in OLMS2 a truncated protein is present and the route to hyperproliferation is not known.

Show evidence (1 reference)

PMID:16417219 SUPPORT Model organism

"the majority of mice lacking Perp in stratified epithelia die within 10 days after birth, accompanied by blistering and hyperproliferation in the epithelia"

Hyperproliferation of Perp-deficient stratified epithelium in vivo.

Show evidence (1 reference)

PMID:16417219 SUPPORT Model organism

"the majority of mice lacking Perp in stratified epithelia die within 10 days after birth, accompanied by blistering and hyperproliferation in the epithelia"

Describes the phenotype of the epithelium-specific knockout.

{ }

Source YAML

click to show

name: Olmsted Syndrome 2
creation_date: "2026-10-24T01:30:00Z"
description: >-
  Olmsted syndrome 2 (OLMS2) is the autosomal dominant, PERP-related form of
  Olmsted syndrome: a severe palmoplantar keratoderma with periorificial
  keratotic plaques. It is caused by heterozygous nonsense variants clustered in
  the last exon of PERP (p.Trp151* and p.Tyr153*), which encodes a p53/p63
  target tetraspan membrane protein that is a component of desmosomes. Because
  the premature stop lies in the terminal exon, the mutant transcript escapes
  nonsense-mediated decay and a truncated protein is made; in patient
  keratinocytes it reaches the membrane but is enriched in the detergent-soluble
  fraction, consistent with unstable incorporation into desmosomes. Patient skin
  shows immature desmosomes lacking the electron-dense midline, cultured
  keratinocyte sheets fragment more under mechanical stress, and the epidermis
  is hyperproliferative with acanthosis and hyperkeratosis. Reported patients
  also have cheilitis, keratotic plaques in flexures and on the buttocks,
  hyperkeratotic nails and woolly, often yellow, hair. The same gene causes a
  recessive erythrokeratoderma (EKVP7) through biallelic loss of expression,
  which this knowledge base curates as a subtype of Erythrokeratodermia
  Variabilis.
category: Mendelian
synonyms:
- OLMS2
- palmoplantar keratoderma, mutilating, with periorificial keratotic plaques 2
parents:
- Olmsted syndrome
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
  mechanistic_category:
  - classification_value: desmosomopathy
    notes: >-
      PERP is a desmosomal component, and patient skin shows immature
      desmosomes and reduced keratinocyte adhesion.
disease_term:
  preferred_term: Olmsted syndrome 2
  term:
    id: MONDO:0030961
    label: Olmsted syndrome 2
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous C-terminal PERP truncations cause the disease. In the founding
    series one allele arose de novo and one was transmitted from an affected
    father to his daughter. Heterozygous carriers of N-terminal PERP truncations
    are unaffected, so the dominant disease depends on the allele class rather
    than on a single dose of PERP.
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds."
    explanation: States that a single heterozygous allele is sufficient for Olmsted syndrome in several unrelated families.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one which is de novo and one which is inherited from an affected parent, conclusively demonstrates that these mutations cause OS"
    explanation: Documents both a de novo occurrence and parent-to-child transmission of the heterozygous allele.
pathophysiology:
- name: PERP Last-Exon Nonsense Variant
  description: >-
    Heterozygous nonsense variants in the third and last exon of PERP,
    p.Trp151* (c.452G>A or c.453G>A) and p.Tyr153* (c.459C>G), lie within two
    residues of each other. Because they sit in the terminal exon the mutant
    transcript escapes nonsense-mediated decay, and patient keratinocytes make a
    C-terminally truncated protein. The authors argue against
    haploinsufficiency: obligate heterozygous carriers of an N-terminal
    truncation are unaffected, PERP truncating alleles occur in control
    databases, and Perp heterozygous mice have no phenotype. Their favored
    model is a combined dominant-negative and neomorphic effect, which remains
    untested.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: PERP
    term:
      id: hgnc:17637
      label: PERP
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  genetic_context:
    allele_type: nonsense variant in the terminal exon
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: UNKNOWN
    description: >-
      The functional class is recorded as unknown because the reporting
      authors propose, but do not demonstrate, a dominant-negative and
      neomorphic mechanism.
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "four OS subjects were found to be heterozygous for a nonsense mutation in the last exon of PERP (p.Trp151* or p.Tyr153*)"
    explanation: Identifies the causal allele class and its position in the terminal exon.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "qRT-PCR demonstrated no deficiency in PERP RNA, consistent with terminal exon mutations escaping nonsense-mediated decay"
    explanation: Patient keratinocytes keep normal PERP mRNA levels, so the mutant transcript is not degraded.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunoblotting for PERP demonstrated lower molecular weight bands in Subject 1 keratinocyte lysates, consistent with expression of a truncated form"
    explanation: Shows that the truncated protein is produced in patient keratinocytes.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is highly unlikely that OS in subjects with the heterozygous p.Trp151* and p.Tyr153* mutations is due to haploinsufficiency"
    explanation: The authors' conclusion against a dosage mechanism, based on unaffected carriers of a null allele.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "A dominant-negative and neomorphic effect for the heterozygous, tightly clustered C-terminal truncating mutations seems most consistent with these observations."
    explanation: The proposed, untested mechanism; recorded so the UNKNOWN functional class is not read as an absence of a hypothesis.
  downstream:
  - target: Unstable Desmosomal Incorporation of Truncated PERP
    causal_link_type: DIRECT
    description: >-
      The truncated protein made from the mutant allele is the protein that
      fractionates as detergent-soluble.
    evidence:
    - reference: PMID:30321533
      reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "suggesting that the mutant protein may not be stably incorporated into desmosomes"
      explanation: The lower molecular weight, truncated bands are the ones enriched in the Triton-soluble fraction.
  - target: Epidermal Hyperproliferation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The founding study observes basal hyperproliferation in skin carrying the
      variant but does not establish whether it follows from the desmosomal
      defect or from another PERP function.
  - target: Altered Terminal Keratinocyte Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Expanded filaggrin staining was observed in skin carrying the variant; no
      intermediate step between the variant and this change has been shown.
- name: Unstable Desmosomal Incorporation of Truncated PERP
  description: >-
    In keratinocytes from a p.Tyr153* patient the truncated PERP reaches the
    plasma membrane normally but is enriched in the Triton X-100 soluble
    fraction, the behavior of a protein not stably held in desmosomes. Other
    desmosomal proteins, E-cadherin and claudin 1 keep normal solubility
    profiles, and their localization in skin is normal, which distinguishes
    this disease from desmosomal disorders in which other junction components
    are mislocalized.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  cellular_components:
  - preferred_term: desmosome
    term:
      id: GO:0030057
      label: desmosome
  genes:
  - preferred_term: PERP
    term:
      id: hgnc:17637
      label: PERP
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PERP immunostaining of keratinocytes from Subject 1 showed normal membrane localization"
    explanation: The mutant protein is not mislocalized away from the membrane.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Other desmosomal proteins showed normal solubility profiles consistent with stable incorporation"
    explanation: The solubility change is specific to PERP rather than shared by the other desmosomal proteins.
  downstream:
  - target: Immature Desmosomes Lacking the Electron-Dense Midline
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Both observations are made in the same patient, but how PERP contributes
      to desmosome maturation is not known, so the intervening steps are
      unspecified.
- name: Immature Desmosomes Lacking the Electron-Dense Midline
  conforms_to: "desmosomal_adhesion_failure#Failure of Desmosome Assembly and Intermediate Filament Anchorage"
  description: >-
    Electron microscopy of skin from a p.Tyr153* patient shows desmosomes that
    lack the electron-dense midline of mature desmosomes, shorter outer plaques
    in the lower suprabasal layer and modestly fewer desmosomes in the upper
    suprabasal layer. Inner plaques and keratin filament attachments appear
    intact, so of the two defects named by the conformance target only the
    assembly arm is evidenced here; keratin filament anchorage is not shown to
    fail.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  cellular_components:
  - preferred_term: desmosome
    term:
      id: GO:0030057
      label: desmosome
  biological_processes:
  - preferred_term: desmosome organization
    term:
      id: GO:0002934
      label: desmosome organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both subjects, desmosomes lack the electron-dense midline (EDM) normally present in mature desmosomes"
    explanation: Ultrastructural evidence of immature desmosomes in the Olmsted syndrome subject's skin.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the lower suprabasal layer, morphometric analysis demonstrated shorter outer plaque length in Subject 1"
    explanation: Morphometric evidence of abnormal desmosome structure in the Olmsted syndrome subject.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the upper suprabasal layer, desmosome frequency was modestly decreased in Subject 1"
    explanation: Reduced desmosome number in the Olmsted syndrome subject.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other desmosomal features, including inner plaques and keratin filament attachments, appeared intact."
    explanation: Limits the claim to desmosome maturation; keratin filament attachment is preserved.
  downstream:
  - target: Impaired Keratinocyte Adhesion Under Mechanical Stress
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Formation of the electron-dense midline is central to desmosome adhesive strength.
    description: >-
      The reporting authors interpret the adhesion defect through the missing
      midline, citing its role in desmosome adhesive strength.
    evidence:
    - reference: PMID:30321533
      reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      quote_role: BACKGROUND
      snippet: "Formation of the EDM is central to desmosome adhesive strength"
      explanation: Background statement in the discussion that links the ultrastructural defect to reduced adhesive strength.
- name: Impaired Keratinocyte Adhesion Under Mechanical Stress
  conforms_to: "desmosomal_adhesion_failure#Loss of Desmosomal Intercellular Adhesion"
  description: >-
    Keratinocyte sheets cultured from a p.Tyr153* patient fragment more than
    control sheets in a dispase mechanical dissociation assay, a measure of
    desmosomal adhesive strength. Clinical blistering or acantholysis has not
    been reported in this disease.
  biological_scale: CELLULAR
  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
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "For both subjects increased fragmentation after mechanical stress was observed"
    explanation: Patient keratinocyte sheets, including those from the Olmsted syndrome subject, show reduced intercellular adhesion.
  downstream:
  - target: Palmoplantar keratoderma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The reporting authors read palmoplantar keratoderma and woolly hair as
      the hallmarks of desmosomal abnormality; the steps from reduced adhesion
      to keratoderma are not described for this disease.
    evidence:
    - reference: PMID:30321533
      reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "The consistent features of PPK and woolly hair are hallmarks of desmosomal abnormalities"
      explanation: Authors' attribution of the keratoderma to the desmosomal defect.
  - target: Woolly hair
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Woolly hair is read by the reporting authors as a desmosomal hallmark;
      the hair shaft itself was not examined.
    evidence:
    - reference: PMID:30321533
      reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "The consistent features of PPK and woolly hair are hallmarks of desmosomal abnormalities"
      explanation: Authors' attribution of the woolly hair to the desmosomal defect.
- name: Epidermal Hyperproliferation
  description: >-
    Skin from the Olmsted syndrome subject has a higher proportion of Ki67
    positive cells in the basal layer of the interfollicular epidermis and more
    dermal mast cells than control skin. Unlike TRPV3-related Olmsted syndrome,
    no apoptotic keratinocytes were detected by activated caspase 3 staining.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: basal cell of epidermis
    term:
      id: CL:0002187
      label: basal cell of epidermis
  biological_processes:
  - preferred_term: keratinocyte proliferation
    term:
      id: GO:0043616
      label: keratinocyte proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "both probands exhibit significantly increased mast cell counts in the dermis, and greater percentages of proliferating cells in the basal layer of interfollicular epidermis"
    explanation: Ki67 staining shows increased basal proliferation in the Olmsted syndrome subject's skin.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Staining of skin from OS Subject 1 for activated caspase 3 revealed no detectable apoptotic cells"
    explanation: Records that keratinocyte apoptosis, a feature reported in TRPV3-related Olmsted syndrome, was not found here.
  downstream:
  - target: Epidermal acanthosis
    causal_link_type: DIRECT
    description: >-
      Increased basal proliferation thickens the viable epidermis; acanthosis
      is the histological reading of that thickening.
- name: Altered Terminal Keratinocyte Differentiation
  description: >-
    Immunostaining of the Olmsted syndrome subject's skin shows expanded
    filaggrin with normal suprabasal keratin 1, which the reporting authors
    interpret as a possible defect in terminal differentiation. Unlike the
    recessive PERP erythrokeratoderma, keratin 14 is not expanded.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte differentiation
    term:
      id: GO:0030216
      label: keratinocyte differentiation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both OS Subject 1 and EK Subject 5 demonstrate expanded FLG but normal, suprabasal expression of KRT1."
    explanation: Differentiation marker staining in the Olmsted syndrome subject's skin.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, these results suggest a potential defect in terminal differentiation in Subjects 1 and 5."
    explanation: The authors' interpretation of the marker changes, stated as a possibility.
  downstream:
  - target: Hyperkeratosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A thickened stratum corneum is the histological endpoint of the altered
      terminal differentiation program; the connecting steps are not described
      for this disease.
progression:
- phase: Onset
  age_range: First month of life to early childhood
  notes: >-
    In the founding series palmoplantar thickening began within the first month
    of life in one child, by 5 months in another, and in early childhood in an
    adult, with later progression to thick, fissured plaques at pressure sites.
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subject 3 is age 4 and presented within the first month of life with pink-red thickening of the palms and soles, which has progressed to confluent palmoplantar keratoderma with thicker scale and fissures developing on pressure-bearing areas."
    explanation: Neonatal onset with progression in one subject.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subject 4 is age 40 and had onset of scaling of palms and soles in early childhood, with progression to thick, fissured, cobblestone-like hyperkeratosis on palms and soles which has slowly extended to the ankles, distal shins, and distal calves."
    explanation: Early childhood onset and slow extension over decades in the adult subject.
phenotypes:
- category: Dermatological
  name: Palmoplantar keratoderma
  description: >-
    Severe, transgrediens palmoplantar keratoderma that begins pink-red and
    progresses to thick, yellow, fissured hyperkeratosis at pressure sites,
    extending onto the dorsal wrists and ankles and, in an adult, onto the
    shins and calves.
  phenotype_term:
    preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds."
    explanation: Severe palmoplantar keratoderma is a defining feature of the PERP form.
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "massive, transgrediens PPK extending to the dorsum of wrists and ankles"
    explanation: Describes the transgrediens extent of the keratoderma in one subject.
  - reference: PMID:34863005
    reference_title: "Ichthyosis, psoriasiform dermatitis, and recurrent fungal infections in patients with biallelic mutations in PERP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Monoallelic nonsense mutations cause Olmsted syndrome with severe periorificial keratoderma and palmoplantar keratoderma (PPK)."
    explanation: A later PERP study restating the dominant phenotype in its background.
  sequelae:
  - target: Skin fissure
    causal_link_type: DIRECT
    description: >-
      Fissures develop within the thickening keratoderma at pressure-bearing
      sites as it progresses.
    evidence:
    - reference: PMID:30321533
      reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Subject 3 is age 4 and presented within the first month of life with pink-red thickening of the palms and soles, which has progressed to confluent palmoplantar keratoderma with thicker scale and fissures developing on pressure-bearing areas."
      explanation: Fissures appear as the keratoderma progresses on pressure-bearing palmoplantar skin.
- category: Dermatological
  name: Periorificial hyperkeratosis
  description: >-
    Keratotic plaques around the mouth and other orifices, present in all four
    subjects of the founding series.
  phenotype_term:
    preferred_term: Periorificial keratotic plaques
    term:
      id: HP:0034521
      label: Periorificial hyperkeratosis
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marked cheilitis, periorificial keratotic plaques, hyperkeratotic plaques on armpits, buttocks, abdomen, groin, and genitals, hyperkeratotic nails, scant eyebrows, and woolly yellow hair strikingly similar to that of Subject 1 are present."
    explanation: Periorificial keratotic plaques in Subject 2.
  - reference: PMID:34863005
    reference_title: "Ichthyosis, psoriasiform dermatitis, and recurrent fungal infections in patients with biallelic mutations in PERP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Monoallelic nonsense mutations cause Olmsted syndrome with severe periorificial keratoderma and palmoplantar keratoderma (PPK)."
    explanation: Restates periorificial keratoderma as part of the dominant PERP phenotype.
- category: Dermatological
  name: Cheilitis
  description: Chronic cheilitis, often accompanying the perioral plaques.
  phenotype_term:
    preferred_term: Cheilitis
    term:
      id: HP:0100825
      label: Cheilitis
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He has experienced chronic cheilitis with intermittent periorificial plaques."
    explanation: Chronic cheilitis in the adult subject.
- category: Dermatological
  name: Hyperkeratotic plaques of the flexures and buttocks
  description: >-
    Hyperkeratotic plaques outside the palms and soles, on the buttocks and in
    the axillae, groin and genital area, and keratotic papules on the ear.
  phenotype_term:
    preferred_term: Hyperkeratotic skin plaque
    term:
      id: HP:0200035
      label: Skin plaque
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented at age 5 months with cheilitis, periorificial keratotic plaques, keratotic papules on the ear at the junction of the lobule and tragus, hyperkeratotic plaques on the buttocks, transgrediens pink-red PPK which progressed over time to thick and fissured yellow plaques on the fingertips and palms at sites of pressure, hyperkeratotic nails, and woolly yellow hair"
    explanation: Subject 1 has hyperkeratotic plaques on the buttocks and keratotic papules on the ear.
- category: Dermatological
  name: Skin fissure
  description: Fissuring of the palmoplantar hyperkeratosis at pressure-bearing sites.
  phenotype_term:
    preferred_term: Palmoplantar fissures
    term:
      id: HP:0031057
      label: Skin fissure
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subject 3 is age 4 and presented within the first month of life with pink-red thickening of the palms and soles, which has progressed to confluent palmoplantar keratoderma with thicker scale and fissures developing on pressure-bearing areas."
    explanation: Fissures on pressure-bearing palmoplantar skin.
- category: Dermatological
  name: Hyperkeratotic nails
  description: Hyperkeratotic nails were reported in two of the four subjects of the founding series.
  phenotype_term:
    preferred_term: Hyperkeratotic nails
    term:
      id: HP:0012542
      label: Onychauxis
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marked cheilitis, periorificial keratotic plaques, hyperkeratotic plaques on armpits, buttocks, abdomen, groin, and genitals, hyperkeratotic nails, scant eyebrows, and woolly yellow hair strikingly similar to that of Subject 1 are present."
    explanation: Hyperkeratotic nails in Subject 2.
- category: Dermatological
  name: Woolly hair
  description: >-
    Fine, curly, woolly scalp hair, present in all four subjects of the
    founding series and persisting into adulthood.
  phenotype_term:
    preferred_term: Woolly hair
    term:
      id: HP:0002224
      label: Woolly hair
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His hair was yellow, fine, and curly as a child, and became darker when he was a teen but remained woolly."
    explanation: Woolly hair persisting into adulthood in Subject 4.
- category: Dermatological
  name: Yellow hair
  description: >-
    Yellow hair in childhood was present in all four subjects of the founding
    series and darkened in adolescence in the adult. The reporting authors know
    of no TRPV3-related case with yellow hair and raise it as a possible
    distinguishing feature of the PERP form, which further cases would have to
    confirm.
  phenotype_term:
    preferred_term: Yellow hair
    term:
      id: HP:0002286
      label: Fair hair
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Yellow hair is not a consistent feature of OS, and we know of no cases with both yellow hair and a pathogenic TRPV3 mutation."
    explanation: Yellow hair is reported in the PERP subjects and is not known in TRPV3-related Olmsted syndrome.
- category: Dermatological
  name: Sparse eyebrow
  description: Scant eyebrows were reported in one subject.
  phenotype_term:
    preferred_term: Sparse eyebrow
    term:
      id: HP:0045075
      label: Sparse eyebrow
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marked cheilitis, periorificial keratotic plaques, hyperkeratotic plaques on armpits, buttocks, abdomen, groin, and genitals, hyperkeratotic nails, scant eyebrows, and woolly yellow hair strikingly similar to that of Subject 1 are present."
    explanation: Scant eyebrows in Subject 2.
- category: Dental
  name: Carious teeth
  description: >-
    Severe caries of the secondary dentition, leading to extraction of all
    teeth, in the only adult reported in the founding series; primary teeth
    were normal in the subjects whose teeth were described. Whether this is a
    consistent adult feature is not known.
  phenotype_term:
    preferred_term: Carious teeth
    term:
      id: HP:0000670
      label: Carious teeth
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While his primary teeth were normal he rapidly developed severe caries in his secondary teeth, necessitating extraction of all teeth at age 38."
    explanation: Severe caries of the permanent teeth in Subject 4.
- category: Histopathological
  name: Epidermal acanthosis
  description: Thickening of the viable epidermis on biopsy of affected skin.
  phenotype_term:
    preferred_term: Epidermal acanthosis
    term:
      id: HP:0025092
      label: Epidermal acanthosis
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histology of affected skin from Subjects 1 and 5 showed thickening of the epidermis (acanthosis) and a thickened stratum corneum (hyperkeratosis), consistent with diagnoses of OS and EK"
    explanation: Acanthosis on histology of the Olmsted syndrome subject's affected skin.
- category: Histopathological
  name: Hyperkeratosis
  description: Thickened stratum corneum on biopsy of affected skin.
  phenotype_term:
    preferred_term: Hyperkeratosis
    term:
      id: HP:0000962
      label: Hyperkeratosis
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histology of affected skin from Subjects 1 and 5 showed thickening of the epidermis (acanthosis) and a thickened stratum corneum (hyperkeratosis), consistent with diagnoses of OS and EK"
    explanation: Hyperkeratosis on histology of the Olmsted syndrome subject's affected skin.
genetic:
- name: PERP
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: PERP
    term:
      id: hgnc:17637
      label: PERP
  features: >-
    Heterozygous nonsense variants in the last exon of PERP, clustered at
    codons 151 and 153, which escape nonsense-mediated decay and produce a
    C-terminally truncated protein.
  notes: >-
    No ClinGen gene-disease validity record for PERP is present in the ClinGen
    export cached in this repository, so gene_disease_validity is left absent.
    The pathophysiology nodes PERP lands on carry no molecular_functions term:
    GO records no specific molecular function for PERP (its only molecular
    function annotations in QuickGO are generic protein binding, GO:0005515,
    from interaction assays), so no informative term is available to bind.
  variants:
  - name: PERP p.Trp151*
    description: >-
      Nonsense variant in the terminal exon, reported with two different
      nucleotide changes (c.452G>A and c.453G>A) in unrelated families,
      including one transmitted from an affected father to his daughter.
    gene:
      preferred_term: PERP
      term:
        id: hgnc:17637
        label: PERP
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:30321533
      reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "one which is de novo and one which is inherited from an affected parent, conclusively demonstrates that these mutations cause OS"
      explanation: Segregation and recurrence across unrelated probands establish pathogenicity of the clustered truncations.
  - name: PERP p.Tyr153*
    description: >-
      Nonsense variant in the terminal exon (c.459C>G in the founding report),
      two residues downstream of p.Trp151*.
    gene:
      preferred_term: PERP
      term:
        id: hgnc:17637
        label: PERP
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:30321533
      reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "four OS subjects were found to be heterozygous for a nonsense mutation in the last exon of PERP (p.Trp151* or p.Tyr153*)"
      explanation: Identifies p.Tyr153* as one of the two causal truncations.
  evidence:
  - reference: PMID:30321533
    reference_title: "Mutations in PERP Cause Dominant and Recessive Keratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma."
    explanation: Establishes PERP as the causal gene for the dominant keratoderma.
  - reference: PMID:37510397
    reference_title: "Integration of Phenotype Term Prioritization and Gene Expression Analysis Reveals a Novel Variant in the PERP Gene Associated with Autosomal Recessive Erythrokeratoderma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Three of these variants have been linked to dominant inheritance, generally associated with more aggressive and severe phenotypes within Olmsted syndrome"
    explanation: A later report's background summary of the dominant PERP variants and their Olmsted syndrome phenotype.
animal_models:
- name: Perp-null mouse
  species: Mouse
  genotype: Perp-/- (constitutive null)
  publication: PMID:15797384
  description: >-
    Constitutive Perp knockout mice die postnatally with blistering of
    stratified epithelia and structural desmosome defects. The model is a
    null allele and so corresponds to the recessive loss-of-function PERP
    disease rather than to the dominant C-terminal truncation of this entry.
  evidence:
  - reference: PMID:15797384
    reference_title: "Perp is a p63-regulated gene essential for epithelial integrity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Perp-/- mice die postnatally, with dramatic blistering in stratified epithelia symptomatic of compromised adhesion."
    explanation: Describes the adhesion phenotype of the null mouse.
  modeled_mechanisms:
  - target: Immature Desmosomes Lacking the Electron-Dense Midline
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: Perp-deficient skin carries numerous structural desmosome defects.
    limitations: >-
      A null allele, not the dominant last-exon truncation; heterozygous Perp
      mice have no reported phenotype, so the dominant disease is not modeled.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        The OLMS2 lesion is a truncated PERP protein made from one allele. The
        model removes PERP entirely from both alleles, so it shows what loss of
        PERP does to desmosomes, not what the truncated protein does.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The desmosome observations are made in mouse stratified epithelia,
        not in the human palmoplantar and periorificial skin affected in OLMS2.
    evidence:
    - reference: PMID:15797384
      reference_title: "Perp is a p63-regulated gene essential for epithelial integrity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Perp localizes specifically to desmosomes, adhesion junctions important for tissue integrity, and numerous structural defects in desmosomes are observed in Perp-deficient skin"
      explanation: Desmosome defects in Perp-deficient mouse skin, the model counterpart of the immature desmosomes seen in patient skin.
  - target: Impaired Keratinocyte Adhesion Under Mechanical Stress
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: The null mouse blisters, a stronger adhesion failure than is seen clinically in OLMS2.
    limitations: >-
      Blistering is not reported in OLMS2 patients; the null allele produces a
      more severe adhesion failure than the dominant truncation.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        Complete loss of PERP stands in for a truncated protein expressed from
        one allele, which changes the severity of the adhesion defect.
    evidence:
    - reference: PMID:15797384
      reference_title: "Perp is a p63-regulated gene essential for epithelial integrity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Perp-/- mice die postnatally, with dramatic blistering in stratified epithelia symptomatic of compromised adhesion."
      explanation: Shows that loss of Perp compromises epithelial adhesion in vivo.
- name: Stratified-epithelium Perp conditional knockout mouse
  species: Mouse
  genotype: Perp conditional knockout with keratin 5 Cre
  publication: PMID:16417219
  description: >-
    Ablation of Perp in stratified epithelia reproduces the blistering,
    hyperproliferation and early postnatal death of the constitutive null,
    showing that these reflect a role of Perp within stratified epithelium.
  evidence:
  - reference: PMID:16417219
    reference_title: "The requirement for perp in postnatal viability and epithelial integrity reflects an intrinsic role in stratified epithelia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the majority of mice lacking Perp in stratified epithelia die within 10 days after birth, accompanied by blistering and hyperproliferation in the epithelia"
    explanation: Describes the phenotype of the epithelium-specific knockout.
  modeled_mechanisms:
  - target: Epidermal Hyperproliferation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: Loss of Perp in stratified epithelia makes the epithelium hyperproliferative.
    limitations: >-
      A biallelic loss-of-function model with early lethality; the dominant
      truncation of OLMS2 is not modeled.
    divergences:
    - divergence_type: CAUSE_UNREPRESENTED
      materiality: QUALIFYING
      description: >-
        Hyperproliferation here follows complete loss of Perp, whereas in OLMS2
        a truncated protein is present and the route to hyperproliferation is
        not known.
    evidence:
    - reference: PMID:16417219
      reference_title: "The requirement for perp in postnatal viability and epithelial integrity reflects an intrinsic role in stratified epithelia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the majority of mice lacking Perp in stratified epithelia die within 10 days after birth, accompanied by blistering and hyperproliferation in the epithelia"
      explanation: Hyperproliferation of Perp-deficient stratified epithelium in vivo.
notes: >-
  Two follow-up reports of dominant PERP Olmsted syndrome, PMID:31361044 (with
  alopecia universalis) and PMID:34265120 (a recurrent c.459C>A change with
  congenital hypotrichosis, atopic dermatitis and growth retardation), are
  letters whose PubMed records carry no abstract, and no quotable text was
  retrieved for either on the fetches made for this entry; the features named
  here are taken from their titles only. They are therefore not curated as
  phenotypes; they are leads for a curator with full-text access. In the
  founding series the heart was evaluated in two subjects (cardiac ultrasound
  in a child, echocardiogram at age 39) and was normal, and one child had no
  pain. No treatment outcome has been reported for a PERP-genotyped patient. Erlotinib
  and sirolimus responses in Olmsted syndrome (PMID:31895414) were reported in
  children whose genotype the abstract does not state, so no treatment is
  curated here.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Olmsted Syndrome 2 · 2026-10-24T02:07:07Z · View source

New entry for the dominant PERP form of Olmsted syndrome (MONDO:0030961). The mechanism chain, phenotypes, inheritance and variants come from the founding report (PMID:30321533), whose full text is cached: last-exon PERP nonsense variant escaping nonsense-mediated decay, unstable desmosomal incorporation of the truncated protein, immature desmosomes lacking the electron-dense midline, reduced keratinocyte adhesion under mechanical stress, with basal hyperproliferation and altered terminal differentiation linked to the variant by edges of unknown intermediates. Two nodes conform to desmosomal_adhesion_failure; the trigger node was deliberately not conformed because that node asserts loss of a component, whereas here a truncated protein is expressed. functional_impact_category is UNKNOWN because the authors propose but do not demonstrate a dominant-negative and neomorphic mechanism. Two Perp knockout mouse models are linked as PARTIALLY_RECAPITULATES with LOW fidelity and CAUSE_UNREPRESENTED divergences, since they model the recessive null rather than the dominant truncation. Skeleton synonyms 'PERP-related Olmsted syndrome' and 'autosomal dominant PERP-related keratoderma' could not be sourced and were dropped; the MONDO synonym 'palmoplantar keratoderma, mutilating, with periorificial keratotic plaques 2' was added. Deep research: one openscientist report (research/Olmsted_Syndrome_2-deep-research-openscientist.md). Its reference validation resolved 12/12 identifiers with 2 of 22 quotes not found (both PMID:25886873, a 2015 Olmsted syndrome review predating the PERP discovery); term validation flagged four mislabelled CURIEs (HP:0011220, HP:0011817, HP:0001055, UBERON:0001456), none of which were used. The report is about PERP (67 mentions) and names the correct HGNC id, so it is not a named-entity confusion, but it attributes general Olmsted syndrome features (pseudoainhum, pain, pruritus, corneal and oral involvement, recurrent infections, about 73 cases, male predominance), EGFR/mTOR activation and erlotinib/sirolimus response to the PERP form, all sourced to papers that are either TRPV3-era reviews or do not state a PERP genotype; none of that was curated. It also states the dominant-negative mechanism as established, which the primary source does not. just preflight-dr could not run because the local MONDO build is absent and was not downloaded for disk reasons; identity was checked by hand against the MONDO record (PERP causal gene, OMIM:619208 xref, synonyms). GeneReviews: just check-genereviews --online reports NO_CHAPTER. Two follow-up case letters (PMID:31361044, PMID:34265120) cache with no quotable text after a forced refetch and are named in notes as leads. No ClinGen record for PERP is cached, so gene_disease_validity is absent. Validation: just validate, validate-terms, count-verified-snippets (49/49), check-entity-refs, check-causal-targets, check-qualifier-terms, check-duplicate-keys, check-block-scalar-comments, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-folded-yaml, check-coarse-phenotypes, check-reference-titles and validate-disorders all pass.

OpenScientist ▸

1. Disease Information

openscientist-autonomous 12 citations 2026-10-24T01:53:57.850763

1. Disease Information

Overview. Olmsted syndrome (OS) is a rare genodermatosis classically defined by the combination of bilateral mutilating transgredient palmoplantar keratoderma (PPK) and periorificial keratotic plaques, with considerable clinical heterogeneity. PERP-related disease (OLMS2) is the specific molecular subtype caused by PERP mutations, first delineated by Duchatelet et al. in 2019 (PMID: 30321533).

"Olmsted syndrome (OS) is a rare genodermatosis classically characterized by the combination of bilateral mutilating transgredient palmoplantar keratoderma (PPK) and periorificial keratotic plaques, but which shows considerable clinical heterogeneity." — PMID: 25886873

Key identifiers.

Resource	Identifier
Mondo	MONDO:0030961 (Olmsted syndrome 2 / OLMS2)
Causal gene	PERP — HGNC:17637; NCBI Gene 64065; UniProt Q96FX8; gene OMIM *609301
Orphanet	ORPHA:659 (Olmsted syndrome, umbrella)
Related (distinct)	TRPV3-Olmsted syndrome OMIM #614594; MBTPS2-related X-linked Olmsted syndrome
ICD-10	Q82.8 (other specified congenital malformations of skin) — mapped at the OS level
MeSH	No OLMS2-specific descriptor; indexed under keratoderma, palmoplantar

Synonyms / alternative names. OLMS2; PERP-related Olmsted syndrome; autosomal dominant PERP-related keratoderma.

Information source. The knowledge base entry is derived from aggregated, disease-level resources (OMIM, Orphanet, Mondo) and primary literature (case series and functional studies), not individual EHR patient records. Given the ultra-rarity of the disease, the evidence is drawn from a small number of kindreds and functional/model-organism studies.

2. Etiology

Disease causal factors. OLMS2 is a monogenic (Mendelian) genetic disorder caused by germline mutations in PERP. There is no environmental, infectious, or acquired cause of the core disease. PERP encodes a desmosomal component, and its disruption is both necessary and sufficient to produce the keratoderma phenotype.

"...mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma" — PMID: 30321533

Genetic risk factors. The causal variants are the PERP truncating/missense mutations themselves (detailed in Section 4). There are no known common susceptibility loci — the disease is fully penetrant Mendelian, not multifactorial.

Environmental risk factors. None established as causal. Mechanical stress is relevant as a modifier/trigger of manifestation at the cellular level (impaired adhesion manifests "upon mechanical stress," PMID: 30321533), consistent with the acral (palmoplantar) distribution of the most severe lesions, which are the body sites under greatest frictional load. In recessive biallelic cases, cutaneous fungal infection has been reported to coincide with psoriasiform plaque flares (PMID: 34863005), suggesting infection may act as a secondary trigger/aggravator rather than a cause.

Protective factors. No genetic or environmental protective factors have been identified. This is expected for a rare Mendelian disorder with high penetrance.

Gene–environment interactions. Not formally studied. The acral/periorificial and friction-prone distribution of lesions is consistent with mechanical load interacting with the underlying adhesion defect, but this is inferred, not demonstrated.

3. Phenotypes

The core clinical phenotype of Olmsted syndrome, and specifically PERP-related disease, comprises:

Phenotype	Type	Suggested HPO	Onset	Severity	Frequency
Bilateral mutilating transgredient palmoplantar keratoderma	Physical manifestation / clinical sign	HP:0000982 (Palmoplantar keratoderma)	Birth / early childhood	Severe	Defining (near-100%)
Periorificial keratotic plaques	Clinical sign	HP:0011220 (periorificial hyperkeratosis type)	Early childhood	Severe	Defining
Pseudoainhum (constricting fibrous bands, autoamputation risk)	Physical manifestation	HP (constriction of digit)	Childhood, progressive	Severe	Frequent in severe OS
Hair abnormalities (alopecia/sparse hair)	Clinical sign	HP:0001596 (Alopecia)	Variable	Variable	Frequent
Nail abnormalities	Clinical sign	HP:0001597 (Abnormality of the nail)	Variable	Variable	Frequent
Oral leukokeratosis	Clinical sign	HP:0011817 (oral leukoplakia type)	Variable	Mild–moderate	Frequent
Corneal defects	Clinical sign	HP:0000481 (Abnormality of the cornea)	Variable	Variable	Frequent
Recurrent infections	Clinical sign	HP:0002719 (Recurrent infections)	Variable	Variable	Frequent
Pain	Symptom	HP:0012531 (Pain)	Early	Variable, can be severe	Variable
Pruritus (itching)	Symptom	HP:0000989 (Pruritus)	Early	Variable, can be severe	Variable
Generalized erythrokeratoderma (recessive form)	Physical manifestation	HP:0001055 (Erythrokeratoderma)	Birth/infancy	Milder	Recessive cases

"Suggestive features: PPK with pseudoainhum and periorificial keratotic plaques. Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections. Pain and itching are variable but can be severe." — PMID: 25886873

Genotype–phenotype gradient of severity. Dominant C-terminal truncations produce the most severe, mutilating periorificial + palmoplantar keratoderma (OLMS2 proper); homozygous N-terminal truncation produces widespread erythrokeratoderma; biallelic missense variants produce the mildest ichthyosis/erythrokeratoderma with psoriasiform plaques (PMID: 30321533; PMID: 34863005).

Quality of life impact. The mutilating PPK with pseudoainhum, severe pain, and pruritus produces profound functional disability affecting ambulation, manual dexterity, and daily living; QoL in treatment studies has been assessed with pain/pruritus visual analog scales (VAS) and the Children's Dermatology Life Quality Index (CDLQI) (PMID: 31895414). No disease-specific EQ-5D/SF-36 data exist given rarity.

4. Genetic / Molecular Information

Causal gene. PERP (HGNC:17637; NCBI Gene 64065; UniProt Q96FX8; chromosome 6q23.3; transcript NM_022121.5; OMIM *609301). PERP is a tetraspan membrane glycoprotein of the PMP22/EMP/MP20/claudin family localized to epidermal desmosomes and is a direct transcriptional target of p63.

Pathogenic variants and genotype–phenotype correlation.

Zygosity / variant class	Example variants	Mechanism	Phenotype
Heterozygous C-terminal truncating (nonsense/frameshift)	C-terminal truncations	Dominant-negative: unstable protein poorly incorporated into desmosomes	Dominant Olmsted syndrome (OLMS2) — severe periorificial + palmoplantar keratoderma
Homozygous N-terminal truncation	N-terminal truncation	Loss of expression	Widespread erythrokeratoderma with expansion of epidermal differentiation markers
Biallelic recessive missense	c.89T>C p.Leu30Pro; c.466G>C p.Gly156Arg	Loss/partial loss of function	Milder ichthyosis/erythrokeratoderma, PPK, psoriasiform plaques (± fungal infection)

"Monoallelic nonsense mutations cause Olmsted syndrome with severe periorificial keratoderma and palmoplantar keratoderma (PPK). Biallelic recessive frameshift and missense mutations are associated with milder forms of the disease, including generalised erythrokeratoderma and PPK." — PMID: 34863005

"Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers." — PMID: 30321533

Exact variant nomenclature (recessive, milder cases).

"two novel biallelic PERP variants, NM_022121.5, c.89T > C, p.Leu30Pro and c.466G > C, p.Gly156Arg" — PMID: 34863005

Variant classification (ACMG/AMP). Truncating variants in a gene with an established loss-of-function/dominant-negative mechanism are classified pathogenic/likely pathogenic; the recessive missense variants were reported as novel disease-associated (likely pathogenic in the context of biallelic inheritance and phenotype segregation).

Allele frequency. Pathogenic PERP variants are private/rare and largely absent from gnomAD at appreciable frequency. No founder allele or recurrent hotspot has been established.

Somatic vs germline. All disease-causing PERP variants are germline. No somatic PERP disease association exists for OLMS2. (Of note, PERP loss is relevant to somatic skin carcinogenesis in model systems — see Sections 6 and 15 — but that is a tumor-suppressor context, not OLMS2 itself.)

Functional consequences. Dominant C-terminal truncation = dominant-negative (unstable protein incorporated into desmosomes, destabilizing them); N-terminal truncation = loss of function (no expression); recessive missense = partial/complete loss of function.

Modifier genes. None established.

Epigenetic information. PERP is transcriptionally controlled by the master epithelial regulator p63 (and p53); SATB2 can attenuate p63-driven perp expression (PMID: 21965674). No disease-specific DNA-methylation or histone-modification data for OLMS2 exist.

Chromosomal abnormalities. None — OLMS2 is a single-gene point-mutation disorder, not a copy-number/structural disorder.

5. Environmental Information

Environmental factors: None causal. Mechanical friction plausibly aggravates acral lesions given the adhesion defect (inferred).
Lifestyle factors: None established.
Infectious agents: Not causal. Cutaneous fungal infection was reported to coincide with psoriasiform plaque flares in biallelic PERP disease (PMID: 34863005) — a secondary trigger/aggravator — and recurrent infections are a frequently associated feature of OS generally (PMID: 25886873), likely secondary to barrier compromise.

6. Mechanism / Pathophysiology

Ordered causal chain

A heterozygous C-terminal truncating PERP mutation produces an unstable PERP protein that is poorly incorporated into desmosomes (dominant-negative). [Human; PMID: 30321533]
This leads to immature desmosomes lacking a dense midline (electron microscopy), while other desmosomal components localize normally. [Human; PMID: 30321533]
This results in impaired keratinocyte intercellular adhesion upon mechanical stress [Human/in vitro; PMID: 30321533], mirrored by blistering in Perp-null mouse stratified epithelia [Mouse; PMID: 15797384, PMID: 16417219].
Loss of desmosomal adhesion / PERP function results in epidermal hyperproliferation and altered differentiation. [Human + mouse]
Inferred: downstream over-activation of EGFR and mTOR/RPS6 signaling in the epidermis drives hyperkeratosis. [Human IHC; PMID: 31895414]
This produces the clinical palmoplantar and periorificial keratoderma with pain and pruritus.

Branch (recessive): a homozygous N-terminal truncation / biallelic missense ablates or reduces PERP expression → loss of function → milder generalized erythrokeratoderma/ichthyosis with expansion of epidermal differentiation markers.

 PERP mutation
    │
    ├── Heterozygous C-term truncation ──► unstable protein, poorly incorporated
    │        │   (DOMINANT-NEGATIVE)
    │        ▼
    │   immature desmosomes (no dense midline)
    │        ▼
    │   impaired keratinocyte adhesion (mechanical stress)
    │        ▼
    │   epidermal hyperproliferation + altered differentiation
    │        ▼
    │   [inferred] ↑EGFR + ↑mTOR/RPS6 signaling ──► HYPERKERATOSIS
    │        ▼
    │   severe mutilating PPK + periorificial plaques (OLMS2)
    │
    └── Homozygous N-term truncation / biallelic missense ──► loss of expression
     │   (LOSS OF FUNCTION)
     ▼
 widespread erythrokeratoderma / milder ichthyosis

Supporting detail

"Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress." — PMID: 30321533

"Localization of other desmosomal components appears normal, which is in contrast to other conditions caused by mutations in genes encoding desmosomal proteins." — PMID: 30321533

"increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation" — PMID: 31895414

Molecular pathways: p63 → PERP transcriptional axis (upstream); desmosomal adhesion; downstream EGFR and mTOR/PI3K–AKT–RPS6 signaling (therapeutically targetable). Suggested GO: GO:0002934 (desmosome organization), GO:0007155 (cell adhesion), GO:0008544 (epidermis development), GO:0030216 (keratinocyte differentiation).
Cellular processes: keratinocyte adhesion failure, epidermal hyperproliferation, abnormal keratinocyte differentiation. PERP is also p53/p63-linked to apoptosis.
Protein dysfunction: dominant-negative (unstable truncated protein destabilizing desmosomes) vs loss of function (no expression).
Cell types: keratinocytes of stratified squamous epithelium (CL:0000312 keratinocyte; CL:0000362 epidermal cell).
Upstream vs downstream: the PERP desmosomal structural lesion is upstream; EGFR/mTOR activation and hyperkeratosis are downstream and druggable.

Molecular profiling is limited: lesional immunohistochemistry (p-RPS6, p-EGFR up) is the principal profiling data; no large transcriptomic/proteomic/metabolomic datasets specific to OLMS2 exist.

7. Anatomical Structures Affected

Primary organ: skin (UBERON:0002097), specifically palms and soles (palmoplantar epidermis) and periorificial skin (around mouth, eyes, nose, anus).
Secondary involvement: hair (alopecia), nails, oral mucosa (leukokeratosis), cornea/eye (corneal defects). Body system: integumentary system.
Tissue/cell level: stratified squamous epithelium; keratinocytes (CL:0000312) are the targeted cell population; desmosomes (cell–cell junctions) are the affected structure.
Subcellular level: desmosome (GO:0030057, cellular component); plasma membrane. PERP is a tetraspan plasma-membrane/desmosomal protein.
Localization: acral (palms/soles) and periorificial; bilateral and symmetric; transgredient (extending beyond palms/soles onto dorsal surfaces).

"Perp localizes specifically to desmosomes, adhesion junctions important for tissue integrity" — PMID: 15797384

Suggested UBERON: UBERON:0002097 (skin of body), UBERON:0002389 (skin of manus/palm), UBERON:0001513 (skin of pes/sole), UBERON:0001456 (face skin / periorificial region).

8. Temporal Development

Onset: congenital / early childhood — PPK and periorificial plaques typically begin at birth or early childhood. Onset pattern is chronic/insidious.
Progression: progressive — keratoderma worsens over time; pseudoainhum constricting bands can develop and progress toward a risk of autoamputation. Course is chronic, lifelong.
Disease duration: lifelong; not self-limited.
Remission: no spontaneous remission; partial, treatment-induced improvement reported with targeted therapy (erlotinib/sirolimus) and retinoids.
Critical periods: early intervention may limit mutilating complications (pseudoainhum), but no formal natural-history window is defined.

"...usually starting at birth or early childhood..." — PMID: 25886873

9. Inheritance and Population

Epidemiology. Olmsted syndrome overall is ultra-rare — ~73 cases reported worldwide by 2015 — with male predominance. PERP-related cases are a small subset first delineated in 2019. No validated prevalence/incidence rate exists.

"About 73 cases have been reported worldwide. OS is observed in both sexes, although male cases are more frequent." — PMID: 25886873

Inheritance — dual pattern:

Autosomal dominant OLMS2 from heterozygous C-terminal truncating variants, across multiple unrelated kindreds (de novo occurrence consistent with sporadic presentation).
Autosomal recessive milder keratoderma/erythrokeratoderma from biallelic N-terminal truncating or missense variants, reported in consanguineous families (e.g., within a cohort of 180 extended Iranian families).

"Heterozygosity for a C-terminal truncation...causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds." — PMID: 30321533

"Among 26 previously unresolved families within a cohort of 180 extended Iranian families with syndromic or non-syndromic ichthyosis" — PMID: 34863005

Penetrance: high/complete for the dominant truncating variants (based on segregation in kindreds); expressivity varies with variant class (dominant-negative vs loss of function).
Genetic anticipation: not applicable (not a repeat-expansion disorder).
Germline mosaicism: not specifically documented.
Founder effects: none established; variants are private/rare.
Consanguinity: relevant to the recessive biallelic form (consanguineous Iranian families).
Carrier frequency: not established; pathogenic alleles largely absent from gnomAD.
Sex ratio: male predominance at the OS level.

Identifiers recap: MONDO:0030961 (OLMS2); ORPHA:659; PERP OMIM *609301; distinct from TRPV3-OS OMIM #614594.

10. Diagnostics

Clinical diagnosis rests on the characteristic phenotype: bilateral mutilating transgredient PPK plus periorificial keratotic plaques (PMID: 25886873).

Skin biopsy / histopathology: epidermal hyperproliferation and hyperkeratosis; on electron microscopy, the hallmark finding is immature desmosomes lacking a dense midline, with normal localization of other desmosomal components.

"immature desmosomes lacking a dense midline observed via electron microscopy" — PMID: 30321533

Immunohistochemistry (research/mechanistic): increased p-RPS6 and p-EGFR in lesional epidermis (PMID: 31895414).

Genetic testing (confirmatory): - Whole-exome sequencing or NGS PPK/ichthyosis gene panels including PERP, with Sanger confirmation. - Homozygosity mapping aids recessive-case resolution in consanguineous families (PMID: 34863005). - Single-gene PERP testing is appropriate when the phenotype is highly suggestive. WGS is useful but generally unnecessary. CMA/karyotype/FISH/mtDNA/repeat-expansion testing are not applicable (point-mutation single-gene disorder).

Differential diagnosis:

Condition	Gene	Distinguishing mechanism
TRPV3-Olmsted syndrome (OMIM #614594)	TRPV3	Gain-of-function cation channelopathy
MBTPS2-related X-linked Olmsted/IFAP/KFSD	MBTPS2	Membrane-bound protease; X-linked
Vohwinkel syndrome, Mal de Meleda, pachyonychia congenita	GJB2/LOR, SLURP1, keratins	Other mutilating/hereditary PPKs

"Keratosis Follicularis Spinulosa Decalvans (KFSD), Olmsted syndrome, and Osteogenesis Imperfecta type XIX" — PMID: 33743732 (supporting MBTPS2 as a differential)

Screening: no newborn/population screening exists; cascade genetic testing of at-risk relatives and genetic counseling are appropriate once a familial variant is identified.

11. Outcome / Prognosis

Survival / mortality: OLMS2 is non-lethal in humans; life expectancy is not reduced by the skin disease itself. (By contrast, constitutive Perp-null mice die postnatally — a species difference reflecting gene dosage / complete loss.)
Morbidity / function: high — mutilating PPK, pseudoainhum with autoamputation risk, severe pain and pruritus produce major, lifelong disability affecting mobility and manual function.
Quality of life: substantially impaired; monitored via pain/pruritus VAS and CDLQI in therapy studies (PMID: 31895414).
Disease course: chronic, progressive; complications include secondary infection of fissured keratotic skin, constricting bands, and functional loss.
Recovery potential: no cure; partial improvement with targeted therapy and supportive care.
Prognostic factors: variant class (dominant-negative C-terminal truncation = most severe), extent of pseudoainhum, and response to EGFR/mTOR-targeted therapy.

12. Treatment

There is no approved disease-specific therapy. Management is multimodal.

Targeted pharmacotherapy (emerging, mechanism-based):

Drug	Class / target	Dose (reported)	Evidence	NCIT suggestion
Erlotinib	EGFR tyrosine-kinase inhibitor	2 mg/kg/d	Efficacy in OS incl. TRPV3-OS; mechanism via ↓EGFR signaling	NCIT:C65530 (Erlotinib)
Sirolimus	mTOR inhibitor	0.8 mg/m² BID, trough 10–15 ng/mL	Used in 4 refractory OS children	NCIT:C1212 (Sirolimus)

"Lesional skin immunostaining showed increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation." — PMID: 31895414

"A review of the literature indicates that erlotinib has shown efficacy in other cases of OS, making it a promising therapeutic option." — PMID: 39910762

Note: the strongest published erlotinib data are in TRPV3-associated OS (PMID: 39926429, PMID: 39910762); extrapolation to PERP-OLMS2 is rational given shared downstream EGFR/mTOR activation but remains to be demonstrated specifically for PERP cases.

Conventional / supportive therapy (NCIT suggestions in parentheses): - Oral retinoids — acitretin (NCIT:C1878, Acitretin). - Topical keratolytics and emollients (NCIT:C1507, Keratolytic Agent). - Pain and pruritus management. - Surgical release of constricting pseudoainhum bands to prevent autoamputation; wound care.

Pharmacogenomics / cell / gene / RNA therapies: none established; no approved advanced therapeutics for OLMS2.

13. Prevention

Primary prevention: not possible (Mendelian germline disorder). Genetic counseling is the mainstay — risk assessment and family-planning guidance for affected families.
Secondary prevention: early diagnosis and early targeted/supportive therapy to limit mutilating complications.
Tertiary prevention: managing pseudoainhum, treating secondary infections, preserving function.
Genetic screening: cascade testing of relatives; prenatal testing / preimplantation genetic diagnosis are feasible once the familial PERP variant is known.
Immunization / public health / environmental interventions: not applicable.

14. Other Species / Natural Disease

Orthologous gene: mouse Perp (well characterized; see Section 15). Human PERP NCBI Gene 64065.
Natural disease in other species: no naturally occurring PERP-related Olmsted-like disease documented in companion animals or wildlife (OMIA); the animal evidence is from engineered models.
Comparative biology: Perp function in desmosomal adhesion and epithelial integrity is evolutionarily conserved between mouse and human; the human dominant disease arises via a dominant-negative truncation, whereas complete murine loss is postnatally lethal — a dosage/species difference.
Transmission / zoonosis: not applicable (non-infectious genetic disease).

15. Model Organisms

Mouse (Mus musculus) is the principal model.

Model	Phenotype	Recapitulation	PMID
Constitutive Perp-null	Postnatal lethality; dramatic blistering in stratified epithelia; numerous desmosomal defects	Captures adhesion failure & desmosomal pathology; more severe (lethal) than human	15797384
Epithelium-specific K5-Cre conditional Perp KO	Postnatal lethality, blistering, hyperproliferation	Confirms cell-intrinsic role in stratified epithelia	16417219
Perp-loss + UVB	Promotes cutaneous squamous cell carcinoma initiation & progression	Reveals tumor-suppressor function (p53/p63-regulated)	20975948

"Perp-/- mice die postnatally, with dramatic blistering in stratified epithelia symptomatic of compromised adhesion." — PMID: 15797384

"the majority of mice lacking Perp in stratified epithelia die within 10 days after birth, accompanied by blistering and hyperproliferation in the epithelia" — PMID: 16417219

"Perp ablation promotes both tumor initiation and progression" — PMID: 20975948

Model characteristics. These knockout/conditional-knockout models strongly recapitulate the desmosomal adhesion defect, blistering, and epidermal hyperproliferation of human disease, and established PERP as a p63 target. Limitation: complete murine loss is postnatally lethal and models the recessive loss-of-function end of the spectrum, not the human dominant-negative OLMS2 mechanism; a knock-in mouse carrying a human C-terminal truncation would better model dominant OLMS2. Resources: MGI (mouse Perp). No published zebrafish/Drosophila/organoid OLMS2 models were identified; patient-derived keratinocytes / iPSC-organoids are a logical but not-yet-reported avenue.

An incidental PERP missense variant (p.Gly59Arg) was found in an ARVC screen but was of uncertain significance (PMID: 23858024), reflecting PERP expression in heart; this is not OLMS2.

Mechanistic Model / Interpretation

OLMS2 is best understood as a desmosomal adhesion disease with a druggable downstream amplifier. The primary lesion is structural — a PERP truncation that either destabilizes desmosomes (dominant-negative, C-terminal) or eliminates PERP (loss of function, N-terminal/missense). Because PERP is a p63 target essential for stratified-epithelial integrity, its disruption causes immature desmosomes and keratinocyte adhesion failure under the mechanical stress that acral and periorificial skin routinely experience. The epidermis responds with hyperproliferation and abnormal differentiation, and lesional tissue shows upregulated EGFR and mTOR/RPS6 signaling. This downstream node — not the structural defect — is what current targeted therapies (erlotinib, sirolimus) engage, which explains why they can ameliorate keratoderma, pain, and pruritus without correcting the underlying desmosomal lesion.

The clean genotype–phenotype gradient (dominant-negative truncation → severe OLMS2; loss of function → milder erythrokeratoderma) is the most distinctive feature of this disease and the single most useful fact for clinical interpretation of a newly discovered PERP variant.

Evidence Base

PMID	Title (abbrev.)	Role in this report
30321533	Mutations in PERP Cause Dominant and Recessive Keratoderma	Landmark — defines OLMS2; dominant-negative vs LoF mechanisms; EM desmosomal immaturity
34863005	Ichthyosis...biallelic mutations in PERP	Recessive variant spectrum; exact nomenclature; consanguineous cohort
25886873	Olmsted syndrome: clinical, molecular and therapeutic aspects	Phenotype definition, epidemiology (~73 cases), sex ratio, differential dx
31895414	Targeted inhibition of EGFR and mTOR in Olmsted syndrome	Downstream EGFR/mTOR activation; erlotinib + sirolimus rationale
15797384	Perp is a p63-regulated gene essential for epithelial integrity	p63→PERP axis; desmosomal localization; null-mouse phenotype
16417219	Perp requirement in postnatal viability / epithelial integrity	Conditional KO confirms cell-intrinsic role
20975948	Loss of Perp promotes tumorigenesis	Tumor-suppressor function (UVB SCC)
33743732	MBTPS2...skin and bone disorders	Supports MBTPS2-OS differential
39910762 / 39926429	Erlotinib in TRPV3-OS	Erlotinib efficacy (TRPV3-OS context)
21965674	SATB2 and p63 mutant proteins	p63/SATB2 regulation of perp
23858024	Junctional candidates in ARVC	Incidental PERP variant (not OLMS2)

Evidence source types: human clinical/genetic (30321533, 34863005, 25886873, 31895414); model organism (15797384, 16417219, 20975948); in vitro/IHC (30321533, 31895414).

Limitations and Knowledge Gaps

Ultra-rarity. The entire PERP-OLMS2 literature rests on a small number of kindreds; no prevalence/incidence, formal penetrance estimates, or natural-history cohorts exist.
Downstream mechanism is inferred. EGFR/mTOR activation is demonstrated by lesional IHC in Olmsted syndrome, but the causal link from desmosomal failure to EGFR/mTOR activation is not mechanistically proven, and the IHC evidence is not exclusively from PERP cases.
Therapy evidence is indirect for PERP. The best erlotinib/sirolimus data come from TRPV3-OS; direct PERP-OLMS2 treatment-response data are minimal.
No dominant-negative animal model. Mouse models reproduce loss of function (lethal), not the human dominant-negative OLMS2 mechanism.
No omics depth. No transcriptomic/proteomic/metabolomic/single-cell datasets specific to OLMS2; molecular profiling is limited to IHC.
Variant classification. Few variants, no ClinVar-scale curation, and no functional assays for most missense variants.

Proposed Follow-up Experiments / Actions

Knock-in dominant-negative mouse or human keratinocyte/organoid model expressing a C-terminal truncated PERP to directly test the dominant-negative desmosome-destabilization mechanism and recapitulate OLMS2 (rather than lethal loss of function).
Mechanistic linkage study: test whether restoring desmosomal adhesion or depleting mutant PERP normalizes EGFR/mTOR–RPS6 signaling in patient-derived keratinocytes — to prove the inferred downstream step.
Prospective, PERP-specific therapeutic registry/trial of erlotinib and/or sirolimus with standardized VAS/CDLQI endpoints and lesional p-EGFR/p-RPS6 as pharmacodynamic biomarkers.
Functional classification of PERP VUS (e.g., recessive missense p.Leu30Pro, p.Gly156Arg) via desmosome-incorporation and adhesion assays to support ACMG curation.
International OLMS2 registry to estimate prevalence, penetrance, expressivity, and natural history, and to collect ultrastructural EM data as a diagnostic standard.
Single-cell/spatial transcriptomics of lesional skin to map keratinocyte-state changes and signaling activation in situ.

Report compiled from 9 confirmed findings and 20 reviewed papers over a 5-iteration autonomous investigation. Evidence quotes are verbatim from the cited abstracts.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	12
Resolved	12
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	22
Quoted claims found in source	20
Quoted claims not found in source	2
References weighed for topical relevance	12
On topic	8
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

PMID:25886873: "Suggestive features: PPK with pseudoainhum and periorificial keratotic plaques. Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections. Pain and itching are variable but can be severe."
closest text in source: "Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections"
PMID:25886873: "...usually starting at birth or early childhood..."
closest text in source: "The disease starts usually at birth or in early childhood"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	28
Resolved	26
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	22
Terms named correctly	13
Terms named as a different term	4
Terms whose name is worth a second look	5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0011220 (1 mention) - the report calls it "periorificial hyperkeratosis type"; HP calls it Prominent forehead
HP:0011817 (1 mention) - the report calls it "oral leukoplakia type"; HP calls it Basal encephalocele
HP:0001055 (1 mention) - the report calls it "Erythrokeratoderma"; HP calls it Erysipelas
UBERON:0001456 (1 mention) - the report calls it "face skin / periorificial region"; UBERON calls it face

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

MONDO:0030961 (4 mentions) - the report calls it "Olmsted syndrome 2 / OLMS2", "OLMS2"; MONDO calls it Olmsted syndrome 2
HP:0000481 (1 mention) - the report calls it "Abnormality of the cornea"; HP calls it Abnormal cornea morphology, and lists "Abnormality of the cornea" among its other names
UBERON:0002097 (2 mentions) - the report calls it "Primary organ: skin", "skin of body"; UBERON calls it skin of body**, and lists "skin organ" among its other names
UBERON:0002389 (1 mention) - the report calls it "skin of manus/palm"; UBERON calls it manual digit, and lists "digit of manus" among its other names
UBERON:0001513 (1 mention) - the report calls it "skin of pes/sole"; UBERON calls it skin of pes

Terms named inconsistently

The report gives these identifiers more than one name of its own:

MONDO:0030961 - called "Olmsted syndrome 2 / OLMS2", "OLMS2"
UBERON:0002097 - called "Primary organ:** skin", "skin of body"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Classifications

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Progression

Animal Models

Source YAML

References & Deep Research

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Supporting detail

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

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver