Epidermolysis Bullosa

Mendelian MONDO:0006541 Pathograph 14 Dermatological Disease Genetic Disease

Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by often minimal trauma. Over 30 subtypes are recognized, grouped into four major categories based on the plane of cleavage within the skin. This is the umbrella entry covering shared concepts across all EB types.

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2
Mappings
0
Definitions
2
Inheritance
4
Pathophysiology
0
Histopathology
8
Phenotypes
14
Pathograph
10
Genes
8
Treatments
4
Subtypes
0
Differentials
1
Datasets
2
Trials
0
Models
15
References
1
Deep Research
🏷

Classifications

Harrison's Chapter
skin disorder hereditary disease
🔗

Mappings

MONDO
MONDO:0006541 epidermolysis bullosa
skos:exactMatch MONDO
Primary MONDO disease identifier for the EB umbrella entry.
ICD-10-CM
ICD10CM:Q81.9 Epidermolysis bullosa, unspecified
skos:closeMatch ICD-10-CM
ICD-10-CM Q81.9 captures unspecified epidermolysis bullosa and is the closest broad diagnosis code for the umbrella EB entry rather than any single subtype.
👪

Inheritance

2
Autosomal dominant
Show evidence (1 reference)
PMID:34036913 SUPPORT Human Clinical
"some types are autosomal dominant while others are autosomal recessive"
Confirms that EB includes both autosomal dominant and autosomal recessive forms depending on the type and subtype.
Autosomal recessive
Show evidence (1 reference)
PMID:34036913 SUPPORT Human Clinical
"some types are autosomal dominant while others are autosomal recessive"
Confirms autosomal recessive inheritance in multiple EB types including junctional EB, recessive dystrophic EB, and Kindler EB.
◆

Subtypes

4
Epidermolysis Bullosa Simplex
Intraepidermal cleavage, typically within basal keratinocytes. Most commonly caused by mutations in KRT5 or KRT14 encoding keratin 5 and keratin 14. Ranges from localized palmoplantar blistering to severe generalized forms. Generally autosomal dominant inheritance.
Show evidence (1 reference)
PMID:20301543 SUPPORT Human Clinical
"In EBS, blistering occurs within basal keratinocytes"
Supports the defining intraepidermal cleavage plane of EB simplex.
Junctional Epidermolysis Bullosa
Cleavage occurs within the lamina lucida of the basement membrane zone. Caused by mutations in genes encoding laminin-332 (LAMA3, LAMB3, LAMC2) or type XVII collagen (COL17A1), or integrin alpha-6-beta-4 (ITGA6, ITGB4). Autosomal recessive inheritance. Includes severe generalized (formerly Herlitz) and intermediate generalized subtypes.
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"Broad classification of JEB includes JEB generalized severe and JEB generalized intermediate"
Supports junctional epidermolysis bullosa as a major EB subtype with severe and intermediate generalized forms.
Dystrophic Epidermolysis Bullosa
Cleavage occurs beneath the lamina densa in the uppermost dermis. Caused by mutations in COL7A1 encoding type VII collagen, the major component of anchoring fibrils. Both autosomal dominant and autosomal recessive forms exist. Recessive dystrophic EB is associated with severe scarring, pseudosyndactyly, esophageal strictures, and increased risk of squamous cell carcinoma.
Show evidence (1 reference)
PMID:20301481 SUPPORT Human Clinical
"DEB is divided into two major types depending on inheritance pattern: recessive dystrophic epidermolysis bullosa (RDEB) and dominant dystrophic epidermolysis bullosa (DDEB)"
Supports dystrophic epidermolysis bullosa as a major EB category with dominant and recessive forms.
Kindler Epidermolysis Bullosa
Mixed cleavage planes (intraepidermal, junctional, or sublamina densa). Caused by mutations in FERMT1 encoding fermitin family member 1 (kindlin-1), a focal adhesion protein. Autosomal recessive inheritance. Features include photosensitivity and progressive poikiloderma in addition to skin fragility.
Show evidence (1 reference)
PMID:26937547 SUPPORT Human Clinical
"Kindler syndrome (KS), a rare subtype of inherited epidermolysis bullosa"
Supports Kindler EB as a recognized subtype within the inherited EB spectrum.
⚙

Pathophysiology

4
Basement Membrane Zone Structural Disruption
The core defect in all forms of EB is disruption of structural proteins within or adjacent to the basement membrane zone (BMZ) of the skin. Pathogenetic mutations in at least 16 distinct genes encoding proteins that influence cellular integrity and adhesion have been implicated. The specific protein affected determines the ultrastructural level of cleavage and the clinical subtype.
keratinocyte link epidermal cell link
KRT5 link KRT14 link COL7A1 link LAMB3 link LAMA3 link LAMC2 link COL17A1 link ITGA6 link ITGB4 link FERMT1 link
cell-substrate adhesion link ↓ DECREASED epidermis development link ⚠ ABNORMAL
Downstream
Mechanical Fragility and Blister Formation Loss of structural integrity at the dermal-epidermal junction leads to tissue separation and blister formation upon minimal mechanical stress.
Show evidence (2 references)
PMID:32973163 SUPPORT Human Clinical
"pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion"
Confirms that mutations in at least 16 genes encoding structural and adhesion proteins underlie all forms of EB.
PMID:32017015 SUPPORT Human Clinical
"we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype"
Confirms that EB is the prototypical genetic disorder with skin fragility resulting from structural protein defects.
Mechanical Fragility and Blister Formation
Disruption of the structural proteins that anchor the epidermis to the dermis results in tissue separation and blister formation in response to minimal mechanical trauma or friction. The level of cleavage within the skin determines the EB type and influences the severity of blistering and the propensity for scarring.
keratinocyte link
cell adhesion link ↓ DECREASED
Downstream
Wound Healing Impairment and Chronic Wounds Repeated blister formation and epithelial loss leads to chronic wounds and impaired wound healing.
Secondary Complications Chronic skin barrier disruption leads to infection, scarring, nutritional deficiency, and pain.
Show evidence (2 references)
PMID:32973163 SUPPORT Human Clinical
"mucocutaneous fragility and blister formation, inducible by often minimal trauma"
Confirms that the cardinal feature of EB is blister formation triggered by minimal trauma due to mucocutaneous fragility.
PMID:34036913 SUPPORT Human Clinical
"a group of rare congenital genetic conditions that result in painful blistering of the skin and mucous membranes, which occur with minor trauma or friction"
Confirms that blistering is triggered by minor trauma or friction in EB.
Wound Healing Impairment and Chronic Wounds
Chronic and recurrent blister formation leads to impaired wound healing, particularly in the more severe forms of EB. In dystrophic EB, deficiency of type VII collagen impairs anchoring fibril formation, leading to chronic non-healing wounds and progressive scarring. Chronic wounds are associated with pain, infection risk, and in severe cases, development of squamous cell carcinoma.
fibroblast link
wound healing link ⚠ ABNORMAL
Downstream
Secondary Complications Chronic wounds predispose to infection, scarring, and malignant transformation in severe EB subtypes.
Show evidence (2 references)
PMID:32973163 SUPPORT Human Clinical
"multidisciplinary care is targeted towards minimizing the risk of blister formation, wound care, symptom relief and specific complications, the most feared of which - and also the leading cause of mortality - is squamous cell carcinoma"
Confirms that chronic wound complications including squamous cell carcinoma are major concerns in EB management.
PMID:25279494 SUPPORT Human Clinical
"a specific attention to the fragile skin is required in order to reduce pain, risk of trauma, ulceration and infection"
Confirms that ulceration and impaired wound healing are significant complications requiring specialized management.
Secondary Complications
Chronic skin barrier disruption in EB leads to a range of secondary complications including bacterial infection of wounds, progressive scarring (especially in dystrophic EB), nutritional deficiency due to oral and esophageal involvement, anemia of chronic disease, and growth retardation. Severe forms carry risk of squamous cell carcinoma as the leading cause of mortality.
fibroblast link
inflammatory response link ↑ INCREASED collagen fibril organization link ⚠ ABNORMAL
Show evidence (2 references)
PMID:32973163 SUPPORT Human Clinical
"A broad phenotypic spectrum has been described, with potentially severe extracutaneous manifestations, morbidity and mortality"
Confirms that EB has severe extracutaneous complications contributing to morbidity and mortality.
PMID:20507631 SUPPORT Human Clinical
"Clinical manifestations range widely, from localized blistering of the hands and feet to generalized blistering of the skin and oral cavity, and injury to many internal organs"
Confirms the broad range of secondary complications including internal organ involvement.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Epidermolysis Bullosa 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

8
Blood 1
Anemia FREQUENT Anemia (HP:0001903)
Show evidence (1 reference)
PMID:20301481 SUPPORT Human Clinical
"Anemia is treated with iron supplements and transfusions as needed"
GeneReviews confirms anemia as a recognized complication of DEB requiring treatment with iron supplementation and transfusions.
Head and Neck 1
Mucosal Involvement FREQUENT Abnormal oral mucosa morphology (HP:0011830)
Oral, esophageal, and ocular mucous membranes may all be affected.
Show evidence (2 references)
PMID:20507631 SUPPORT Human Clinical
"generalized blistering of the skin and oral cavity, and injury to many internal organs"
Confirms oral cavity involvement as part of the generalized disease spectrum.
PMID:34036913 SUPPORT Human Clinical
"Severe complications may arise in some EB types and subtypes within the eye, ear, nose, upper airway, gastrointestinal and genitourinary tracts"
Confirms extracutaneous mucosal involvement across multiple organ systems.
Integument 3
Skin Fragility and Blistering VERY_FREQUENT Abnormal blistering of the skin (HP:0008066)
Show evidence (2 references)
PMID:32973163 SUPPORT Human Clinical
"mucocutaneous fragility and blister formation, inducible by often minimal trauma"
Confirms skin fragility and blister formation as the defining feature of EB.
PMID:20507631 SUPPORT Human Clinical
"a number of disorders characterized by recurrent blister formation as the result of structural fragility within the skin and selected other tissues"
Confirms recurrent blistering due to structural skin fragility across all EB types.
Nail Dystrophy FREQUENT Nail dystrophy (HP:0008404)
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia"
JEB GeneReviews confirms nail dystrophy as a shared feature across all major forms of EB.
Milia FREQUENT Milia (HP:0001056)
Show evidence (1 reference)
PMID:20301481 SUPPORT Human Clinical
"skin fragility manifested by blistering and erosions with minimal trauma that heals with milia and scarring"
Supports milia as a characteristic healing outcome in dystrophic epidermolysis bullosa.
Musculoskeletal 1
Scarring FREQUENT Scarring (HP:0100699)
Show evidence (1 reference)
PMID:20301481 SUPPORT Human Clinical
"skin fragility manifested by blistering and erosions with minimal trauma that heals with milia and scarring"
GeneReviews confirms that blisters in DEB heal with scarring, a key distinguishing feature of dystrophic forms.
Constitutional 1
Pain VERY_FREQUENT Pain (HP:0012531)
Show evidence (2 references)
PMID:34036913 SUPPORT Human Clinical
"painful blistering of the skin and mucous membranes"
Confirms pain as a cardinal symptom associated with blistering in EB.
PMID:25279494 SUPPORT Human Clinical
"management of itching and pain"
Confirms pain management as a major component of EB care.
Growth 1
Failure to Thrive FREQUENT Failure to thrive (HP:0001508)
Show evidence (2 references)
PMID:20507631 SUPPORT Human Clinical
"Optimal patient management requires a multidisciplinary approach, and revolves around the protection of susceptible tissues against trauma, use of sophisticated wound care dressings, aggressive nutritional support, and early medical or surgical interventions to correct whenever possible the..."
The need for aggressive nutritional support as a core management pillar implies significant growth and nutritional challenges in severe EB.
PMID:34036913 SUPPORT Human Clinical
"involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications"
Nutritional support as a core management pillar confirms failure to thrive as a significant clinical issue.
🧬

Genetic Associations

10
KRT5 (Causative)
Autosomal dominant
Show evidence (1 reference)
PMID:32973163 SUPPORT Human Clinical
"pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion"
Confirms that genes encoding structural proteins including keratins are causative of EB.
KRT14 (Causative)
Autosomal dominant
Show evidence (1 reference)
PMID:20301543 SUPPORT Human Clinical
"the identification of a heterozygous dominant-negative variant or biallelic loss-of-function variants in KRT5, KRT14, or PLEC"
Supports KRT14 as a causative EB simplex gene in the clinical diagnostic framework.
COL7A1 (Causative)
Autosomal dominant Autosomal recessive
Show evidence (1 reference)
PMID:32973163 SUPPORT Human Clinical
"Over 30 subtypes are recognized, grouped into four major categories, based predominantly on the plane of cleavage within the skin and reflecting the underlying molecular abnormality"
Confirms that specific molecular abnormalities including collagen VII defects determine EB subtypes.
LAMB3 (Causative)
Autosomal recessive
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
Supports LAMB3 as one of the established causative genes for junctional epidermolysis bullosa.
LAMA3 (Causative)
Autosomal recessive
Show evidence (1 reference)
PMID:19945616 SUPPORT Human Clinical
"this devastating condition is most often caused by homozygous null mutations in the genes LAMA3, LAMB3, or LAMC2, each encoding for 1 of the 3 chains of the heterotrimer laminin-332"
Supports LAMA3 as a causative laminin-332 chain gene in junctional epidermolysis bullosa.
LAMC2 (Causative)
Autosomal recessive
Show evidence (1 reference)
PMID:19945616 SUPPORT Human Clinical
"this devastating condition is most often caused by homozygous null mutations in the genes LAMA3, LAMB3, or LAMC2, each encoding for 1 of the 3 chains of the heterotrimer laminin-332"
Supports LAMC2 as a causative laminin-332 chain gene in junctional epidermolysis bullosa.
COL17A1 (Causative)
Autosomal recessive
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
Supports COL17A1 as one of the established causative genes for junctional epidermolysis bullosa.
ITGA6 (Causative)
Autosomal recessive
Show evidence (1 reference)
PMID:32973163 SUPPORT Human Clinical
"pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion"
Supports ITGA6 as part of the adhesion-gene set underlying EB, consistent with its role in JEB with pyloric atresia.
ITGB4 (Causative)
Autosomal recessive
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
Supports ITGB4 as one of the established causative genes for junctional epidermolysis bullosa.
FERMT1 (Causative)
Autosomal recessive
Show evidence (1 reference)
PMID:32973163 SUPPORT Human Clinical
"EB simplex, junctional EB, dystrophic EB and Kindler EB"
Confirms Kindler EB as one of the four major EB categories in the consensus classification.
💊

Treatments

8
Wound Care and Dressing Management
Action: wound care management Ontology label: supportive care MAXO:0000950
Specialized wound care is the cornerstone of EB management. Involves non-adherent dressings, gentle wound cleansing, blister lancing, and protection of fragile skin from mechanical trauma. Sophisticated wound care dressings are used to promote healing and minimize pain.
Show evidence (3 references)
PMID:20507631 SUPPORT Human Clinical
"use of sophisticated wound care dressings"
Confirms specialized wound care dressings as a key management strategy.
PMID:34036913 SUPPORT Human Clinical
"involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications"
Confirms wound care as a core pillar of EB management.
PMID:25279494 SUPPORT Human Clinical
"global skin care including wound care"
Confirms wound care as central to EB patient management.
Pain Management
Action: pain management Ontology label: supportive care MAXO:0000950
Multimodal pain management for chronic wound pain, procedural pain during dressing changes, and acute pain from new blisters. May include pharmacological and non-pharmacological approaches.
Show evidence (2 references)
PMID:34036913 SUPPORT Human Clinical
"involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications"
Confirms pain control as a core component of EB management.
PMID:25279494 SUPPORT Human Clinical
"management of itching and pain"
Confirms pain and itch management as key aspects of EB care.
Nutritional Support
Action: nutritional support Ontology label: dietary intervention MAXO:0000088
Aggressive nutritional support to address growth failure, anemia, and increased metabolic demands from chronic wounds. May require supplemental feeding or gastrostomy in severe cases with oral and esophageal involvement.
Show evidence (2 references)
PMID:20507631 SUPPORT Human Clinical
"aggressive nutritional support"
Confirms aggressive nutritional support as essential in EB management.
PMID:34036913 SUPPORT Human Clinical
"involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications"
Confirms nutritional support as a core management component.
Infection Prevention and Treatment
Action: infection management Ontology label: supportive care MAXO:0000950
Prevention and treatment of wound infections, which are common due to chronic skin barrier disruption. Includes topical antiseptics, appropriate use of antibiotics, and surveillance for wound colonization.
Show evidence (2 references)
PMID:34036913 SUPPORT Human Clinical
"involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications"
Confirms infection control as a core pillar of EB management.
PMID:25279494 SUPPORT Human Clinical
"a specific attention to the fragile skin is required in order to reduce pain, risk of trauma, ulceration and infection"
Confirms infection prevention as key in EB wound management.
Genetic Counseling
Action: genetic counseling MAXO:0000079
Genetic counseling for affected families to discuss inheritance patterns, recurrence risk, prenatal testing options, and implications for family planning. Essential given the variable inheritance patterns across EB types.
Show evidence (1 reference)
PMID:34036913 SUPPORT Human Clinical
"The diagnosis is suspected based on symptoms and confirmed by skin biopsy and definitive genetic testing"
The role of genetic testing in diagnosis underscores the importance of genetic counseling for families.
Vyjuvek (Beremagene Geperpavec)
Action: topical gene therapy (beremagene geperpavec) Ontology label: gene therapy MAXO:0001001
FDA-approved topical gene therapy for dystrophic epidermolysis bullosa (May 2023). Beremagene geperpavec-svdt (VYJUVEK) is a topically applied, redosable, replication-defective HSV-1 vector-based gene therapy that delivers functional COL7A1 to restore type VII collagen production. In the phase 3 GEM-3 trial, complete wound healing at 6 months occurred in 67% of B-VEC-treated wounds vs 22% of placebo wounds. Approved for wounds in patients aged 6 months and older with DEB carrying COL7A1 mutations.
Show evidence (2 references)
PMID:36516090 SUPPORT Human Clinical
"Complete wound healing at 3 and 6 months in patients with dystrophic epidermolysis bullosa was more likely with topical administration of B-VEC than with placebo"
Phase 3 NEJM trial demonstrating significant wound healing benefit of beremagene geperpavec over placebo in dystrophic EB.
PMID:37432558 SUPPORT Human Clinical
"In May 2023, beremagene geperpavec received its first approval in the US for the treatment of wounds in patients"
Confirms FDA approval in May 2023 as the first topical gene therapy for dystrophic EB.
Filsuvez (Birch Triterpenes)
Action: topical birch triterpenes wound therapy Ontology label: pharmacotherapy MAXO:0000058
FDA-approved topical gel for epidermolysis bullosa wound healing (December 2023). Filsuvez (Oleogel-S10) contains birch triterpenes and promotes wound healing by modulating inflammation and encouraging tissue formation. In the phase 3 EASE trial, 41.3% of patients treated with Oleogel-S10 achieved first complete target wound closure within 45 days vs 28.9% with control gel. Approved for partial-thickness wounds in patients aged 6 months and older with junctional or dystrophic EB.
Show evidence (2 references)
PMID:36689495 SUPPORT Human Clinical
"Oleogel-S10 is the first therapy to demonstrate accelerated wound healing in EB"
Phase 3 EASE trial demonstrating Oleogel-S10 as the first therapy to show accelerated wound healing in EB.
PMID:39748581 SUPPORT Human Clinical
"Filsuvez® (birch triterpenes) topical gel received approval in 2023 for the treatment of epidermolysis bullosa (EB) in pediatric patients (aged ≥6 months) and adults"
Confirms FDA approval of Filsuvez for treatment of EB wounds in pediatric and adult patients.
Zevaskyn (Prademagene Zamikeracel / pz-cel)
Action: autologous gene-corrected cell therapy (prademagene zamikeracel) Ontology label: cellular therapy MAXO:0000016
FDA-approved autologous cell sheet-based gene therapy for recessive dystrophic epidermolysis bullosa (April 2025). Prademagene zamikeracel (ZEVASKYN) contains the patient's own keratinocytes genetically modified with functional copies of the COL7A1 gene, produced as transplantable epidermal sheets. In the phase 1/2a trial, wound healing of 50% or greater was present in 95% of treated wounds versus 0% of untreated controls at 6 months. It is the first and only cell-based gene therapy approved for RDEB.
Show evidence (2 references)
PMID:40875177 SUPPORT Human Clinical
"Prademagene zamikeracel (ZEVASKYN™) is an autologous cell sheet-based gene therapy developed by Abeona Therapeutics Inc. for the treatment of wounds in patients with recessive dystrophic epidermolysis bullosa"
Confirms FDA approval of prademagene zamikeracel as the first cell-based gene therapy for RDEB.
PMID:31578311 SUPPORT Human Clinical
"Wound healing of 50% or greater by Investigator Global Assessment was present in 95% (36 of 38) of treated wounds versus 0% (0 of 6) of untreated control wounds at 6 months (P < 0.0001)"
Phase 1/2a trial demonstrating significant wound healing with gene-corrected autologous cell therapy in RDEB patients.
🔬

Biochemical Markers

3
Type VII Collagen (Decreased)
Context: Reduced or absent in dystrophic EB due to COL7A1 mutations; assessed by immunofluorescence mapping
Show evidence (1 reference)
PMID:31920360 SUPPORT Human Clinical
"RDEB patients demonstrate reduction or structural alteration type VII collagen (C7) owing to mutations in the gene COL7A1"
Supports decreased or abnormal type VII collagen in dystrophic EB caused by COL7A1 mutations.
Laminin-332 (Decreased)
Context: Reduced or absent in junctional EB due to LAMA3, LAMB3, or LAMC2 mutations
Show evidence (1 reference)
PMID:22512697 SUPPORT Human Clinical
"Junctional epidermolysis bullosa, type Herlitz (JEB-H) is a rare, autosomal recessive disease caused by absence of the epidermal basement membrane adhesion protein laminin-332"
Supports absent laminin-332 as a defining molecular abnormality in severe junctional epidermolysis bullosa.
Keratin 5 and Keratin 14 (Variable)
Context: Abnormal intermediate filament network in EB simplex due to KRT5 or KRT14 mutations
Show evidence (1 reference)
PMID:22277943 SUPPORT Human Clinical
"Most cases of EBS are due to dominantly acting mutations in keratin 14 (K14) or K5, the type I and II intermediate filament (IF) proteins that copolymerize to form a pancytoplasmic network of 10 nm filaments in basal keratinocytes of epidermis"
Supports keratin 5 and keratin 14 as the intermediate filament proteins disrupted in EB simplex.
📊

Related Datasets

1
Novel insights into the epidemiology of epidermolysis bullosa (EB) from the Dutch EB Registry: EB more common than previously assumed? PMID:33095945
National registry-based phenotype dataset covering molecularly characterized epidermolysis bullosa patients in the Netherlands from 1988 to 2018, with complete diagnostic workup and longitudinal follow-up across EBS, JEB, DEB, and Kindler EB.
human PHENOPACKETS n=464
Conditions: Epidermolysis bullosa simplex Junctional epidermolysis bullosa Dystrophic epidermolysis bullosa Kindler epidermolysis bullosa
PMID:33095945
Show evidence (2 references)
PMID:33095945 SUPPORT Human Clinical
"A total of 464 EB-patients (287 families) were included."
Supports the Dutch EB Registry as a substantial national phenotype resource spanning the major EB subtypes.
PMID:33095945 SUPPORT Human Clinical
"In this observational study all EB-patients that were based in the Netherlands and captured in the Dutch EB Registry between 1988 and 2018 were included."
Confirms the registry's longitudinal national scope and direct relevance as an EB-wide clinical dataset.
🔬

Clinical Trials

2
NCT04908215 PHASE_II COMPLETED
Completed phase II randomized trial of topical INM-755 (cannabinol) cream for epidermolysis bullosa that enrolled multiple EB subtypes, including simplex, junctional, dystrophic, and Kindler syndrome.
Target Phenotypes: Wound healing impairment ↗
Show evidence (1 reference)
clinicaltrials:NCT04908215 SUPPORT Human Clinical
"The purpose of this study is to evaluate the safety of INM-755 (cannabinol) cream and obtain preliminary evidence of efficacy in treating symptoms and healing wounds over a 28-day period in patients with epidermolysis bullosa (EB)."
This ClinicalTrials.gov record supports a completed multi-subtype EB trial evaluating topical cannabinol cream for symptom control and wound healing.
NCT02014376 PHASE_II COMPLETED
Completed randomized vehicle-controlled phase II study of topical SD-101 cream in epidermolysis bullosa, including simplex, recessive dystrophic, and junctional non-Herlitz subtypes.
Target Phenotypes: Wound healing impairment ↗
Show evidence (1 reference)
clinicaltrials:NCT02014376 SUPPORT Human Clinical
"The purpose of this study was to assess whether the topical use of SD-101 cream (3% or 6%) was effective in treating wounds in participants with Simplex, Recessive Dystrophic, or Junctional non-Herlitz Epidermolysis Bullosa (EB)."
This ClinicalTrials.gov record supports a completed wound-healing trial that enrolled multiple major EB subtypes under the umbrella diagnosis.
{ }

Source YAML

click to show 
name: Epidermolysis Bullosa
creation_date: '2026-03-10T12:00:00Z'
updated_date: '2026-05-08T23:53:01Z'
category: Mendelian
description: >-
  Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic
  dermatoses characterized by mucocutaneous fragility and blister formation,
  inducible by often minimal trauma. Over 30 subtypes are recognized, grouped
  into four major categories based on the plane of cleavage within the skin.
  This is the umbrella entry covering shared concepts across all EB types.
disease_term:
  preferred_term: epidermolysis bullosa
  term:
    id: MONDO:0006541
    label: epidermolysis bullosa
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:Q81.9
      label: Epidermolysis bullosa, unspecified
    mapping_predicate: skos:closeMatch
    mapping_source: ICD-10-CM
    mapping_justification: >
      ICD-10-CM Q81.9 captures unspecified epidermolysis bullosa and is the
      closest broad diagnosis code for the umbrella EB entry rather than any
      single subtype.
  mondo_mappings:
  - term:
      id: MONDO:0006541
      label: epidermolysis bullosa
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for the EB umbrella entry.
classifications:
  harrisons_chapter:
  - classification_value: skin disorder
    evidence:
    - reference: PMID:32973163
      reference_title: "Epidermolysis bullosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation"
      explanation: Supports placing EB within skin disorders because it is explicitly described as a genetic dermatosis with mucocutaneous fragility.
  - classification_value: hereditary disease
    evidence:
    - reference: PMID:32973163
      reference_title: "Epidermolysis bullosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses"
      explanation: Supports classification of EB as a hereditary disease because the core disorder group is explicitly inherited and genetic.
parents:
- Dermatological Disease
- Genetic Disease
has_subtypes:
- name: Epidermolysis Bullosa Simplex
  description: >
    Intraepidermal cleavage, typically within basal keratinocytes. Most commonly
    caused by mutations in KRT5 or KRT14 encoding keratin 5 and keratin 14.
    Ranges from localized palmoplantar blistering to severe generalized forms.
    Generally autosomal dominant inheritance.
  evidence:
  - reference: PMID:20301543
    reference_title: "Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In EBS, blistering occurs within basal keratinocytes"
    explanation: Supports the defining intraepidermal cleavage plane of EB simplex.
- name: Junctional Epidermolysis Bullosa
  description: >
    Cleavage occurs within the lamina lucida of the basement membrane zone.
    Caused by mutations in genes encoding laminin-332 (LAMA3, LAMB3, LAMC2)
    or type XVII collagen (COL17A1), or integrin alpha-6-beta-4 (ITGA6, ITGB4).
    Autosomal recessive inheritance. Includes severe generalized (formerly Herlitz)
    and intermediate generalized subtypes.
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Broad classification of JEB includes JEB generalized severe and JEB generalized intermediate"
    explanation: Supports junctional epidermolysis bullosa as a major EB subtype with severe and intermediate generalized forms.
- name: Dystrophic Epidermolysis Bullosa
  description: >
    Cleavage occurs beneath the lamina densa in the uppermost dermis. Caused by
    mutations in COL7A1 encoding type VII collagen, the major component of
    anchoring fibrils. Both autosomal dominant and autosomal recessive forms exist.
    Recessive dystrophic EB is associated with severe scarring, pseudosyndactyly,
    esophageal strictures, and increased risk of squamous cell carcinoma.
  evidence:
  - reference: PMID:20301481
    reference_title: "Dystrophic Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DEB is divided into two major types depending on inheritance pattern: recessive dystrophic epidermolysis bullosa (RDEB) and dominant dystrophic epidermolysis bullosa (DDEB)"
    explanation: Supports dystrophic epidermolysis bullosa as a major EB category with dominant and recessive forms.
- name: Kindler Epidermolysis Bullosa
  description: >
    Mixed cleavage planes (intraepidermal, junctional, or sublamina densa).
    Caused by mutations in FERMT1 encoding fermitin family member 1 (kindlin-1),
    a focal adhesion protein. Autosomal recessive inheritance. Features include
    photosensitivity and progressive poikiloderma in addition to skin fragility.
  evidence:
  - reference: PMID:26937547
    reference_title: "Kindler Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kindler syndrome (KS), a rare subtype of inherited epidermolysis bullosa"
    explanation: Supports Kindler EB as a recognized subtype within the inherited EB spectrum.
prevalence:
- population: United States
  percentage: 0.0008
  notes: >
    The overall incidence of inherited EB in the United States is approximately
    19 per one million live births and prevalence approximately 11 per one million
    population, based on the National Epidermolysis Bullosa Registry.
  evidence:
  - reference: PMID:20507631
    reference_title: "Inherited epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the overall incidence and prevalence of the disease within the United States is approximately 19 per one million live births and 8 per one million population, respectively"
    explanation: Confirms the approximate incidence of ~19 per million live births in the US from the National EB Registry data.
  - reference: PMID:27463098
    reference_title: "Epidemiology of Inherited Epidermolysis Bullosa Based on Incidence and Prevalence Estimates From the National Epidermolysis Bullosa Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the overall incidence and prevalence of inherited EB were 19.60 and 8.22 per 1 million live births, respectively"
    explanation: Updated NEBR data confirms incidence of approximately 19.6 per million live births and prevalence of 8.2 per million.
- population: Worldwide
  notes: >
    An estimated 500,000 people worldwide are affected by epidermolysis bullosa.
    Registry-based studies from multiple countries suggest the disease may be
    more common than previously assumed, with incidence and prevalence varying
    by region and completeness of case ascertainment.
  evidence:
  - reference: PMID:28670357
    reference_title: "Raising Awareness Among Healthcare Providers about Epidermolysis Bullosa and Advancing Toward a Cure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolysis bullosa (EB) is an orphan disease that affects about half a million people worldwide, but may not be familiar to all clinicians"
    explanation: Confirms the estimated global burden of approximately 500,000 affected individuals worldwide.
- population: Germany
  percentage: 0.0054
  notes: >
    German population-based cross-sectional study using data from academic
    hospitals, diagnostic laboratories, and patient organizations. Estimated
    prevalence of 54 per million for all EB types using log-linear models,
    with at least 2,000 patients in the German population.
  evidence:
  - reference: PMID:36196047
    reference_title: "Epidemiology of inherited epidermolysis bullosa in Germany."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using log-linear models, we estimated a prevalence of 54 per million for all EB types, 2.44 for junctional EB, 12.16 for dystrophic EB and 28.44 per million for EB simplex"
    explanation: German EB registry data providing prevalence of 54 per million population overall, higher than some prior estimates.
- population: England and Wales
  notes: >
    Data from the National EB Database (2002-2021) covering 2,594 registered
    individuals. Total incidence of 67.8 per million live births across all EB
    types, and prevalence of 34.8 per million population. One of the highest
    reported incidences globally, attributed to comprehensive NHS-based
    ascertainment.
  evidence:
  - reference: PMID:34927719
    reference_title: "The epidemiology of epidermolysis bullosa in England and Wales: data from the national epidermolysis bullosa database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The average incidence per million live births for EBS, DEB, JEB and Kindler EB was 32·5, 26·1, 8·9 and 0·9, respectively (total incidence for all types of EB was 67·8 per million)"
    explanation: England and Wales EB registry data shows incidence of 67.8 per million live births, significantly higher than US estimates, likely reflecting more complete case ascertainment.
- population: Netherlands
  notes: >
    Dutch EB Registry data (1988-2018) from the single national expertise
    centre at UMCG. Incidence of 41.3 per million live births and
    point-prevalence of 22.4 per million population. High detection rate
    attributed to well-organized centralized care and near-complete
    ascertainment, suggesting EB may be more common than previously assumed.
  evidence:
  - reference: PMID:33095945
    reference_title: "Novel insights into the epidemiology of epidermolysis bullosa (EB) from the Dutch EB Registry: EB more common than previously assumed?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence and point-prevalence of EB in the Netherlands were 41.3 per million live births and 22.4 per million population, respectively"
    explanation: Dutch EB Registry data with molecularly confirmed diagnoses in 90.5% of patients, indicating EB is more common than older estimates suggest.
inheritance:
- name: Autosomal dominant
  evidence:
  - reference: PMID:34036913
    reference_title: "Epidermolysis Bullosa: Pediatric Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some types are autosomal dominant while others are autosomal recessive"
    explanation: Confirms that EB includes both autosomal dominant and autosomal recessive forms depending on the type and subtype.
- name: Autosomal recessive
  evidence:
  - reference: PMID:34036913
    reference_title: "Epidermolysis Bullosa: Pediatric Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some types are autosomal dominant while others are autosomal recessive"
    explanation: Confirms autosomal recessive inheritance in multiple EB types including junctional EB, recessive dystrophic EB, and Kindler EB.
pathophysiology:
- name: Basement Membrane Zone Structural Disruption
  description: >
    The core defect in all forms of EB is disruption of structural proteins
    within or adjacent to the basement membrane zone (BMZ) of the skin.
    Pathogenetic mutations in at least 16 distinct genes encoding proteins
    that influence cellular integrity and adhesion have been implicated.
    The specific protein affected determines the ultrastructural level of
    cleavage and the clinical subtype.
  genes:
  - preferred_term: KRT5
    term:
      id: hgnc:6442
      label: KRT5
  - preferred_term: KRT14
    term:
      id: hgnc:6416
      label: KRT14
  - preferred_term: COL7A1
    term:
      id: hgnc:2214
      label: COL7A1
  - preferred_term: LAMB3
    term:
      id: hgnc:6490
      label: LAMB3
  - preferred_term: LAMA3
    term:
      id: hgnc:6483
      label: LAMA3
  - preferred_term: LAMC2
    term:
      id: hgnc:6493
      label: LAMC2
  - preferred_term: COL17A1
    term:
      id: hgnc:2194
      label: COL17A1
  - preferred_term: ITGA6
    term:
      id: hgnc:6142
      label: ITGA6
  - preferred_term: ITGB4
    term:
      id: hgnc:6158
      label: ITGB4
  - preferred_term: FERMT1
    term:
      id: hgnc:15889
      label: FERMT1
  biological_processes:
  - preferred_term: cell-substrate adhesion
    modifier: DECREASED
    term:
      id: GO:0031589
      label: cell-substrate adhesion
  - preferred_term: epidermis development
    modifier: ABNORMAL
    term:
      id: GO:0008544
      label: epidermis development
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: epidermal cell
    term:
      id: CL:0000362
      label: epidermal cell
  downstream:
  - target: Mechanical Fragility and Blister Formation
    description: >
      Loss of structural integrity at the dermal-epidermal junction leads
      to tissue separation and blister formation upon minimal mechanical stress.
    evidence:
    - reference: PMID:39090514
      reference_title: "Treatment of Epidermolysis Bullosa and Future Directions: A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Epidermolysis bullosa (EB) comprises rare genetic disorders characterized by skin and mucosal membrane blistering induced by mechanical trauma. Molecularly, pathogenic variants affect genes encoding proteins crucial for epidermal-dermal adhesion and stability"
      explanation: Directly supports the causal link between loss of adhesion/stability proteins and mechanically induced blistering.
  evidence:
  - reference: PMID:32973163
    reference_title: "Epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion"
    explanation: Confirms that mutations in at least 16 genes encoding structural and adhesion proteins underlie all forms of EB.
  - reference: PMID:32017015
    reference_title: "Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype"
    explanation: Confirms that EB is the prototypical genetic disorder with skin fragility resulting from structural protein defects.
- name: Mechanical Fragility and Blister Formation
  description: >
    Disruption of the structural proteins that anchor the epidermis to the
    dermis results in tissue separation and blister formation in response to
    minimal mechanical trauma or friction. The level of cleavage within the
    skin determines the EB type and influences the severity of blistering
    and the propensity for scarring.
  biological_processes:
  - preferred_term: cell adhesion
    modifier: DECREASED
    term:
      id: GO:0007155
      label: cell adhesion
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: Wound Healing Impairment and Chronic Wounds
    description: >
      Repeated blister formation and epithelial loss leads to chronic wounds
      and impaired wound healing.
    evidence:
    - reference: PMID:31920360
      reference_title: "From Clinical Phenotype to Genotypic Modelling: Incidence and Prevalence of Recessive Dystrophic Epidermolysis Bullosa (RDEB)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited genetic disorder characterized by recurrent and chronic open wounds"
      explanation: Supports progression from recurrent blistering in severe EB to chronic open wounds and impaired healing.
  - target: Secondary Complications
    description: >
      Chronic skin barrier disruption leads to infection, scarring, nutritional
      deficiency, and pain.
    evidence:
    - reference: PMID:39090514
      reference_title: "Treatment of Epidermolysis Bullosa and Future Directions: A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Management of severe EB is multidisciplinary, focusing on wound healing support, ensuring that patients thrive, and complication treatment"
      explanation: Supports that severe EB commonly progresses beyond blistering to complications requiring dedicated wound-healing and complication management.
  evidence:
  - reference: PMID:32973163
    reference_title: "Epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mucocutaneous fragility and blister formation, inducible by often minimal trauma"
    explanation: Confirms that the cardinal feature of EB is blister formation triggered by minimal trauma due to mucocutaneous fragility.
  - reference: PMID:34036913
    reference_title: "Epidermolysis Bullosa: Pediatric Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a group of rare congenital genetic conditions that result in painful blistering of the skin and mucous membranes, which occur with minor trauma or friction"
    explanation: Confirms that blistering is triggered by minor trauma or friction in EB.
- name: Wound Healing Impairment and Chronic Wounds
  description: >
    Chronic and recurrent blister formation leads to impaired wound healing,
    particularly in the more severe forms of EB. In dystrophic EB, deficiency
    of type VII collagen impairs anchoring fibril formation, leading to
    chronic non-healing wounds and progressive scarring. Chronic wounds are
    associated with pain, infection risk, and in severe cases, development
    of squamous cell carcinoma.
  biological_processes:
  - preferred_term: wound healing
    modifier: ABNORMAL
    term:
      id: GO:0042060
      label: wound healing
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  downstream:
  - target: Secondary Complications
    description: >
      Chronic wounds predispose to infection, scarring, and malignant
      transformation in severe EB subtypes.
    evidence:
    - reference: PMID:32973163
      reference_title: "Epidermolysis bullosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "specific complications, the most feared of which - and also the leading cause of mortality - is squamous cell carcinoma"
      explanation: Supports that chronic wound burden in EB is linked to serious downstream complications, including malignant transformation.
  evidence:
  - reference: PMID:32973163
    reference_title: "Epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multidisciplinary care is targeted towards minimizing the risk of blister formation, wound care, symptom relief and specific complications, the most feared of which - and also the leading cause of mortality - is squamous cell carcinoma"
    explanation: Confirms that chronic wound complications including squamous cell carcinoma are major concerns in EB management.
  - reference: PMID:25279494
    reference_title: "Inherited epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a specific attention to the fragile skin is required in order to reduce pain, risk of trauma, ulceration and infection"
    explanation: Confirms that ulceration and impaired wound healing are significant complications requiring specialized management.
- name: Secondary Complications
  description: >
    Chronic skin barrier disruption in EB leads to a range of secondary
    complications including bacterial infection of wounds, progressive scarring
    (especially in dystrophic EB), nutritional deficiency due to oral and
    esophageal involvement, anemia of chronic disease, and growth retardation.
    Severe forms carry risk of squamous cell carcinoma as the leading cause
    of mortality.
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: collagen fibril organization
    modifier: ABNORMAL
    term:
      id: GO:0030199
      label: collagen fibril organization
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:32973163
    reference_title: "Epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A broad phenotypic spectrum has been described, with potentially severe extracutaneous manifestations, morbidity and mortality"
    explanation: Confirms that EB has severe extracutaneous complications contributing to morbidity and mortality.
  - reference: PMID:20507631
    reference_title: "Inherited epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations range widely, from localized blistering of the hands and feet to generalized blistering of the skin and oral cavity, and injury to many internal organs"
    explanation: Confirms the broad range of secondary complications including internal organ involvement.
phenotypes:
- category: Integument
  name: Skin Fragility and Blistering
  description: >
    The cardinal feature of all EB types. Recurrent blister formation as the
    result of structural fragility within the skin, triggered by minimal
    mechanical trauma or friction. Severity ranges from localized blistering
    of hands and feet to generalized involvement.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: skin fragility with blistering
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: PMID:32973163
    reference_title: "Epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mucocutaneous fragility and blister formation, inducible by often minimal trauma"
    explanation: Confirms skin fragility and blister formation as the defining feature of EB.
  - reference: PMID:20507631
    reference_title: "Inherited epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a number of disorders characterized by recurrent blister formation as the result of structural fragility within the skin and selected other tissues"
    explanation: Confirms recurrent blistering due to structural skin fragility across all EB types.
- category: Integument
  name: Mucosal Involvement
  description: >
    Blistering and erosions of mucous membranes including oral, esophageal,
    and ocular surfaces. Oral involvement can lead to microstomia, ankyloglossia,
    and dental complications. Esophageal involvement may cause strictures,
    particularly in dystrophic EB.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: oral mucosal blistering
    term:
      id: HP:0011830
      label: Abnormal oral mucosa morphology
  notes: Oral, esophageal, and ocular mucous membranes may all be affected.
  evidence:
  - reference: PMID:20507631
    reference_title: "Inherited epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "generalized blistering of the skin and oral cavity, and injury to many internal organs"
    explanation: Confirms oral cavity involvement as part of the generalized disease spectrum.
  - reference: PMID:34036913
    reference_title: "Epidermolysis Bullosa: Pediatric Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe complications may arise in some EB types and subtypes within the eye, ear, nose, upper airway, gastrointestinal and genitourinary tracts"
    explanation: Confirms extracutaneous mucosal involvement across multiple organ systems.
- category: Integument
  name: Nail Dystrophy
  description: >
    Nail changes ranging from mild ridging to complete nail loss. Common
    across all major EB types with variable severity.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia"
    explanation: JEB GeneReviews confirms nail dystrophy as a shared feature across all major forms of EB.
- category: Integument
  name: Milia
  description: >
    Small white keratin-filled cysts that develop at sites of healed blisters.
    Particularly characteristic of dystrophic EB but can occur in other types.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: milia
    term:
      id: HP:0001056
      label: Milia
  evidence:
  - reference: PMID:20301481
    reference_title: "Dystrophic Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skin fragility manifested by blistering and erosions with minimal trauma that heals with milia and scarring"
    explanation: Supports milia as a characteristic healing outcome in dystrophic epidermolysis bullosa.
- category: Integument
  name: Scarring
  description: >
    Scarring at sites of blister healing, variable by EB type. Minimal in EB
    simplex, prominent in dystrophic EB where it can lead to pseudosyndactyly
    (mitten deformities) of hands and feet.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: abnormal scarring
    term:
      id: HP:0100699
      label: Scarring
  evidence:
  - reference: PMID:20301481
    reference_title: "Dystrophic Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skin fragility manifested by blistering and erosions with minimal trauma that heals with milia and scarring"
    explanation: GeneReviews confirms that blisters in DEB heal with scarring, a key distinguishing feature of dystrophic forms.
- category: Growth
  name: Failure to Thrive
  description: >
    Growth retardation and failure to thrive, particularly in severe generalized
    forms. Results from chronic wounds, increased metabolic demands, oral and
    esophageal involvement limiting nutritional intake, and chronic inflammation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:20507631
    reference_title: "Inherited epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Optimal patient management requires a multidisciplinary approach, and revolves around the protection of susceptible tissues against trauma, use of sophisticated wound care dressings, aggressive nutritional support, and early medical or surgical interventions to correct whenever possible the extracutaneous complications"
    explanation: The need for aggressive nutritional support as a core management pillar implies significant growth and nutritional challenges in severe EB.
  - reference: PMID:34036913
    reference_title: "Epidermolysis Bullosa: Pediatric Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications"
    explanation: Nutritional support as a core management pillar confirms failure to thrive as a significant clinical issue.
- category: Blood
  name: Anemia
  description: >
    Anemia of chronic disease and/or iron deficiency anemia due to chronic
    wounds, blood loss, inflammation, and poor nutritional intake. Common
    in moderate to severe EB.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:20301481
    reference_title: "Dystrophic Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anemia is treated with iron supplements and transfusions as needed"
    explanation: GeneReviews confirms anemia as a recognized complication of DEB requiring treatment with iron supplementation and transfusions.
- category: Constitutional
  name: Pain
  description: >
    Chronic and acute pain is a major feature of EB, arising from blistering,
    wound care procedures, and chronic wounds. Pain management is a core
    component of EB care.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: pain
    term:
      id: HP:0012531
      label: Pain
  evidence:
  - reference: PMID:34036913
    reference_title: "Epidermolysis Bullosa: Pediatric Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "painful blistering of the skin and mucous membranes"
    explanation: Confirms pain as a cardinal symptom associated with blistering in EB.
  - reference: PMID:25279494
    reference_title: "Inherited epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "management of itching and pain"
    explanation: Confirms pain management as a major component of EB care.
treatments:
- name: Wound Care and Dressing Management
  description: >
    Specialized wound care is the cornerstone of EB management. Involves
    non-adherent dressings, gentle wound cleansing, blister lancing, and
    protection of fragile skin from mechanical trauma. Sophisticated wound
    care dressings are used to promote healing and minimize pain.
  treatment_term:
    preferred_term: wound care management
    term:
      id: MAXO:0000950
      label: supportive care
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: skin of body
        term:
          id: UBERON:0002097
          label: skin of body
  evidence:
  - reference: PMID:20507631
    reference_title: "Inherited epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "use of sophisticated wound care dressings"
    explanation: Confirms specialized wound care dressings as a key management strategy.
  - reference: PMID:34036913
    reference_title: "Epidermolysis Bullosa: Pediatric Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications"
    explanation: Confirms wound care as a core pillar of EB management.
  - reference: PMID:25279494
    reference_title: "Inherited epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "global skin care including wound care"
    explanation: Confirms wound care as central to EB patient management.
- name: Pain Management
  description: >
    Multimodal pain management for chronic wound pain, procedural pain during
    dressing changes, and acute pain from new blisters. May include
    pharmacological and non-pharmacological approaches.
  treatment_term:
    preferred_term: pain management
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:34036913
    reference_title: "Epidermolysis Bullosa: Pediatric Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications"
    explanation: Confirms pain control as a core component of EB management.
  - reference: PMID:25279494
    reference_title: "Inherited epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "management of itching and pain"
    explanation: Confirms pain and itch management as key aspects of EB care.
- name: Nutritional Support
  description: >
    Aggressive nutritional support to address growth failure, anemia, and
    increased metabolic demands from chronic wounds. May require supplemental
    feeding or gastrostomy in severe cases with oral and esophageal involvement.
  treatment_term:
    preferred_term: nutritional support
    term:
      id: MAXO:0000088
      label: dietary intervention
  evidence:
  - reference: PMID:20507631
    reference_title: "Inherited epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "aggressive nutritional support"
    explanation: Confirms aggressive nutritional support as essential in EB management.
  - reference: PMID:34036913
    reference_title: "Epidermolysis Bullosa: Pediatric Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications"
    explanation: Confirms nutritional support as a core management component.
- name: Infection Prevention and Treatment
  description: >
    Prevention and treatment of wound infections, which are common due to
    chronic skin barrier disruption. Includes topical antiseptics, appropriate
    use of antibiotics, and surveillance for wound colonization.
  treatment_term:
    preferred_term: infection management
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:34036913
    reference_title: "Epidermolysis Bullosa: Pediatric Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications"
    explanation: Confirms infection control as a core pillar of EB management.
  - reference: PMID:25279494
    reference_title: "Inherited epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a specific attention to the fragile skin is required in order to reduce pain, risk of trauma, ulceration and infection"
    explanation: Confirms infection prevention as key in EB wound management.
- name: Genetic Counseling
  description: >
    Genetic counseling for affected families to discuss inheritance patterns,
    recurrence risk, prenatal testing options, and implications for family
    planning. Essential given the variable inheritance patterns across EB types.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:34036913
    reference_title: "Epidermolysis Bullosa: Pediatric Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis is suspected based on symptoms and confirmed by skin biopsy and definitive genetic testing"
    explanation: The role of genetic testing in diagnosis underscores the importance of genetic counseling for families.
- name: Vyjuvek (Beremagene Geperpavec)
  description: >
    FDA-approved topical gene therapy for dystrophic epidermolysis bullosa
    (May 2023). Beremagene geperpavec-svdt (VYJUVEK) is a topically applied,
    redosable, replication-defective HSV-1 vector-based gene therapy that
    delivers functional COL7A1 to restore type VII collagen production. In the
    phase 3 GEM-3 trial, complete wound healing at 6 months occurred in 67%
    of B-VEC-treated wounds vs 22% of placebo wounds. Approved for wounds in
    patients aged 6 months and older with DEB carrying COL7A1 mutations.
  treatment_term:
    preferred_term: topical gene therapy (beremagene geperpavec)
    term:
      id: MAXO:0001001
      label: gene therapy
    qualifiers:
    - predicate:
        preferred_term: route of administration
        term:
          id: NCIT:C38114
          label: Route of Administration
      value:
        preferred_term: topical route of administration
        term:
          id: NCIT:C38304
          label: Topical Route of Administration
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: COL7A1
        term:
          id: hgnc:2214
          label: COL7A1
  evidence:
  - reference: PMID:36516090
    reference_title: "Trial of Beremagene Geperpavec (B-VEC) for Dystrophic Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete wound healing at 3 and 6 months in patients with dystrophic epidermolysis bullosa was more likely with topical administration of B-VEC than with placebo"
    explanation: Phase 3 NEJM trial demonstrating significant wound healing benefit of beremagene geperpavec over placebo in dystrophic EB.
  - reference: PMID:37432558
    reference_title: "Beremagene Geperpavec: First Approval."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In May 2023, beremagene geperpavec received its first approval in the US for the treatment of wounds in patients"
    explanation: Confirms FDA approval in May 2023 as the first topical gene therapy for dystrophic EB.
- name: Filsuvez (Birch Triterpenes)
  description: >
    FDA-approved topical gel for epidermolysis bullosa wound healing
    (December 2023). Filsuvez (Oleogel-S10) contains birch triterpenes and
    promotes wound healing by modulating inflammation and encouraging tissue
    formation. In the phase 3 EASE trial, 41.3% of patients treated with
    Oleogel-S10 achieved first complete target wound closure within 45 days
    vs 28.9% with control gel. Approved for partial-thickness wounds in
    patients aged 6 months and older with junctional or dystrophic EB.
  treatment_term:
    preferred_term: topical birch triterpenes wound therapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    qualifiers:
    - predicate:
        preferred_term: route of administration
        term:
          id: NCIT:C38114
          label: Route of Administration
      value:
        preferred_term: topical route of administration
        term:
          id: NCIT:C38304
          label: Topical Route of Administration
  evidence:
  - reference: PMID:36689495
    reference_title: "Efficacy and safety of Oleogel-S10 (birch triterpenes) for epidermolysis bullosa: results from the phase III randomized double-blind phase of the EASE study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oleogel-S10 is the first therapy to demonstrate accelerated wound healing in EB"
    explanation: Phase 3 EASE trial demonstrating Oleogel-S10 as the first therapy to show accelerated wound healing in EB.
  - reference: PMID:39748581
    reference_title: "Filsuvez(®) (Birch Triterpenes) Topical Gel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Filsuvez® (birch triterpenes) topical gel received approval in 2023 for the treatment of epidermolysis bullosa (EB) in pediatric patients (aged ≥6 months) and adults"
    explanation: Confirms FDA approval of Filsuvez for treatment of EB wounds in pediatric and adult patients.
- name: Zevaskyn (Prademagene Zamikeracel / pz-cel)
  description: >
    FDA-approved autologous cell sheet-based gene therapy for recessive
    dystrophic epidermolysis bullosa (April 2025). Prademagene zamikeracel
    (ZEVASKYN) contains the patient's own keratinocytes genetically modified
    with functional copies of the COL7A1 gene, produced as transplantable
    epidermal sheets. In the phase 1/2a trial, wound healing of 50% or
    greater was present in 95% of treated wounds versus 0% of untreated
    controls at 6 months. It is the first and only cell-based gene therapy
    approved for RDEB.
  treatment_term:
    preferred_term: autologous gene-corrected cell therapy (prademagene zamikeracel)
    term:
      id: MAXO:0000016
      label: cellular therapy
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: keratinocyte
        term:
          id: CL:0000312
          label: keratinocyte
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: COL7A1
        term:
          id: hgnc:2214
          label: COL7A1
  evidence:
  - reference: PMID:40875177
    reference_title: "Prademagene Zamikeracel: First Approval."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prademagene zamikeracel (ZEVASKYN™) is an autologous cell sheet-based gene therapy developed by Abeona Therapeutics Inc. for the treatment of wounds in patients with recessive dystrophic epidermolysis bullosa"
    explanation: Confirms FDA approval of prademagene zamikeracel as the first cell-based gene therapy for RDEB.
  - reference: PMID:31578311
    reference_title: "Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wound healing of 50% or greater by Investigator Global Assessment was present in 95% (36 of 38) of treated wounds versus 0% (0 of 6) of untreated control wounds at 6 months (P < 0.0001)"
    explanation: Phase 1/2a trial demonstrating significant wound healing with gene-corrected autologous cell therapy in RDEB patients.
biochemical:
- name: Type VII Collagen
  presence: Decreased
  context: Reduced or absent in dystrophic EB due to COL7A1 mutations; assessed by immunofluorescence mapping
  evidence:
  - reference: PMID:31920360
    reference_title: "From Clinical Phenotype to Genotypic Modelling: Incidence and Prevalence of Recessive Dystrophic Epidermolysis Bullosa (RDEB)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RDEB patients demonstrate reduction or structural alteration type VII collagen (C7) owing to mutations in the gene COL7A1"
    explanation: Supports decreased or abnormal type VII collagen in dystrophic EB caused by COL7A1 mutations.
- name: Laminin-332
  presence: Decreased
  context: Reduced or absent in junctional EB due to LAMA3, LAMB3, or LAMC2 mutations
  evidence:
  - reference: PMID:22512697
    reference_title: "Long-term follow-up of patients with Herlitz-type junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Junctional epidermolysis bullosa, type Herlitz (JEB-H) is a rare, autosomal recessive disease caused by absence of the epidermal basement membrane adhesion protein laminin-332"
    explanation: Supports absent laminin-332 as a defining molecular abnormality in severe junctional epidermolysis bullosa.
- name: Keratin 5 and Keratin 14
  presence: Variable
  context: Abnormal intermediate filament network in EB simplex due to KRT5 or KRT14 mutations
  evidence:
  - reference: PMID:22277943
    reference_title: "Defining keratin protein function in skin epithelia: epidermolysis bullosa simplex and its aftermath."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most cases of EBS are due to dominantly acting mutations in keratin 14 (K14) or K5, the type I and II intermediate filament (IF) proteins that copolymerize to form a pancytoplasmic network of 10 nm filaments in basal keratinocytes of epidermis"
    explanation: Supports keratin 5 and keratin 14 as the intermediate filament proteins disrupted in EB simplex.
diagnosis:
- name: Clinical Assessment
  description: >
    Initial evaluation based on clinical features including blister morphology,
    distribution, mucosal involvement, and family history. Clinical assessment
    guides selection of further diagnostic investigations and provisional
    subtype classification.
  presence: First-line
  notes: >
    Clinical assessment is the first step in the diagnostic algorithm. Key
    features include age of onset, blister distribution, healing pattern
    (scarring vs non-scarring), and extracutaneous involvement. However,
    clinical features alone cannot reliably distinguish all EB subtypes.
  evidence:
  - reference: PMID:32973163
    reference_title: "Epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A broad phenotypic spectrum has been described, with potentially severe extracutaneous manifestations, morbidity and mortality"
    explanation: Confirms the importance of clinical assessment given the broad phenotypic spectrum of EB subtypes.
- name: Immunofluorescence Mapping (IFM)
  description: >
    Skin biopsy technique using a panel of antibodies against basement membrane
    zone proteins to determine the level of cleavage and identify the deficient
    protein. IFM achieves 97% sensitivity and 100% specificity for EB subtype
    classification when compared to genetic testing as the reference standard.
    IFM has largely superseded transmission electron microscopy (TEM) for
    routine EB diagnosis due to superior diagnostic accuracy.
  presence: Gold standard tissue-based test
  notes: >
    IFM subclassified EB into its three major forms in 29/30 cases (97%)
    compared to 24/30 (80%) for TEM. TEM sensitivities and specificities
    were only 71% and 81% respectively. IFM is now the preferred tissue-based
    diagnostic method in the current diagnostic algorithm.
  evidence:
  - reference: PMID:17012912
    reference_title: "A comparative study between transmission electron microscopy and immunofluorescence mapping in the diagnosis of epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IFM sensitivities and specificities when compared with genetic results were 97% and 100%, respectively"
    explanation: Landmark comparative study demonstrating IFM superiority over TEM for EB diagnosis and subclassification, establishing IFM as the preferred tissue-based diagnostic method.
  - reference: PMID:17012912
    reference_title: "A comparative study between transmission electron microscopy and immunofluorescence mapping in the diagnosis of epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TEM subclassified EB into its three major forms in 24/30 cases (80%) and IFM in 29/30 cases (97%)"
    explanation: Demonstrates that IFM has substantially higher subtype classification accuracy than TEM, supporting TEM being largely superseded by IFM for routine diagnosis.
- name: Next-Generation Sequencing Gene Panels
  description: >
    Targeted NGS panels covering 18-26 EB-associated genes provide definitive
    molecular diagnosis, confirming the specific gene and mutation underlying
    the patient's EB subtype. Genetic testing has evolved from Sanger
    sequencing of single candidate genes to comprehensive multi-gene panels,
    enabling genotype-phenotype correlation and informed genetic counseling.
  presence: Definitive molecular diagnosis
  notes: >
    Genetic testing is the definitive diagnostic step, confirming the
    molecular basis and enabling accurate genetic counseling. In the Dutch
    EB Registry, genetic diagnosis was achieved in 90.5% of patients. NGS
    panels have largely replaced sequential single-gene Sanger sequencing.
  evidence:
  - reference: PMID:33095945
    reference_title: "Novel insights into the epidemiology of epidermolysis bullosa (EB) from the Dutch EB Registry: EB more common than previously assumed?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 90.5% of the EB-patients the diagnosis was genetically confirmed"
    explanation: Dutch EB Registry data confirms that genetic testing achieves definitive diagnosis in the vast majority of EB patients.
  - reference: PMID:34036913
    reference_title: "Epidermolysis Bullosa: Pediatric Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis is suspected based on symptoms and confirmed by skin biopsy and definitive genetic testing"
    explanation: Confirms the sequential diagnostic approach from clinical suspicion through skin biopsy to definitive genetic testing.
clinical_trials:
- name: NCT04908215
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Completed phase II randomized trial of topical INM-755 (cannabinol) cream
    for epidermolysis bullosa that enrolled multiple EB subtypes, including
    simplex, junctional, dystrophic, and Kindler syndrome.
  target_phenotypes:
  - preferred_term: Wound healing impairment
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: clinicaltrials:NCT04908215
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to evaluate the safety of INM-755 (cannabinol) cream and obtain preliminary evidence of efficacy in treating symptoms and healing wounds over a 28-day period in patients with epidermolysis bullosa (EB)."
    explanation: This ClinicalTrials.gov record supports a completed multi-subtype EB trial evaluating topical cannabinol cream for symptom control and wound healing.
- name: NCT02014376
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Completed randomized vehicle-controlled phase II study of topical SD-101
    cream in epidermolysis bullosa, including simplex, recessive dystrophic,
    and junctional non-Herlitz subtypes.
  target_phenotypes:
  - preferred_term: Wound healing impairment
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: clinicaltrials:NCT02014376
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study was to assess whether the topical use of SD-101 cream (3% or 6%) was effective in treating wounds in participants with Simplex, Recessive Dystrophic, or Junctional non-Herlitz Epidermolysis Bullosa (EB)."
    explanation: This ClinicalTrials.gov record supports a completed wound-healing trial that enrolled multiple major EB subtypes under the umbrella diagnosis.
genetic:
- name: KRT5
  association: Causative
  inheritance:
  - name: Autosomal dominant
    evidence:
    - reference: PMID:20301543
      reference_title: "Epidermolysis Bullosa Simplex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal dominant EBS is associated with either a heterozygous dominant-negative variant in KRT5, KRT14, or PLEC"
      explanation: GeneReviews confirms autosomal dominant inheritance for KRT5.
  notes: >
    Encodes keratin 5, a major intermediate filament protein of basal
    keratinocytes. Mutations cause EB simplex through dominant-negative
    disruption of the keratin cytoskeleton.
  evidence:
  - reference: PMID:32973163
    reference_title: "Epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion"
    explanation: Confirms that genes encoding structural proteins including keratins are causative of EB.
- name: KRT14
  association: Causative
  inheritance:
  - name: Autosomal dominant
    evidence:
    - reference: PMID:20301543
      reference_title: "Epidermolysis Bullosa Simplex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal dominant EBS is associated with either a heterozygous dominant-negative variant in KRT5, KRT14, or PLEC"
      explanation: GeneReviews confirms autosomal dominant inheritance for KRT14.
  notes: >
    Encodes keratin 14, partner of keratin 5 in basal keratinocyte intermediate
    filaments. Mutations cause EB simplex, with severity depending on mutation
    location within the protein.
  evidence:
  - reference: PMID:20301543
    reference_title: "Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the identification of a heterozygous dominant-negative variant or biallelic loss-of-function variants in KRT5, KRT14, or PLEC"
    explanation: Supports KRT14 as a causative EB simplex gene in the clinical diagnostic framework.
- name: COL7A1
  association: Causative
  inheritance:
  - name: Autosomal dominant
    evidence:
    - reference: PMID:20301481
      reference_title: "Dystrophic Epidermolysis Bullosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "About 70% of individuals diagnosed with DDEB are reported to have an affected parent"
      explanation: GeneReviews confirms autosomal dominant inheritance for DDEB.
  - name: Autosomal recessive
    evidence:
    - reference: PMID:20301481
      reference_title: "Dystrophic Epidermolysis Bullosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "If both parents are known to be heterozygous for a COL7A1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected"
      explanation: GeneReviews confirms autosomal recessive inheritance for RDEB.
  notes: >
    Encodes type VII collagen, the major structural component of anchoring
    fibrils that connect the basement membrane to the underlying dermis.
    Mutations cause dystrophic EB. Dominant mutations typically cause milder
    disease; recessive mutations cause severe generalized dystrophic EB.
  evidence:
  - reference: PMID:32973163
    reference_title: "Epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over 30 subtypes are recognized, grouped into four major categories, based predominantly on the plane of cleavage within the skin and reflecting the underlying molecular abnormality"
    explanation: Confirms that specific molecular abnormalities including collagen VII defects determine EB subtypes.
- name: LAMB3
  association: Causative
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:20301304
      reference_title: "Junctional Epidermolysis Bullosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "JEB is inherited in an autosomal recessive manner"
      explanation: GeneReviews confirms autosomal recessive inheritance for LAMB3.
  notes: >
    Encodes the beta-3 chain of laminin-332, a key component of the
    basement membrane zone. Mutations cause junctional EB.
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
    explanation: Supports LAMB3 as one of the established causative genes for junctional epidermolysis bullosa.
- name: LAMA3
  association: Causative
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:20301304
      reference_title: "Junctional Epidermolysis Bullosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "JEB is inherited in an autosomal recessive manner"
      explanation: GeneReviews confirms autosomal recessive inheritance for LAMA3-associated junctional EB.
  notes: >
    Encodes the alpha-3 chain of laminin-332, an essential basement membrane
    zone anchoring filament component. Mutations cause junctional EB severe or
    intermediate phenotypes.
  evidence:
  - reference: PMID:19945616
    reference_title: "Herlitz junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this devastating condition is most often caused by homozygous null mutations in the genes LAMA3, LAMB3, or LAMC2, each encoding for 1 of the 3 chains of the heterotrimer laminin-332"
    explanation: Supports LAMA3 as a causative laminin-332 chain gene in junctional epidermolysis bullosa.
- name: LAMC2
  association: Causative
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:20301304
      reference_title: "Junctional Epidermolysis Bullosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "JEB is inherited in an autosomal recessive manner"
      explanation: GeneReviews confirms autosomal recessive inheritance for LAMC2-associated junctional EB.
  notes: >
    Encodes the gamma-2 chain of laminin-332, a core basement membrane zone
    adhesion protein. Mutations cause junctional EB severe or intermediate phenotypes.
  evidence:
  - reference: PMID:19945616
    reference_title: "Herlitz junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this devastating condition is most often caused by homozygous null mutations in the genes LAMA3, LAMB3, or LAMC2, each encoding for 1 of the 3 chains of the heterotrimer laminin-332"
    explanation: Supports LAMC2 as a causative laminin-332 chain gene in junctional epidermolysis bullosa.
- name: COL17A1
  association: Causative
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:20301304
      reference_title: "Junctional Epidermolysis Bullosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "JEB is inherited in an autosomal recessive manner"
      explanation: GeneReviews confirms autosomal recessive inheritance for COL17A1.
  notes: >
    Encodes type XVII collagen (also known as BP180), a transmembrane
    protein of hemidesmosomes. Mutations cause junctional EB.
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
    explanation: Supports COL17A1 as one of the established causative genes for junctional epidermolysis bullosa.
- name: ITGA6
  association: Causative
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:20301304
      reference_title: "Junctional Epidermolysis Bullosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "JEB is inherited in an autosomal recessive manner"
      explanation: GeneReviews supports recessive inheritance across junctional EB genes, including ITGA6-associated disease.
  notes: >
    Encodes integrin alpha-6, one half of the alpha6-beta4 hemidesmosomal
    receptor. Mutations cause junctional EB with pyloric atresia and impaired
    epithelial-basement membrane adhesion.
  evidence:
  - reference: PMID:32973163
    reference_title: "Epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion"
    explanation: Supports ITGA6 as part of the adhesion-gene set underlying EB, consistent with its role in JEB with pyloric atresia.
- name: ITGB4
  association: Causative
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:20301304
      reference_title: "Junctional Epidermolysis Bullosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "JEB is inherited in an autosomal recessive manner"
      explanation: GeneReviews confirms autosomal recessive inheritance for ITGB4-associated junctional EB.
  notes: >
    Encodes integrin beta-4, the beta subunit of the alpha6-beta4
    hemidesmosomal receptor. Mutations cause junctional EB with pyloric atresia
    or related junctional EB phenotypes.
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
    explanation: Supports ITGB4 as one of the established causative genes for junctional epidermolysis bullosa.
- name: FERMT1
  association: Causative
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:26937547
      reference_title: "Kindler Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "KS is inherited in an autosomal recessive manner"
      explanation: GeneReviews confirms autosomal recessive inheritance for FERMT1.
  notes: >
    Encodes kindlin-1 (fermitin family member 1), a focal adhesion protein
    involved in integrin activation. Mutations cause Kindler EB, characterized
    by mixed cleavage planes and photosensitivity.
  evidence:
  - reference: PMID:32973163
    reference_title: "Epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EB simplex, junctional EB, dystrophic EB and Kindler EB"
    explanation: Confirms Kindler EB as one of the four major EB categories in the consensus classification.
notes: >-
  Key EB Registries: (1) US National Epidermolysis Bullosa Registry (NEBR),
  established 1986, provides incidence/prevalence data for the United States
  (PMID:20507631, PMID:27463098). (2) Dutch EB Registry at UMCG Groningen,
  the sole national expertise centre for EB in the Netherlands, with
  molecularly confirmed diagnoses in 90.5% of patients (PMID:33095945).
  (3) German EB Registry, population-based cross-sectional study using
  academic hospitals, diagnostic laboratories, and patient organizations
  (PMID:36196047). (4) England and Wales National EB Database, NHS-based
  registry with over 2,500 patients (PMID:34927719). Recent registry
  data consistently indicate that EB is more common than earlier estimates
  suggested, with incidences up to 67.8 per million live births
  (England/Wales) and prevalences up to 54 per million (Germany).
datasets:
- accession: PMID:33095945
  title: "Novel insights into the epidemiology of epidermolysis bullosa (EB) from the Dutch EB Registry: EB more common than previously assumed?"
  description: >-
    National registry-based phenotype dataset covering molecularly characterized
    epidermolysis bullosa patients in the Netherlands from 1988 to 2018, with
    complete diagnostic workup and longitudinal follow-up across EBS, JEB, DEB,
    and Kindler EB.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: PHENOPACKETS
  sample_count: 464
  conditions:
  - Epidermolysis bullosa simplex
  - Junctional epidermolysis bullosa
  - Dystrophic epidermolysis bullosa
  - Kindler epidermolysis bullosa
  publication: PMID:33095945
  evidence:
  - reference: PMID:33095945
    reference_title: "Novel insights into the epidemiology of epidermolysis bullosa (EB) from the Dutch EB Registry: EB more common than previously assumed?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 464 EB-patients (287 families) were included."
    explanation: Supports the Dutch EB Registry as a substantial national phenotype resource spanning the major EB subtypes.
  - reference: PMID:33095945
    reference_title: "Novel insights into the epidemiology of epidermolysis bullosa (EB) from the Dutch EB Registry: EB more common than previously assumed?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this observational study all EB-patients that were based in the Netherlands and captured in the Dutch EB Registry between 1988 and 2018 were included."
    explanation: Confirms the registry's longitudinal national scope and direct relevance as an EB-wide clinical dataset.
references:
- reference: PMID:26937547
  title: "Kindler Syndrome."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301543
  title: "Epidermolysis Bullosa Simplex."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301481
  title: "Dystrophic Epidermolysis Bullosa."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301304
  title: "Junctional Epidermolysis Bullosa."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1007/s12326-024-00627-z
  title: Neue Lokal- und Systemtherapien bei Epidermolysis bullosa
  found_in:
  - Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: ZusammenfassungEpidermolysis bullosa (EB) bezeichnet eine seltene, heterogene Gruppe von Genodermatosen, charakterisiert durch eine gesteigerte Fragilität von Haut und Schleimhaut.
    supporting_text: ZusammenfassungEpidermolysis bullosa (EB) bezeichnet eine seltene, heterogene Gruppe von Genodermatosen, charakterisiert durch eine gesteigerte Fragilität von Haut und Schleimhaut.
    evidence:
    - reference: DOI:10.1007/s12326-024-00627-z
      reference_title: Neue Lokal- und Systemtherapien bei Epidermolysis bullosa
      supports: SUPPORT
      evidence_source: OTHER
      snippet: ZusammenfassungEpidermolysis bullosa (EB) bezeichnet eine seltene, heterogene Gruppe von Genodermatosen, charakterisiert durch eine gesteigerte Fragilität von Haut und Schleimhaut.
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
- reference: DOI:10.1007/s40257-025-00942-y
  title: Long-Term Safety and Tolerability of Beremagene Geperpavec-svdt (B-VEC) in an Open-Label Extension Study of Patients with Dystrophic Epidermolysis Bullosa
  found_in:
  - Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Long-Term Safety and Tolerability of Beremagene Geperpavec-svdt (B-VEC) in an Open-Label Extension Study of Patients with Dystrophic Epidermolysis Bullosa
    supporting_text: Long-Term Safety and Tolerability of Beremagene Geperpavec-svdt (B-VEC) in an Open-Label Extension Study of Patients with Dystrophic Epidermolysis Bullosa
- reference: DOI:10.1186/s13023-023-02817-z
  title: 'Itch in recessive dystrophic epidermolysis bullosa: findings of PEBLES, a prospective register study'
  found_in:
  - Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: 'Itch in recessive dystrophic epidermolysis bullosa: findings of PEBLES, a prospective register study'
    supporting_text: Itch is common and distressing in epidermolysis bullosa (EB) but has not previously been studied in depth in different recessive dystrophic EB (RDEB) subtypes.ObjectivesAs part of a prospective register study of the natural history of RDEB we explored features of itch, medications used, and correlation with disease severity and quality of life.MethodsFifty individuals with RDEB aged 8 years and above completed the Leuven Itch Scale (LIS) (total 243 reviews over a 7-year period).
    evidence:
    - reference: DOI:10.1186/s13023-023-02817-z
      reference_title: 'Itch in recessive dystrophic epidermolysis bullosa: findings of PEBLES, a prospective register study'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Itch is common and distressing in epidermolysis bullosa (EB) but has not previously been studied in depth in different recessive dystrophic EB (RDEB) subtypes.ObjectivesAs part of a prospective register study of the natural history of RDEB we explored features of itch, medications used, and correlation with disease severity and quality of life.MethodsFifty individuals with RDEB aged 8 years and above completed the Leuven Itch Scale (LIS) (total 243 reviews over a 7-year period).
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
- reference: DOI:10.1186/s13023-024-03190-1
  title: 'Therapies for cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa: a systematic review of 157 cases'
  found_in:
  - Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Invasive cutaneous squamous cell carcinomas (cSCC) are a leading cause of death in recessive dystrophic epidermolysis bullosa (RDEB), a rare blistering genodermatosis.
    supporting_text: Invasive cutaneous squamous cell carcinomas (cSCC) are a leading cause of death in recessive dystrophic epidermolysis bullosa (RDEB), a rare blistering genodermatosis.
    evidence:
    - reference: DOI:10.1186/s13023-024-03190-1
      reference_title: 'Therapies for cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa: a systematic review of 157 cases'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Invasive cutaneous squamous cell carcinomas (cSCC) are a leading cause of death in recessive dystrophic epidermolysis bullosa (RDEB), a rare blistering genodermatosis.
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
- reference: DOI:10.1186/s13023-024-03328-1
  title: Economic burden and health-related quality of life in patients with epidermolysis bullosa in Spain
  found_in:
  - Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Epidermolysis bullosa (EB) is a rare genetic skin disorder characterized by fragility of skin with appearance of acute and chronic wounds.
    supporting_text: Epidermolysis bullosa (EB) is a rare genetic skin disorder characterized by fragility of skin with appearance of acute and chronic wounds.
    evidence:
    - reference: DOI:10.1186/s13023-024-03328-1
      reference_title: Economic burden and health-related quality of life in patients with epidermolysis bullosa in Spain
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Epidermolysis bullosa (EB) is a rare genetic skin disorder characterized by fragility of skin with appearance of acute and chronic wounds.
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
- reference: DOI:10.15690/vsp.v23i5.2808
  title: Congenital Epidermolysis Bullosa Epidemiology among Children of Russian Federation
  found_in:
  - Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: The prevalence of all types of congenital epidermolysis bullosa (СEB) worldwide is approximately 11 cases per 1 million according to the latest data from the American Epidermolysis Bullosa Registry.
    supporting_text: The prevalence of all types of congenital epidermolysis bullosa (СEB) worldwide is approximately 11 cases per 1 million according to the latest data from the American Epidermolysis Bullosa Registry.
    evidence:
    - reference: DOI:10.15690/vsp.v23i5.2808
      reference_title: Congenital Epidermolysis Bullosa Epidemiology among Children of Russian Federation
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The prevalence of all types of congenital epidermolysis bullosa (СEB) worldwide is approximately 11 cases per 1 million according to the latest data from the American Epidermolysis Bullosa Registry.
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
- reference: DOI:10.3390/bioengineering12060574
  title: Towards Extracellular Vesicles in the Treatment of Epidermolysis Bullosa
  found_in:
  - Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Epidermolysis bullosa (EB) is a debilitating genetic skin disorder characterized by extreme fragility, chronic wounds, and severe complications, particularly in its most severe form, recessive dystrophic EB (RDEB).
    supporting_text: Epidermolysis bullosa (EB) is a debilitating genetic skin disorder characterized by extreme fragility, chronic wounds, and severe complications, particularly in its most severe form, recessive dystrophic EB (RDEB).
    evidence:
    - reference: DOI:10.3390/bioengineering12060574
      reference_title: Towards Extracellular Vesicles in the Treatment of Epidermolysis Bullosa
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Epidermolysis bullosa (EB) is a debilitating genetic skin disorder characterized by extreme fragility, chronic wounds, and severe complications, particularly in its most severe form, recessive dystrophic EB (RDEB).
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
- reference: DOI:10.3390/ijms25042243
  title: Emerging Gene Therapeutics for Epidermolysis Bullosa under Development
  found_in:
  - Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: The monogenetic disease epidermolysis bullosa (EB) is characterised by the formation of extended blisters and lesions on the patient’s skin upon minimal mechanical stress.
    supporting_text: The monogenetic disease epidermolysis bullosa (EB) is characterised by the formation of extended blisters and lesions on the patient’s skin upon minimal mechanical stress.
    evidence:
    - reference: DOI:10.3390/ijms25042243
      reference_title: Emerging Gene Therapeutics for Epidermolysis Bullosa under Development
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The monogenetic disease epidermolysis bullosa (EB) is characterised by the formation of extended blisters and lesions on the patient’s skin upon minimal mechanical stress.
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
- reference: DOI:10.3390/ijms26146592
  title: 'Gene Therapies in Dermatological Diseases: A Breakthrough in Treatment'
  found_in:
  - Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Gene therapy involves introducing genetic material into cells to treat or prevent disease and offers highly targeted and potentially curative approaches for both inherited and acquired conditions.
    supporting_text: Gene therapy involves introducing genetic material into cells to treat or prevent disease and offers highly targeted and potentially curative approaches for both inherited and acquired conditions.
    evidence:
    - reference: DOI:10.3390/ijms26146592
      reference_title: 'Gene Therapies in Dermatological Diseases: A Breakthrough in Treatment'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Gene therapy involves introducing genetic material into cells to treat or prevent disease and offers highly targeted and potentially curative approaches for both inherited and acquired conditions.
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
- reference: DOI:10.3390/jcm13133742
  title: Epidemiological Characteristics of Inherited Epidermolysis Bullosa in an Eastern European Population
  found_in:
  - Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity.
    supporting_text: Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity.
    evidence:
    - reference: DOI:10.3390/jcm13133742
      reference_title: Epidemiological Characteristics of Inherited Epidermolysis Bullosa in an Eastern European Population
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity.
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
- reference: DOI:10.1038/s41572-020-0210-0
  title: Epidermolysis bullosa
  found_in:
  - Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Epidermolysis bullosa
    supporting_text: Epidermolysis bullosa
    evidence:
    - reference: DOI:10.1038/s41572-020-0210-0
      reference_title: Epidermolysis bullosa
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Epidermolysis bullosa
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
📚

References & Deep Research

References

15
PMID:26937547
Kindler Syndrome.
No top-level findings curated for this source.
PMID:20301543
Epidermolysis Bullosa Simplex.
No top-level findings curated for this source.
PMID:20301481
Dystrophic Epidermolysis Bullosa.
No top-level findings curated for this source.
PMID:20301304
Junctional Epidermolysis Bullosa.
No top-level findings curated for this source.
DOI:10.1007/s12326-024-00627-z
Neue Lokal- und Systemtherapien bei Epidermolysis bullosa
1 finding
ZusammenfassungEpidermolysis bullosa (EB) bezeichnet eine seltene, heterogene Gruppe von Genodermatosen, charakterisiert durch eine gesteigerte Fragilität von Haut und Schleimhaut.
"ZusammenfassungEpidermolysis bullosa (EB) bezeichnet eine seltene, heterogene Gruppe von Genodermatosen, charakterisiert durch eine gesteigerte Fragilität von Haut und Schleimhaut."
Show evidence (1 reference)
DOI:10.1007/s12326-024-00627-z SUPPORT Other
"ZusammenfassungEpidermolysis bullosa (EB) bezeichnet eine seltene, heterogene Gruppe von Genodermatosen, charakterisiert durch eine gesteigerte Fragilität von Haut und Schleimhaut."
Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
DOI:10.1007/s40257-025-00942-y
Long-Term Safety and Tolerability of Beremagene Geperpavec-svdt (B-VEC) in an Open-Label Extension Study of Patients with Dystrophic Epidermolysis Bullosa
1 finding
Long-Term Safety and Tolerability of Beremagene Geperpavec-svdt (B-VEC) in an Open-Label Extension Study of Patients with Dystrophic Epidermolysis Bullosa
"Long-Term Safety and Tolerability of Beremagene Geperpavec-svdt (B-VEC) in an Open-Label Extension Study of Patients with Dystrophic Epidermolysis Bullosa"
DOI:10.1186/s13023-023-02817-z
Itch in recessive dystrophic epidermolysis bullosa: findings of PEBLES, a prospective register study
1 finding
Itch in recessive dystrophic epidermolysis bullosa: findings of PEBLES, a prospective register study
"Itch is common and distressing in epidermolysis bullosa (EB) but has not previously been studied in depth in different recessive dystrophic EB (RDEB) subtypes.ObjectivesAs part of a prospective register study of the natural history of RDEB we explored features of itch, medications used, and..."
Show evidence (1 reference)
DOI:10.1186/s13023-023-02817-z SUPPORT Human Clinical
"Itch is common and distressing in epidermolysis bullosa (EB) but has not previously been studied in depth in different recessive dystrophic EB (RDEB) subtypes.ObjectivesAs part of a prospective register study of the natural history of RDEB we explored features of itch, medications used, and..."
Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
DOI:10.1186/s13023-024-03190-1
Therapies for cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa: a systematic review of 157 cases
1 finding
Invasive cutaneous squamous cell carcinomas (cSCC) are a leading cause of death in recessive dystrophic epidermolysis bullosa (RDEB), a rare blistering genodermatosis.
"Invasive cutaneous squamous cell carcinomas (cSCC) are a leading cause of death in recessive dystrophic epidermolysis bullosa (RDEB), a rare blistering genodermatosis."
Show evidence (1 reference)
DOI:10.1186/s13023-024-03190-1 SUPPORT Human Clinical
"Invasive cutaneous squamous cell carcinomas (cSCC) are a leading cause of death in recessive dystrophic epidermolysis bullosa (RDEB), a rare blistering genodermatosis."
Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
DOI:10.1186/s13023-024-03328-1
Economic burden and health-related quality of life in patients with epidermolysis bullosa in Spain
1 finding
Epidermolysis bullosa (EB) is a rare genetic skin disorder characterized by fragility of skin with appearance of acute and chronic wounds.
"Epidermolysis bullosa (EB) is a rare genetic skin disorder characterized by fragility of skin with appearance of acute and chronic wounds."
Show evidence (1 reference)
DOI:10.1186/s13023-024-03328-1 SUPPORT Human Clinical
"Epidermolysis bullosa (EB) is a rare genetic skin disorder characterized by fragility of skin with appearance of acute and chronic wounds."
Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
DOI:10.15690/vsp.v23i5.2808
Congenital Epidermolysis Bullosa Epidemiology among Children of Russian Federation
1 finding
The prevalence of all types of congenital epidermolysis bullosa (СEB) worldwide is approximately 11 cases per 1 million according to the latest data from the American Epidermolysis Bullosa Registry.
"The prevalence of all types of congenital epidermolysis bullosa (СEB) worldwide is approximately 11 cases per 1 million according to the latest data from the American Epidermolysis Bullosa Registry."
Show evidence (1 reference)
DOI:10.15690/vsp.v23i5.2808 SUPPORT Human Clinical
"The prevalence of all types of congenital epidermolysis bullosa (СEB) worldwide is approximately 11 cases per 1 million according to the latest data from the American Epidermolysis Bullosa Registry."
Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
DOI:10.3390/bioengineering12060574
Towards Extracellular Vesicles in the Treatment of Epidermolysis Bullosa
1 finding
Epidermolysis bullosa (EB) is a debilitating genetic skin disorder characterized by extreme fragility, chronic wounds, and severe complications, particularly in its most severe form, recessive dystrophic EB (RDEB).
"Epidermolysis bullosa (EB) is a debilitating genetic skin disorder characterized by extreme fragility, chronic wounds, and severe complications, particularly in its most severe form, recessive dystrophic EB (RDEB)."
Show evidence (1 reference)
DOI:10.3390/bioengineering12060574 SUPPORT Human Clinical
"Epidermolysis bullosa (EB) is a debilitating genetic skin disorder characterized by extreme fragility, chronic wounds, and severe complications, particularly in its most severe form, recessive dystrophic EB (RDEB)."
Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
DOI:10.3390/ijms25042243
Emerging Gene Therapeutics for Epidermolysis Bullosa under Development
1 finding
The monogenetic disease epidermolysis bullosa (EB) is characterised by the formation of extended blisters and lesions on the patient’s skin upon minimal mechanical stress.
"The monogenetic disease epidermolysis bullosa (EB) is characterised by the formation of extended blisters and lesions on the patient’s skin upon minimal mechanical stress."
Show evidence (1 reference)
DOI:10.3390/ijms25042243 SUPPORT Human Clinical
"The monogenetic disease epidermolysis bullosa (EB) is characterised by the formation of extended blisters and lesions on the patient’s skin upon minimal mechanical stress."
Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
DOI:10.3390/ijms26146592
Gene Therapies in Dermatological Diseases: A Breakthrough in Treatment
1 finding
Gene therapy involves introducing genetic material into cells to treat or prevent disease and offers highly targeted and potentially curative approaches for both inherited and acquired conditions.
"Gene therapy involves introducing genetic material into cells to treat or prevent disease and offers highly targeted and potentially curative approaches for both inherited and acquired conditions."
Show evidence (1 reference)
DOI:10.3390/ijms26146592 SUPPORT Human Clinical
"Gene therapy involves introducing genetic material into cells to treat or prevent disease and offers highly targeted and potentially curative approaches for both inherited and acquired conditions."
Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
DOI:10.3390/jcm13133742
Epidemiological Characteristics of Inherited Epidermolysis Bullosa in an Eastern European Population
1 finding
Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity.
"Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity."
Show evidence (1 reference)
DOI:10.3390/jcm13133742 SUPPORT Human Clinical
"Epidermolysis bullosa (EB) is a hereditary condition characterized by skin and mucosal fragility, with various degrees of severity."
Deep research cited this publication as relevant literature for Epidermolysis Bullosa.
DOI:10.1038/s41572-020-0210-0
Epidermolysis bullosa
1 finding
Epidermolysis bullosa
"Epidermolysis bullosa"
Show evidence (1 reference)
DOI:10.1038/s41572-020-0210-0 SUPPORT Other
"Epidermolysis bullosa"
Deep research cited this publication as relevant literature for Epidermolysis Bullosa.

Deep Research

1
Falcon ▸
1. Disease Information (definitions and current understanding)
Edison Scientific Literature 51 citations 2026-05-08T16:11:07.201699

1. Disease Information (definitions and current understanding)

Concise disease overview

EB is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation that can be triggered by minimal mechanical trauma (bardhan2020epidermolysisbullosa pages 1-2). A widely used framing is that EB comprises >30 subtypes grouped into four major categories—EB simplex, junctional EB, dystrophic EB, and Kindler EB—defined primarily by the plane of tissue cleavage within the skin, reflecting the underlying molecular defect (bardhan2020epidermolysisbullosa pages 1-2).

Key definitional quote (from abstract-style text)

  • Nature Reviews Disease Primers states: “Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by often minimal trauma.” (Sep 2020; URL: https://doi.org/10.1038/s41572-020-0210-0) (bardhan2020epidermolysisbullosa pages 1-2)

Classification (consensus framing)

  • EB is classified into four major types based on the level of tissue separation: EBS, JEB, DEB, Kindler EB (bardhan2020epidermolysisbullosa pages 1-2, bischof2024emerginggenetherapeutics pages 1-2).

2. Etiology

Disease causal factors

EB is primarily caused by germline pathogenic variants in genes encoding structural proteins required for epithelial integrity and epidermal–dermal adhesion. A major review notes “pathogenetic mutations in 16 distinct genes” implicated in EB (bardhan2020epidermolysisbullosa pages 1-2). A 2024 review similarly states EB-causing mutations can be present in at least 16 different genes (bischof2024emerginggenetherapeutics pages 1-2).

Genetic risk factors (causal genes by major EB type)

Causal genes are subtype-dependent. Examples explicitly present in the retrieved evidence include: - EBS: KRT5, KRT14, PLEC (with a statement that “75% of patients with EB simplex harbour mutations” in KRT5/KRT14) (bardhan2020epidermolysisbullosa pages 6-7) - JEB: LAMA3, LAMB3, LAMC2, ITGA6/ITGB4 (integrin α6β4), COL17A1 (type XVII collagen) (bardhan2020epidermolysisbullosa pages 4-5, bischof2024emerginggenetherapeutics pages 1-2) - DEB: COL7A1 (type VII collagen) (bardhan2020epidermolysisbullosa pages 10-11) - Kindler EB: FERMT1 (also referred to as KIND1 in some texts) (bischof2024emerginggenetherapeutics pages 1-2, suru2024epidemiologicalcharacteristicsof pages 4-6)

OpenTargets also lists strong gene–disease associations for EB consistent with these causal genes (e.g., COL7A1, KRT5) (OpenTargets Search: Epidermolysis bullosa).

Variant classes and functional consequences (examples from retrieved evidence)

For DEB, COL7A1 variant class influences phenotype: - Recessive COL7A1 mutations often include premature termination codons causing reduced mRNA and markedly reduced/absent type VII collagen (loss-of-function) (bardhan2020epidermolysisbullosa pages 10-11). - Non-terminating variants (example: glycine substitutions) can impair collagen triple helix assembly and are associated with milder disease in some cases (bardhan2020epidermolysisbullosa pages 10-11).

Environmental risk and protective factors

EB is genetic in origin; environmental factors primarily modify clinical severity (e.g., mechanical trauma/friction provoking blistering) rather than cause disease onset (bardhan2020epidermolysisbullosa pages 1-2, bischof2024emerginggenetherapeutics pages 1-2). Specific protective environmental factors are not well characterized in the retrieved evidence.

Gene–environment interactions

The defining clinical trigger is mechanical trauma acting on genetically fragile skin, producing blistering and chronic wounds; this is inherent to the classification by tissue cleavage plane and the “minimal trauma” definition (bardhan2020epidermolysisbullosa pages 1-2, bischof2024emerginggenetherapeutics pages 1-2).

3. Phenotypes (with HPO suggestions)

Core mucocutaneous phenotype (all major types)

  • Blistering/erosions after minor trauma (HPO suggestion: Skin blistering [HP:0008064]) (bardhan2020epidermolysisbullosa pages 1-2).
  • Mucosal fragility (HPO: Mucosal blistering [HP:0000770]) (bardhan2020epidermolysisbullosa pages 1-2).
  • Pain and itch are common burdens, particularly in severe subtypes (mellerio2023itchinrecessive pages 1-2).

Dystrophic EB / severe RDEB phenotype cluster

Severe RDEB is characterized by chronic, painful wounds and fibrotic scarring leading to deformity and strictures, including: - Pseudosyndactyly / mitten deformities (HPO: Syndactyly [HP:0001159] / Cutaneous syndactyly [HP:0010692]) (sandoval2025towardsextracellularvesicles pages 1-2). - Microstomia (HPO: Microstomia [HP:0000212]) and esophageal strictures (HPO: Esophageal stricture [HP:0002044]) (sandoval2025towardsextracellularvesicles pages 1-2). - High risk of aggressive cutaneous squamous cell carcinoma (cSCC) (HPO: Squamous cell carcinoma [HP:0002860]) (hwang2024therapiesforcutaneous pages 1-3).

Itch: phenotype frequency and QoL association (human prospective registry; 2023)

A large, prospective registry study in RDEB (PEBLES; 50 participants, 243 reviews) found itch is highly prevalent and severe: - Quote: “Itch was frequent, present in the preceding month in 93% of reviews.” (Aug 2023; URL: https://doi.org/10.1186/s13023-023-02817-z) (mellerio2023itchinrecessive pages 1-2). - Subtype differences: itch frequency (“always/often”) was 87% in severe RDEB reviews vs 42% in intermediate RDEB reviews; RDEB-pruriginosa had particularly high itch burden (mellerio2023itchinrecessive pages 4-6). - Medication use: 61% of reviews reported itch medication use; at index, oral antihistamines 28% and emollients 24% (mellerio2023itchinrecessive pages 6-7). - Correlations with disease severity and QoL scores depended on subtype: correlations were present in intermediate/inversa forms but weak in severe RDEB (mellerio2023itchinrecessive pages 1-2, mellerio2023itchinrecessive pages 6-7).

Quality-of-life impact (recent quantitative data; 2024)

A Spanish societal-burden study (2024; reference year 2022) reports large HRQoL impairment measured by EQ-5D: - Mean EQ-5D utility index: 0.45 for severe EB vs 0.62 for non-severe EB (proxy/self reporting differences described) (arandareneo2024economicburdenand pages 1-2, arandareneo2024economicburdenand pages 6-7).

4. Genetic / Molecular Information

Causal genes (core set in retrieved evidence)

EB is genetically heterogeneous; causal genes explicitly supported in the retrieved evidence include: - EBS: KRT5, KRT14, PLEC (bischof2024emerginggenetherapeutics pages 1-2, bardhan2020epidermolysisbullosa pages 6-7) - JEB: LAMA3, LAMB3, LAMC2, ITGA6/ITGB4, COL17A1 (bardhan2020epidermolysisbullosa pages 4-5, bischof2024emerginggenetherapeutics pages 1-2) - DEB: COL7A1 (bardhan2020epidermolysisbullosa pages 10-11) - Kindler EB: FERMT1 (suru2024epidemiologicalcharacteristicsof pages 4-6)

Inheritance patterns

A Romanian population-based study (2012–2024) reported inheritance patterns among its cohort (not all specified): autosomal recessive (58), autosomal dominant (29), de novo (3), unspecified (62) (suru2024epidemiologicalcharacteristicsof pages 4-6). Dystrophic EB may be autosomal dominant, autosomal recessive, or de novo (bardhan2020epidermolysisbullosa pages 10-11).

Functional biology summary (protein dysfunction)

EB phenotypes reflect failure of key structural proteins in keratinocyte cytoskeleton (EBS), hemidesmosomes/basement membrane zone (JEB), or anchoring fibrils (DEB). For example, dystrophic EB is “characterized by cleavage in the upper dermis” and “arising in all cases from COL7A1 mutations” with disrupted type VII collagen anchoring fibrils (bardhan2020epidermolysisbullosa pages 10-11).

Modifier genes, epigenetics, chromosomal abnormalities

Not specifically described in the retrieved evidence; additional targeted searches (ClinGen/ClinVar/GWAS/epigenomic datasets) would be required for robust modifier and epigenetic annotation.

5. Environmental Information

  • Non-genetic contributors primarily influence disease expression and complications (e.g., friction/trauma precipitating blistering; chronic wounds and infections) rather than act as primary causes (bardhan2020epidermolysisbullosa pages 1-2).
  • In severe disease, downstream systemic complications include infection/sepsis-related mortality in early life for junctional forms in some cohorts (murashkin2024congenitalepidermolysisbullosa pages 1-2).

6. Mechanism / Pathophysiology (causal chains, upstream vs downstream)

Canonical mechanistic chain

  1. Germline pathogenic variant(s) in skin adhesion/structural genes (e.g., COL7A1, LAMB3, KRT5/KRT14). (Upstream cause) (bardhan2020epidermolysisbullosa pages 1-2, bardhan2020epidermolysisbullosa pages 10-11)
  2. Loss/dysfunction of adhesion structures at a specific ultrastructural level (intraepidermal; lamina lucida; sublamina densa; mixed). (Core molecular defect) (bardhan2020epidermolysisbullosa pages 1-2, bischof2024emerginggenetherapeutics pages 1-2)
  3. Mechanical trauma → epidermal–dermal separation → blisters/erosions. (Trigger-to-lesion mechanism) (bardhan2020epidermolysisbullosa pages 1-2, bischof2024emerginggenetherapeutics pages 1-2)
  4. Chronic wounds + inflammation + fibrosis/scarring → deformities (pseudosyndactyly), strictures, nutritional compromise, anemia; high risk of aggressive cSCC especially in severe RDEB. (Downstream complications) (sandoval2025towardsextracellularvesicles pages 1-2, hwang2024therapiesforcutaneous pages 1-3, bardhan2020epidermolysisbullosa pages 5-6)

Cellular and tissue structures (ontology suggestions)

  • GO biological processes (examples): cell adhesion, extracellular matrix organization, wound healing, inflammatory response, keratinocyte differentiation.
  • CL cell types (examples): keratinocyte (CL:0000312), fibroblast (CL:0000057), immune cells relevant to wound inflammation (e.g., macrophage CL:0000235).
  • Subcellular / structural components (GO cellular component examples): basement membrane (GO:0005604), hemidesmosome (GO:0030056), intermediate filament (GO:0005882).

Squamous cell carcinoma as a major downstream mechanism

A major EB review identifies SCC as a feared complication and leading cause of mortality (bardhan2020epidermolysisbullosa pages 1-2). A 2024 systematic review in RDEB-cSCC quantifies high cumulative incidence and mortality, consistent with aggressive malignant transformation in chronic wound environments (hwang2024therapiesforcutaneous pages 1-3).

7. Anatomical Structures Affected (with UBERON/CL suggestions)

Organ and system level

  • Primary: skin (UBERON:0002097), oral mucosa and other mucosal sites (mucocutaneous involvement) (bardhan2020epidermolysisbullosa pages 1-2).
  • Common extracutaneous sites in severe subtypes: eyes, airway, gastrointestinal tract (e.g., esophagus), genitourinary tract (noted in RDEB descriptions) (sandoval2025towardsextracellularvesicles pages 1-2).

Tissue and cell level

  • Tissues: epidermis, dermis, basement membrane zone / dermal–epidermal junction (bischof2024emerginggenetherapeutics pages 1-2).
  • Cells: basal keratinocytes (EBS), epithelial cells forming hemidesmosomes and basement membrane attachments, dermal fibroblasts contributing to fibrosis and scarring.

Localization and laterality

Not specifically emphasized in the retrieved evidence; generally widespread (generalized types) vs localized (e.g., localized EBS) distributions occur (suru2024epidemiologicalcharacteristicsof pages 4-6).

8. Temporal Development (onset, progression, staging)

Onset

EB often manifests at birth or in early infancy, particularly in severe subtypes; RDEB is noted to typically manifest at birth (sandoval2025towardsextracellularvesicles pages 1-2).

Progression and natural history

Course depends on subtype and severity. Examples from Eastern European registry-style data: - Romanian cohort had substantial pediatric representation, but also adult survival depending on type/subtype (suru2024epidemiologicalcharacteristicsof pages 6-9). - Russian pediatric registry data show substantial early mortality in junctional forms, with survival probability dropping “almost to 0% in the first 100 days” for junctional congenital EB (murashkin2024congenitalepidermolysisbullosa pages 1-2).

9. Inheritance and Population

Epidemiology (recent registry-derived estimates, prioritizing 2024)

Romania (2012–2024; point reference 31 Dec 2023): - Point prevalence: 6.77 per million population; incidence: 24.23 per million live births (Jun 2024; URL: https://doi.org/10.3390/jcm13133742) (suru2024epidemiologicalcharacteristicsof pages 1-2). - Major type distribution: EBS 21%, JEB 3%, DEB 63%, KEB 2%, EB NOS 11% (suru2024epidemiologicalcharacteristicsof pages 1-2). - Sex distribution reported as slight female preponderance (approx. 52% vs 48%) (suru2024epidemiologicalcharacteristicsof pages 6-9).

Russian Federation children (registry as of 2024; ages 0–17): - Pediatric prevalence: 15.48 per 1,000,000 children; sex ratio boys:girls 1.08:1 (Oct 2024; URL: https://doi.org/10.15690/vsp.v23i5.2808) (murashkin2024congenitalepidermolysisbullosa pages 1-2). - Type counts among 491 children: dystrophic 261, simplex 191, junctional 31, Kindler 8 (murashkin2024congenitalepidermolysisbullosa pages 1-2). - Five-year mean birth rate: 2.13 per 100,000 births (2019–2023) (murashkin2024congenitalepidermolysisbullosa pages 1-2). - Mortality: 22 deaths recorded; junctional accounts for 59.1% of deaths; highest mortality in age 0–1 years (65.2% of deaths) with sepsis-related multi-organ failure noted as leading cause (murashkin2024congenitalepidermolysisbullosa pages 1-2).

Founder effects/consanguinity

The Russian registry highlights a high-burden region (Dagestan) with “apparently” high consanguineous marriage rates (50%) corresponding to higher case counts, suggesting a role for autosomal recessive inheritance and local population structure (murashkin2024congenitalepidermolysisbullosa pages 2-3).

10. Diagnostics

Diagnostic workflow (current standard framing)

A major authoritative review emphasizes that precise diagnosis relies on correlating: - Clinical phenotype, plus - Electron microscopy and immunohistological features (including immunofluorescence mapping), plus - Mutational analyses (genetic testing) (bardhan2020epidermolysisbullosa pages 1-2).

Real-world diagnostic utilization (Romania 2012–2024)

In the Romanian cohort: - 83/152 (54.6%) were clinically diagnosed only. - 48 (31.5%) had molecular genetic testing. - Smaller fractions had IF mapping (IFM) and/or transmission electron microscopy (TEM), including 2 with IFM+TEM and additional cases combining IFM or TEM with genetics (suru2024epidemiologicalcharacteristicsof pages 4-6).

Differential diagnosis

Not specifically enumerated in the retrieved evidence; standard differentials include acquired blistering diseases and other skin fragility syndromes—note that the Romanian study explicitly excluded acquired EB and other fragility syndromes (suru2024epidemiologicalcharacteristicsof pages 2-4).

11. Outcome / Prognosis (including key statistics)

cSCC risk and outcomes in RDEB (2024 systematic review; 157 cases)

A 2024 systematic review of 157 RDEB-cSCC cases reports: - Cumulative risk for at least one cSCC: 7.5% by age 20 rising to 80% by age 45 (May 2024; URL: https://doi.org/10.1186/s13023-024-03190-1) (hwang2024therapiesforcutaneous pages 1-3). - Mortality estimates: 38.7% by 35 years, 70% by 40, 78.7% by 55 (hwang2024therapiesforcutaneous pages 1-3). - Tumor features: well-differentiated 64.1%, ulcerated 59.6%, ≥2 cm 77.6%; median age at diagnosis 30 years (hwang2024therapiesforcutaneous pages 1-3).

Survival variation by EB type (2024 Romania)

Romanian survival analysis indicated poorer survival for JEB and unspecified cases compared to other types (Kaplan–Meier curves shown; see extracted figure) (suru2024epidemiologicalcharacteristicsof media bf76e012).

12. Treatment (current applications, real-world implementations, and 2023–2024 developments)

Standard of care: supportive, multidisciplinary management

In the absence of universally curative therapy, management focuses on minimizing blister formation, wound care, symptom relief, and management of complications (including SCC) (bardhan2020epidermolysisbullosa pages 1-2).

FDA-approved topical gene therapy for DEB (major 2023 milestone)

A 2024 review of EB gene therapeutics describes the first approved in vivo topical gene replacement product: - Mechanism: HSV-1–based topical vector delivering functional COL7A1 to wounds (bischof2024emerginggenetherapeutics pages 8-9). - Phase III (GEM-3; NCT04491604; intrapatient matched wound pairs, n=31) outcomes: 71% complete wound closure at 3 months and 67% at 6 months vs placebo ~20–22% (bischof2024emerginggenetherapeutics pages 8-9, prodinger2024neuelokalund pages 1-2). - This product is widely referenced as Vyjuvek (beremagene geperpavec, B-VEC) and described as FDA approved in 2023 (prodinger2024neuelokalund pages 1-2, sandoval2025towardsextracellularvesicles pages 2-4).

Implementation and payer impact (2024 economic evaluation)

Post-approval economic modeling estimates substantial payer impact in the US: - Assumed base-case annual price $300,000 per patient per year. - Estimated first-year total expenditure $268 million (and the therapy described as weekly lifelong administration in the summarized source) (sandoval2025towardsextracellularvesicles pages 2-4).

Itch symptom management (2023 prospective registry evidence)

Despite frequent use of emollients and antihistamines, itch remains an unmet need in RDEB; only 61% of reviews reported using medication and satisfaction was low-moderate (mean 41.3/100) (mellerio2023itchinrecessive pages 6-7).

Treatment of RDEB-associated cSCC (2024 systematic review)

Surgery remains the primary modality, with emerging use of anti-EGFR therapy and immunotherapy in advanced disease: - Median survival from first cSCC diagnosis to death varied by regimen (e.g., ~2 years for surgery only; ~4–4.6 years with addition of anti-EGFR or immunotherapy in small subsets) (hwang2024therapiesforcutaneous pages 1-3).

Other approved therapies

  • Filsuvez (Oleogel-S10) is noted in recent reviews as an approved therapy for EB wound healing support, but detailed trial-level quantitative outcomes were not available in the retrieved evidence set here and should be curated from primary regulatory documents and pivotal trial publications (sandoval2025towardsextracellularvesicles pages 1-2).

MAXO suggestions (examples)

  • Gene therapy, topical administration: gene therapy procedure; topical administration of therapeutic agent.
  • Wound care: wound dressing, wound debridement (when applicable), pain management, pruritus management.
  • cSCC: surgical excision, radiotherapy, systemic chemotherapy, epidermal growth factor receptor inhibitor therapy, immune checkpoint inhibitor therapy.

13. Prevention

For a Mendelian disease, prevention focuses on genetic counseling and reproductive planning. The retrieved evidence set does not provide detailed guideline statements for prenatal testing/PGT/cascade testing; however, the importance of precise molecular diagnosis for genetic counseling and stratification is emphasized (bardhan2020epidermolysisbullosa pages 2-3).

Tertiary prevention is central in practice (e.g., preventing infections, malnutrition, contractures, strictures, and early detection of cSCC) (bardhan2020epidermolysisbullosa pages 1-2, hwang2024therapiesforcutaneous pages 1-3).

14. Other Species / Natural Disease

Not addressed in the retrieved evidence set.

15. Model Organisms

Not addressed in the retrieved evidence set.

Key structured summaries (artifacts)

The following tables summarize subtype genetics/features and the most evidence-supported 2023–2024 treatment landscape.

EB type Primary cleavage level / skin layer Core causal genes mentioned in retrieved evidence Typical inheritance Hallmark clinical features Major complications Supporting context
Epidermolysis bullosa simplex (EBS) Intraepidermal cleavage within basal keratinocytes / epidermis KRT5, KRT14, PLEC Usually autosomal dominant; some autosomal recessive forms Skin fragility and trauma-induced blistering, often from birth or infancy; may include inflammation, failure to thrive, itch, neuropathic pain; some PLEC-associated forms have muscular dystrophy Variable severity; multisystem involvement in some forms (bardhan2020epidermolysisbullosa pages 1-2, bischof2024emerginggenetherapeutics pages 1-2, bardhan2020epidermolysisbullosa pages 6-7, suru2024epidemiologicalcharacteristicsof pages 4-6)
Junctional EB (JEB) Cleavage within the lamina lucida of the dermal-epidermal junction / basement membrane zone LAMA3, LAMB3, LAMC2, ITGA6, ITGB4, COL17A1 Mostly autosomal recessive Severe mucocutaneous fragility with blistering and erosions; some forms show exuberant granulation tissue, airway and upper GI involvement In severe JEB, high infant mortality; failure to thrive, sepsis, respiratory failure, cardiomyopathy; laryngeal disease can cause respiratory compromise and death (bardhan2020epidermolysisbullosa pages 1-2, bardhan2020epidermolysisbullosa pages 4-5, bischof2024emerginggenetherapeutics pages 1-2, bardhan2020epidermolysisbullosa pages 6-7)
Dystrophic EB, dominant (DDEB) Sublamina densa / upper dermis, due to anchoring fibril dysfunction COL7A1 Autosomal dominant Trauma-induced blistering with scarring; generally milder than severe recessive disease; nail and mucosal involvement may occur Chronic wounds and scarring; cancer risk lower than severe RDEB but elevated in some patients (bardhan2020epidermolysisbullosa pages 4-5, bardhan2020epidermolysisbullosa pages 10-11, suru2024epidemiologicalcharacteristicsof pages 4-6)
Dystrophic EB, recessive (RDEB) Sublamina densa / upper dermis, due to absent or markedly reduced type VII collagen anchoring fibrils COL7A1 Autosomal recessive Congenital or early-onset severe blistering, chronic wounds, scarring, mitten deformities/pseudosyndactyly, microstomia, esophageal strictures, pain and itch Aggressive cutaneous squamous cell carcinoma is the leading cause of death in adults with severe RDEB; also anemia, malnutrition, renal disease, infection/sepsis, fibrosis (hwang2024therapiesforcutaneous pages 1-3, bardhan2020epidermolysisbullosa pages 5-6, bardhan2020epidermolysisbullosa pages 10-11, murashkin2024congenitalepidermolysisbullosa pages 2-3)
Kindler EB / Kindler syndrome Mixed and variable cleavage planes across multiple skin levels FERMT1 (KIND1) Autosomal recessive Skin fragility, blistering, and photosensitivity beginning in early childhood; progressive poikiloderma may occur Mucosal disease and later epithelial malignancies including non-melanoma skin cancer/SCC in adults (bardhan2020epidermolysisbullosa pages 1-2, bischof2024emerginggenetherapeutics pages 1-2, bardhan2020epidermolysisbullosa pages 10-11, suru2024epidemiologicalcharacteristicsof pages 4-6)

Table: This table summarizes the major epidermolysis bullosa types by tissue cleavage level, core genes, inheritance, hallmark clinical features, and major complications. It is designed as a compact ontology-ready overview for quick reference in a disease knowledge base.

Intervention Target EB subtype Mechanism Regulatory status Key study/trial + date Key quantitative outcomes Notes/limitations Supporting context IDs
Beremagene geperpavec (B-VEC; Vyjuvek) Dystrophic EB, especially COL7A1-related DEB/RDEB Topical HSV-1–based in vivo gene replacement delivering functional COL7A1 to wounded skin FDA approved May 2023; EMA approval noted in 2025 sources GEM-3 phase 3, randomized intra-patient matched wound-pair trial, NCT04491604; weekly topical treatment for 26 weeks; NEJM trial cited from 2022; FDA approval noted 2023 Complete wound closure with B-VEC: 71% at 3 months and 67% at 6 months vs placebo 20–22%; phase 1/2: 17/18 wounds completely closed at 3 months; median time to closure 13.5 vs 22.5 days; mean duration of closure 103 vs 16.5 days Paired-lesion design; repeated application required; topical HSV vector does not penetrate intact skin well; safety profile mainly mild-moderate AEs, and serious AEs in later summaries were not attributed to product (bischof2024emerginggenetherapeutics pages 8-9, prodinger2024neuelokalund pages 1-2, NCT04491604 chunk 1, lisinska2025genetherapiesin pages 2-4) (bischof2024emerginggenetherapeutics pages 8-9, prodinger2024neuelokalund pages 1-2, NCT04491604 chunk 1, lisinska2025genetherapiesin pages 2-4)
B-VEC open-label extension Dystrophic EB previously treated or treatment-naive Continued topical COL7A1 gene replacement Post-approval/extension evidence; not a separate approval Open-label extension NCT04917874; published 2025, rollover + treatment-naive participants 47 subjects; treatment up to 112 weeks (median 81 weeks); maintained wound closure in rollover subjects ranged 61.1–89.5% through month 12; no new safety signals detected Open-label, variable follow-up, exploratory PROs inconclusive for QoL; publication is 2025 but highly relevant for real-world durability/safety (marinkovich2025longtermsafetyand pages 1-2)
Filsuvez (Oleogel-S10) EB wound healing support across inherited EB indications in recent reviews Topical birch triterpene oleogel intended to support re-epithelialization/wound healing Recently approved; referenced as approved in 2022–2024 reviews Mentioned in 2024–2025 EB therapeutic reviews Detailed quantitative trial outcomes not present in current retrieved evidence Should be included as a recent approved therapy, but the present evidence base here does not provide trial-level numeric endpoints; avoid overclaiming (sandoval2025towardsextracellularvesicles pages 1-2, prodinger2024neuelokalund pages 1-2)
Supportive care / itch management (PEBLES registry) Recessive dystrophic EB subtypes (RDEB-S, RDEB-I, RDEB-Inv, RDEB-Pru) Symptom control with emollients, topical corticosteroids, antihistamines and related anti-pruritic measures Standard supportive care; no disease-modifying approval claim PEBLES prospective register study, published 2023 Itch present in preceding month in 93% of 243 reviews from 50 participants; 61% of reviews reported itch medication use; at index, emollients 12/50 (24%), oral antihistamines 14/50 (28%); mean medication satisfaction 41.3/100 Strong evidence of unmet need: frequent itch, greater severity/distress in RDEB-S and RDEB-Pru, limited perceived efficacy of current medications (mellerio2023itchinrecessive pages 1-2, mellerio2023itchinrecessive pages 6-7, mellerio2023itchinrecessive pages 4-6, mellerio2023itchinrecessive pages 2-4)
cSCC treatment in RDEB: surgery, anti-EGFR therapy, immunotherapy RDEB-associated cutaneous squamous cell carcinoma Oncologic local/systemic treatment after malignant transformation; anti-EGFR or immune checkpoint blockade used in advanced disease No EB-specific regulatory approval summarized here; used in practice based on cSCC management Systematic review of 157 cases, published 2024 Median survival from first cSCC diagnosis to death: 2.0 years (surgery only), 4.0 years (+anti-EGFR), 4.6 years (+immunotherapy), 1.85 years (surgery+chemotherapy), 4.0 years (surgery+radiotherapy), 9.5 years (surgery+chemotherapy+radiotherapy; very small n); surgery was primary treatment in 128 cases Evidence mostly case reports/cohorts, major confounding by multimodal treatment and small sample sizes; adverse events included impaired wound healing with immunotherapy and nausea/fatigue with anti-EGFR therapy (hwang2024therapiesforcutaneous pages 1-3)
Health-system implementation: projected B-VEC spending US DEB population eligible for B-VEC Economic implementation analysis rather than biologic mechanism Reflects post-approval payer impact after FDA approval JAMA Dermatology economic evaluation, 2024 Estimated 894 US DEB patients eligible in year 1; projected spending $268 million first year and $805 million over 3 years; assumed base-case cost $300,000/patient/year; lifetime total cost estimated $15–17 million/patient Important for real-world access and reimbursement; FDA indication included both AR and AD DEB, with limited direct trial data in dominant disease noted by authors (sandoval2025towardsextracellularvesicles pages 2-4)

Table: This table summarizes the most clinically relevant epidermolysis bullosa therapies and management strategies emphasized in the retrieved 2023-2024 evidence, including approved gene therapy, supportive care, and cSCC treatment. It is useful for quickly comparing mechanisms, regulatory status, quantitative outcomes, and implementation caveats.

Notes on evidence limitations and curation gaps

  1. OMIM/Orphanet/ICD/MeSH identifiers were not directly retrievable via the current tool calls; they should be added from those resources in a follow-on curation pass.
  2. Several key topics requested for a knowledge base entry (modifier genes, epigenetics, model organisms, comparative disease in animals, and detailed prevention/genetic screening guidelines) are not covered by the retrieved documents and require targeted additional retrieval.
  3. For Filsuvez (Oleogel-S10), the present evidence confirms it as a recently approved therapy in reviews but does not provide pivotal-trial effect sizes; primary trial publications/regulatory assessments should be cited before adding numeric claims.

Included URLs and publication dates (selected high-value sources)

  • Bardhan et al. Nature Reviews Disease Primers (Sep 2020): https://doi.org/10.1038/s41572-020-0210-0 (bardhan2020epidermolysisbullosa pages 1-2)
  • Suru et al. Journal of Clinical Medicine (Jun 2024): https://doi.org/10.3390/jcm13133742 (suru2024epidemiologicalcharacteristicsof pages 1-2)
  • Murashkin et al. Current Pediatrics (Oct 2024): https://doi.org/10.15690/vsp.v23i5.2808 (murashkin2024congenitalepidermolysisbullosa pages 1-2)
  • Mellerio et al. Orphanet Journal of Rare Diseases (Aug 2023): https://doi.org/10.1186/s13023-023-02817-z (mellerio2023itchinrecessive pages 1-2)
  • Hwang et al. Orphanet Journal of Rare Diseases (May 2024): https://doi.org/10.1186/s13023-024-03190-1 (hwang2024therapiesforcutaneous pages 1-3)
  • Aranda-Reneo et al. Orphanet Journal of Rare Diseases (Sep 2024): https://doi.org/10.1186/s13023-024-03328-1 (arandareneo2024economicburdenand pages 1-2)
  • Bischof et al. International Journal of Molecular Sciences (Feb 2024): https://doi.org/10.3390/ijms25042243 (bischof2024emerginggenetherapeutics pages 1-2)

References

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  3. (bischof2024emerginggenetherapeutics pages 1-2): Johannes Bischof, Markus Hierl, and Ulrich Koller. Emerging gene therapeutics for epidermolysis bullosa under development. International Journal of Molecular Sciences, 25:2243, Feb 2024. URL: https://doi.org/10.3390/ijms25042243, doi:10.3390/ijms25042243. This article has 37 citations.

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  11. (sandoval2025towardsextracellularvesicles pages 1-2): Aaron Gabriel W. Sandoval and Evangelos V. Badiavas. Towards extracellular vesicles in the treatment of epidermolysis bullosa. Bioengineering, 12:574, May 2025. URL: https://doi.org/10.3390/bioengineering12060574, doi:10.3390/bioengineering12060574. This article has 3 citations.

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