Skin Fragility-Woolly Hair Syndrome

Genetic MONDO:0011882 Pathograph 6 Show in embeddings browser Genodermatosis Desmosomal Disease

Skin fragility-woolly hair-palmoplantar keratoderma syndrome is a rare autosomal recessive genodermatosis caused by compound heterozygous loss-of-function mutations in the desmoplakin (DSP) gene. It is characterized by focal and diffuse palmoplantar keratoderma, hyperkeratotic plaques on the trunk and limbs, skin fragility with blistering, and varying degrees of alopecia. Unlike Carvajal syndrome, cardiac anomalies are not initially apparent, though cardiac involvement may develop over time. Desmoplakin haploinsufficiency can be tolerated, but compound heterozygosity with a missense mutation on the other allele causes severe cutaneous disease through disruption of desmosome-keratin intermediate filament interactions.

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1
Inheritance
3
Pathophys.
3
Phenotypes
6
Pathograph
1
Genes
3
Medical Actions
🏷

Classifications

Harrison's Part
DERMATOLOGY GENETICS ENVIRONMENT DISEASE
Mechanistic Nosology
desmosomopathy
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:11841538 SUPPORT Human Clinical
"a new autosomal recessive genodermatosis characterized by focal and diffuse palmoplantar keratoderma, hyperkeratotic plaques on the trunk and limbs, varying degrees of alopecia, but no apparent cardiac anomalies"
Establishes the autosomal recessive inheritance pattern of this genodermatosis.
⚙

Pathophysiology

3
DSP Compound Heterozygous Loss-of-Function
Compound heterozygosity for nonsense and missense DSP mutations. Haploinsufficiency alone is tolerated, but combination with a missense allele yields a severe skin phenotype.
Keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
Skin UBERON:0002097 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Skin, annotated with skin of body (UBERON:0002097). UBERON:0002097 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Desmoplakin Mislocalization
Show evidence (1 reference)
PMID:11841538 SUPPORT Human Clinical
"Mutation screening of desmoplakin demonstrated compound heterozygosity for a non-sense/mis-sense combination of mutations in both cases, C809X/N287K and Q664X/R2366C, respectively."
Identifies compound heterozygous DSP mutations as the molecular basis for skin fragility-woolly hair syndrome.
Desmoplakin Mislocalization
Immunohistochemistry of skin biopsies shows desmoplakin protein mislocalized to the cytoplasm rather than its normal cell-peripheral (desmosomal) location.
Keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
Skin UBERON:0002097 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Skin, annotated with skin of body (UBERON:0002097). UBERON:0002097 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Desmosome-Keratin Detachment
Show evidence (1 reference)
PMID:11841538 SUPPORT Human Clinical
"Immunohistochemistry of skin biopsies from both affected individuals revealed that desmoplakin was not just located at the cell periphery but there was also cytoplasmic staining."
Demonstrates aberrant cytoplasmic localization of desmoplakin in keratinocytes of affected patients.
Desmosome-Keratin Detachment
Loss of functional desmoplakin at the cell periphery causes acantholysis, focal detachment of desmosomes into the intercellular space, and perinuclear condensation of the keratin intermediate filament network — i.e., failure of desmosome–keratin attachment in keratinocytes.
Keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
Desmosome organization GO:0002934 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Desmosome organization (GO:0002934). GO:0002934 is a biological process from the Gene Ontology. ↓ DECREASED Cell-cell junction assembly GO:0007043 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Cell-cell junction assembly (GO:0007043). GO:0007043 is a biological process from the Gene Ontology. ↓ DECREASED
Skin UBERON:0002097 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Skin, annotated with skin of body (UBERON:0002097). UBERON:0002097 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Skin Fragility
Palmoplantar Keratoderma
Woolly Hair and Alopecia Desmosome-keratin attachment failure in keratinizing ectodermal tissues is associated with the woolly hair and alopecia phenotype; the hair-follicle-specific intermediate is not separately modeled.
Show evidence (1 reference)
PMID:11841538 SUPPORT Human Clinical
"electron microscopy demonstrated acantholysis throughout all layers of the skin, focal detachment of desmosomes into the intercellular spaces, and perinuclear condensation of the suprabasal keratin intermediate filament network"
Demonstrates the cellular pathology of desmosomal disruption in this condition.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Skin Fragility-Woolly Hair Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

3
Skin Fragility Very frequent Dermatologic HP:0007585 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin fragility, annotated with Skin fragility with non-scarring blistering (HP:0007585). HP:0007585 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11841538 SUPPORT Human Clinical
"electron microscopy demonstrated acantholysis throughout all layers of the skin, focal detachment of desmosomes into the intercellular spaces, and perinuclear condensation of the suprabasal keratin intermediate filament network"
EM evidence of acantholysis and desmosome detachment directly demonstrates skin fragility at the ultrastructural level.
Palmoplantar Keratoderma Very frequent Dermatologic HP:0000982 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Palmoplantar keratoderma (HP:0000982). HP:0000982 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11841538 SUPPORT Human Clinical
"focal and diffuse palmoplantar keratoderma, hyperkeratotic plaques on the trunk and limbs"
Confirms focal and diffuse palmoplantar keratoderma with hyperkeratotic plaques as a defining feature.
Woolly Hair and Alopecia Very frequent Dermatologic HP:0002224 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Woolly hair (HP:0002224). HP:0002224 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11841538 SUPPORT Human Clinical
"varying degrees of alopecia, but no apparent cardiac anomalies"
The defining two-patient series documents varying degrees of alopecia accompanying the woolly hair phenotype.
🧬

Genetic Associations

1
DSP Compound Heterozygous Mutations (Pathogenic Variants)
Gene: DSP hgnc:3052 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DSP (hgnc:3052). hgnc:3052 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal Recessive
Show evidence (2 references)
PMID:11841538 SUPPORT Human Clinical
"Heterozygous carriers of any of these mutations displayed no phenotypic abnormalities."
Confirms that haploinsufficiency alone is tolerated; compound heterozygosity is required for the skin fragility phenotype.
PMID:11841538 SUPPORT Human Clinical
"desmoplakin haploinsufficiency can be tolerated in some cases, but that in combination with a mis-sense mutation on the other allele, the consequences are a severe genodermatosis with specific clinical manifestations"
Establishes the genotype-phenotype correlation for compound heterozygosity.
💊

Medical Actions

3
Dermatologic Care
Action: Dermatologic careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dermatologic care, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Emollients, wound care for skin fragility, and monitoring for skin complications.
Cardiac Surveillance
Action: Cardiac surveillanceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Cardiac surveillance, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Periodic echocardiographic screening is recommended given the potential for cardiac involvement to develop over time.
Genetic Counseling
Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling for autosomal recessive inheritance and carrier testing.
📊

Prevalence

1
Global
Rare Rare
Show evidence (1 reference)
PMID:11841538 SUPPORT Human Clinical
"Here, we describe two unrelated individuals with a new autosomal recessive genodermatosis"
The defining report describes only two unrelated individuals, consistent with a rare disorder.
{ }

Source YAML

click to show 
name: Skin Fragility-Woolly Hair Syndrome
creation_date: "2026-04-04T00:00:00Z"
description: >-
  Skin fragility-woolly hair-palmoplantar keratoderma syndrome is a rare
  autosomal recessive genodermatosis caused by compound heterozygous
  loss-of-function mutations in the desmoplakin (DSP) gene. It is characterized
  by focal and diffuse palmoplantar keratoderma, hyperkeratotic plaques on the
  trunk and limbs, skin fragility with blistering, and varying degrees of
  alopecia. Unlike Carvajal syndrome, cardiac anomalies are not initially
  apparent, though cardiac involvement may develop over time. Desmoplakin
  haploinsufficiency can be tolerated, but compound heterozygosity with a
  missense mutation on the other allele causes severe cutaneous disease through
  disruption of desmosome-keratin intermediate filament interactions.
category: Genetic
parents:
- Genodermatosis
- Desmosomal Disease
disease_term:
  preferred_term: skin fragility-woolly hair-palmoplantar keratoderma syndrome
  term:
    id: MONDO:0011882
    label: skin fragility-woolly hair-palmoplantar keratoderma syndrome
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  mechanistic_category:
  - classification_value: desmosomopathy
prevalence:
- population: Global
  prevalence_class: RARE
  percentage: Rare
  evidence:
  - reference: PMID:11841538
    reference_title: "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe two unrelated individuals with a new autosomal
      recessive genodermatosis
    explanation: >-
      The defining report describes only two unrelated individuals,
      consistent with a rare disorder.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:11841538
    reference_title: "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a new autosomal recessive genodermatosis characterized by focal and
      diffuse palmoplantar keratoderma, hyperkeratotic plaques on the trunk
      and limbs, varying degrees of alopecia, but no apparent cardiac
      anomalies
    explanation: >-
      Establishes the autosomal recessive inheritance pattern of this
      genodermatosis.
pathophysiology:
- name: DSP Compound Heterozygous Loss-of-Function
  conforms_to: "desmosomal_adhesion_failure#Desmosomal Component Loss or Blockade"
  description: >-
    Compound heterozygosity for nonsense and missense DSP mutations.
    Haploinsufficiency alone is tolerated, but combination with a
    missense allele yields a severe skin phenotype.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: Skin
    term:
      id: UBERON:0002097
      label: skin of body
  downstream:
  - target: Desmoplakin Mislocalization
  evidence:
  - reference: PMID:11841538
    reference_title: "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation screening of desmoplakin demonstrated compound
      heterozygosity for a non-sense/mis-sense combination of mutations
      in both cases, C809X/N287K and Q664X/R2366C, respectively.
    explanation: >-
      Identifies compound heterozygous DSP mutations as the molecular
      basis for skin fragility-woolly hair syndrome.
- name: Desmoplakin Mislocalization
  description: >-
    Immunohistochemistry of skin biopsies shows desmoplakin protein
    mislocalized to the cytoplasm rather than its normal cell-peripheral
    (desmosomal) location.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  locations:
  - preferred_term: Skin
    term:
      id: UBERON:0002097
      label: skin of body
  downstream:
  - target: Desmosome-Keratin Detachment
  evidence:
  - reference: PMID:11841538
    reference_title: "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemistry of skin biopsies from both affected
      individuals revealed that desmoplakin was not just located at the
      cell periphery but there was also cytoplasmic staining.
    explanation: >-
      Demonstrates aberrant cytoplasmic localization of desmoplakin in
      keratinocytes of affected patients.
- name: Desmosome-Keratin Detachment
  conforms_to: "desmosomal_adhesion_failure#Failure of Desmosome Assembly and Intermediate Filament Anchorage"
  description: >-
    Loss of functional desmoplakin at the cell periphery causes
    acantholysis, focal detachment of desmosomes into the intercellular
    space, and perinuclear condensation of the keratin intermediate
    filament network — i.e., failure of desmosome–keratin attachment in
    keratinocytes.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: Desmosome organization
    term:
      id: GO:0002934
      label: desmosome organization
    modifier: DECREASED
  - preferred_term: Cell-cell junction assembly
    term:
      id: GO:0007043
      label: cell-cell junction assembly
    modifier: DECREASED
  locations:
  - preferred_term: Skin
    term:
      id: UBERON:0002097
      label: skin of body
  downstream:
  - target: Skin Fragility
  - target: Palmoplantar Keratoderma
  - target: Woolly Hair and Alopecia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Desmosome-keratin attachment failure in keratinizing ectodermal
      tissues is associated with the woolly hair and alopecia phenotype;
      the hair-follicle-specific intermediate is not separately modeled.
    evidence:
    - reference: PMID:11841538
      reference_title: "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        characterized by focal and diffuse palmoplantar keratoderma,
        hyperkeratotic plaques on the trunk and limbs, varying degrees of
        alopecia, but no apparent cardiac anomalies
      explanation: >-
        The defining report lists alopecia among the clinical
        manifestations of this desmoplakin-related skin fragility/woolly
        hair syndrome.
  evidence:
  - reference: PMID:11841538
    reference_title: "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      electron microscopy demonstrated acantholysis throughout all layers
      of the skin, focal detachment of desmosomes into the intercellular
      spaces, and perinuclear condensation of the suprabasal keratin
      intermediate filament network
    explanation: >-
      Demonstrates the cellular pathology of desmosomal disruption in
      this condition.
phenotypes:
- category: Dermatologic
  name: Skin Fragility
  frequency: Very frequent
  description: >-
    Skin fragility with non-scarring blistering throughout all layers
    of the epidermis due to acantholysis.
  phenotype_term:
    preferred_term: Skin fragility
    term:
      id: HP:0007585
      label: Skin fragility with non-scarring blistering
  evidence:
  - reference: PMID:11841538
    reference_title: "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      electron microscopy demonstrated acantholysis throughout all layers
      of the skin, focal detachment of desmosomes into the intercellular
      spaces, and perinuclear condensation of the suprabasal keratin
      intermediate filament network
    explanation: >-
      EM evidence of acantholysis and desmosome detachment directly
      demonstrates skin fragility at the ultrastructural level.
- category: Dermatologic
  name: Palmoplantar Keratoderma
  frequency: Very frequent
  description: >-
    Focal and diffuse palmoplantar keratoderma with hyperkeratotic
    plaques extending to trunk and limbs.
  phenotype_term:
    preferred_term: Palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:11841538
    reference_title: "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      focal and diffuse palmoplantar keratoderma, hyperkeratotic plaques
      on the trunk and limbs
    explanation: >-
      Confirms focal and diffuse palmoplantar keratoderma with
      hyperkeratotic plaques as a defining feature.
- category: Dermatologic
  name: Woolly Hair and Alopecia
  frequency: Very frequent
  description: >-
    Woolly hair with varying degrees of alopecia reflecting desmosomal
    dysfunction in hair follicles.
  phenotype_term:
    preferred_term: Woolly hair
    term:
      id: HP:0002224
      label: Woolly hair
  evidence:
  - reference: PMID:11841538
    reference_title: "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      varying degrees of alopecia, but no apparent cardiac anomalies
    explanation: >-
      The defining two-patient series documents varying degrees of
      alopecia accompanying the woolly hair phenotype.
genetic:
- name: DSP Compound Heterozygous Mutations
  association: Pathogenic Variants
  gene_term:
    preferred_term: DSP
    term:
      id: hgnc:3052
      label: DSP
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:11841538
      reference_title: "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Heterozygous carriers of any of these mutations displayed no
        phenotypic abnormalities.
      explanation: >-
        The recessive inheritance pattern is confirmed by the absence
        of phenotype in heterozygous carriers of single DSP mutations.
  features: >-
    Compound heterozygosity for nonsense/missense DSP mutations.
    Heterozygous carriers of individual mutations show no phenotype.
  evidence:
  - reference: PMID:11841538
    reference_title: "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous carriers of any of these mutations displayed no
      phenotypic abnormalities.
    explanation: >-
      Confirms that haploinsufficiency alone is tolerated; compound
      heterozygosity is required for the skin fragility phenotype.
  - reference: PMID:11841538
    reference_title: "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      desmoplakin haploinsufficiency can be tolerated in some cases, but
      that in combination with a mis-sense mutation on the other allele,
      the consequences are a severe genodermatosis with specific clinical
      manifestations
    explanation: >-
      Establishes the genotype-phenotype correlation for compound
      heterozygosity.
treatments:
- name: Dermatologic Care
  description: >-
    Emollients, wound care for skin fragility, and monitoring for
    skin complications.
  treatment_term:
    preferred_term: Dermatologic care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Cardiac Surveillance
  description: >-
    Periodic echocardiographic screening is recommended given the
    potential for cardiac involvement to develop over time.
  treatment_term:
    preferred_term: Cardiac surveillance
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic Counseling
  description: >-
    Genetic counseling for autosomal recessive inheritance and
    carrier testing.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
datasets: