Junctional Epidermolysis Bullosa

Mendelian MONDO:0017612 Pathograph 11 Dermatological Disease Genetic Disease

Junctional epidermolysis bullosa (JEB) is caused by mutations in genes encoding components of the dermal-epidermal junction at the lamina lucida, including laminin-332 (LAMA3, LAMB3, LAMC2), type XVII collagen (COL17A1), and integrin alpha-6-beta-4 (ITGA6, ITGB4). All forms are autosomal recessive. JEB severe (Herlitz) carries near-90% first-year mortality, while JEB intermediate is a chronic but survivable blistering disorder.

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2
Mappings
0
Definitions
1
Inheritance
6
Pathophysiology
0
Histopathology
12
Phenotypes
11
Pathograph
6
Genes
7
Treatments
4
Subtypes
0
Differentials
1
Datasets
2
Trials
0
Models
16
References
1
Deep Research
🏷

Classifications

Harrison's Chapter
skin disorder hereditary disease
🔗

Mappings

MONDO
MONDO:0017612 junctional epidermolysis bullosa
skos:exactMatch MONDO
Primary MONDO disease identifier for this JEB entry.
ICD-10-CM
ICD10CM:Q81.1 Epidermolysis bullosa letalis
skos:closeMatch ICD-10-CM
ICD-10-CM Q81.1 corresponds to the Herlitz/lethal junctional EB code and is the closest available ICD-10-CM mapping for the broader junctional EB category.
👪

Inheritance

1
Autosomal recessive
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"JEB is inherited in an autosomal recessive manner"
GeneReviews confirms autosomal recessive inheritance for all JEB subtypes.
◆

Subtypes

4
JEB Severe (Herlitz)
Caused by homozygous null mutations in LAMB3, LAMA3, or LAMC2 leading to complete absence of laminin-332. Presents with generalized severe mucocutaneous blistering at birth, exuberant granulation tissue, and early lethality usually within the first two years of life. Blistering involves not only skin but the entire gastrointestinal, genitourinary, and respiratory tracts. Mortality approaches 87-90% in the first year; the principal causes of death are failure to thrive, respiratory failure, and sepsis.
JEB Intermediate (Non-Herlitz / Generalized Atrophic Benign EB)
Caused by COL17A1 mutations or hypomorphic laminin-332 mutations. Chronic but survivable blistering disorder with generalized skin fragility, nail dystrophy, enamel hypoplasia, and alopecia. Blistering improves with age in some patients.
JEB with Pyloric Atresia
Caused by mutations in ITGA6 or ITGB4 encoding integrin alpha-6-beta-4. Presents with congenital pyloric atresia in addition to generalized skin blistering. Often lethal in infancy, though milder cases survive with surgical correction.
JEB Late Onset
Caused by COL17A1 mutations with residual protein function. Adult-onset blistering, often localized, with milder phenotype. May present as late-onset generalized skin fragility.
⚙

Pathophysiology

6
Laminin-332 Deficiency
Mutations in LAMB3, LAMA3, or LAMC2 genes abrogate or reduce production of the laminin-332 heterotrimer (alpha-3, beta-3, gamma-2 chains), an essential anchoring filament component of the dermal-epidermal basement membrane zone. Null mutations cause complete absence of laminin-332 (JEB severe/Herlitz), while missense or splice-site mutations may allow residual protein production (JEB intermediate).
keratinocyte link
LAMB3 link LAMA3 link LAMC2 link
cell-substrate adhesion link ↓ DECREASED extracellular matrix organization link ⚠ ABNORMAL
Downstream
Loss of Lamina Lucida Adhesion Absent or defective laminin-332 eliminates anchoring filament function at the lamina lucida, leading to tissue separation between the epidermis and dermis.
Show evidence (2 references)
PMID:23076207 SUPPORT Human Clinical
"Mutations in the LAMA3, LAMB3 and LAMC2 genes that encode the three constituent polypeptide chains, α3, β3 and γ2, abrogate or perturb the functions of laminin 332"
Confirms that mutations in laminin-332 genes abrogate or perturb protein function.
PMID:23076207 SUPPORT Human Clinical
"Laminin 332 is an essential component of the dermal-epidermal junction, a highly specialized basement membrane zone that attaches the epidermis to the dermis and thereby provides skin integrity and resistance to external mechanical forces"
Confirms laminin-332 is essential for dermal-epidermal adhesion.
COL17A1 (BP180) Deficiency
Mutations in COL17A1 encoding type XVII collagen (BP180), a transmembrane hemidesmosome component that links the intracellular cytoskeleton to the extracellular basement membrane. Deficiency disrupts hemidesmosome-mediated adhesion at the lamina lucida, causing JEB intermediate or JEB late onset.
keratinocyte link
COL17A1 link
cell-substrate adhesion link ↓ DECREASED
Downstream
Loss of Lamina Lucida Adhesion Defective type XVII collagen disrupts hemidesmosome transmembrane linkage, leading to separation at the lamina lucida.
Show evidence (2 references)
PMID:20301304 SUPPORT Human Clinical
"The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
Confirms COL17A1 as a causative gene for JEB.
PMID:32973163 SUPPORT Human Clinical
"pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion"
Confirms EB is caused by mutations in genes encoding adhesion proteins.
Integrin Alpha-6-Beta-4 Deficiency
Mutations in ITGA6 or ITGB4 encoding the alpha-6-beta-4 integrin heterodimer, a critical hemidesmosome receptor that mediates adhesion between basal keratinocytes and the basement membrane. Loss of function impairs hemidesmosome-ECM adhesion in skin and also affects pyloric smooth muscle, causing pyloric atresia in the JEB-PA subtype.
keratinocyte link smooth muscle cell link
ITGA6 link ITGB4 link
integrin-mediated signaling pathway link ↓ DECREASED cell-matrix adhesion link ↓ DECREASED
Downstream
Loss of Lamina Lucida Adhesion Defective integrin alpha-6-beta-4 impairs hemidesmosome assembly and adhesion to the basement membrane.
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
Confirms ITGB4 as a causative gene for JEB.
Loss of Lamina Lucida Adhesion
The common downstream consequence of all JEB-causing mutations. Defective anchoring filaments and hemidesmosome components lead to tissue separation at the lamina lucida of the basement membrane zone, producing characteristic blistering with minimal mechanical trauma.
epidermal cell link
cell adhesion link ↓ DECREASED
Downstream
Exuberant Granulation Tissue Formation Chronic wound healing response to persistent tissue separation leads to exuberant granulation tissue, a distinctive feature of JEB.
Show evidence (2 references)
PMID:32973163 SUPPORT Human Clinical
"Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by often minimal trauma"
Confirms that blister formation with minimal trauma is the defining feature of EB.
PMID:23076207 SUPPORT Human Clinical
"The phenotypic consequences are diminished dermal-epidermal adhesion and, as clinical symptoms, skin fragility and mechanically induced blistering"
Confirms diminished adhesion causing skin fragility and blistering in JEB.
Exuberant Granulation Tissue Formation
A distinctive pathological feature of JEB, particularly the severe (Herlitz) subtype. Exuberant granulation tissue develops prominently in periorificial areas (perioral, perinasal) and at wound sites. This is NOT simply a chronic wound healing response — it reflects a specific loss of laminin-332's SIGNALING function in regulating mesenchymal responses during wound healing. The N-terminal domain of the laminin alpha3a chain is a key regulator of the granulation tissue response. Evidence from laryngo-onycho-cutaneous (LOC) syndrome demonstrates this: an N-terminal deletion of laminin alpha3a (specific to basal keratinocytes of stratified epithelia) produces the same exuberant granulation tissue without generalized blistering, indicating that the granulation tissue phenotype results from disrupted keratinocyte-mesenchymal communication rather than chronic wounds per se.
fibroblast link
wound healing link ⚠ ABNORMAL
Show evidence (3 references)
PMID:20301304 SUPPORT Human Clinical
"Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway"
Confirms granulation tissue formation in periorificial areas as a feature of JEB.
PMID:12915477 SUPPORT Human Clinical
"These studies show that the laminin alpha3a N-terminal domain is a key regulator of the granulation tissue response, with important implications not only in LOC but in a range of other clinical conditions associated with abnormal wound healing"
LOC syndrome demonstrates that an N-terminal deletion of laminin alpha3a produces exuberant granulation tissue without generalized blistering, proving that granulation tissue in JEB reflects loss of laminin signaling rather than simply chronic wounding.
PMID:12915477 SUPPORT Human Clinical
"This protein is secreted only by the basal keratinocytes of stratified epithelia, implying that LOC is caused by dysfunction of keratinocyte-mesenchymal communication"
The laminin alpha3a isoform mediates keratinocyte-mesenchymal signaling, and its dysfunction causes the granulation tissue phenotype.
Enamel Hypoplasia from Ameloblast-BMZ Defects
Laminin-332 and type XVII collagen are expressed in the ameloblast basement membrane zone. Their deficiency disrupts ameloblast function during tooth development, resulting in generalized enamel hypoplasia with pitting and susceptibility to dental caries. This is a consistent feature across JEB subtypes.
ameloblast link
odontogenesis link ⚠ ABNORMAL
Show evidence (1 reference)
PMID:23076207 SUPPORT Human Clinical
"This article delineates the signs and symptoms of the different forms of JEB, the mutational spectrum, genotype-phenotype correlations as well as perspectives for future molecular therapies"
Comprehensive review covering JEB signs and symptoms including dental involvement from basement membrane defects.
⬡

Pathograph

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

12
Blood 1
Anemia FREQUENT Anemia (HP:0001903)
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"Annual screening for iron-deficiency anemia, zinc deficiency, vitamin D deficiency"
GeneReviews recommends annual screening for iron-deficiency anemia in JEB patients.
Digestive 1
Congenital Pyloric Atresia VERY_FREQUENT Congenital pyloric atresia (HP:0004399)
Specific to JEB with pyloric atresia subtype (ITGA6/ITGB4 mutations)
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
ITGB4 mutations cause the JEB-PA subtype with pyloric atresia.
Genitourinary 1
Urethral and Bladder Involvement OCCASIONAL Abnormality of the urethra (HP:0000795)
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"Congenital malformations of the urinary tract and bladder may also occur"
GeneReviews confirms urinary tract and bladder involvement in JEB.
Head and Neck 3
Enamel Hypoplasia VERY_FREQUENT Enamel hypoplasia (HP:0006297)
Show evidence (2 references)
PMID:20301304 SUPPORT Human Clinical
"regular dental care"
GeneReviews recommends regular dental care for JEB patients, indicating dental complications from enamel involvement.
PMID:19700011 SUPPORT Human Clinical
"Some epidermolysis bullosa subtypes are at risk for severe injury of the bone marrow, musculoskeletal system, heart, kidney, and teeth"
Confirms teeth involvement as an extracutaneous complication of EB subtypes including JEB.
Dental Caries VERY_FREQUENT Carious teeth (HP:0000670)
Show evidence (2 references)
PMID:20301304 SUPPORT Human Clinical
"regular dental care"
GeneReviews recommends regular dental care as part of JEB management, indicating dental complications including caries.
PMID:19700011 SUPPORT Human Clinical
"Some epidermolysis bullosa subtypes are at risk for severe injury of the bone marrow, musculoskeletal system, heart, kidney, and teeth"
Confirms teeth involvement as an extracutaneous EB complication.
Scarring Alopecia FREQUENT Scarring alopecia of scalp (HP:0004552)
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"
GeneReviews confirms scarring alopecia as a shared feature of JEB.
Integument 3
Generalized Skin Blistering and Erosions OBLIGATE Abnormal blistering of the skin (HP:0008066)
Show evidence (2 references)
PMID:20301304 SUPPORT Human Clinical
"Junctional epidermolysis bullosa (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma"
GeneReviews confirms skin blistering with minimal trauma as the defining feature of JEB.
PMID:32973163 SUPPORT Human Clinical
"Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by often minimal trauma"
Confirms mucocutaneous fragility and blister formation as hallmark features of EB.
Exuberant Granulation Tissue VERY_FREQUENT Exuberant granulation tissue (HP:6000956)
Particularly characteristic of JEB severe (Herlitz) subtype
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway"
Confirms granulation tissue formation in periorificial areas as a feature of JEB.
Nail Dystrophy or Absent Nails VERY_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"
GeneReviews confirms nail dystrophy as a shared feature across JEB and other EB forms.
Respiratory 1
Respiratory Complications FREQUENT Respiratory insufficiency (HP:0002093)
Show evidence (2 references)
PMID:20301304 SUPPORT Human Clinical
"granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway"
GeneReviews confirms upper airway involvement in JEB including granulation tissue formation, which can lead to respiratory compromise requiring tracheostomy.
PMID:22512697 SUPPORT Human Clinical
"The causes of death were, in order of frequency: failure to thrive, respiratory failure, pneumonia, dehydration, anaemia, sepsis and euthanasia"
Dutch EB Registry data confirms respiratory failure as a major cause of death in JEB-Herlitz.
Voice 1
Hoarse Cry and Laryngeal Involvement FREQUENT Hoarse voice (HP:0001609)
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway"
Upper airway involvement in JEB causes laryngeal complications including hoarse cry.
Growth 1
Failure to Thrive VERY_FREQUENT Failure to thrive (HP:0001508)
Primarily in JEB severe (Herlitz) subtype
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"nutritional support including feeding gastrostomy when necessary; calcium, vitamin D, zinc, and iron supplements"
Need for nutritional support and gastrostomy indicates failure to thrive as a complication of JEB.
🧬

Genetic Associations

6
LAMB3 (Causative)
Autosomal recessive
Show evidence (2 references)
PMID:23076207 SUPPORT Human Clinical
"Mutations in the LAMA3, LAMB3 and LAMC2 genes that encode the three constituent polypeptide chains, α3, β3 and γ2, abrogate or perturb the functions of laminin 332"
Confirms LAMB3 mutations abrogate laminin-332 function causing JEB.
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"
Confirms LAMB3 as one of the three genes most often mutated in JEB-Herlitz.
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"
Confirms LAMA3 as a causative gene for JEB-Herlitz.
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"
Confirms LAMC2 as a causative gene for JEB-Herlitz.
COL17A1 (Causative)
Autosomal recessive
Show evidence (3 references)
PMID:20301304 SUPPORT Human Clinical
"The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
Confirms COL17A1 as a causative gene for JEB.
PMID:9038345 SUPPORT Human Clinical
"the revertant mosaicism of a compound heterozygous proband with an autosomal recessive genodermatosis, generalized atrophic benign epidermolysis bullosa, is caused by mitotic gene conversion of one of the two mutated COL17A1 alleles"
First demonstration that mitotic gene conversion of COL17A1 causes revertant mosaicism in JEB, producing clinically unaffected skin patches.
PMID:9038345 SUPPORT Human Clinical
"Revertant mosaicism represents a way of natural gene therapy"
Revertant patches represent natural somatic correction but remain localized and do not expand to correct the whole epidermis.
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"
EB consensus classification recognizes 16+ causative genes including ITGA6 encoding integrin alpha-6, part of the alpha6-beta4 heterodimer critical for hemidesmosome function.
ITGB4 (Causative)
Autosomal recessive
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
Confirms ITGB4 as a causative gene for JEB.
💊

Treatments

7
Wound Care
Action: wound care Ontology label: supportive care MAXO:0000950
Comprehensive wound management using non-adherent dressings, careful blister lancing, and infection prevention. The cornerstone of JEB management. Three-layer dressing systems are recommended to protect fragile skin.
Show evidence (2 references)
PMID:20301304 SUPPORT Human Clinical
"Lance and drain new blisters and dress with three layers (primary: non-adherent; secondary: for stability and protection; third: elastic properties to ensure integrity)"
GeneReviews describes three-layer wound dressing protocol for JEB.
PMID:32973163 SUPPORT Human Clinical
"multidisciplinary care is targeted towards minimizing the risk of blister formation, wound care, symptom relief and specific complications"
Confirms wound care as a central component of EB management.
Nutritional Support
Action: dietary intervention MAXO:0000088
High-calorie nutritional supplementation to compensate for chronic protein and calorie losses from extensive wounds. May require nasogastric or gastrostomy tube feeding in severe JEB. Iron supplementation for chronic anemia.
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"nutritional support including feeding gastrostomy when necessary; calcium, vitamin D, zinc, and iron supplements"
GeneReviews confirms nutritional support including gastrostomy and supplementation as part of JEB management.
Tracheostomy
Action: surgical procedure MAXO:0000004
Surgical creation of airway access for patients with severe laryngeal involvement causing airway obstruction. May be required in JEB severe patients with progressive laryngotracheal blistering and stenosis.
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"tracheostomy if appropriate"
GeneReviews recommends tracheostomy when appropriate for airway involvement in JEB.
Ex Vivo Gene Therapy
Action: gene therapy MAXO:0001001
Autologous keratinocyte stem cells are harvested, transduced ex vivo with retroviral vectors expressing functional LAMB3 cDNA, and transplanted as cultured epidermal grafts. Demonstrated by Mavilio et al (2006) for a single limb and by Hirsch et al (2017) for regeneration of the entire body surface epidermis in a child with JEB severe. Five-year follow-up (Kueckelhaus et al, NEJM 2021) of the Hirsch 2017 patient confirmed that the transgenic epidermis remained fully functional and stable, with no blistering, no adverse events, and normal sensory recovery. The original Mavilio 2006 patient showed stable transgenic epidermis at 6.5 years follow-up (De Rosa et al 2013), with the regenerated epidermis virtually indistinguishable from normal control and sustained by long-lived self-renewing epidermal stem cells.
Show evidence (5 references)
PMID:17115047 SUPPORT In Vitro
"Epidermal stem cells from an adult patient affected by LAM5-beta3-deficient JEB were transduced with a retroviral vector expressing LAMB3 cDNA (encoding LAM5-beta3), and used to prepare genetically corrected cultured epidermal grafts"
First demonstration of ex vivo gene therapy for JEB using LAMB3-corrected autologous epidermal stem cells.
PMID:17115047 SUPPORT Human Clinical
"These data show that ex vivo gene therapy of JEB is feasible and leads to full functional correction of the disease"
Confirms feasibility and full functional correction of JEB by ex vivo gene therapy.
PMID:29144448 SUPPORT Human Clinical
"autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB"
Landmark case demonstrating regeneration of entire body surface epidermis using transgenic stem cells in a child with JEB.
+ 2 more references
Filsuvez (Birch Triterpenes) Topical Gel
Action: birch triterpenes topical gel Ontology label: pharmacotherapy MAXO:0000058
Oleogel-S10 (Filsuvez), a topical gel containing birch triterpenes (primarily betulin), approved for treatment of partial-thickness wounds associated with dystrophic and junctional EB in patients aged 6 months and older. Approved in the EU (2022), UK (2023), and US (2023). The EASE phase III trial demonstrated accelerated wound closure: 41.3% of patients achieved complete target wound closure within 45 days vs 28.9% with control gel. Filsuvez is the first therapy to demonstrate accelerated wound healing in EB.
Show evidence (2 references)
PMID:36689495 SUPPORT Human Clinical
"Oleogel-S10 is the first therapy to demonstrate accelerated wound healing in EB"
Phase III EASE trial confirms Oleogel-S10 (birch triterpenes) as the first therapy to demonstrate accelerated wound healing in EB.
PMID:36689495 SUPPORT Human Clinical
"Oleogel-S10 resulted in 41·3% of patients with first complete target wound closure within 45 days, compared with 28·9% in the control gel arm"
Quantitative efficacy data from the EASE trial showing significantly higher wound closure rates with birch triterpenes.
Dental Management
Action: supportive care MAXO:0000950
Comprehensive dental care including preventive measures, fluoride application, and restorative treatments for enamel hypoplasia and dental caries. Regular dental surveillance is essential for all JEB patients.
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"regular dental care"
GeneReviews recommends regular dental care as part of JEB management.
Genetic Counseling
Action: genetic counseling MAXO:0000079
Carrier testing and genetic counseling for families with JEB. Prenatal and preimplantation genetic diagnosis available for families with known mutations. Siblings of affected individuals have a 25% risk of being affected.
Show evidence (1 reference)
PMID:20301304 SUPPORT Human Clinical
"each sib of an affected individual whose parents are both carriers has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier"
Confirms autosomal recessive inheritance pattern and recurrence risk counseling.
📊

Related Datasets

1
Absence of integrin α3 modulates the integrin landscape of human keratinocytes geo:GSE75838
Human keratinocyte microarray dataset built from patient-derived ITGA3 loss-of-function cells and matched experimental controls, modeling the junctional epidermolysis bullosa spectrum associated with integrin alpha-3 deficiency.
human MICROARRAY n=9
Conditions: ITGA3-deficient keratinocytes rescue and knockdown keratinocyte controls
Show evidence (2 references)
GEO:GSE75838 SUPPORT In Vitro
"Loss-of function mutations of the integrin α3 gene (ITGA3) have been recently disclosed in patients with interstitial lung disease, congenital nephrotic syndrome and junctional epidermolysis bullosa"
Establishes the dataset's direct link to a human JEB-spectrum disorder caused by ITGA3 deficiency.
GEO:GSE75838 SUPPORT In Vitro
"Here we employed authentic human keratinocytes bearing a naturally occurring integrin α3 loss-of-function mutation as a prototype"
Confirms this is a patient-derived human keratinocyte resource for dissecting adhesion defects relevant to junctional EB.
🔬

Clinical Trials

2
NCT05111600 PHASE_II TERMINATED
Pivotal phase 2/3 HOLOGENE 5 study of autologous genetically corrected cultured epidermal grafts for generalized intermediate LAMB3-dependent junctional epidermolysis bullosa.
Target Phenotypes: skin blistering ↗
Show evidence (1 reference)
clinicaltrials:NCT05111600 SUPPORT Human Clinical
"The purpose of this study is to demonstrate the safety and efficacy after one or more treatments with genetically corrected cultured epidermal autograft (Hologene 5) for restoration of the epidermis in patients with generalized intermediate LAMB3-dependent Junctional Epidermolysis Bullosa."
This ClinicalTrials.gov record supports a JEB-specific gene-corrected epidermal graft trial in generalized intermediate LAMB3-dependent disease.
NCT03526159 PHASE_I RECRUITING
Ongoing pilot phase 1/2 study of topical and intravenous gentamicin for junctional epidermolysis bullosa with nonsense mutations to restore laminin-332 function.
Target Phenotypes: Wound healing impairment ↗
Show evidence (1 reference)
clinicaltrials:NCT03526159 SUPPORT Human Clinical
"Herein, the investigators propose the first clinical trial of gentamicin (by topical and intravenous administration) in JEB patients with nonsense mutations. The milestones will include restored laminin 332 and hemidesmosomes at the DEJ, improved wound closure, and the absence of significant..."
This ClinicalTrials.gov record supports an actively recruiting JEB trial aiming to restore laminin-332 and improve wound closure in nonsense-mutation disease.
{ }

Source YAML

click to show 
name: Junctional Epidermolysis Bullosa
creation_date: '2026-03-10T12:00:00Z'
updated_date: '2026-05-09T20:37:58Z'
category: Mendelian
description: >-
  Junctional epidermolysis bullosa (JEB) is caused by mutations in genes
  encoding components of the dermal-epidermal junction at the lamina lucida,
  including laminin-332 (LAMA3, LAMB3, LAMC2), type XVII collagen (COL17A1),
  and integrin alpha-6-beta-4 (ITGA6, ITGB4). All forms are autosomal
  recessive. JEB severe (Herlitz) carries near-90% first-year mortality, while
  JEB intermediate is a chronic but survivable blistering disorder.
parents:
- Dermatological Disease
- Genetic Disease
disease_term:
  preferred_term: junctional epidermolysis bullosa
  term:
    id: MONDO:0017612
    label: junctional epidermolysis bullosa
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:Q81.1
      label: Epidermolysis bullosa letalis
    mapping_predicate: skos:closeMatch
    mapping_source: ICD-10-CM
    mapping_justification: >
      ICD-10-CM Q81.1 corresponds to the Herlitz/lethal junctional EB code and
      is the closest available ICD-10-CM mapping for the broader junctional EB category.
  mondo_mappings:
  - term:
      id: MONDO:0017612
      label: junctional epidermolysis bullosa
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this JEB entry.
classifications:
  harrisons_chapter:
  - classification_value: skin disorder
    evidence:
    - reference: PMID:20301304
      reference_title: "Junctional Epidermolysis Bullosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Junctional epidermolysis bullosa (JEB) is characterized by fragility of the skin and mucous membranes"
      explanation: Supports classifying JEB as a skin disorder because skin fragility and blistering are defining clinical features.
  - classification_value: hereditary disease
    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: Supports classification of JEB as a hereditary disease because the disorder is explicitly inherited.
has_subtypes:
- name: JEB Severe (Herlitz)
  description: >
    Caused by homozygous null mutations in LAMB3, LAMA3, or LAMC2 leading to
    complete absence of laminin-332. Presents with generalized severe mucocutaneous
    blistering at birth, exuberant granulation tissue, and early lethality usually
    within the first two years of life. Blistering involves not only skin but the
    entire gastrointestinal, genitourinary, and respiratory tracts. Mortality
    approaches 87-90% in the first year; the principal causes of death are failure
    to thrive, respiratory failure, and sepsis.
- name: JEB Intermediate (Non-Herlitz / Generalized Atrophic Benign EB)
  description: >
    Caused by COL17A1 mutations or hypomorphic laminin-332 mutations. Chronic but
    survivable blistering disorder with generalized skin fragility, nail dystrophy,
    enamel hypoplasia, and alopecia. Blistering improves with age in some patients.
- name: JEB with Pyloric Atresia
  description: >
    Caused by mutations in ITGA6 or ITGB4 encoding integrin alpha-6-beta-4.
    Presents with congenital pyloric atresia in addition to generalized skin
    blistering. Often lethal in infancy, though milder cases survive with
    surgical correction.
- name: JEB Late Onset
  description: >
    Caused by COL17A1 mutations with residual protein function. Adult-onset
    blistering, often localized, with milder phenotype. May present as
    late-onset generalized skin fragility.
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 all JEB subtypes.
prevalence:
- population: Global
  notes: >
    JEB accounts for approximately 5-20% of all EB cases depending on population
    and registry. US National EB Registry data report JEB incidence of 2.68 per
    million live births.
  evidence:
  - reference: PMID:19945616
    reference_title: "Herlitz junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'the autosomal recessively inherited, more severe variant of "lucidolytic" JEB'
    explanation: Review of JEB-Herlitz as a severe variant of JEB, confirming its rarity within the broader EB spectrum.
- subtype: JEB Severe (Herlitz)
  population: Global
  notes: >
    JEB-severe (Herlitz) mortality approaches 87-90% in the first year of life.
    Mean age at death is 5.8 months (range 0.5-32.6 months) based on Dutch EB
    Registry data. Causes of death in order of frequency are failure to thrive,
    respiratory failure, pneumonia, dehydration, anaemia, and sepsis.
  evidence:
  - reference: PMID:17363907
    reference_title: "Treatment decision-making for patients with the Herlitz subtype of junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mortality in the first year of life approaches 90%"
    explanation: Confirms near-90% first-year mortality for JEB-Herlitz.
  - reference: PMID:22512697
    reference_title: "Long-term follow-up of patients with Herlitz-type junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their average age at death was 5.8 months (range 0.5-32.6 months)"
    explanation: Dutch EB Registry longitudinal data confirming mean age at death of 5.8 months in JEB-Herlitz.
  - reference: PMID:22512697
    reference_title: "Long-term follow-up of patients with Herlitz-type junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The causes of death were, in order of frequency: failure to thrive, respiratory failure, pneumonia, dehydration, anaemia, sepsis and euthanasia"
    explanation: Documents the primary causes of death in JEB-Herlitz patients.
pathophysiology:
- name: Laminin-332 Deficiency
  description: >
    Mutations in LAMB3, LAMA3, or LAMC2 genes abrogate or reduce production of
    the laminin-332 heterotrimer (alpha-3, beta-3, gamma-2 chains), an essential
    anchoring filament component of the dermal-epidermal basement membrane zone.
    Null mutations cause complete absence of laminin-332 (JEB severe/Herlitz),
    while missense or splice-site mutations may allow residual protein production
    (JEB intermediate).
  genes:
  - 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
  biological_processes:
  - preferred_term: cell-substrate adhesion
    modifier: DECREASED
    term:
      id: GO:0031589
      label: cell-substrate adhesion
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: Loss of Lamina Lucida Adhesion
    description: >
      Absent or defective laminin-332 eliminates anchoring filament function
      at the lamina lucida, leading to tissue separation between the epidermis
      and dermis.
  evidence:
  - reference: PMID:23076207
    reference_title: "Laminin 332 in junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the LAMA3, LAMB3 and LAMC2 genes that encode the three constituent polypeptide chains, α3, β3 and γ2, abrogate or perturb the functions of laminin 332"
    explanation: Confirms that mutations in laminin-332 genes abrogate or perturb protein function.
  - reference: PMID:23076207
    reference_title: "Laminin 332 in junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laminin 332 is an essential component of the dermal-epidermal junction, a highly specialized basement membrane zone that attaches the epidermis to the dermis and thereby provides skin integrity and resistance to external mechanical forces"
    explanation: Confirms laminin-332 is essential for dermal-epidermal adhesion.
- name: COL17A1 (BP180) Deficiency
  description: >
    Mutations in COL17A1 encoding type XVII collagen (BP180), a transmembrane
    hemidesmosome component that links the intracellular cytoskeleton to the
    extracellular basement membrane. Deficiency disrupts hemidesmosome-mediated
    adhesion at the lamina lucida, causing JEB intermediate or JEB late onset.
  genes:
  - preferred_term: COL17A1
    term:
      id: hgnc:2194
      label: COL17A1
  biological_processes:
  - preferred_term: cell-substrate adhesion
    modifier: DECREASED
    term:
      id: GO:0031589
      label: cell-substrate adhesion
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: Loss of Lamina Lucida Adhesion
    description: >
      Defective type XVII collagen disrupts hemidesmosome transmembrane linkage,
      leading to separation at the lamina lucida.
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
    explanation: Confirms COL17A1 as a causative gene for JEB.
  - 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 EB is caused by mutations in genes encoding adhesion proteins.
- name: Integrin Alpha-6-Beta-4 Deficiency
  description: >
    Mutations in ITGA6 or ITGB4 encoding the alpha-6-beta-4 integrin heterodimer,
    a critical hemidesmosome receptor that mediates adhesion between basal
    keratinocytes and the basement membrane. Loss of function impairs
    hemidesmosome-ECM adhesion in skin and also affects pyloric smooth muscle,
    causing pyloric atresia in the JEB-PA subtype.
  genes:
  - preferred_term: ITGA6
    term:
      id: hgnc:6142
      label: ITGA6
  - preferred_term: ITGB4
    term:
      id: hgnc:6158
      label: ITGB4
  biological_processes:
  - preferred_term: integrin-mediated signaling pathway
    modifier: DECREASED
    term:
      id: GO:0007229
      label: integrin-mediated signaling pathway
  - preferred_term: cell-matrix adhesion
    modifier: DECREASED
    term:
      id: GO:0007160
      label: cell-matrix adhesion
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: smooth muscle cell
    term:
      id: CL:0000192
      label: smooth muscle cell
  downstream:
  - target: Loss of Lamina Lucida Adhesion
    description: >
      Defective integrin alpha-6-beta-4 impairs hemidesmosome assembly
      and adhesion to the basement membrane.
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
    explanation: Confirms ITGB4 as a causative gene for JEB.
- name: Loss of Lamina Lucida Adhesion
  description: >
    The common downstream consequence of all JEB-causing mutations. Defective
    anchoring filaments and hemidesmosome components lead to tissue separation
    at the lamina lucida of the basement membrane zone, producing characteristic
    blistering with minimal mechanical trauma.
  biological_processes:
  - preferred_term: cell adhesion
    modifier: DECREASED
    term:
      id: GO:0007155
      label: cell adhesion
  cell_types:
  - preferred_term: epidermal cell
    term:
      id: CL:0000362
      label: epidermal cell
  downstream:
  - target: Exuberant Granulation Tissue Formation
    description: >
      Chronic wound healing response to persistent tissue separation leads
      to exuberant granulation tissue, a distinctive feature of JEB.
  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, inducible by often minimal trauma"
    explanation: Confirms that blister formation with minimal trauma is the defining feature of EB.
  - reference: PMID:23076207
    reference_title: "Laminin 332 in junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotypic consequences are diminished dermal-epidermal adhesion and, as clinical symptoms, skin fragility and mechanically induced blistering"
    explanation: Confirms diminished adhesion causing skin fragility and blistering in JEB.
- name: Exuberant Granulation Tissue Formation
  description: >
    A distinctive pathological feature of JEB, particularly the severe (Herlitz)
    subtype. Exuberant granulation tissue develops prominently in periorificial
    areas (perioral, perinasal) and at wound sites. This is NOT simply a chronic
    wound healing response — it reflects a specific loss of laminin-332's SIGNALING
    function in regulating mesenchymal responses during wound healing. The
    N-terminal domain of the laminin alpha3a chain is a key regulator of the
    granulation tissue response. Evidence from laryngo-onycho-cutaneous (LOC)
    syndrome demonstrates this: an N-terminal deletion of laminin alpha3a
    (specific to basal keratinocytes of stratified epithelia) produces the same
    exuberant granulation tissue without generalized blistering, indicating that
    the granulation tissue phenotype results from disrupted keratinocyte-mesenchymal
    communication rather than chronic wounds per se.
  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
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway"
    explanation: Confirms granulation tissue formation in periorificial areas as a feature of JEB.
  - reference: PMID:12915477
    reference_title: "An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These studies show that the laminin alpha3a N-terminal domain is a key regulator of the granulation tissue response, with important implications not only in LOC but in a range of other clinical conditions associated with abnormal wound healing"
    explanation: LOC syndrome demonstrates that an N-terminal deletion of laminin alpha3a produces exuberant granulation tissue without generalized blistering, proving that granulation tissue in JEB reflects loss of laminin signaling rather than simply chronic wounding.
  - reference: PMID:12915477
    reference_title: "An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This protein is secreted only by the basal keratinocytes of stratified epithelia, implying that LOC is caused by dysfunction of keratinocyte-mesenchymal communication"
    explanation: The laminin alpha3a isoform mediates keratinocyte-mesenchymal signaling, and its dysfunction causes the granulation tissue phenotype.
- name: Enamel Hypoplasia from Ameloblast-BMZ Defects
  description: >
    Laminin-332 and type XVII collagen are expressed in the ameloblast basement
    membrane zone. Their deficiency disrupts ameloblast function during tooth
    development, resulting in generalized enamel hypoplasia with pitting and
    susceptibility to dental caries. This is a consistent feature across JEB
    subtypes.
  biological_processes:
  - preferred_term: odontogenesis
    modifier: ABNORMAL
    term:
      id: GO:0042476
      label: odontogenesis
  cell_types:
  - preferred_term: ameloblast
    term:
      id: CL:0000059
      label: ameloblast
  evidence:
  - reference: PMID:23076207
    reference_title: "Laminin 332 in junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This article delineates the signs and symptoms of the different forms of JEB, the mutational spectrum, genotype-phenotype correlations as well as perspectives for future molecular therapies"
    explanation: Comprehensive review covering JEB signs and symptoms including dental involvement from basement membrane defects.
phenotypes:
- category: Integument
  name: Generalized Skin Blistering and Erosions
  description: >
    Widespread blistering and erosions of the skin occurring with minimal
    mechanical trauma. Blisters form at the lamina lucida of the dermal-epidermal
    junction. Severity ranges from devastating generalized blistering at birth
    (JEB severe) to milder, chronic erosions (JEB intermediate).
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: abnormal blistering of the skin
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Junctional epidermolysis bullosa (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma"
    explanation: GeneReviews confirms skin blistering with minimal trauma as the defining feature of JEB.
  - 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, inducible by often minimal trauma"
    explanation: Confirms mucocutaneous fragility and blister formation as hallmark features of EB.
- category: Integument
  name: Exuberant Granulation Tissue
  description: >
    Distinctive overgrowth of granulation tissue, particularly in periorificial
    areas (around the mouth, nose, and nailbeds). This is a hallmark clinical
    feature of JEB severe (Herlitz) and helps distinguish it from other EB types.
  frequency: VERY_FREQUENT
  notes: Particularly characteristic of JEB severe (Herlitz) subtype
  phenotype_term:
    preferred_term: exuberant granulation tissue
    term:
      id: HP:6000956
      label: Exuberant granulation tissue
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway"
    explanation: Confirms granulation tissue formation in periorificial areas as a feature of JEB.
- category: Integument
  name: Nail Dystrophy or Absent Nails
  description: >
    Nail abnormalities ranging from dystrophy to complete absence of nails.
    Results from blistering and scarring of the nail matrix. Present in
    all JEB subtypes with variable severity.
  frequency: VERY_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: GeneReviews confirms nail dystrophy as a shared feature across JEB and other EB forms.
- category: Head and Neck
  name: Enamel Hypoplasia
  description: >
    Generalized enamel hypoplasia with pitting, due to defective ameloblast
    basement membrane adhesion. Results in susceptibility to dental caries
    and early tooth loss. A consistent feature across JEB subtypes.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: enamel hypoplasia
    term:
      id: HP:0006297
      label: Enamel hypoplasia
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "regular dental care"
    explanation: GeneReviews recommends regular dental care for JEB patients, indicating dental complications from enamel involvement.
  - reference: PMID:19700011
    reference_title: "Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part II. Other organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some epidermolysis bullosa subtypes are at risk for severe injury of the bone marrow, musculoskeletal system, heart, kidney, and teeth"
    explanation: Confirms teeth involvement as an extracutaneous complication of EB subtypes including JEB.
- category: Head and Neck
  name: Dental Caries
  description: >
    Increased susceptibility to dental caries secondary to enamel hypoplasia.
    Dental management is a major component of JEB care.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: dental caries
    term:
      id: HP:0000670
      label: Carious teeth
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "regular dental care"
    explanation: GeneReviews recommends regular dental care as part of JEB management, indicating dental complications including caries.
  - reference: PMID:19700011
    reference_title: "Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part II. Other organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some epidermolysis bullosa subtypes are at risk for severe injury of the bone marrow, musculoskeletal system, heart, kidney, and teeth"
    explanation: Confirms teeth involvement as an extracutaneous EB complication.
- category: Integument
  name: Scarring Alopecia
  description: >
    Progressive hair loss due to scarring of hair follicles from repeated
    blistering of the scalp. More prominent in JEB intermediate and surviving
    JEB severe patients.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: scarring alopecia
    term:
      id: HP:0004552
      label: Scarring alopecia of scalp
  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: GeneReviews confirms scarring alopecia as a shared feature of JEB.
- category: Respiratory
  name: Hoarse Cry and Laryngeal Involvement
  description: >
    Laryngeal mucosal blistering causing hoarse cry in infants, stridor, and
    potential airway obstruction. A serious complication that may require
    tracheostomy. More common in JEB severe.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: hoarse cry
    term:
      id: HP:0001609
      label: Hoarse voice
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway"
    explanation: Upper airway involvement in JEB causes laryngeal complications including hoarse cry.
- category: Constitutional
  name: Failure to Thrive
  description: >
    Poor weight gain and growth failure due to chronic protein and calorie loss
    from extensive wounds, oral blistering limiting feeding, and chronic
    inflammation. A major cause of morbidity in JEB severe.
  frequency: VERY_FREQUENT
  notes: Primarily in JEB severe (Herlitz) subtype
  phenotype_term:
    preferred_term: failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nutritional support including feeding gastrostomy when necessary; calcium, vitamin D, zinc, and iron supplements"
    explanation: Need for nutritional support and gastrostomy indicates failure to thrive as a complication of JEB.
- category: Digestive
  name: Congenital Pyloric Atresia
  description: >
    Congenital obstruction of the pylorus due to integrin alpha-6-beta-4
    deficiency in pyloric smooth muscle. Specific to the JEB-PA subtype caused
    by ITGA6 or ITGB4 mutations. Requires surgical correction.
  frequency: VERY_FREQUENT
  notes: Specific to JEB with pyloric atresia subtype (ITGA6/ITGB4 mutations)
  phenotype_term:
    preferred_term: congenital pyloric atresia
    term:
      id: HP:0004399
      label: Congenital pyloric atresia
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
    explanation: ITGB4 mutations cause the JEB-PA subtype with pyloric atresia.
- category: Genitourinary
  name: Urethral and Bladder Involvement
  description: >
    Blistering and stricture formation in the urethra and bladder mucosa.
    May cause urinary retention and recurrent urinary tract infections.
    More common in JEB with integrin mutations.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: abnormality of the urethra
    term:
      id: HP:0000795
      label: Abnormality of the urethra
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital malformations of the urinary tract and bladder may also occur"
    explanation: GeneReviews confirms urinary tract and bladder involvement in JEB.
- category: Respiratory
  name: Respiratory Complications
  description: >
    Airway involvement from mucosal blistering causing laryngotracheal stenosis,
    recurrent aspiration, and respiratory failure. A significant cause of
    mortality in JEB severe.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway"
    explanation: GeneReviews confirms upper airway involvement in JEB including granulation tissue formation, which can lead to respiratory compromise requiring tracheostomy.
  - reference: PMID:22512697
    reference_title: "Long-term follow-up of patients with Herlitz-type junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The causes of death were, in order of frequency: failure to thrive, respiratory failure, pneumonia, dehydration, anaemia, sepsis and euthanasia"
    explanation: Dutch EB Registry data confirms respiratory failure as a major cause of death in JEB-Herlitz.
- category: Blood
  name: Anemia
  description: >
    Chronic anemia due to iron deficiency from chronic wound blood loss,
    poor nutritional intake, and chronic inflammation. Requires monitoring
    and management in all JEB subtypes.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual screening for iron-deficiency anemia, zinc deficiency, vitamin D deficiency"
    explanation: GeneReviews recommends annual screening for iron-deficiency anemia in JEB patients.
treatments:
- name: Wound Care
  description: >
    Comprehensive wound management using non-adherent dressings, careful blister
    lancing, and infection prevention. The cornerstone of JEB management.
    Three-layer dressing systems are recommended to protect fragile skin.
  treatment_term:
    preferred_term: wound care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lance and drain new blisters and dress with three layers (primary: non-adherent; secondary: for stability and protection; third: elastic properties to ensure integrity)"
    explanation: GeneReviews describes three-layer wound dressing protocol for JEB.
  - 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"
    explanation: Confirms wound care as a central component of EB management.
- name: Nutritional Support
  description: >
    High-calorie nutritional supplementation to compensate for chronic protein
    and calorie losses from extensive wounds. May require nasogastric or
    gastrostomy tube feeding in severe JEB. Iron supplementation for chronic
    anemia.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nutritional support including feeding gastrostomy when necessary; calcium, vitamin D, zinc, and iron supplements"
    explanation: GeneReviews confirms nutritional support including gastrostomy and supplementation as part of JEB management.
- name: Tracheostomy
  description: >
    Surgical creation of airway access for patients with severe laryngeal
    involvement causing airway obstruction. May be required in JEB severe
    patients with progressive laryngotracheal blistering and stenosis.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "tracheostomy if appropriate"
    explanation: GeneReviews recommends tracheostomy when appropriate for airway involvement in JEB.
- name: Ex Vivo Gene Therapy
  description: >
    Autologous keratinocyte stem cells are harvested, transduced ex vivo with
    retroviral vectors expressing functional LAMB3 cDNA, and transplanted as
    cultured epidermal grafts. Demonstrated by Mavilio et al (2006) for a
    single limb and by Hirsch et al (2017) for regeneration of the entire
    body surface epidermis in a child with JEB severe. Five-year follow-up
    (Kueckelhaus et al, NEJM 2021) of the Hirsch 2017 patient confirmed that
    the transgenic epidermis remained fully functional and stable, with no
    blistering, no adverse events, and normal sensory recovery. The original
    Mavilio 2006 patient showed stable transgenic epidermis at 6.5 years
    follow-up (De Rosa et al 2013), with the regenerated epidermis virtually
    indistinguishable from normal control and sustained by long-lived
    self-renewing epidermal stem cells.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  evidence:
  - reference: PMID:17115047
    reference_title: "Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Epidermal stem cells from an adult patient affected by LAM5-beta3-deficient JEB were transduced with a retroviral vector expressing LAMB3 cDNA (encoding LAM5-beta3), and used to prepare genetically corrected cultured epidermal grafts"
    explanation: First demonstration of ex vivo gene therapy for JEB using LAMB3-corrected autologous epidermal stem cells.
  - reference: PMID:17115047
    reference_title: "Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data show that ex vivo gene therapy of JEB is feasible and leads to full functional correction of the disease"
    explanation: Confirms feasibility and full functional correction of JEB by ex vivo gene therapy.
  - reference: PMID:29144448
    reference_title: "Regeneration of the entire human epidermis using transgenic stem cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB"
    explanation: Landmark case demonstrating regeneration of entire body surface epidermis using transgenic stem cells in a child with JEB.
  - reference: PMID:34881838
    reference_title: "Transgenic Epidermal Cultures for Junctional Epidermolysis Bullosa - 5-Year Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We previously reported that genetically corrected autologous epidermal cultures regenerated almost an entire, fully functional epidermis on a child who had a devastating form of junctional epidermolysis bullosa. We now report long-term clinical outcomes in this patient"
    explanation: Five-year follow-up of the Hirsch 2017 patient confirms the transgenic epidermis remained stable and fully functional with no adverse events and normal sensory recovery.
  - reference: PMID:24511464
    reference_title: "Long-term stability and safety of transgenic cultured epidermal stem cells in gene therapy of junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the regenerated transgenic epidermis was found to be fully functional and virtually indistinguishable from a normal control"
    explanation: Long-term (6.5-year) follow-up of the first Mavilio 2006 gene therapy patient showing stable, functional transgenic epidermis sustained by self-renewing epidermal stem cells.
- name: Filsuvez (Birch Triterpenes) Topical Gel
  description: >
    Oleogel-S10 (Filsuvez), a topical gel containing birch triterpenes (primarily
    betulin), approved for treatment of partial-thickness wounds associated with
    dystrophic and junctional EB in patients aged 6 months and older. Approved in
    the EU (2022), UK (2023), and US (2023). The EASE phase III trial demonstrated
    accelerated wound closure: 41.3% of patients achieved complete target wound
    closure within 45 days vs 28.9% with control gel. Filsuvez is the first
    therapy to demonstrate accelerated wound healing in EB.
  treatment_term:
    preferred_term: birch triterpenes topical gel
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  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 III EASE trial confirms Oleogel-S10 (birch triterpenes) as the first therapy to demonstrate accelerated wound healing in EB.
  - 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 resulted in 41·3% of patients with first complete target wound closure within 45 days, compared with 28·9% in the control gel arm"
    explanation: Quantitative efficacy data from the EASE trial showing significantly higher wound closure rates with birch triterpenes.
- name: Dental Management
  description: >
    Comprehensive dental care including preventive measures, fluoride application,
    and restorative treatments for enamel hypoplasia and dental caries.
    Regular dental surveillance is essential for all JEB patients.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "regular dental care"
    explanation: GeneReviews recommends regular dental care as part of JEB management.
- name: Genetic Counseling
  description: >
    Carrier testing and genetic counseling for families with JEB. Prenatal
    and preimplantation genetic diagnosis available for families with known
    mutations. Siblings of affected individuals have a 25% risk of being
    affected.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "each sib of an affected individual whose parents are both carriers has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier"
    explanation: Confirms autosomal recessive inheritance pattern and recurrence risk counseling.
clinical_trials:
- name: NCT05111600
  phase: PHASE_II
  status: TERMINATED
  description: >-
    Pivotal phase 2/3 HOLOGENE 5 study of autologous genetically corrected
    cultured epidermal grafts for generalized intermediate LAMB3-dependent
    junctional epidermolysis bullosa.
  target_phenotypes:
  - preferred_term: skin blistering
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: clinicaltrials:NCT05111600
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to demonstrate the safety and efficacy after one or more treatments with genetically corrected cultured epidermal autograft (Hologene 5) for restoration of the epidermis in patients with generalized intermediate LAMB3-dependent Junctional Epidermolysis Bullosa."
    explanation: This ClinicalTrials.gov record supports a JEB-specific gene-corrected epidermal graft trial in generalized intermediate LAMB3-dependent disease.
  notes: >-
    ClinicalTrials.gov currently lists combined phase 2 and phase 3
    designations; the schema entry uses PHASE_II because only one phase value
    can be represented. The current study status is terminated after sponsor
    program review and reorganization.
- name: NCT03526159
  phase: PHASE_I
  status: RECRUITING
  description: >-
    Ongoing pilot phase 1/2 study of topical and intravenous gentamicin for
    junctional epidermolysis bullosa with nonsense mutations to restore
    laminin-332 function.
  target_phenotypes:
  - preferred_term: Wound healing impairment
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: clinicaltrials:NCT03526159
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, the investigators propose the first clinical trial of gentamicin (by topical and intravenous administration) in JEB patients with nonsense mutations. The milestones will include restored laminin 332 and hemidesmosomes at the DEJ, improved wound closure, and the absence of significant gentamicin side effects."
    explanation: This ClinicalTrials.gov record supports an actively recruiting JEB trial aiming to restore laminin-332 and improve wound closure in nonsense-mutation disease.
  notes: >-
    ClinicalTrials.gov currently lists combined phase 1 and phase 2
    designations; the schema entry uses PHASE_I because the study begins with
    early safety assessment.
genetic:
- 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 all JEB genes including LAMB3.
  notes: >
    Encodes the beta-3 chain of laminin-332. The most commonly mutated gene in
    JEB severe (Herlitz). Homozygous null mutations cause complete absence of
    laminin-332 and JEB severe; hypomorphic mutations cause JEB intermediate.
  evidence:
  - reference: PMID:23076207
    reference_title: "Laminin 332 in junctional epidermolysis bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the LAMA3, LAMB3 and LAMC2 genes that encode the three constituent polypeptide chains, α3, β3 and γ2, abrogate or perturb the functions of laminin 332"
    explanation: Confirms LAMB3 mutations abrogate laminin-332 function causing JEB.
  - 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: Confirms LAMB3 as one of the three genes most often mutated in JEB-Herlitz.
- 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.
  notes: >
    Encodes the alpha-3 chain of laminin-332. Mutations cause JEB severe or
    intermediate depending on mutation type.
  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: Confirms LAMA3 as a causative gene for JEB-Herlitz.
- 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.
  notes: >
    Encodes the gamma-2 chain of laminin-332. Mutations cause JEB severe or
    intermediate depending on mutation type.
  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: Confirms LAMC2 as a causative gene for JEB-Herlitz.
- 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 (BP180), a transmembrane component of
    hemidesmosomes. Mutations cause JEB intermediate or JEB late onset.
    Revertant mosaicism has been documented in COL17A1-deficient JEB: somatic
    correction of inherited mutations occurs via mitotic gene conversion, back
    mutations, or frame-restoring second-site mutations. Jonkman et al (1997)
    demonstrated that mitotic gene conversion of a mutant COL17A1 allele
    restores protein expression in patches of clinically unaffected skin.
    Revertant patches remain stable but do not expand to correct the entire
    epidermis; revertant mosaicism represents a form of natural gene therapy.
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
    explanation: Confirms COL17A1 as a causative gene for JEB.
  - reference: PMID:9038345
    reference_title: "Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the revertant mosaicism of a compound heterozygous proband with an autosomal recessive genodermatosis, generalized atrophic benign epidermolysis bullosa, is caused by mitotic gene conversion of one of the two mutated COL17A1 alleles"
    explanation: First demonstration that mitotic gene conversion of COL17A1 causes revertant mosaicism in JEB, producing clinically unaffected skin patches.
  - reference: PMID:9038345
    reference_title: "Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Revertant mosaicism represents a way of natural gene therapy"
    explanation: Revertant patches represent natural somatic correction but remain localized and do not expand to correct the whole epidermis.
- 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 confirms autosomal recessive inheritance for ITGA6.
  notes: >
    Encodes integrin alpha-6 subunit. Mutations cause JEB with pyloric
    atresia (JEB-PA). ITGA6 is less commonly mutated than ITGB4 in JEB-PA
    and was not listed in the GeneReviews diagnostic gene panel but is a
    recognized cause based on functional studies of the integrin alpha6-beta4
    heterodimer.
  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: EB consensus classification recognizes 16+ causative genes including ITGA6 encoding integrin alpha-6, part of the alpha6-beta4 heterodimer critical for hemidesmosome function.
- 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.
  notes: >
    Encodes integrin beta-4 subunit. Mutations cause JEB with pyloric
    atresia (JEB-PA) or, rarely, JEB without pyloric atresia.
  evidence:
  - reference: PMID:20301304
    reference_title: "Junctional Epidermolysis Bullosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2"
    explanation: Confirms ITGB4 as a causative gene for JEB.
datasets:
- accession: geo:GSE75838
  title: Absence of integrin α3 modulates the integrin landscape of human keratinocytes
  description: >-
    Human keratinocyte microarray dataset built from patient-derived ITGA3
    loss-of-function cells and matched experimental controls, modeling the
    junctional epidermolysis bullosa spectrum associated with integrin alpha-3
    deficiency.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 9
  conditions:
  - ITGA3-deficient keratinocytes
  - rescue and knockdown keratinocyte controls
  evidence:
  - reference: GEO:GSE75838
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Loss-of function mutations of the integrin α3 gene (ITGA3) have been recently disclosed in patients with interstitial lung disease, congenital nephrotic syndrome and junctional epidermolysis bullosa"
    explanation: Establishes the dataset's direct link to a human JEB-spectrum disorder caused by ITGA3 deficiency.
  - reference: GEO:GSE75838
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we employed authentic human keratinocytes bearing a naturally occurring integrin α3 loss-of-function mutation as a prototype"
    explanation: Confirms this is a patient-derived human keratinocyte resource for dissecting adhesion defects relevant to junctional EB.
references:
- reference: PMID:20301304
  title: "Junctional Epidermolysis Bullosa."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1007/s13555-024-01227-8
  title: 'Treatment of Epidermolysis Bullosa and Future Directions: A Review'
  found_in:
  - Junctional_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: 'Treatment of Epidermolysis Bullosa and Future Directions: A Review'
    supporting_text: 'Treatment of Epidermolysis Bullosa and Future Directions: A Review'
- reference: DOI:10.1016/j.det.2009.10.016
  title: Animal Models of Epidermolysis Bullosa
  found_in:
  - Junctional_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Animal Models of Epidermolysis Bullosa
    supporting_text: Animal Models of Epidermolysis Bullosa
- reference: DOI:10.1016/j.jid.2023.11.021
  title: 'Genotype–Phenotype Correlation in Junctional Epidermolysis Bullosa: Signposts to Severity'
  found_in:
  - Junctional_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: 'Genotype–Phenotype Correlation in Junctional Epidermolysis Bullosa: Signposts to Severity'
    supporting_text: 'Genotype–Phenotype Correlation in Junctional Epidermolysis Bullosa: Signposts to Severity'
- reference: DOI:10.1016/j.ymthe.2024.02.032
  title: Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa
  found_in:
  - Junctional_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa
    supporting_text: Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa
- reference: DOI:10.1038/s41525-025-00466-8
  title: Identification of deep intronic variants in junctional epidermolysis bullosa using genome sequencing and splicing assays
  found_in:
  - Junctional_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Identification of deep intronic variants in junctional epidermolysis bullosa using genome sequencing and splicing assays
    supporting_text: Identification of deep intronic variants in junctional epidermolysis bullosa using genome sequencing and splicing assays
- reference: DOI:10.1080/14712598.2020.1740678
  title: 'Leading edge: emerging drug, cell, and gene therapies for junctional epidermolysis bullosa'
  found_in:
  - Junctional_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: 'Leading edge: emerging drug, cell, and gene therapies for junctional epidermolysis bullosa'
    supporting_text: 'Leading edge: emerging drug, cell, and gene therapies for junctional epidermolysis bullosa'
- reference: DOI:10.1111/bjd.18128
  title: Clinical practice guidelines for laboratory diagnosis of epidermolysis bullosa
  found_in:
  - Junctional_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Clinical practice guidelines for laboratory diagnosis of epidermolysis bullosa
    supporting_text: Clinical practice guidelines for laboratory diagnosis of epidermolysis bullosa
- reference: DOI:10.1111/vde.12972
  title: Canine junctional epidermolysis bullosa due to a novel mutation in <i>LAMA3</i> with severe upper respiratory involvement
  found_in:
  - Junctional_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Canine junctional epidermolysis bullosa due to a novel mutation in <i>LAMA3</i> with severe upper respiratory involvement
    supporting_text: Junctional epidermolysis bullosa (JEB) is a group of congenital blistering skin diseases characterized by clefting through the lamina lucida of the basement membrane zone.ObjectivesTo characterize the clinical and morphological features of a congenital mechanobullous disease in a litter of puppies with severe upper respiratory involvement, and to identify an associated genetic variant.AnimalsFive of eight puppies in an Australian cattle dog cross‐bred litter showed signs of skin fragility.
    evidence:
    - reference: DOI:10.1111/vde.12972
      reference_title: Canine junctional epidermolysis bullosa due to a novel mutation in <i>LAMA3</i> with severe upper respiratory involvement
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Junctional epidermolysis bullosa (JEB) is a group of congenital blistering skin diseases characterized by clefting through the lamina lucida of the basement membrane zone.ObjectivesTo characterize the clinical and morphological features of a congenital mechanobullous disease in a litter of puppies with severe upper respiratory involvement, and to identify an associated genetic variant.AnimalsFive of eight puppies in an Australian cattle dog cross‐bred litter showed signs of skin fragility.
      explanation: Deep research cited this publication as relevant literature for Junctional Epidermolysis Bullosa.
- reference: DOI:10.1371/journal.pgen.1004068
  title: Molecular Identification of Collagen 17a1 as a Major Genetic Modifier of Laminin Gamma 2 Mutation-Induced Junctional Epidermolysis Bullosa in Mice
  found_in:
  - Junctional_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Molecular Identification of Collagen 17a1 as a Major Genetic Modifier of Laminin Gamma 2 Mutation-Induced Junctional Epidermolysis Bullosa in Mice
    supporting_text: Molecular Identification of Collagen 17a1 as a Major Genetic Modifier of Laminin Gamma 2 Mutation-Induced Junctional Epidermolysis Bullosa in Mice
- reference: DOI:10.1371/journal.pone.0288263
  title: Seven naturally variant loci serve as genetic modifiers of Lamc2jeb induced non-Herlitz junctional Epidermolysis Bullosa in mice
  found_in:
  - Junctional_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma.
    supporting_text: Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma.
    evidence:
    - reference: DOI:10.1371/journal.pone.0288263
      reference_title: Seven naturally variant loci serve as genetic modifiers of Lamc2jeb induced non-Herlitz junctional Epidermolysis Bullosa in mice
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma.
      explanation: Deep research cited this publication as relevant literature for Junctional Epidermolysis Bullosa.
- reference: DOI:10.15690/vsp.v23i5.2808
  title: Congenital Epidermolysis Bullosa Epidemiology among Children of Russian Federation
  found_in:
  - Junctional_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 Junctional Epidermolysis Bullosa.
- reference: DOI:10.3389/fgene.2021.705019
  title: 'Hologene 5: A Phase II/III Clinical Trial of Combined Cell and Gene Therapy of Junctional Epidermolysis Bullosa'
  found_in:
  - Junctional_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Epidermolysis bullosa (EB) is a group of devastating genetic diseases characterized by skin and mucosal fragility and formation of blisters, which develop either spontaneously or in response to minor mechanical trauma.
    supporting_text: Epidermolysis bullosa (EB) is a group of devastating genetic diseases characterized by skin and mucosal fragility and formation of blisters, which develop either spontaneously or in response to minor mechanical trauma.
    evidence:
    - reference: DOI:10.3389/fgene.2021.705019
      reference_title: 'Hologene 5: A Phase II/III Clinical Trial of Combined Cell and Gene Therapy of Junctional Epidermolysis Bullosa'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Epidermolysis bullosa (EB) is a group of devastating genetic diseases characterized by skin and mucosal fragility and formation of blisters, which develop either spontaneously or in response to minor mechanical trauma.
      explanation: Deep research cited this publication as relevant literature for Junctional Epidermolysis Bullosa.
- reference: DOI:10.3390/cancers17193211
  title: 'Cutaneous Squamous Cell Carcinoma in Epidermolysis Bullosa: A Review of Pathogenesis, Diagnosis and Management'
  found_in:
  - Junctional_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Epidermolysis bullosa (EB) is a group of debilitating, genetic skin disorders characterized by excessive skin fragility, blistering, and ulcerations that cause a cyclical wound healing process.
    supporting_text: Epidermolysis bullosa (EB) is a group of debilitating, genetic skin disorders characterized by excessive skin fragility, blistering, and ulcerations that cause a cyclical wound healing process.
    evidence:
    - reference: DOI:10.3390/cancers17193211
      reference_title: 'Cutaneous Squamous Cell Carcinoma in Epidermolysis Bullosa: A Review of Pathogenesis, Diagnosis and Management'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Epidermolysis bullosa (EB) is a group of debilitating, genetic skin disorders characterized by excessive skin fragility, blistering, and ulcerations that cause a cyclical wound healing process.
      explanation: Deep research cited this publication as relevant literature for Junctional Epidermolysis Bullosa.
- reference: DOI:10.3390/genes14101835
  title: Independent COL17A1 Variants in Cats with Junctional Epidermolysis Bullosa
  found_in:
  - Junctional_Epidermolysis_Bullosa-deep-research-falcon.md
  findings:
  - statement: Epidermolysis bullosa (EB), characterized by defective adhesion of the epidermis to the dermis, is a heterogeneous disease with many subtypes in human patients and domestic animals.
    supporting_text: Epidermolysis bullosa (EB), characterized by defective adhesion of the epidermis to the dermis, is a heterogeneous disease with many subtypes in human patients and domestic animals.
    evidence:
    - reference: DOI:10.3390/genes14101835
      reference_title: Independent COL17A1 Variants in Cats with Junctional Epidermolysis Bullosa
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Epidermolysis bullosa (EB), characterized by defective adhesion of the epidermis to the dermis, is a heterogeneous disease with many subtypes in human patients and domestic animals.
      explanation: Deep research cited this publication as relevant literature for Junctional Epidermolysis Bullosa.
- reference: DOI:10.3390/ijms25042243
  title: Emerging Gene Therapeutics for Epidermolysis Bullosa under Development
  found_in:
  - Junctional_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 Junctional Epidermolysis Bullosa.
📚

References & Deep Research

References

16
PMID:20301304
Junctional Epidermolysis Bullosa.
No top-level findings curated for this source.
DOI:10.1007/s13555-024-01227-8
Treatment of Epidermolysis Bullosa and Future Directions: A Review
1 finding
Treatment of Epidermolysis Bullosa and Future Directions: A Review
"Treatment of Epidermolysis Bullosa and Future Directions: A Review"
DOI:10.1016/j.det.2009.10.016
Animal Models of Epidermolysis Bullosa
1 finding
Animal Models of Epidermolysis Bullosa
"Animal Models of Epidermolysis Bullosa"
DOI:10.1016/j.jid.2023.11.021
Genotype–Phenotype Correlation in Junctional Epidermolysis Bullosa: Signposts to Severity
1 finding
Genotype–Phenotype Correlation in Junctional Epidermolysis Bullosa: Signposts to Severity
"Genotype–Phenotype Correlation in Junctional Epidermolysis Bullosa: Signposts to Severity"
DOI:10.1016/j.ymthe.2024.02.032
Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa
1 finding
Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa
"Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa"
DOI:10.1038/s41525-025-00466-8
Identification of deep intronic variants in junctional epidermolysis bullosa using genome sequencing and splicing assays
1 finding
Identification of deep intronic variants in junctional epidermolysis bullosa using genome sequencing and splicing assays
"Identification of deep intronic variants in junctional epidermolysis bullosa using genome sequencing and splicing assays"
DOI:10.1080/14712598.2020.1740678
Leading edge: emerging drug, cell, and gene therapies for junctional epidermolysis bullosa
1 finding
Leading edge: emerging drug, cell, and gene therapies for junctional epidermolysis bullosa
"Leading edge: emerging drug, cell, and gene therapies for junctional epidermolysis bullosa"
DOI:10.1111/bjd.18128
Clinical practice guidelines for laboratory diagnosis of epidermolysis bullosa
1 finding
Clinical practice guidelines for laboratory diagnosis of epidermolysis bullosa
"Clinical practice guidelines for laboratory diagnosis of epidermolysis bullosa"
DOI:10.1111/vde.12972
Canine junctional epidermolysis bullosa due to a novel mutation in <i>LAMA3</i> with severe upper respiratory involvement
1 finding
Canine junctional epidermolysis bullosa due to a novel mutation in <i>LAMA3</i> with severe upper respiratory involvement
"Junctional epidermolysis bullosa (JEB) is a group of congenital blistering skin diseases characterized by clefting through the lamina lucida of the basement membrane zone.ObjectivesTo characterize the clinical and morphological features of a congenital mechanobullous disease in a litter of..."
Show evidence (1 reference)
DOI:10.1111/vde.12972 SUPPORT Model Organism
"Junctional epidermolysis bullosa (JEB) is a group of congenital blistering skin diseases characterized by clefting through the lamina lucida of the basement membrane zone.ObjectivesTo characterize the clinical and morphological features of a congenital mechanobullous disease in a litter of..."
Deep research cited this publication as relevant literature for Junctional Epidermolysis Bullosa.
DOI:10.1371/journal.pgen.1004068
Molecular Identification of Collagen 17a1 as a Major Genetic Modifier of Laminin Gamma 2 Mutation-Induced Junctional Epidermolysis Bullosa in Mice
1 finding
Molecular Identification of Collagen 17a1 as a Major Genetic Modifier of Laminin Gamma 2 Mutation-Induced Junctional Epidermolysis Bullosa in Mice
"Molecular Identification of Collagen 17a1 as a Major Genetic Modifier of Laminin Gamma 2 Mutation-Induced Junctional Epidermolysis Bullosa in Mice"
DOI:10.1371/journal.pone.0288263
Seven naturally variant loci serve as genetic modifiers of Lamc2jeb induced non-Herlitz junctional Epidermolysis Bullosa in mice
1 finding
Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma.
"Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma."
Show evidence (1 reference)
DOI:10.1371/journal.pone.0288263 SUPPORT Model Organism
"Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma."
Deep research cited this publication as relevant literature for Junctional 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 Junctional Epidermolysis Bullosa.
DOI:10.3389/fgene.2021.705019
Hologene 5: A Phase II/III Clinical Trial of Combined Cell and Gene Therapy of Junctional Epidermolysis Bullosa
1 finding
Epidermolysis bullosa (EB) is a group of devastating genetic diseases characterized by skin and mucosal fragility and formation of blisters, which develop either spontaneously or in response to minor mechanical trauma.
"Epidermolysis bullosa (EB) is a group of devastating genetic diseases characterized by skin and mucosal fragility and formation of blisters, which develop either spontaneously or in response to minor mechanical trauma."
Show evidence (1 reference)
DOI:10.3389/fgene.2021.705019 SUPPORT Human Clinical
"Epidermolysis bullosa (EB) is a group of devastating genetic diseases characterized by skin and mucosal fragility and formation of blisters, which develop either spontaneously or in response to minor mechanical trauma."
Deep research cited this publication as relevant literature for Junctional Epidermolysis Bullosa.
DOI:10.3390/cancers17193211
Cutaneous Squamous Cell Carcinoma in Epidermolysis Bullosa: A Review of Pathogenesis, Diagnosis and Management
1 finding
Epidermolysis bullosa (EB) is a group of debilitating, genetic skin disorders characterized by excessive skin fragility, blistering, and ulcerations that cause a cyclical wound healing process.
"Epidermolysis bullosa (EB) is a group of debilitating, genetic skin disorders characterized by excessive skin fragility, blistering, and ulcerations that cause a cyclical wound healing process."
Show evidence (1 reference)
DOI:10.3390/cancers17193211 SUPPORT Human Clinical
"Epidermolysis bullosa (EB) is a group of debilitating, genetic skin disorders characterized by excessive skin fragility, blistering, and ulcerations that cause a cyclical wound healing process."
Deep research cited this publication as relevant literature for Junctional Epidermolysis Bullosa.
DOI:10.3390/genes14101835
Independent COL17A1 Variants in Cats with Junctional Epidermolysis Bullosa
1 finding
Epidermolysis bullosa (EB), characterized by defective adhesion of the epidermis to the dermis, is a heterogeneous disease with many subtypes in human patients and domestic animals.
"Epidermolysis bullosa (EB), characterized by defective adhesion of the epidermis to the dermis, is a heterogeneous disease with many subtypes in human patients and domestic animals."
Show evidence (1 reference)
DOI:10.3390/genes14101835 SUPPORT Human Clinical
"Epidermolysis bullosa (EB), characterized by defective adhesion of the epidermis to the dermis, is a heterogeneous disease with many subtypes in human patients and domestic animals."
Deep research cited this publication as relevant literature for Junctional 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 Junctional Epidermolysis Bullosa.

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 52 citations 2026-05-09T09:51:08.047179

1. Disease Information

1.1 What is the disease?

JEB is an EB subtype defined by cleavage within the lamina lucida at the epithelial–subepithelial junction, producing mucocutaneous blistering and erosions. It is a rare autosomal recessive genodermatosis with broad phenotypic variability and systemic involvement (e.g., gastrointestinal, renal, respiratory). (keith2020leadingedgeemerging pages 1-6, wen2024genotype–phenotypecorrelationin pages 13-17, wen2024genotype–phenotypecorrelationin pages 17-22)

1.2 Key identifiers (available in retrieved evidence)

  • MONDO: MONDO_0017612 (junctional epidermolysis bullosa) (OpenTargets Search: Junctional epidermolysis bullosa)
  • Related MONDO terms listed in the same ontology context:
  • JEB, non-Herlitz type: MONDO_0009180 (OpenTargets Search: Junctional epidermolysis bullosa)
  • JEB, Herlitz type: MONDO_0009182 (OpenTargets Search: Junctional epidermolysis bullosa)
  • JEB with pyloric atresia: MONDO_0009183 (OpenTargets Search: Junctional epidermolysis bullosa)

Not retrieved in this tool run (evidence unavailable here): OMIM numbers, Orphanet IDs, ICD-10/ICD-11 codes, MeSH IDs. (No citeable context in this run.)

1.3 Synonyms / alternative names (from retrieved evidence)

  • Generalized severe JEB ≈ Herlitz JEB (historical terminology) (keith2020leadingedgeemerging pages 1-6, wen2024genotype–phenotypecorrelationin pages 13-17, bischof2024emerginggenetherapeutics pages 1-2)
  • Generalized intermediate JEB ≈ non-Herlitz JEB (keith2020leadingedgeemerging pages 1-6, wen2024genotype–phenotypecorrelationin pages 13-17)
  • Laryngo-onycho-cutaneous syndrome (LOC) is described as a rare JEB variant associated with LAMA3 (laminin-332 α3) involvement and airway manifestations. (wen2024genotype–phenotypecorrelationin pages 13-17, lau2024lentiviralexpressionof pages 1-2)

1.4 Evidence source type

This report is based on aggregated disease-level resources and peer-reviewed literature (reviews, cohort studies, registry epidemiology, guidelines), supplemented by clinical trial registry entries (ClinicalTrials.gov). (wen2024genotype–phenotypecorrelationin pages 13-17, chen2025identificationofdeep pages 1-2, NCT03526159 chunk 1)

2. Etiology

2.1 Disease causal factors

Primary cause: inherited pathogenic variants in genes encoding proteins required for dermal–epidermal adhesion at the basement membrane zone, producing defective adhesion and tissue cleavage in the lamina lucida. (keith2020leadingedgeemerging pages 1-6, wen2024genotype–phenotypecorrelationin pages 13-17, wen2024genotype–phenotypecorrelationin pages 17-22)

2.2 Risk factors

  • Genetic (causal) risk: biallelic pathogenic variants in core JEB genes (below). (wen2024genotype–phenotypecorrelationin pages 13-17, wen2024genotype–phenotypecorrelationin pages 17-22)
  • Consanguinity: a contributor to higher prevalence of congenital EB in some regions; Russian registry reported high prevalence in Dagestan and noted high consanguineous marriage rates (50%). (murashkin2024congenitalepidermolysisbullosa pages 2-3, murashkin2024congenitalepidermolysisbullosa pages 1-2)

Environmental risk factors as causes of JEB are not applicable (monogenic disease); environmental exposures mainly influence complications (wound infection, trauma). (keith2020leadingedgeemerging pages 1-6)

2.3 Protective factors

No established genetic or environmental protective factors were identified in the retrieved evidence.

2.4 Gene–environment interactions

Not specifically addressed in the retrieved evidence; clinically, mechanical trauma and infection interact with genetic skin fragility to drive lesion burden. (keith2020leadingedgeemerging pages 1-6)

3. Phenotypes

3.1 Core phenotype spectrum (with HPO suggestions)

Commonly reported features include: - Skin and mucosal blistering/erosions after minor trauma; chronic wounds (HPO: Skin blistering; Erosions) (keith2020leadingedgeemerging pages 1-6, wen2024genotype–phenotypecorrelationin pages 13-17) - Nail dystrophy / anonychia (HPO: Nail dystrophy, Anonychia) (wen2024genotype–phenotypecorrelationin pages 13-17, murashkin2024congenitalepidermolysisbullosa pages 1-2) - Enamel defects (HPO: Enamel hypoplasia) (wen2024genotype–phenotypecorrelationin pages 13-17) - Scarring / alopecia (HPO: Scarring, Alopecia) (wen2024genotype–phenotypecorrelationin pages 13-17) - Airway/laryngeal involvement (laryngotracheal stenosis, airway obstruction) (HPO: Laryngeal stenosis, Tracheal stenosis, Respiratory distress) (lau2024lentiviralexpressionof pages 1-2, lau2024lentiviralexpressionof pages 2-4) - Ocular involvement (HPO: Eye irritation/erosion—non-quantified here) (wen2024genotype–phenotypecorrelationin pages 13-17) - Anemia, failure to thrive, sepsis risk (HPO: Anemia, Failure to thrive, Sepsis) (wen2024genotype–phenotypecorrelationin pages 13-17, murashkin2024congenitalepidermolysisbullosa pages 1-2)

3.2 Phenotype characteristics (onset, severity, progression)

  • Onset: typically congenital/neonatal or early infancy (widespread blistering and erosions). (wen2024genotype–phenotypecorrelationin pages 13-17, murashkin2024congenitalepidermolysisbullosa pages 1-2)
  • Severe JEB (Herlitz/generalized severe): often fatal in early childhood, with mortality linked to sepsis, dehydration, airway obstruction, metabolic disturbances. (wen2024genotype–phenotypecorrelationin pages 13-17, bischof2024emerginggenetherapeutics pages 1-2)
  • Intermediate JEB: survival into adulthood, heterogeneous course with chronic wounds and extracutaneous involvement. (wen2024genotype–phenotypecorrelationin pages 13-17)

3.3 Quality of life impact

QoL instruments/statistics specific to JEB were not retrieved in the available evidence; however, airway-involved EB patients experience high morbidity and require repeated airway procedures. (lau2024lentiviralexpressionof pages 1-2, lau2024lentiviralexpressionof pages 2-4)

4. Genetic / Molecular Information

4.1 Causal genes (human)

From a 2024 genotype–phenotype study and ontology evidence, JEB is caused by pathogenic variants in: - LAMA3, LAMB3, LAMC2 (laminin-332 chains) - COL17A1 (type XVII collagen) - ITGA6, ITGB4 (integrin α6β4) - ITGA3 (integrin α3) (wen2024genotype–phenotypecorrelationin pages 13-17, wen2024genotype–phenotypecorrelationin pages 17-22, OpenTargets Search: Junctional epidermolysis bullosa)

4.2 Variant classes and functional consequences

Common variant types include nonsense, frameshift, splice-site, deletions, and missense variants. (wen2024genotype–phenotypecorrelationin pages 17-22)

Genotype–phenotype correlation (severity): - Biallelic premature termination codon (PTC) / loss-of-function variants in laminin-332 genes often lead to severe JEB due to nonsense-mediated decay and absent laminin-332 staining. (wen2024genotype–phenotypecorrelationin pages 17-22) - Non–loss-of-function alleles (missense/in-frame changes/exon skipping) can preserve partial protein; ~5–10% residual laminin-332 may meaningfully ameliorate severity. (wen2024genotype–phenotypecorrelationin pages 17-22)

4.3 Modifier genes

Mouse-model genetic evidence supports strong modifier effects: - Col17a1 identified as a major genetic modifier of Lamc2 hypomorphic JEB severity in mice; 1–3 amino-acid differences in the NC4 domain of collagen XVII altered dermal–epidermal adhesion and disease severity. (Sproule et al., 2014; https://doi.org/10.1371/journal.pgen.1004068) (sproule2014molecularidentificationof pages 1-2) - Additional modifier loci/QTL reported in Lamc2jeb mice include intervals containing Dst-e/Bpag1-e and candidate metabolic/nuclear receptor pathways (Ppargc1a, Pparg, Igf1). (Sproule et al., 2023; https://doi.org/10.1371/journal.pone.0288263) (sproule2023sevennaturallyvariant pages 1-2)

4.4 Deep intronic variants and diagnostic “missing heritability”

A 2025 study highlights that exome sequencing can miss causative alleles: - Among 69 recessive JEB cases, 13.0% remained genetically undiagnosed after initial exome sequencing; among COL17A1-associated cases, unresolved proportion reached 31.6%. (Chen et al., 2025; https://doi.org/10.1038/s41525-025-00466-8) (chen2025identificationofdeep pages 1-2) - Deep intronic variants identified: COL17A1 c.4156+117G>A, c.2039-104G>A, c.1267+237dupC and LAMB3 c.-38+2T>C in six cases; splicing assays showed exon skipping/pseudoexon insertion in HaCaT cells but not HEK293, emphasizing cell-context dependence of transcript assays. (chen2025identificationofdeep pages 1-2)

5. Environmental Information

JEB is monogenic; no specific toxins/lifestyle/infectious agents were identified as causes. Environmental factors (mechanical trauma, wound colonization/infection) act as downstream exacerbators of disease burden and complications. (keith2020leadingedgeemerging pages 1-6)

6. Mechanism / Pathophysiology

6.1 Causal chain (molecular → clinical)

  1. Biallelic pathogenic variants in laminin-332 / COL17A1 / integrin genes reduce/abolish functional adhesion complexes at the basement membrane zone. (keith2020leadingedgeemerging pages 1-6, wen2024genotype–phenotypecorrelationin pages 17-22)
  2. Defective hemidesmosomes / dermal–epidermal adhesion at the lamina lucida causes mechanical fragility. (keith2020leadingedgeemerging pages 1-6, NCT03526159 chunk 1)
  3. Minimal trauma leads to blistering and erosions, evolving into chronic wounds. (keith2020leadingedgeemerging pages 1-6, wen2024genotype–phenotypecorrelationin pages 13-17)
  4. Chronic wounds promote inflammation, infection risk, fluid/protein loss, and systemic complications including failure to thrive, anemia, and sepsis. (wen2024genotype–phenotypecorrelationin pages 13-17, murashkin2024congenitalepidermolysisbullosa pages 1-2)

6.2 Cell types and processes (ontology suggestions)

  • Key cell types (CL): basal keratinocytes; airway epithelial basal stem cells (supported by Human Lung Cell Atlas expression context and primary basal-cell experiments). (lau2024lentiviralexpressionof pages 2-4)
  • Biological processes (GO suggestions): cell–substrate adhesion; hemidesmosome assembly; basement membrane organization; wound healing; epithelial cell differentiation. Mechanistic relevance is supported by the central role of laminin-332 and by gene-restoration phenotypes in airway basal cells. (lau2024lentiviralexpressionof pages 1-2, lau2024lentiviralexpressionof pages 4-5)

6.3 Molecular profiling / advanced technologies

Direct multi-omics profiling for JEB was not retrieved in available evidence; however, Lau et al. performed RNA-seq after LAMA3A transduction in EB airway basal cells and observed 373 differentially expressed transcripts (149 up, 224 down), consistent with broad epithelial phenotype shifts. (lau2024lentiviralexpressionof pages 4-5)

7. Anatomical Structures Affected

7.1 Organ/system involvement

  • Skin and mucous membranes (primary) (UBERON: skin; mucosa) (wen2024genotype–phenotypecorrelationin pages 13-17, keith2020leadingedgeemerging pages 1-6)
  • Upper and lower airway (larynx/trachea) in severe JEB/LOC and some intermediate cases; airway stenosis requiring endoscopic management is documented. (lau2024lentiviralexpressionof pages 1-2, lau2024lentiviralexpressionof pages 2-4)
  • Eyes (ocular involvement) (wen2024genotype–phenotypecorrelationin pages 13-17)

7.2 Tissue/cell level

  • Basement membrane zone of stratified epithelia; basal epithelial attachment structures are central. (keith2020leadingedgeemerging pages 1-6, wen2024genotype–phenotypecorrelationin pages 17-22)

8. Temporal Development

8.1 Onset

Typically at birth or in the first months of life. (murashkin2024congenitalepidermolysisbullosa pages 1-2, wen2024genotype–phenotypecorrelationin pages 13-17)

8.2 Progression/course

  • Severe forms show rapid decline in infancy due to infections/sepsis and airway complications. (wen2024genotype–phenotypecorrelationin pages 13-17, murashkin2024congenitalepidermolysisbullosa pages 1-2)
  • Chronic course in survivors includes persistent wounds and extracutaneous complications. (keith2020leadingedgeemerging pages 1-6, wen2024genotype–phenotypecorrelationin pages 13-17)

9. Inheritance and Population

9.1 Inheritance

JEB is primarily autosomal recessive. (wen2024genotype–phenotypecorrelationin pages 13-17, chandrasekaran2025cutaneoussquamouscell pages 1-2)

9.2 Epidemiology (statistics)

From Wen et al. (2024, J Invest Dermatol; https://doi.org/10.1016/j.jid.2023.11.021): - Incidence ~2.68 per million live births - Prevalence ~0.49 per million (wen2024genotype–phenotypecorrelationin pages 13-17, wen2024genotype–phenotypecorrelationin pages 17-22)

Russian pediatric registry paper (Murashkin et al., 2024; https://doi.org/10.15690/vsp.v23i5.2808; accepted 16 Oct 2024): - 491 children with congenital EB in registry (all EB types) - 31 (6%) were junctional - Registry recorded 22 deaths, with JEB comprising 59.1% (13/22) and mean age at death 0.40 ± 0.22 years - Survival probability for JEB reportedly drops to almost 0% in the first 100 days (murashkin2024congenitalepidermolysisbullosa pages 2-3, murashkin2024congenitalepidermolysisbullosa pages 1-2)

Airway EB cohort (Lau et al., 2024; https://doi.org/10.1016/j.ymthe.2024.02.032): - 16 EB patients with airway disease; 8 had died at time of writing (lau2024lentiviralexpressionof pages 2-4)

10. Diagnostics

10.1 Recommended diagnostic modalities (laboratory and genetic)

Wen et al. (2024) describes a combined approach: - Genetic testing (Sanger, targeted NGS panels, WES/WGS) - Immunofluorescence mapping (IFM/antigen mapping) to localize cleavage plane and infer missing proteins - Transmission electron microscopy (TEM) for ultrastructural defects in selected cases (wen2024genotype–phenotypecorrelationin pages 13-17)

International laboratory guideline (Has et al., 2019; BJD; https://doi.org/10.1111/bjd.18128): - Genetic testing is “always recommended” and should include the index case and, if possible, parents for reliable counseling. - IFM is recommended for rapid diagnosis/prognosis and to prioritize genetics; TEM is reserved for limited inconclusive cases. - States: “DNA-based prenatal diagnosis is technically feasible for all EB subtypes” and should be considered upon family request/national regulations. (has2019clinicalpracticeguidelines pages 1-2, has2019clinicalpracticeguidelines pages 2-3)

10.2 Diagnostic yield improvements (WGS + splicing assays)

Genome sequencing can identify deep intronic alleles missed by exome; splicing assays require a relevant cell model (HaCaT vs HEK293) (chen2025identificationofdeep pages 1-2).

10.3 Differential diagnosis

Not comprehensively retrievable from the provided evidence in this run.

11. Outcome / Prognosis

11.1 Mortality and survival

  • Severe JEB is often fatal in early childhood; one recent review states severe JEB is generally lethal within 6–24 months and that ~70% of JEB cases are associated with LAMB3 mutations (review context). (bischof2024emerginggenetherapeutics pages 1-2)
  • Registry data demonstrate very high early mortality for JEB within the first months of life (Murashkin et al., 2024). (murashkin2024congenitalepidermolysisbullosa pages 1-2)

11.2 Prognostic factors

Severity correlates with degree of residual protein (e.g., laminin-332) and mutation type (biallelic PTC/LoF vs residual expression). (wen2024genotype–phenotypecorrelationin pages 17-22)

12. Treatment

12.1 Standard-of-care (current real-world implementation)

Supportive multidisciplinary care remains foundational, including wound care, infection control, and systemic support (nutrition, pain management), as emphasized in both JEB-focused and EB-wide reviews. (keith2020leadingedgeemerging pages 1-6, danescu2024treatmentofepidermolysis pages 1-4)

12.2 Recently approved/marketed therapies (context)

A 2024 review notes that “the first drugs for the treatment of EB wounds in dystrophic and junctional EB have recently achieved US FDA and EMA approval” but does not specify product names in the excerpt. It also notes B-VEC licensing approval on May 19, 2023 for dystrophic EB as a milestone of in vivo gene therapy reaching clinical application. (Danescu et al., published online Aug 2, 2024; https://doi.org/10.1007/s13555-024-01227-8) (danescu2024treatmentofepidermolysis pages 1-4, danescu2024treatmentofepidermolysis pages 4-5)

12.3 Advanced therapeutics (gene/cell/RNA)

Ex vivo gene therapy for LAMB3-related JEB (skin): - Danescu et al. describes de Luca group’s “groundbreaking” life-saving transplantation of transgenic keratinocytes (80% TBSA) in intermediate JEB with LAMB3 mutations and notes that 5-year follow-up showed genetically repaired stem cells continued to regenerate near-normal epidermis. (danescu2024treatmentofepidermolysis pages 4-5) - A formal phase II/III protocol (Hologene 5; EudraCT 2018-000261-36; https://doi.org/10.3389/fgene.2021.705019) describes autologous keratinocytes corrected with γ-retroviral LAMB3 cDNA on fibrin support with 12-month efficacy endpoints and 15-year follow-up. (rosa2021hologene5a pages 1-2)

Nonsense suppression (gentamicin readthrough): - ClinicalTrials.gov pilot study: NCT03526159 (first posted 2018-05-16; last update posted 2020-04-07) evaluates topical (0.5% ointment BID ×14 days) and IV (7.5 mg/kg daily ×14 days) gentamicin in JEB patients with LAMB3 nonsense mutations; primary endpoints include laminin-332 immunofluorescence and EM hemidesmosomes; safety monitoring includes ototoxicity/nephrotoxicity and anti-laminin-332 antibodies. URL: https://clinicaltrials.gov/study/NCT03526159 (NCT03526159 chunk 1) - Optimization study: NCT04140786 (first posted 2019-10-28; last update posted 2022-11-03) tests IV gentamicin 10 mg/kg regimens and includes EB Disease Activity and Scarring Index (EBDASI) outcomes. URL: https://clinicaltrials.gov/study/NCT04140786 (NCT04140786 chunk 1)

Airway-directed combined cell/gene therapy proof-of-concept (2024): - Lau et al. (Molecular Therapy; accepted 27 Feb 2024; https://doi.org/10.1016/j.ymthe.2024.02.032) report airway disease in EB and show in vitro rescue of EB patient-derived airway basal cells by lentiviral LAMA3A expression. LAMA3 variants were found in 10/15 genotyped airway EB patients; basal cells showed adhesion defects. After transduction, LAMA3 mRNA increased 45.5-fold and 79.6-fold in two independent cultures; ALI cultures showed TEER within normal range (>250 Ω) and ciliary beat frequency within expected non-EB range (7–16 Hz); adhesion restored to near control. (lau2024lentiviralexpressionof pages 4-5, lau2024lentiviralexpressionof pages 1-2, lau2024lentiviralexpressionof pages 2-4)

12.4 MAXO suggestions (treatment action ontology; illustrative)

  • Wound care / dressing management (supportive wound management) (keith2020leadingedgeemerging pages 1-6)
  • Infection prophylaxis/treatment (topical/systemic antimicrobial therapy) (keith2020leadingedgeemerging pages 1-6)
  • Ex vivo gene therapy / autologous gene-corrected epidermal grafting (rosa2021hologene5a pages 1-2, danescu2024treatmentofepidermolysis pages 4-5)
  • Aminoglycoside nonsense suppression therapy (gentamicin) (NCT03526159 chunk 1, NCT04140786 chunk 1)

13. Prevention

13.1 Primary prevention

For Mendelian JEB, primary prevention focuses on reproductive options: - Has et al. (2019 guideline) states accurate EB diagnosis enables informed genetic counseling and prenatal/PGT options and that “DNA-based prenatal diagnosis is technically feasible for all EB subtypes”; prenatal diagnosis requires a known familial mutation. (has2019clinicalpracticeguidelines pages 1-2, has2019clinicalpracticeguidelines pages 2-3)

13.2 Secondary/tertiary prevention

  • Avoiding skin trauma, meticulous wound care, and infection control reduce complications (sepsis) and improve outcomes. (keith2020leadingedgeemerging pages 1-6, murashkin2024congenitalepidermolysisbullosa pages 1-2)

14. Other Species / Natural Disease

Naturally occurring JEB has been reported in multiple domestic species and can inform genotype–phenotype correlations. - Cats (COL17A1): Two unrelated cats with homozygous COL17A1 splice(-region) variants showed marked severity differences; transcript analysis demonstrated residual wildtype splicing in the milder case, supporting a molecular basis for severity variation. (Genes, 2023; https://doi.org/10.3390/genes14101835) (natsuga2010animalmodelsof pages 1-2) - Dogs (LAMA3): A litter with severe mucocutaneous ulcers and upper airway obstruction had a novel LAMA3 missense variant with AR inheritance; EM confirmed lamina-lucida splitting. (Vet Dermatol, 2021; https://doi.org/10.1111/vde.12972) (not extracted as evidence snippet in gather_evidence, but paper is in state; no citeable context id provided beyond tool results)

Note: dog/horse/cat models are also referenced in EB animal-model reviews. (natsuga2010animalmodelsof pages 1-2)

15. Model Organisms

  • A 2010 review reports 12 JEB animal models and lists multiple gene KO/hypomorphic models; most are perinatally lethal. The authors’ Col17a1 KO mouse survived ~12 months, with ~20% showing long survival enabling therapy experiments; transgenic rescue with human COL17A1 cDNA restored normal skin and fertility. (Dermatol Clin, 2010; https://doi.org/10.1016/j.det.2009.10.016) (natsuga2010animalmodelsof pages 1-2)
  • Mouse modifier models: Lamc2jeb hypomorphic JEB model used to map modifiers including Col17a1 and additional QTL, demonstrating strong epistasis and potential therapeutic modifier pathways. (sproule2014molecularidentificationof pages 1-2, sproule2023sevennaturallyvariant pages 1-2)

Recent developments (prioritizing 2023–2025 evidence retrieved here)

  1. Genotype–phenotype “signposts to severity” (2024): detailed correlation between LoF/PTC alleles and severe disease; residual laminin-332 (~5–10%) associated with milder/intermediate disease. (Wen et al., 2024; https://doi.org/10.1016/j.jid.2023.11.021) (wen2024genotype–phenotypecorrelationin pages 17-22)
  2. Airway gene therapy concepts (2024): first detailed pediatric airway cohort + in vitro LAMA3A lentiviral functional correction in airway basal cells, expanding the therapeutic target tissue beyond skin. (Lau et al., 2024; https://doi.org/10.1016/j.ymthe.2024.02.032) (lau2024lentiviralexpressionof pages 4-5, lau2024lentiviralexpressionof pages 1-2, lau2024lentiviralexpressionof pages 2-4)
  3. Genome sequencing resolves ES-negative JEB (2025): deep intronic COL17A1/LAMB3 variants and cell-type–specific splicing assay considerations. (Chen et al., 2025; https://doi.org/10.1038/s41525-025-00466-8) (chen2025identificationofdeep pages 1-2)

Evidence gaps in this tool run (explicit)

  • OMIM, Orphanet, ICD-10/ICD-11, and MeSH identifiers were not available in retrieved citeable evidence.
  • Detailed differential diagnosis tables and validated QoL statistics/instruments specific to JEB were not retrieved.
  • Human protective factors and gene–environment interaction datasets were not retrieved.

Structured summary table

Topic Key details
Disease / identifiers Junctional epidermolysis bullosa (JEB); MONDO: MONDO_0017612. Open Targets also lists related subtype MONDO terms including JEB, non-Herlitz type (MONDO_0009180), JEB Herlitz type (MONDO_0009182), and JEB with pyloric atresia (MONDO_0009183). OMIM identifiers are not directly provided in the extracted evidence here. Disease is defined as an EB subtype with tissue cleavage in the lamina lucida / epithelial-subepithelial junction, usually inherited as autosomal recessive (https://platform.opentargets.org/disease/MONDO_0017612; 2026 access context) (OpenTargets Search: Junctional epidermolysis bullosa, wen2024genotype–phenotypecorrelationin pages 13-17, wen2024genotype–phenotypecorrelationin pages 17-22)
Main causal genes Core JEB genes repeatedly identified across recent evidence: LAMA3, LAMB3, LAMC2 (laminin-332 chains), COL17A1 (type XVII collagen), ITGA6, ITGB4 (integrin α6β4), and ITGA3. Open Targets disease-target evidence supports these as the principal disease-associated genes for JEB (https://platform.opentargets.org/disease/MONDO_0017612; context accessed 2026) (OpenTargets Search: Junctional epidermolysis bullosa, wen2024genotype–phenotypecorrelationin pages 13-17, wen2024genotype–phenotypecorrelationin pages 17-22)
Inheritance / molecular basis JEB is described as a rare autosomal recessive genodermatosis caused by loss or dysfunction of proteins required for dermal-epidermal adhesion. Laminin-332 deficiency, type XVII collagen deficiency, or integrin α6β4 dysfunction are major molecular categories (Wen et al., J Invest Dermatol, published Jun 2024, https://doi.org/10.1016/j.jid.2023.11.021; Keith et al., Mar 2020, https://doi.org/10.1080/14712598.2020.1740678) (keith2020leadingedgeemerging pages 1-6, wen2024genotype–phenotypecorrelationin pages 13-17, wen2024genotype–phenotypecorrelationin pages 17-22)
Subtypes / severity correlation Recent literature distinguishes severe/generalized severe (formerly Herlitz) versus intermediate/generalized intermediate (formerly non-Herlitz) JEB. Biallelic premature termination codon / loss-of-function variants in laminin-332 genes usually correlate with severe JEB, often with absent laminin-332 staining and early lethality; missense, splice-altering, in-frame, or exon-skipping alleles with residual protein expression (~5–10%) more often correlate with intermediate/milder disease. Severe JEB is often fatal in infancy/early childhood; intermediate JEB can survive into adulthood but remains multisystemic (Wen et al., Jun 2024, https://doi.org/10.1016/j.jid.2023.11.021; Bischof et al., Feb 2024, https://doi.org/10.3390/ijms25042243) (wen2024genotype–phenotypecorrelationin pages 13-17, wen2024genotype–phenotypecorrelationin pages 17-22, bischof2024emerginggenetherapeutics pages 1-2)
Clinical phenotype highlights Typical manifestations include widespread skin and mucosal blistering/erosions, chronic wounds, nail dystrophy/anonychia, enamel defects, scarring, alopecia, airway/laryngeal involvement, ocular involvement, anemia, and in severe forms failure to thrive, sepsis, and airway obstruction. Airway disease is especially linked to LAMA3-associated JEB severe / LOC-like disease (Wen et al., Jun 2024, https://doi.org/10.1016/j.jid.2023.11.021; Lau et al., May 2024, https://doi.org/10.1016/j.ymthe.2024.02.032) (wen2024genotype–phenotypecorrelationin pages 13-17, lau2024lentiviralexpressionof pages 1-2, lau2024lentiviralexpressionof pages 2-4)
Diagnostic modalities Key modalities include clinical phenotyping, immunofluorescence mapping (IFM / antigen mapping) to localize the cleavage plane and assess BMZ protein expression, transmission electron microscopy (TEM) for ultrastructural defects/hemidesmosomes, and molecular testing using Sanger sequencing, targeted panels, WES, and WGS/GS. Recent evidence shows a role for RNA/splicing assays when exome sequencing is inconclusive (Wen et al., Jun 2024, https://doi.org/10.1016/j.jid.2023.11.021; Chen et al., Feb 2025, https://doi.org/10.1038/s41525-025-00466-8) (wen2024genotype–phenotypecorrelationin pages 13-17, wen2024genotype–phenotypecorrelationin pages 17-22, chen2025identificationofdeep pages 1-2)
Diagnostic yield / deep intronic findings In a 2025 JEB genomics study of 69 recessive JEB cases, 13.0% remained genetically undiagnosed after initial exome sequencing; among COL17A1 cases, unresolved rate reached 31.6%. Genome sequencing plus splicing assays identified deep intronic variants COL17A1 c.4156+117G>A, c.2039-104G>A, c.1267+237dupC and LAMB3 c.-38+2T>C; these caused exon skipping or pseudoexon insertion in HaCaT keratinocyte cells but not HEK293 cells, supporting GS + cell-appropriate transcript testing for ES-negative JEB (Chen et al., published Feb 2025, https://doi.org/10.1038/s41525-025-00466-8) (chen2025identificationofdeep pages 1-2)
Epidemiology A 2024 genotype-phenotype study cites JEB incidence ~2.68 per million live births and prevalence ~0.49 per million. A 2020 review states JEB affects about 3 in 1 million children. Broader EB epidemiology reported in some recent reviews is higher because it covers all EB subtypes rather than JEB specifically (Wen et al., Jun 2024, https://doi.org/10.1016/j.jid.2023.11.021; Keith et al., Mar 2020, https://doi.org/10.1080/14712598.2020.1740678) (keith2020leadingedgeemerging pages 1-6, wen2024genotype–phenotypecorrelationin pages 13-17, wen2024genotype–phenotypecorrelationin pages 17-22)
Russian registry data (all congenital EB, with JEB-specific mortality note) Russian pediatric registry, publication accepted 16 Oct 2024 / journal issue 2024, DOI https://doi.org/10.15690/vsp.v23i5.2808: 491 children with congenital EB; pediatric prevalence 15.48 per 1,000,000; subtype distribution 261 dystrophic (53%), 191 simplex (39%), 31 junctional (6%), 8 Kindler (2%). Mean birth rate 2019–2023: 2.13 per 100,000 births. Registry recorded 22 deaths; JEB accounted for 59.1% of fatal outcomes (13/22) with mean age at death 0.40 ± 0.22 years; survival curve showed probability of survival falling to almost 0% in the first 100 days for JEB (Murashkin et al., 2024, https://doi.org/10.15690/vsp.v23i5.2808) (murashkin2024congenitalepidermolysisbullosa pages 2-3, murashkin2024congenitalepidermolysisbullosa pages 1-2)
Standard/current management Current standard of care remains supportive and multidisciplinary: blister lancing, atraumatic wound care, infection control, pain management, nutritional and systemic support, and treatment of complications. Reviews emphasize that despite therapeutic advances, most care remains palliative/symptom-directed (Keith et al., Mar 2020, https://doi.org/10.1080/14712598.2020.1740678; Danescu et al., published online Aug 2, 2024, https://doi.org/10.1007/s13555-024-01227-8) (keith2020leadingedgeemerging pages 1-6, danescu2024treatmentofepidermolysis pages 1-4)
Recently approved / wound-directed therapies relevant to EB A 2024 therapeutic review states that “the first drugs for the treatment of EB wounds in dystrophic and junctional EB have recently achieved US FDA and EMA approval”; it also notes that B-VEC became the first gene therapy clinically available for DEB on May 19, 2023, illustrating regulatory momentum in EB even though B-VEC is not JEB-specific (Danescu et al., Aug 2, 2024, https://doi.org/10.1007/s13555-024-01227-8) (danescu2024treatmentofepidermolysis pages 1-4, danescu2024treatmentofepidermolysis pages 4-5)
Gentamicin nonsense readthrough trials NCT03526159 (“Gentamicin for Junctional Epidermolysis Bullosa”; first posted 2018-05-16; recruiting per available registry snapshot) tests topical 0.5% gentamicin twice daily for 14 days or IV gentamicin 7.5 mg/kg daily for 14 days in JEB with LAMB3 nonsense mutations, with endpoints including laminin-332 IF signal, EM hemidesmosomes, wound closure, and safety. NCT04140786 (“Optimizing IV Gentamicin in JEB”; first posted 2019-10-28) studies 10 mg/kg IV regimens (daily x24 days or biweekly x3 months) in JEB with LAMA3/LAMB3 nonsense mutations, with endpoints including laminin-332 expression, EBDASI, ototoxicity, nephrotoxicity, and anti-laminin-332 antibodies (https://clinicaltrials.gov/study/NCT03526159; https://clinicaltrials.gov/study/NCT04140786) (NCT03526159 chunk 1, NCT03526159 chunk 2, NCT04140786 chunk 1, NCT04140786 chunk 2)
Ex vivo LAMB3 gene-corrected epidermal grafts Ex vivo autologous LAMB3-corrected keratinocyte / epidermal stem-cell grafting is the most mature JEB-specific gene-therapy paradigm. Hologene 5 (EudraCT 2018-000261-36; protocol paper 2021, https://doi.org/10.3389/fgene.2021.705019) is a phase II/III multicenter study using γ-retroviral full-length LAMB3 cDNA in autologous clonogenic keratinocytes on fibrin support for grafting. A 2024 review highlights prior life-saving transplantation over ~80% TBSA and durable 5-year maintenance of genetically repaired epidermis (Danescu et al., 2024; De Rosa et al., 2021) (rosa2021hologene5a pages 1-2, danescu2024treatmentofepidermolysis pages 4-5)
Airway-targeted gene/cell proof-of-concept In Lau et al. (Molecular Therapy, published May 2024, https://doi.org/10.1016/j.ymthe.2024.02.032), a cohort of 16 EB patients with airway disease was described; 10/15 genotyped patients had at least one LAMA3 pathogenic variant, median age at referral 9 months, and 8/16 had died by time of report. Patient airway basal cells showed adhesion defects; lentiviral LAMA3A overexpression increased LAMA3 mRNA by 45.5-fold and 79.6-fold in two cultures, enabled ALI differentiation with normal-range TEER (>250 Ω) and normal ciliary beat frequency (7–16 Hz), and restored adhesion to near non-EB control levels—supporting a future combined airway cell/gene therapy approach (lau2024lentiviralexpressionof pages 4-5, lau2024lentiviralexpressionof pages 1-2, lau2024lentiviralexpressionof pages 2-4)
Other/adjunct experimental wound therapies RGN-137 topical gel (thymosin β4-related wound-healing approach) was studied in JEB/DEB in NCT03578029 (CELEB), a randomized placebo-controlled phase II trial first posted 2018-07-05; status later terminated (business decision) with only 4 enrolled, illustrating the difficulty of wound-therapy trials in rare EB (https://clinicaltrials.gov/study/NCT03578029) (NCT03578029 chunk 1, NCT03578029 chunk 2)

Table: This table condenses the most clinically relevant facts about Junctional Epidermolysis Bullosa, including genes, inheritance, severity correlations, diagnostics, epidemiology, and current or emerging therapies. It is designed as a quick reference for building a disease knowledge base entry with directly citeable evidence contexts.

References

  1. (OpenTargets Search: Junctional epidermolysis bullosa): Open Targets Query (Junctional epidermolysis bullosa, 34 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (keith2020leadingedgeemerging pages 1-6): Allison R. Keith, Kirk Twaroski, Christen L. Ebens, and Jakub Tolar. Leading edge: emerging drug, cell, and gene therapies for junctional epidermolysis bullosa. Expert Opinion on Biological Therapy, 20:911-923, Mar 2020. URL: https://doi.org/10.1080/14712598.2020.1740678, doi:10.1080/14712598.2020.1740678. This article has 22 citations and is from a peer-reviewed journal.

  3. (wen2024genotype–phenotypecorrelationin pages 13-17): David Wen, Manrup Hunjan, Ajoy Bardhan, Natasha Harper, Malobi Ogboli, Linda Ozoemena, Lu Liu, Jo-David Fine, Iain Chapple, Dario L. Balacco, and Adrian Heagerty. Genotype–phenotype correlation in junctional epidermolysis bullosa: signposts to severity. Journal of Investigative Dermatology, 144:1334-1343.e14, Jun 2024. URL: https://doi.org/10.1016/j.jid.2023.11.021, doi:10.1016/j.jid.2023.11.021. This article has 10 citations and is from a highest quality peer-reviewed journal.

  4. (wen2024genotype–phenotypecorrelationin pages 17-22): David Wen, Manrup Hunjan, Ajoy Bardhan, Natasha Harper, Malobi Ogboli, Linda Ozoemena, Lu Liu, Jo-David Fine, Iain Chapple, Dario L. Balacco, and Adrian Heagerty. Genotype–phenotype correlation in junctional epidermolysis bullosa: signposts to severity. Journal of Investigative Dermatology, 144:1334-1343.e14, Jun 2024. URL: https://doi.org/10.1016/j.jid.2023.11.021, doi:10.1016/j.jid.2023.11.021. This article has 10 citations and is from a highest quality peer-reviewed journal.

  5. (chen2025identificationofdeep pages 1-2): Fuying Chen, Ruoqu Wei, Yumeng Wang, Qiaoyu Cao, Jianbo Wang, Chenfei Wang, Dingjin Yao, Zhirong Yao, Cheng Ni, and Ming Li. Identification of deep intronic variants in junctional epidermolysis bullosa using genome sequencing and splicing assays. NPJ Genomic Medicine, Feb 2025. URL: https://doi.org/10.1038/s41525-025-00466-8, doi:10.1038/s41525-025-00466-8. This article has 2 citations and is from a peer-reviewed journal.

  6. (lau2024lentiviralexpressionof pages 1-2): Chun Hang Lau, Maral J. Rouhani, Elizabeth F. Maughan, Jessica C. Orr, Krishna K. Kolluri, David R. Pearce, Elizabeth K. Haughey, Liam Sutton, Sam Flatau, Pablo Lopez Balboa, Maria Laura Bageta, Christopher O’Callaghan, Claire M. Smith, Sam M. Janes, Richard Hewitt, Gabriela Petrof, Anna E. Martinez, John A. McGrath, Colin R. Butler, and Robert E. Hynds. Lentiviral expression of wild-type lama3a restores cell adhesion in airway basal cells from children with epidermolysis bullosa. Molecular Therapy, 32:1497-1509, May 2024. URL: https://doi.org/10.1016/j.ymthe.2024.02.032, doi:10.1016/j.ymthe.2024.02.032. This article has 8 citations and is from a highest quality peer-reviewed journal.

  7. (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.

  8. (NCT03526159 chunk 1): David Woodley. Gentamicin for Junctional Epidermolysis Bullosa. University of Southern California. 2018. ClinicalTrials.gov Identifier: NCT03526159

  9. (murashkin2024congenitalepidermolysisbullosa pages 2-3): Nikolay N. Murashkin, Roman V. Epishev, Olga S. Orlova, Alena А. Kuratova, and Victoriya S. Polenova. Congenital epidermolysis bullosa epidemiology among children of russian federation. Current Pediatrics, 23:316-328, Oct 2024. URL: https://doi.org/10.15690/vsp.v23i5.2808, doi:10.15690/vsp.v23i5.2808. This article has 2 citations.

  10. (murashkin2024congenitalepidermolysisbullosa pages 1-2): Nikolay N. Murashkin, Roman V. Epishev, Olga S. Orlova, Alena А. Kuratova, and Victoriya S. Polenova. Congenital epidermolysis bullosa epidemiology among children of russian federation. Current Pediatrics, 23:316-328, Oct 2024. URL: https://doi.org/10.15690/vsp.v23i5.2808, doi:10.15690/vsp.v23i5.2808. This article has 2 citations.

  11. (lau2024lentiviralexpressionof pages 2-4): Chun Hang Lau, Maral J. Rouhani, Elizabeth F. Maughan, Jessica C. Orr, Krishna K. Kolluri, David R. Pearce, Elizabeth K. Haughey, Liam Sutton, Sam Flatau, Pablo Lopez Balboa, Maria Laura Bageta, Christopher O’Callaghan, Claire M. Smith, Sam M. Janes, Richard Hewitt, Gabriela Petrof, Anna E. Martinez, John A. McGrath, Colin R. Butler, and Robert E. Hynds. Lentiviral expression of wild-type lama3a restores cell adhesion in airway basal cells from children with epidermolysis bullosa. Molecular Therapy, 32:1497-1509, May 2024. URL: https://doi.org/10.1016/j.ymthe.2024.02.032, doi:10.1016/j.ymthe.2024.02.032. This article has 8 citations and is from a highest quality peer-reviewed journal.

  12. (sproule2014molecularidentificationof pages 1-2): Thomas J. Sproule, Jason A. Bubier, Fiorella C. Grandi, Victor Z. Sun, Vivek M. Philip, Caroline G. McPhee, Elisabeth B. Adkins, John P. Sundberg, and Derry C. Roopenian. Molecular identification of collagen 17a1 as a major genetic modifier of laminin gamma 2 mutation-induced junctional epidermolysis bullosa in mice. PLoS Genetics, 10:e1004068, Feb 2014. URL: https://doi.org/10.1371/journal.pgen.1004068, doi:10.1371/journal.pgen.1004068. This article has 38 citations and is from a domain leading peer-reviewed journal.

  13. (sproule2023sevennaturallyvariant pages 1-2): Thomas J. Sproule, Vivek M. Philip, Nabig A. Chaudhry, Derry C. Roopenian, and John P. Sundberg. Seven naturally variant loci serve as genetic modifiers of lamc2jeb induced non-herlitz junctional epidermolysis bullosa in mice. PLOS ONE, 18:e0288263, Jul 2023. URL: https://doi.org/10.1371/journal.pone.0288263, doi:10.1371/journal.pone.0288263. This article has 7 citations and is from a peer-reviewed journal.

  14. (lau2024lentiviralexpressionof pages 4-5): Chun Hang Lau, Maral J. Rouhani, Elizabeth F. Maughan, Jessica C. Orr, Krishna K. Kolluri, David R. Pearce, Elizabeth K. Haughey, Liam Sutton, Sam Flatau, Pablo Lopez Balboa, Maria Laura Bageta, Christopher O’Callaghan, Claire M. Smith, Sam M. Janes, Richard Hewitt, Gabriela Petrof, Anna E. Martinez, John A. McGrath, Colin R. Butler, and Robert E. Hynds. Lentiviral expression of wild-type lama3a restores cell adhesion in airway basal cells from children with epidermolysis bullosa. Molecular Therapy, 32:1497-1509, May 2024. URL: https://doi.org/10.1016/j.ymthe.2024.02.032, doi:10.1016/j.ymthe.2024.02.032. This article has 8 citations and is from a highest quality peer-reviewed journal.

  15. (chandrasekaran2025cutaneoussquamouscell pages 1-2): Abarajithan Chandrasekaran and Justin C. Moser. Cutaneous squamous cell carcinoma in epidermolysis bullosa: a review of pathogenesis, diagnosis and management. Cancers, 17:3211, Oct 2025. URL: https://doi.org/10.3390/cancers17193211, doi:10.3390/cancers17193211. This article has 0 citations.

  16. (has2019clinicalpracticeguidelines pages 1-2): C. Has, L. Liu, M.C. Bolling, A.V. Charlesworth, M. El Hachem, M.J. Escámez, I. Fuentes, S. Büchel, R. Hiremagalore, G. Pohla‐Gubo, P.C. Akker, K. Wertheim‐Tysarowska, and G. Zambruno. Clinical practice guidelines for laboratory diagnosis of epidermolysis bullosa. The British Journal of Dermatology, 182:574-592, Aug 2019. URL: https://doi.org/10.1111/bjd.18128, doi:10.1111/bjd.18128. This article has 186 citations.

  17. (has2019clinicalpracticeguidelines pages 2-3): C. Has, L. Liu, M.C. Bolling, A.V. Charlesworth, M. El Hachem, M.J. Escámez, I. Fuentes, S. Büchel, R. Hiremagalore, G. Pohla‐Gubo, P.C. Akker, K. Wertheim‐Tysarowska, and G. Zambruno. Clinical practice guidelines for laboratory diagnosis of epidermolysis bullosa. The British Journal of Dermatology, 182:574-592, Aug 2019. URL: https://doi.org/10.1111/bjd.18128, doi:10.1111/bjd.18128. This article has 186 citations.

  18. (danescu2024treatmentofepidermolysis pages 1-4): Sorina Danescu, Mircea Negrutiu, and Cristina Has. Treatment of epidermolysis bullosa and future directions: a review. Dermatology and Therapy, 14:2059-2075, Aug 2024. URL: https://doi.org/10.1007/s13555-024-01227-8, doi:10.1007/s13555-024-01227-8. This article has 14 citations.

  19. (danescu2024treatmentofepidermolysis pages 4-5): Sorina Danescu, Mircea Negrutiu, and Cristina Has. Treatment of epidermolysis bullosa and future directions: a review. Dermatology and Therapy, 14:2059-2075, Aug 2024. URL: https://doi.org/10.1007/s13555-024-01227-8, doi:10.1007/s13555-024-01227-8. This article has 14 citations.

  20. (rosa2021hologene5a pages 1-2): Laura De Rosa, Elena Enzo, Giulia Zardi, Christine Bodemer, Cristina Magnoni, Holm Schneider, and Michele De Luca. Hologene 5: a phase ii/iii clinical trial of combined cell and gene therapy of junctional epidermolysis bullosa. Frontiers in Genetics, Sep 2021. URL: https://doi.org/10.3389/fgene.2021.705019, doi:10.3389/fgene.2021.705019. This article has 35 citations and is from a peer-reviewed journal.

  21. (NCT04140786 chunk 1): David Woodley. Optimizing IV Gentamicin in JEB. University of Southern California. 2019. ClinicalTrials.gov Identifier: NCT04140786

  22. (natsuga2010animalmodelsof pages 1-2): Ken Natsuga, Satoru Shinkuma, Wataru Nishie, and Hiroshi Shimizu. Animal models of epidermolysis bullosa. Dermatologic clinics, 28 1:137-42, Jan 2010. URL: https://doi.org/10.1016/j.det.2009.10.016, doi:10.1016/j.det.2009.10.016. This article has 32 citations and is from a peer-reviewed journal.

  23. (NCT03526159 chunk 2): David Woodley. Gentamicin for Junctional Epidermolysis Bullosa. University of Southern California. 2018. ClinicalTrials.gov Identifier: NCT03526159

  24. (NCT04140786 chunk 2): David Woodley. Optimizing IV Gentamicin in JEB. University of Southern California. 2019. ClinicalTrials.gov Identifier: NCT04140786

  25. (NCT03578029 chunk 1): Evaluation of the Safety and Efficacy Study of RGN-137 Topical Gel for Junctional and Dystrophic Epidermolysis Bullosa. Lenus Therapeutics, LLC. 2019. ClinicalTrials.gov Identifier: NCT03578029

  26. (NCT03578029 chunk 2): Evaluation of the Safety and Efficacy Study of RGN-137 Topical Gel for Junctional and Dystrophic Epidermolysis Bullosa. Lenus Therapeutics, LLC. 2019. ClinicalTrials.gov Identifier: NCT03578029