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Classifications

Harrison's Part

🔗

Mappings

MONDO

MONDO:0017610 epidermolysis bullosa simplex

Primary MONDO disease identifier for this EBS entry.

ICD-10-CM

ICD10CM:Q81.0 Epidermolysis bullosa simplex

ICD-10-CM Q81.0 directly names epidermolysis bullosa simplex.

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Inheritance

2

Autosomal dominant

Most EBS subtypes (localized, intermediate, severe/Dowling-Meara) are inherited in an autosomal dominant manner due to dominant-negative keratin mutations in KRT5 or KRT14.

Show evidence (2 references)

PMID:20301543 SUPPORT Human Clinical

"The diagnosis of EBS is established in a proband by: the identification of a heterozygous dominant-negative variant or biallelic loss-of-function variants in KRT5, KRT14, or PLEC"

GeneReviews confirms dominant-negative variants in KRT5/KRT14 as a major cause of EBS.

PMID:16098032 SUPPORT Human Clinical

"18 were found to harbor heterozygous mutations in the keratin 5 or keratin 14 genes, KRT5 and KRT14, respectively"

Confirms heterozygous (dominant) keratin mutations as a cause of EBS.

Autosomal recessive

EBS with muscular dystrophy (PLEC mutations) and EBS autosomal recessive (KRT14 null) are inherited in an autosomal recessive manner.

Show evidence (2 references)

PMID:34572129 SUPPORT Human Clinical

"The most common disorder is autosomal recessive disease epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), which is characterized by skin blistering and progressive muscle weakness"

Confirms autosomal recessive inheritance of EBS-MD caused by PLEC mutations.

PMID:25530118 SUPPORT Human Clinical

"Plectin deficiency causes autosomal recessive epidermolysis bullosa simplex (EBS) with involvement of the skin and other organs"

Confirms autosomal recessive inheritance pattern for plectin-related EBS.

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Subtypes

14

EBS localized (EBS-loc; formerly Weber-Cockayne) MONDO:0007551 MONDO:0030527

KRT14 hgnc:6416 KRT5 hgnc:6442 Autosomal dominant inheritance MONDO MONDO:0030527

Blistering mainly confined to hands and feet, exacerbated by heat and increased physical activity. The mildest form of EBS and one of its most frequent variants. Onset typically in infancy or early childhood. Caused by heterozygous dominant-negative variants in either KRT14 or KRT5, which OMIM and MONDO now code as two separate terms (EBS1C and EBS2C respectively) despite the same clinical picture. This row binds MONDO:0007551, the term that carries the Weber-Cockayne eponym together with the Orphanet localized-EBS and SNOMED cross-references, and records the KRT5-side term as a mapping.

Show evidence (3 references)

PMID:9804357 SUPPORT DIRECT Human Clinical

"We report novel keratin 5 and 14 gene mutations in four unrelated German families with the localized subtype of the dominantly inherited blistering disease epidermolysis bullosa simplex Weber-Cockayne (MIM# 131800)"

Ties this row's three identities together in one sentence: the localized subtype, the Weber-Cockayne eponym, and MIM 131800 - the OMIM number that MONDO:0007551 cross-references. Also shows that both KRT14 and KRT5 variants produce the localized phenotype, and that it is dominantly inherited.

PMID:7688477 SUPPORT DIRECT Human Clinical

"Here, we show that the mildest type of EBS, Weber-Cockayne, is also a disorder of these keratins"

Supports describing the localized/Weber-Cockayne form as the mildest EBS type and places it in the same basal-keratin disease family as the generalized forms.

PMID:26432462 SUPPORT DIRECT BACKGROUND Human Clinical

"The most frequent variants are: EBS, localised (EBS-loc) with blistering confined to the hands and feet"

Supports both the frequency claim and the palmoplantar distribution. The sentence sits in the paper's introduction restating the established classification rather than reporting its own cohort, hence BACKGROUND.

EBS, generalized intermediate (EBS-gen intermed; formerly Koebner) MONDO:0007554 MONDO:0030525

KRT14 hgnc:6416 KRT5 hgnc:6442 Autosomal dominant inheritance MONDO MONDO:0030525

Generalized non-scarring blistering that may affect any body site. More widespread than localized EBS but less severe than the severe form. Blisters heal without significant scarring. Caused by heterozygous dominant-negative variants in either KRT14 or KRT5.

Show evidence (2 references)

PMID:26432462 SUPPORT DIRECT BACKGROUND Human Clinical

"EBS-generalised intermediate (EBS-gen intermed, formerly non-Dowling-Meara or EBS-gen nDM), in which blistering occurs on the whole body area"

Defines the generalized intermediate subtype and records the Koebner eponym this row is named after, distinguishing it from the localized and generalized severe forms.

PMID:26432462 SUPPORT DIRECT Human Clinical

"In 38/47 probands, we detected mutations in either KRT5 or KRT14 and, in one case, we found mutations in both genes."

The cohort result behind binding both KRT5 and KRT14 to this row: the study genotyped EBS probands classified by subtype and found causal variants in either keratin gene.

EBS, generalized severe (EBS-gen sev; formerly Dowling-Meara) MONDO:0007550 MONDO:0030489

KRT14 hgnc:6416 KRT5 hgnc:6442 Autosomal dominant inheritance MONDO MONDO:0030489

Grouped herpetiform blistering, palmoplantar keratoderma, and nail dystrophy. The most severe keratin-associated form of EBS. Blistering tends to improve with age, likely due to the suprabasal switch from K5/K14 to K1/K10 during keratinocyte differentiation reducing dependence on mutant basal keratins. Improvement with age is common in all variants of EBS but is not invariable. The pathognomonic transmission electron microscopy (TEM) finding is tonofilament (keratin) clumping in basal cells. Laryngeal involvement may occur. Caused by heterozygous dominant-negative variants in either KRT14 or KRT5, typically in the central rod domain.

Show evidence (2 references)

PMID:26432462 SUPPORT DIRECT BACKGROUND Human Clinical

"more severe: EBS-generalised severe (EBS-gen sev, formerly Dowling-Meara or EBS-gen DM), where mucosa is also involved"

Defines the generalized severe subtype, records the Dowling-Meara eponym this row is named after, and gives the mucosal involvement that separates it from the generalized intermediate row above.

PMID:26432462 SUPPORT DIRECT BACKGROUND Human Clinical

"Regardless of the keratin type affected, most of these mutations change amino acid residues in the central L-helical rod domain, leading to more severe EBS phenotypes."

Supports the rod-domain genotype correlation stated in this row's description, and that it holds for both KRT5 and KRT14.

EBS with muscular dystrophy (EBS-MD) MONDO:0009181

PLEC hgnc:9069 Autosomal recessive inheritance

Caused by PLEC mutations leading to skin fragility combined with progressive muscular dystrophy. Autosomal recessive inheritance. Plectin deficiency disrupts both epidermal and muscle cytoskeletal integrity.

Show evidence (1 reference)

PMID:20447487 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Autosomal recessive forms of EBS associated with extracutaneous manifestations, such as muscular dystrophy (MIM 226670) or pyloric atresia (MIM 612138), have been linked to genetic mutations in the gene for plectin (PLEC)."

Ties this row's three identities together: the muscular dystrophy phenotype, autosomal recessive inheritance, and PLEC as the causal gene.

EBS, generalized, intermediate or severe, autosomal recessive (KRT14) MONDO:0010976

KRT14 hgnc:6416 Autosomal recessive inheritance

Severe, generalized blistering caused by biallelic loss-of-function mutations in KRT14 resulting in complete absence of keratin 14 protein. More severe than typical dominant EBS.

Show evidence (2 references)

PMID:7525408 SUPPORT DIRECT Human Clinical

"Genetic analyses revealed a homozygous point mutation that yielded a premature termination codon in the major basal type I keratin gene and caused complete ablation of K14."

The founding observation for this row: a homozygous KRT14 null allele abolishing keratin 14 protein in a patient with severe recessive EBS.

PMID:7525408 SUPPORT DIRECT Human Clinical

"The consanguineous parents were normal, each harboring one copy of the null K14 mutation."

Establishes autosomal recessive inheritance for this row: heterozygous KRT14-null carriers are unaffected.

EBS, generalized, intermediate or severe, autosomal recessive (KRT5) MONDO:0030535

KRT5 hgnc:6442 Autosomal recessive inheritance

The KRT5 counterpart of the recessive KRT14-null row above. Biallelic KRT5 variants, both missense and null, cause EBS with a phenotypic range from localized and generalized blistering to death in the neonatal period. This route had not been reported before, on the hypothesis that biallelic KRT5 mutations would result in prenatal lethality.

Show evidence (2 references)

PMID:31302245 SUPPORT DIRECT Human Clinical

"Two pathogenic, homozygous missense variants of KRT5 in two patients with generalized EBS and a homozygous null mutation in a patient who died as a neonate from complications of EB were found."

Establishes biallelic KRT5 as a cause of recessive EBS and gives the phenotypic range this row records, including the neonatal-death end.

PMID:31302245 SUPPORT DIRECT BACKGROUND Human Clinical

"recessive EBS due to homozygous biallelic KRT5 mutations has not been reported previously; it has been hypothesized that it would result in prenatal lethality"

Sources the description's statement that this route was expected to be prenatally lethal and had not been observed before this report.

EBS, Ogna type (EBS-Ogna) MONDO:0007555

PLEC hgnc:9069 Autosomal dominant inheritance

A dominant blistering form caused by a site-specific missense variant in the rod domain of plectin. It is the dominant counterpart of the recessive PLEC diseases: the same gene, but without the muscular dystrophy of the EBS-MD row, and with normal plectin staining on muscle biopsy. MONDO's definition of this subtype describes the blistering as sometimes widespread but primarily acral.

Show evidence (2 references)

PMID:11851880 SUPPORT DIRECT Human Clinical

"We found that the epidermolysis bullosa simplex Ogna phenotype is due to a site-specific missense mutation within plectin's rod domain."

Establishes PLEC as the causal gene for the Ogna subtype and the site-specific rod-domain mechanism this row records.

PMID:11851880 SUPPORT DIRECT Human Clinical

"Consistent with the absence of muscular symptoms in these patients, muscle biopsies from several epidermolysis bullosa simplex Ogna members of the Norwegian kindred showed normal staining patterns using antibodies to plectin."

Supports separating this row from EBS with muscular dystrophy despite the shared gene: plectin staining in muscle is normal and there is no myopathy.

EBS with mottled pigmentation (EBS-MP) MONDO:0007556

KRT5 hgnc:6442 Autosomal dominant inheritance

Generalized blistering accompanied by mottled or reticulate pigmentation of the trunk and extremities and punctate palmoplantar hyperkeratosis. Reported cases carry a recurrent P25L substitution in the non-helical V1 head domain of keratin 5.

Show evidence (2 references)

PMID:17229601 SUPPORT DIRECT BACKGROUND Human Clinical

"Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP) is an autosomal dominant inherited disorder of the skin, which manifests as recurrent blistering, punctate palmo-plantar hyperkeratoses, and mottled pigmentation of the trunk and extremities."

Defines the clinical picture and the dominant inheritance recorded on this row.

PMID:17229601 SUPPORT DIRECT BACKGROUND Human Clinical

"Previous reports have identified the P25L mutation within the non-helical V1 domain of keratin 5 as the unique cause of the disease."

Sources KRT5 as this row's gene and the V1 head-domain location of the recurrent substitution. Graded BACKGROUND because the sentence summarizes prior reports; this paper's own contribution is a further de novo case carrying the same substitution.

EBS with migratory circinate erythema (EBS-migr) MONDO:0012258

KRT5 hgnc:6442 Autosomal dominant inheritance

Belt-like annular areas of erythema carrying vesicles and small blisters at the advancing edge. Reported cases carry a KRT5 frameshift with a delayed termination codon, producing an elongated keratin 5 protein rather than the missense substitutions of the common subtypes, and electron microscopy shows reduced keratin filament numbers without the tonofilament clumping of the generalized severe form.

Show evidence (3 references)

PMID:12925204 SUPPORT DIRECT Human Clinical

"The patients showed migratory circinate erythema and multiple vesicles on the circular belt-like areas affected by erythema."

Defines the clinical picture this row is named for.

PMID:12925204 SUPPORT DIRECT Human Clinical

"We identified a novel heterozygous deletion mutation (1649delG of KRT5) in both cases. This deletion is predicted to produce a mutant keratin 5 protein with a frameshift of its terminal 41 amino acids and 35 amino acids longer than the wild-type keratin 5 protein due to a delayed termination codon."

Binds KRT5 to this row and sources the elongated-protein mechanism that separates it from the missense subtypes.

PMID:12925204 SUPPORT DIRECT Human Clinical

"Electron microscopy of skin biopsies showed a reduction in the number of keratin intermediate filaments in the basal cells without tonofilament clumping."

Sources the ultrastructural finding recorded in this row's description. The absence of tonofilament clumping is what separates this subtype from the generalized severe row, where that clumping is the pathognomonic electron microscopy finding.

EBS, localized or generalized intermediate, with BP230 deficiency (DST) MONDO:0014180

DST hgnc:1090 Autosomal recessive inheritance

A recessive form in which the hemidesmosomal inner plaque is lost because the epithelial isoform of bullous pemphigoid antigen 1 (BPAG1-e, BP230), encoded by DST, is absent. Blistering is lifelong, trauma-induced and spontaneous, and particularly affects the ankles.

Show evidence (3 references)

PMID:20164846 SUPPORT DIRECT Human Clinical

"We now report an inherited skin fragility disorder with a homozygous nonsense mutation in the dystonin gene (DST) that encodes the coiled-coil domain of the epithelial isoform of bullous pemphigoid antigen 1, BPAG1-e (also known as BP230)."

Binds DST to this row and identifies the BP230 protein the MONDO term is named after.

PMID:20164846 SUPPORT DIRECT Human Clinical

"The mutation, p.Gln1124X, leads to the loss of hemidesmosomal inner plaques and a complete absence of skin immunostaining for BPAG1-e, as well as reduced labeling for plectin, the beta4 integrin subunit, and for type XVII collagen."

Sources the hemidesmosomal inner-plaque loss recorded in this row's description, and shows the defect also destabilizes plectin, the protein behind the EBS-MD and Ogna rows.

PMID:20164846 SUPPORT DIRECT Human Clinical

"The 38-year-old affected individual has lifelong generalized trauma-induced spontaneous blisters and erosions, particularly around the ankles."

Sources the clinical course recorded in this row's description. Note the report describes a single affected individual, so the ankle predilection is that individual's presentation rather than an established feature of the subtype.

EBS, localized or generalized intermediate, autosomal recessive (EXPH5) MONDO:0014014

EXPH5 hgnc:30578 Autosomal recessive inheritance

A recessive form caused by biallelic EXPH5 variants. Exophilin-5 (Slac2-b) is a Rab27B effector in intracellular vesicle trafficking rather than a structural component of the keratin-hemidesmosome axis, so the route to skin fragility here runs through vesicle handling. Reported features are generalized trauma-induced scale-crusts with occasional blisters and mild mottled pigmentation.

Show evidence (2 references)

PMID:23176819 SUPPORT DIRECT Human Clinical

"By using whole-exome sequencing, we identified a homozygous frameshift mutation in EXPH5 in three siblings with inherited skin fragility born to consanguineous Iraqi parents."

Binds EXPH5 to this row and establishes biallelic, recessive transmission in a consanguineous pedigree.

PMID:23176819 SUPPORT DIRECT Human Clinical

"The clinical features comprised generalized scale-crusts and occasional blisters, mostly induced by trauma, as well as mild diffuse pigmentary mottling on the trunk and proximal limbs."

Sources the clinical picture recorded in this row's description.

EBS, generalized, with scarring and hair loss (KLHL24) MONDO:0015006

KLHL24 hgnc:25947 Autosomal dominant inheritance

A dominant form in which the causal gene is not a structural protein at all: KLHL24 is the substrate receptor of a cullin-3 ubiquitin ligase, and start-codon variants produce a truncated receptor that escapes autoubiquitination and drives excessive degradation of keratin 14. The result is keratin 14 loss without a keratin mutation. The allelic recessive KLHL24 cardiomyopathy is curated separately as KLHL24-Related_Hypertrophic_Cardiomyopathy.

Show evidence (2 references)

PMID:27798626 SUPPORT DIRECT Human Clinical

"We have identified start-codon mutations in the KLHL24 gene in five patients with EB."

Binds KLHL24 to this row in five patients with epidermolysis bullosa.

PMID:27798626 SUPPORT DIRECT In Vitro

"We have further identified keratin 14 (KRT14) as a KLHL24 substrate and found that KLHL24-ΔN28 induces excessive ubiquitination and degradation of KRT14."

Sources the mechanism recorded in this row's description: the truncated receptor degrades keratin 14, so keratin 14 is lost without a KRT14 mutation.

EBS due to plakophilin deficiency (ectodermal dysplasia-skin fragility syndrome) MONDO:0011472

PKP1 hgnc:9023 Autosomal recessive inheritance

A suprabasal subtype, also called ectodermal dysplasia-skin fragility syndrome, caused by biallelic loss-of-function variants in PKP1. Plakophilin 1 is a desmosomal plaque protein expressed mainly in the spinous layer, so the cleavage plane is above the basal keratinocytes rather than within them, and the picture is dominated by superficial erosions, palmoplantar keratoderma, nail involvement and alopecia/hypotrichosis rather than by blistering. MONDO files this concept under epidermolysis bullosa simplex through suprabasal epidermolysis bullosa simplex (MONDO:0015550); see this entry's notes for why it is carried here rather than as a separate entry.

Show evidence (3 references)

PMID:19016709 SUPPORT DIRECT Human Clinical

"In patient 1 we identified a homozygous nonsense mutation, p.R672X, in the PKP1 gene (encoding plakophilin 1)."

Binds PKP1 to this row in a patient with clinical features consistent with ectodermal dysplasia-skin fragility syndrome.

PMID:32248567 SUPPORT DIRECT BACKGROUND Human Clinical

"One specific component of desmosomes is plakophilin 1 (PKP1), which is mainly expressed in the spinous layer of the epidermis. Loss-of-function autosomal recessive mutations in PKP1 result in ectodermal dysplasia-skin fragility (EDSF) syndrome"

Sources both the suprabasal (spinous-layer) expression that places this row above the basal-cleavage subtypes and its recessive loss-of-function mechanism.

PMID:32248567 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Skin fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases)."

Sources the clinical features recorded in this row's description, from the authors' review of all published biallelic PKP1 cases.

Lethal acantholytic epidermolysis bullosa MONDO:0012323

DSP hgnc:3052 Autosomal recessive inheritance

The second suprabasal subtype, caused by biallelic DSP variants that truncate the desmoplakin tail and remove its intermediate filament-binding subdomains. Keratin filaments disconnect from desmosomes, producing acantholysis throughout the spinous layer and neonatal death from transcutaneous fluid loss, with universal alopecia, neonatal teeth and nail loss. Other biallelic DSP phenotypes are curated separately as Skin_Fragility_Woolly_Hair_Syndrome and Carvajal_Syndrome.

Show evidence (3 references)

PMID:16175511 SUPPORT DIRECT Human Clinical

"Mutational analysis of the patient demonstrated compound heterozygosity for two DP mutations, 6079C-->T (R1934X) and 6370delTT, respectively."

Binds DSP to this row and establishes biallelic transmission in the index patient.

PMID:16175511 SUPPORT DIRECT Human Clinical

"Histology showed suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. Electron microscopy revealed disconnection of keratin intermediate filaments from desmosomes."

Sources the suprabasal cleavage plane and the keratin-desmosome disconnection recorded in this row's description.

PMID:16175511 SUPPORT DIRECT Human Clinical

"The new phenotype is lethal in the neonatal period because of immense transcutaneous fluid loss. The phenotype also comprised universal alopecia, neonatal teeth, and nail loss."

Sources the lethal neonatal course and associated features recorded here.

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Pathophysiology

9

KRT5/KRT14 Mutations Disrupt Keratin Intermediate Filament Network

Mutations in KRT5 or KRT14 genes disrupt the keratin intermediate filament network in basal keratinocytes of the epidermis. Keratins 5 and 14 are the obligate type II and type I intermediate filament partners that copolymerize to form the 10 nm filament network providing mechanical resilience to basal keratinocytes.

epidermal cell CL:0000362

KRT5 hgnc:6442 KRT14 hgnc:6416

intermediate filament organization GO:0045109 ⚠ ABNORMAL

Downstream

Dominant-Negative Disruption of Filament Assembly Mutant keratins poison the filament network by incorporating into filaments and destabilizing them.

Show evidence (2 references)

PMID:22277943 SUPPORT Human Clinical

"Most cases of EBS are due to dominantly acting mutations in keratin 14 (K14) or K5, the type I and II intermediate filament (IF) proteins that copolymerize to form a pancytoplasmic network of 10 nm filaments in basal keratinocytes of epidermis and related epithelia"

Confirms K5/K14 as the obligate IF pair in basal keratinocytes and dominant mutations as the cause of EBS.

PMID:30078200 SUPPORT Human Clinical

"the most important and most commonly occurring molecular defects in these patients are the defects of keratins 5 and14 (KRT5 and KRT14)"

Confirms KRT5 and KRT14 defects as the primary molecular basis of EBS.

Dominant-Negative Disruption of Filament Assembly

Mutant keratins exert a dominant-negative effect by incorporating into keratin filaments and poisoning the entire filament network. This disrupts filament architecture and leads to keratin aggregate formation, particularly under conditions of mechanical or thermal stress.

epidermal cell CL:0000362

intermediate filament cytoskeleton organization GO:0045104 ⚠ ABNORMAL

Downstream

Mechanical Stress-Induced Keratinocyte Cytolysis Disrupted keratin network renders basal keratinocytes fragile and prone to rupture under mechanical stress.

Show evidence (2 references)

PMID:22277943 SUPPORT Human Clinical

"Defects in K5-K14 filament network architecture cause basal keratinocytes to become fragile, and account for their rupture upon exposure to mechanical trauma"

Confirms that disrupted keratin filament architecture causes basal keratinocyte fragility and rupture.

PMID:34830328 SUPPORT In Vitro

"Keratin aggregates display impaired dynamics of assembly and diminished solubility and appear to be the trigger for endoplasmic reticulum (ER) stress upon being phosphorylated by MAPKs"

Confirms that mutant keratins form aggregates with impaired dynamics, triggering downstream ER stress signaling.

Mechanical Stress-Induced Keratinocyte Cytolysis

Basal keratinocytes with disrupted keratin networks rupture (cytolyse) when subjected to mechanical trauma. The blistering in EBS is intraepidermal, occurring within the basal cell layer rather than at tissue interfaces, distinguishing it from junctional and dystrophic EB.

epidermal cell CL:0000362

cell death GO:0008219 ↑ INCREASED

Downstream

Skin Blistering Cytolysis of the basal keratinocyte is what produces the clinical blister, and is why the cleavage plane is intraepidermal rather than at the dermal-epidermal junction. Every mechanistic route in this entry except the suprabasal desmosomal one reaches the clinical phenotype through this node.

Show evidence (2 references)

PMID:16098032 SUPPORT Human Clinical

"Epidermolysis bullosa simplex (EBS) is a mechano-bullous disorder characterized by intraepidermal blistering within the basal keratinocytes as a result of trauma to the skin"

Confirms intraepidermal blistering within basal keratinocytes as the hallmark of EBS.

PMID:34830328 SUPPORT In Vitro

"Epidermolysis bullosa simplex (EBS) is a group of inherited keratinopathies that, in most cases, arise due to mutations in keratins and lead to intraepidermal ruptures"

Confirms that keratin mutations lead to intraepidermal rupture.

PLEC Mutations Disrupt Hemidesmosome-Cytoskeleton Linkage

Mutations in PLEC disrupt plectin, a giant cytoskeletal crosslinker that connects the keratin intermediate filament network to hemidesmosomes at the dermal-epidermal junction and to the desmin cytoskeleton in muscle. Loss of plectin causes a dual phenotype affecting both skin (blistering) and skeletal muscle (progressive dystrophy).

epidermal cell CL:0000362 skeletal muscle fiber CL:0008002

PLEC hgnc:9069

cell-substrate junction organization GO:0150115 ⚠ ABNORMAL

Downstream

Mechanical Stress-Induced Keratinocyte Cytolysis Disrupted hemidesmosome-cytoskeleton linkage leads to skin fragility.

Muscular Dystrophy The same plectin loss disrupts the desmin cytoskeleton of skeletal muscle, which is the extracutaneous half of the EBS-MD phenotype and is why that subtype row is the only one in this entry carrying a myopathy.

Show evidence (2 references)

PMID:34572129 SUPPORT Human Clinical

"Plectin is a giant cytoskeletal crosslinker and intermediate filament stabilizing protein. Mutations in the human plectin gene (PLEC) cause several rare diseases that are grouped under the term plectinopathies"

Confirms plectin as a cytoskeletal crosslinker whose mutations cause plectinopathies including EBS-MD.

PMID:25530118 SUPPORT Human Clinical

"Plectin deficiency causes autosomal recessive epidermolysis bullosa simplex (EBS) with involvement of the skin and other organs, such as muscle and gastrointestinal tract, depending on the expression pattern of the defective protein"

Confirms plectin deficiency causes EBS with multi-organ involvement including skin and muscle.

Heat Sensitivity of Mutant Keratin Networks

Mutant keratin filament networks are thermally unstable. Elevated temperature causes filament breakdown into aggregates, explaining the clinical observation that blistering worsens in warm weather and with increased perspiration. This is particularly prominent in localized EBS.

response to heat GO:0009408 ⚠ ABNORMAL

Downstream

Heat-Exacerbated Blistering Thermal breakdown of the mutant filament network is the mechanism behind the seasonal and exertional worsening recorded as a phenotype.

Show evidence (1 reference)

PMID:8586658 SUPPORT In Vitro

"after thermal stress a reduced stability of the keratin filaments was demonstrable in the epidermolysis bullosa simplex cell lines, with filaments breaking into aggregates"

Demonstrates that thermal stress causes keratin filament breakdown into aggregates in EBS cell lines, explaining heat-exacerbated blistering.

BPAG1-e Deficiency Disrupts the Hemidesmosomal Inner Plaque

Biallelic DST nonsense variants abolish the epithelial isoform of bullous pemphigoid antigen 1 (BPAG1-e, BP230), the hemidesmosomal inner-plaque protein that anchors keratin intermediate filaments at the basal pole of the keratinocyte. Inner plaques are lost and labelling for plectin, the beta-4 integrin subunit and type XVII collagen is reduced, so the defect destabilizes the wider hemidesmosome rather than one component alone. This is the node the EBS BP230 subtype row acts at.

basal keratinocyte CL:0002187

DST hgnc:1090

hemidesmosome assembly GO:0031581 ⚠ ABNORMAL

Downstream

Mechanical Stress-Induced Keratinocyte Cytolysis Loss of the hemidesmosomal inner plaque leaves basal keratinocytes unable to resist shear, producing the same trauma-induced intraepidermal separation as the keratin and plectin routes.

Show evidence (2 references)

PMID:20164846 SUPPORT DIRECT Human Clinical

"The mutation, p.Gln1124X, leads to the loss of hemidesmosomal inner plaques and a complete absence of skin immunostaining for BPAG1-e, as well as reduced labeling for plectin, the beta4 integrin subunit, and for type XVII collagen."

Direct observation in patient skin of the inner-plaque loss and wider hemidesmosomal destabilization this node asserts.

PMID:20164846 SUPPORT DIRECT Human Clinical

"The 38-year-old affected individual has lifelong generalized trauma-induced spontaneous blisters and erosions, particularly around the ankles."

Supports the downstream edge to keratinocyte cytolysis: the same individual has lifelong trauma-induced blistering.

Exophilin-5 Deficiency Impairs Keratinocyte Vesicle Trafficking and Adhesion

Biallelic EXPH5 truncating variants remove the C-terminus of exophilin-5 (Slac2-b), a Rab27B effector in intracellular vesicle trafficking. The product is not a structural component of the keratin-hemidesmosome apparatus, as the keratin, plectin and BPAG1-e routes' products are; the route to fragility runs instead through disordered vesicle handling, with perinuclear and plasma-membrane-proximal vesicle accumulation, keratin filament disruption and reduced keratinocyte adhesion in the lower epidermis. This is the node the EBS EXPH5 subtype row acts at.

keratinocyte CL:0000312

EXPH5 hgnc:30578

vesicle-mediated transport GO:0016192 ⚠ ABNORMAL

Downstream

Mechanical Stress-Induced Keratinocyte Cytolysis Reduced keratinocyte adhesion and keratin filament disruption in the lower epidermis converge on the same trauma-induced intraepidermal separation as the structural routes.

Show evidence (2 references)

PMID:23176819 SUPPORT DIRECT Human Clinical

"Analysis of an affected person's skin showed loss of Slac2-b immunostaining (C-terminal antibody), disruption of keratinocyte adhesion within the lower epidermis, and an increased number of perinuclear vesicles."

Direct observation in patient skin of the vesicle accumulation and adhesion loss this node asserts.

PMID:23176819 SUPPORT DIRECT In Vitro

"A role for Slac2-b in keratinocyte biology was supported by findings of cytoskeletal disruption (mainly keratin intermediate filaments) and decreased keratinocyte adhesion in both keratinocytes from an affected subject and after shRNA knockdown of Slac2-b in normal keratinocytes."

Cultured-keratinocyte and knockdown evidence that the adhesion and keratin-filament defect follows from loss of Slac2-b specifically.

KLHL24 Gain-of-Function Drives Ubiquitin-Mediated Keratin 14 Degradation

Heterozygous start-codon variants in KLHL24 produce a receptor lacking its first 28 residues, which can no longer autoubiquitinate and therefore accumulates. Keratin 14 is a substrate of this receptor, so the stabilized form drives excessive ubiquitination and degradation of keratin 14. The basal keratin network is depleted without any mutation in a keratin gene, which is why this node is drawn separately from the dominant-negative route. This is the node the EBS KLHL24 subtype row acts at.

basal keratinocyte CL:0002187

KLHL24 hgnc:25947

ubiquitination of keratin 14 GO:0016567 ↑ INCREASED

Downstream

Mechanical Stress-Induced Keratinocyte Cytolysis Depletion of keratin 14 protein leaves the basal keratin network unable to bear mechanical load, reaching the same cytolysis node as the dominant-negative keratin variants.

Show evidence (2 references)

PMID:27798626 SUPPORT DIRECT In Vitro

"We have further identified keratin 14 (KRT14) as a KLHL24 substrate and found that KLHL24-ΔN28 induces excessive ubiquitination and degradation of KRT14."

Establishes the substrate relationship and the direction of the effect this node asserts.

PMID:27798626 SUPPORT DIRECT Model Organism

"Using a knock-in mouse model, we have confirmed that the Klhl24 mutations lead to stabilized Klhl24-ΔN28 and cause Krt14 degradation."

In vivo confirmation in a knock-in mouse that the stabilized receptor is what degrades keratin 14.

Desmosomal Plaque Deficiency Causes Suprabasal Acantholysis

The two suprabasal routes in this entry. Loss of plakophilin 1, a desmosomal plaque protein expressed mainly in the spinous layer, or truncation of the desmoplakin tail that carries desmoplakin's intermediate filament-binding subdomains, detaches keratin filaments from desmosomes above the basal layer. The cleavage plane is therefore suprabasal rather than intrabasal, and the histology is acantholysis resembling pemphigus rather than basal-cell cytolysis. This node is drawn separately from the basal routes for that reason, and is where the EBS-PD and LAEB subtype rows act.

keratinocyte CL:0000312

PKP1 hgnc:9023 DSP hgnc:3052

desmosome organization GO:0002934 ⚠ ABNORMAL

Downstream

Skin Blistering Suprabasal acantholysis produces superficial erosions and blistering, the shared clinical endpoint with the basal routes even though the cleavage plane differs.

Palmoplantar Keratoderma Palmoplantar keratoderma is a cardinal feature of the plakophilin route rather than an incidental one, reported in 16 of 18 published biallelic PKP1 cases, so the desmosomal defect reaches this phenotype directly and not only through blistering.

Nail Dystrophy Nail involvement is present in every published biallelic PKP1 case, making it one of the two constant features of the plakophilin route alongside skin fragility.

Show evidence (3 references)

PMID:16175511 SUPPORT DIRECT Human Clinical

"Histology showed suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. Electron microscopy revealed disconnection of keratin intermediate filaments from desmosomes."

Direct observation of the suprabasal cleavage plane and the keratin-desmosome disconnection this node asserts, in the desmoplakin route.

PMID:32248567 SUPPORT DIRECT BACKGROUND Human Clinical

"One specific component of desmosomes is plakophilin 1 (PKP1), which is mainly expressed in the spinous layer of the epidermis. Loss-of-function autosomal recessive mutations in PKP1 result in ectodermal dysplasia-skin fragility (EDSF) syndrome"

Sources the plakophilin route and the spinous-layer expression that puts this node's cleavage plane above the basal keratinocytes.

PMID:32248567 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Skin fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases)."

The frequencies behind this node's edges to palmoplantar keratoderma and nail dystrophy, from the authors' review of all published biallelic PKP1 cases.

⬡

Pathograph

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

●

Phenotypes

7

Integument 6

Skin Blistering OCCASIONAL Abnormal blistering of the skin HP:0008066

Show evidence (2 references)

PMID:20301543 SUPPORT Human Clinical

"Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some instances) that results in non-scarring blisters and erosions caused by minor mechanical trauma"

GeneReviews confirms non-scarring blisters from minor mechanical trauma as the hallmark of EBS.

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"

Nature Reviews Disease Primers confirms blister formation from minimal trauma as the defining feature of EB.

Heat-Exacerbated Blistering VERY_FREQUENT Abnormal blistering of the skin HP:0008066

Show evidence (1 reference)

PMID:8586658 SUPPORT In Vitro

"after thermal stress a reduced stability of the keratin filaments was demonstrable in the epidermolysis bullosa simplex cell lines, with filaments breaking into aggregates"

Demonstrates thermal instability of mutant keratin filaments, providing the molecular basis for heat-exacerbated blistering.

Palmoplantar Keratoderma FREQUENT HP:0000982

Primarily seen in EBS severe (Dowling-Meara)

Show evidence (1 reference)

PMID:20301543 SUPPORT Human Clinical

"Additional features can include hyperkeratosis of the palms and soles (keratoderma), nail dystrophy, milia, and hyper- and/or hypopigmentation"

GeneReviews confirms palmoplantar keratoderma as an additional feature of EBS.

Herpetiform Blistering Pattern FREQUENT Abnormal blistering of the skin HP:0008066

Characteristic of EBS severe (Dowling-Meara) subtype

Show evidence (1 reference)

PMID:34830328 SUPPORT In Vitro

"Mutations in keratins 5/14 or in other genes that encode associated proteins induce structural disarrangements of different strengths depending on their locations in the genes"

Confirms that mutation location determines severity of structural disarrangement, explaining the severe herpetiform phenotype in Dowling-Meara EBS.

Nail Dystrophy FREQUENT HP:0008404

Show evidence (1 reference)

PMID:34572129 SUPPORT Human Clinical

"PLEC mutations lead to EBS with nail dystrophy"

Confirms nail dystrophy as a recognized feature of PLEC-associated EBS.

Milia OCCASIONAL HP:0001056

Show evidence (1 reference)

PMID:20301543 SUPPORT Human Clinical

"Additional features can include hyperkeratosis of the palms and soles (keratoderma), nail dystrophy, milia, and hyper- and/or hypopigmentation"

GeneReviews lists milia as an additional feature of EBS.

Musculoskeletal 1

Muscular Dystrophy OBLIGATE HP:0003560

Specific to EBS with muscular dystrophy (PLEC mutations)

Show evidence (2 references)

PMID:34572129 SUPPORT Human Clinical

"The most common disorder is autosomal recessive disease epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), which is characterized by skin blistering and progressive muscle weakness"

Confirms progressive muscle weakness as a defining feature of EBS-MD.

PMID:34572129 SUPPORT Model Organism

"Skeletal muscle biopsies from EBS-MD patients and plectin-deficient mice revealed severe dystrophic features with variation in fiber size, degenerative myofibrillar changes, mitochondrial alterations, and pathological desmin-positive protein aggregates"

Confirms dystrophic muscle pathology in both human EBS-MD patients and plectin-deficient mouse models.

🧬

Genetic Associations

8

KRT5 (Causative)

Gene: KRT5 hgnc:6442 gene page

Autosomal dominant

Show evidence (2 references)

PMID:16098032 SUPPORT Human Clinical

"18 were found to harbor heterozygous mutations in the keratin 5 or keratin 14 genes, KRT5 and KRT14, respectively"

Confirms heterozygous KRT5 mutations as a cause of EBS.

PMID:30078200 SUPPORT Human Clinical

"the most important and most commonly occurring molecular defects in these patients are the defects of keratins 5 and14 (KRT5 and KRT14)"

Confirms KRT5 as one of the two principal genes mutated in EBS.

KRT14 (Causative)

Gene: KRT14 hgnc:6416 gene page

Autosomal dominant Autosomal recessive

Show evidence (2 references)

PMID:22277943 SUPPORT Human Clinical

"Most cases of EBS are due to dominantly acting mutations in keratin 14 (K14) or K5"

Confirms dominant KRT14 mutations as a major cause of EBS.

PMID:16098032 SUPPORT Human Clinical

"many cases result from de novo mutations in KRT5 and KRT14 genes"

Confirms that many EBS cases arise from de novo KRT14 mutations.

PLEC (Causative)

Gene: PLEC hgnc:9069

Autosomal recessive

Show evidence (2 references)

PMID:34572129 SUPPORT Human Clinical

"Mutations in the human plectin gene (PLEC) cause several rare diseases that are grouped under the term plectinopathies"

Confirms PLEC mutations as causative for plectinopathies including EBS-MD.

PMID:16098032 SUPPORT Human Clinical

"in 14 cases, the disease was associated with mutations in both alleles of the plectin gene"

Confirms biallelic plectin mutations in EBS patients, establishing recessive inheritance.

DST (Causative)

Gene: DST hgnc:1090 gene page

Autosomal recessive

Show evidence (1 reference)

PMID:20301543 SUPPORT Human Clinical

"biallelic pathogenic variants in CD151, DST, or EXPH5"

GeneReviews lists DST as a gene with biallelic pathogenic variants causing autosomal recessive EBS.

EXPH5 (Causative)

Gene: EXPH5 hgnc:30578

Autosomal recessive

Show evidence (1 reference)

PMID:20301543 SUPPORT Human Clinical

"biallelic pathogenic variants in CD151, DST, or EXPH5"

GeneReviews lists EXPH5 as a gene with biallelic pathogenic variants causing autosomal recessive EBS.

KLHL24 (Causative)

Gene: KLHL24 hgnc:25947 gene page

Autosomal dominant

Show evidence (2 references)

PMID:27798626 SUPPORT Human Clinical

"We have identified start-codon mutations in the KLHL24 gene in five patients with EB."

Identifies KLHL24 start-codon mutations as a novel cause of EBS through stabilized truncated protein that excessively degrades KRT14.

PMID:27889062 SUPPORT Human Clinical

"monoallelic mutations, c.1A>G and c.2T>C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes"

Independently confirms KLHL24 initiation codon mutations in 14 individuals with skin fragility and basal keratinocyte cleavage.

PKP1 (Causative)

Gene: PKP1 hgnc:9023

Autosomal recessive

Show evidence (2 references)

PMID:19016709 SUPPORT DIRECT Human Clinical

"In patient 1 we identified a homozygous nonsense mutation, p.R672X, in the PKP1 gene (encoding plakophilin 1)."

A biallelic PKP1 truncating variant in a patient with ectodermal dysplasia-skin fragility syndrome.

PMID:19016709 SUPPORT DIRECT Human Clinical

"In contrast, PKP1 is not expressed in the heart, which accounts for the lack of cardiomyopathy in patient 1."

Sources the cardiac contrast recorded in these notes, which is the main clinical discriminator between the PKP1 and DSP suprabasal routes.

DSP (Causative)

Gene: DSP hgnc:3052 gene page

Autosomal recessive

Show evidence (2 references)

PMID:16175511 SUPPORT DIRECT Human Clinical

"Aberrant mRNA transcripts that predict premature termination of translation with loss of the three intermediate filament-binding subdomains in the DP tail were detected by RT-PCR."

Identifies the specific functional consequence, loss of the intermediate filament-binding subdomains of the desmoplakin tail.

PMID:19016709 SUPPORT DIRECT Human Clinical

"Loss-of-function mutations in the DSP gene can result in a phenotype similar to ectodermal dysplasia-skin fragility syndrome resulting from PKP1 mutations but only DSP pathology is associated with cardiac disease."

Sources the phenotypic overlap with the PKP1 route and the cardiac expression difference recorded in these notes.

💊

Medical Actions

8

Wound Care

Action: wound care Ontology label: Supportive Care NCIT:C15747

Supportive wound care is the mainstay of EBS management. Includes use of non-adherent dressings to protect fragile skin and promote healing of blistered areas. Blister lancing with sterile technique to prevent blister extension.

Show evidence (1 reference)

PMID:20301543 SUPPORT Human Clinical

"Supportive care to protect the skin from blistering; use of dressings that will protect the skin and promote healing of wounds"

GeneReviews confirms supportive wound care as the primary management strategy for EBS.

Avoidance of Heat and Friction

Action: avoidance of triggers Ontology label: Supportive Care NCIT:C15747

Minimizing exposure to heat, excessive physical activity, and friction to prevent blistering episodes. Includes wearing loose-fitting clothing, soft footwear, and avoiding high ambient temperatures.

Show evidence (1 reference)

PMID:20301543 SUPPORT Human Clinical

"Excessive heat exposure may exacerbate blistering and infection. Avoid poorly fitting or coarse-textured clothing/footwear and activities that traumatize the skin"

GeneReviews lists heat exposure and skin trauma as agents to avoid in EBS management.

Antiperspirants for Palmoplantar Disease

Action: topical antiperspirant therapy Ontology label: Supportive Care NCIT:C15747

Topical antiperspirant application to palms and soles to reduce perspiration-induced blistering, especially in localized EBS.

Show evidence (1 reference)

PMID:20301543 SUPPORT Human Clinical

"Aluminum chloride (20%) applied to palms and soles can reduce sweating and therefore minimize blister formation in some individuals with EBS"

GeneReviews confirms aluminum chloride antiperspirant as a treatment to reduce sweating-induced blistering.

Pain Management

Action: pain management Ontology label: Supportive Care NCIT:C15747

Analgesic therapy for pain associated with blistering and erosions. May include topical and systemic pain medications depending on severity.

Show evidence (1 reference)

PMID:20301543 SUPPORT Human Clinical

"Identification and management of specific causes of pain and itching; management with a pain specialist as needed"

GeneReviews confirms pain and itch management as part of EBS care.

Physical Therapy

Action: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Rehabilitation and physical therapy for patients with EBS-MD to maintain mobility and muscle function as muscular dystrophy progresses.

Show evidence (1 reference)

PMID:20301543 SUPPORT Human Clinical

"appropriate footwear and physical therapy to preserve ambulation"

GeneReviews confirms physical therapy to preserve ambulation as part of EBS management.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling for affected families regarding inheritance patterns, recurrence risk, and prenatal diagnosis options. Important given both dominant and recessive forms and significant de novo mutation rate.

Show evidence (1 reference)

PMID:16098032 SUPPORT Human Clinical

"These findings have implications for genetic counseling and prenatal diagnosis for EBS"

Confirms the importance of genetic counseling for EBS families, particularly given de novo mutations and mixed inheritance patterns.

Diacerein (Anti-IL-1beta Therapy)

Action: diacerein anti-IL-1beta therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: Diacerein NCIT:C166759

Topical diacerein 1% ointment, an anti-inflammatory agent that inhibits IL-1beta signaling. A phase 2/3 crossover trial (n=17) showed 86% of diacerein-treated patients achieved >40% blister reduction versus 14% with placebo. However, a larger randomized controlled trial (n=54) found no significant difference in the primary endpoint (>=60% BSA reduction at 8 weeks), though post hoc analysis in severe EBS showed a potential signal (46.2% vs 15.4% achieving optimal skin scores). Multiple ongoing trials continue to evaluate diacerein in EBS.

Show evidence (2 references)

PMID:29410318 SUPPORT Human Clinical

"Of the patients receiving diacerein, 86% in episode 1 and 37.5% in episode 2 met the primary end point (vs 14% and 17% with placebo, respectively). This effect was still significant after the follow-up"

Phase 2/3 crossover trial demonstrating diacerein efficacy in reducing EBS blisters compared to placebo.

PMID:37276163 SUPPORT Human Clinical

"Although there was no significant difference in outcomes between the groups, further study may elucidate the effects of diacerein on EBS lesions, especially in patients with severe EBS"

Larger RCT (n=54) did not meet primary endpoint overall, though post hoc analysis suggested benefit in severe EBS subgroup.

Sulforaphane (Nrf2 Activator, Preclinical)

Action: sulforaphane Nrf2 activator therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: sulforaphane CHEBI:47807

Sulforaphane, a natural product from cruciferous vegetables, activates the Nrf2 transcription factor to induce compensatory keratins K16/K17 in basal keratinocytes. In an EBS mouse model with K14 deficiency, sulforaphane treatment alleviated blistering by upregulating K17 expression. This represents an attractive preclinical approach exploiting functional redundancy within the keratin gene family.

Show evidence (1 reference)

PMID:17724334 SUPPORT Model Organism

"treatment with a pharmacological activator of Nrf2, two transcription factors eliciting distinct transcriptional programs, alleviates the blistering caused by a K14 deficiency in an EBS mouse model, correlating with K17 induction in basal epidermal keratinocytes. Nrf2 induction is brought about..."

Mouse model demonstrates sulforaphane activates Nrf2 to induce compensatory K17 expression in basal keratinocytes, alleviating blistering in K14-deficient EBS.

📊

Prevalence

1

Global

EBS is the most common type of epidermolysis bullosa, accounting for approximately 70% of all EB cases. Estimated prevalence is 1 in 30,000 to 50,000. US National EB Registry data (1986-2002) reported an overall EB incidence of 19.57 per million live births, with EBS prevalence increasing by 30.4% over the 16-year study period as ascertainment improved.

Show evidence (2 references)

PMID:27463098 SUPPORT Human Clinical

"the overall incidence and prevalence of inherited EB were 19.60 and 8.22 per 1 million live births, respectively"

US National EB Registry provides incidence and prevalence estimates for inherited EB including EBS as the most common subtype.

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"

Nature Reviews Disease Primers confirms EB as a group of rare genetic skin fragility disorders with EBS being the most common major type.

📊

Related Datasets

1

Transcriptomic Repositioning Analysis Identifies mTOR Inhibitor as Potential Therapy for Epidermolysis Bullosa Simplex geo:GSE179508

Human bulk RNA-seq dataset profiling blistered and non-blistered EBS skin, used to define disease-associated signaling programs and prioritize repositionable therapies.

human BULK RNA SEQ n=20

Conditions: blistered EBS skin non-blistered EBS skin

Show evidence (2 references)

GEO:GSE179508 SUPPORT Human Clinical

"In this study, we characterize significant molecular pathways activated in the blisters that form in EBS"

Supports this GEO series as a direct transcriptomic resource for EBS lesional biology.

GEO:GSE179508 SUPPORT Human Clinical

"We implicate the PI3K/AKT/mTOR pathway as central in the EBS disease pathway"

Confirms that the dataset captures disease-relevant signaling programs and supports downstream therapeutic inference.

🔬

Clinical Trials

2

NCT06073132 PHASE_II RECRUITING

Ongoing international phase 2/3 EBShield study evaluating topical diacerein 1% ointment in generalized epidermolysis bullosa simplex.

Target Phenotypes: skin blistering HP:0008066

Show evidence (1 reference)

clinicaltrials:NCT06073132 SUPPORT Human Clinical

"The proposed Phase 2/3 trial with double-blind and open-label extension phases is an international, multicenter study designed to assess the efficacy and safety of diacerein 1% ointment in patients with generalized EBS."

This ClinicalTrials.gov record supports an actively recruiting diacerein trial focused specifically on generalized EBS.

NCT03154333 PHASE_II TERMINATED

Terminated randomized phase II study of topical diacerein 1% ointment versus vehicle in epidermolysis bullosa simplex.

Target Phenotypes: skin blistering HP:0008066

Show evidence (1 reference)

clinicaltrials:NCT03154333 SUPPORT Human Clinical

"Epidermolysis bullosa simplex (EBS) is a rare genetic skin disease characterized by fragility of the skin and mucous membranes resulting in painful blisters and erosions after minor trauma. The purpose of this study is to compare the efficacy of diacerein 1% ointment to vehicle ointment when..."

This ClinicalTrials.gov record supports a disease-specific randomized EBS trial of topical diacerein.

{ }

Source YAML

click to show

name: Epidermolysis Bullosa Simplex
creation_date: '2026-03-10T00:00:00Z'
category: Mendelian
description: >-
  Epidermolysis bullosa simplex (EBS) is the most common form of EB,
  characterized by intraepidermal blistering within the basal cell layer.
  Most cases are caused by dominant-negative mutations in KRT5 or KRT14
  encoding keratins 5 and 14 in basal keratinocytes. Blisters generally heal
  without significant scarring. Subtypes range from localized palmoplantar
  blistering to severe generalized forms with herpetiform blistering, and
  include EBS with muscular dystrophy caused by PLEC mutations. Beyond the two
  keratins and plectin, four further genes reach the same clinical picture:
  DST (loss of the hemidesmosomal inner plaque),
  EXPH5 (disordered keratinocyte vesicle trafficking), KLHL24 (a stabilized
  ubiquitin-ligase receptor that degrades keratin 14 without any keratin
  mutation), and CD151. Two subtypes blister above the basal layer rather
  than within it, through loss of the desmosomal plaque proteins plakophilin
  1 (PKP1) or desmoplakin (DSP); MONDO files these under this entry's term
  through suprabasal epidermolysis bullosa simplex, and they are curated here
  as suprabasal rows with their own mechanism node.
parents:
- Dermatological Disease
- Genetic Disease
disease_term:
  preferred_term: epidermolysis bullosa simplex
  term:
    id: MONDO:0017610
    label: epidermolysis bullosa simplex
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:Q81.0
      label: Epidermolysis bullosa simplex
    mapping_predicate: skos:exactMatch
    mapping_source: ICD-10-CM
    mapping_justification: ICD-10-CM Q81.0 directly names epidermolysis bullosa simplex.
  mondo_mappings:
  - term:
      id: MONDO:0017610
      label: epidermolysis bullosa simplex
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this EBS entry.
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
    evidence:
    - reference: PMID:20301543
      reference_title: "Epidermolysis Bullosa Simplex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin"
      explanation: Supports classifying EBS as a skin disorder because the disease is defined by cutaneous fragility and blistering.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:22277943
      reference_title: "Defining keratin protein function in skin epithelia: epidermolysis bullosa simplex and its aftermath."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Epidermolysis bullosa simplex (EBS) is a rare genetic condition"
      explanation: Supports classification of EBS as a hereditary disease because it is explicitly described as a genetic condition.
has_subtypes:
- name: EBS Localized (formerly Weber-Cockayne)
  display_name: EBS localized (EBS-loc; formerly Weber-Cockayne)
  subtype_term:
    preferred_term: epidermolysis bullosa simplex 1C, localized
    term:
      id: MONDO:0007551
      label: epidermolysis bullosa simplex 1C, localized
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0030527
        label: epidermolysis bullosa simplex 2C, localized
      mapping_predicate: skos:closeMatch
      mapping_source: MONDO
      mapping_justification: >-
        OMIM and MONDO split localized EBS by causal keratin gene. EBS1C
        (MONDO:0007551, OMIM 131800) carries MONDO's KRT14 gene association;
        EBS2C (MONDO:0030527, OMIM 619594) carries the KRT5 one. This row is
        the single clinical localized subtype and covers both routes, so the
        KRT5-side term is recorded here as a close match. Deliberately not an
        exact or narrow match, which would retire an uncurated concept from the
        curation queue.
  description: >
    Blistering mainly confined to hands and feet, exacerbated by heat and
    increased physical activity. The mildest form of EBS and one of its most
    frequent variants. Onset typically in infancy or early childhood. Caused by
    heterozygous dominant-negative variants in either KRT14 or KRT5, which OMIM
    and MONDO now code as two separate terms (EBS1C and EBS2C respectively)
    despite the same clinical picture. This row binds MONDO:0007551, the term
    that carries the Weber-Cockayne eponym together with the Orphanet
    localized-EBS and SNOMED cross-references, and records the KRT5-side term
    as a mapping.
  genes:
  - preferred_term: KRT14
    term:
      id: hgnc:6416
      label: KRT14
  - preferred_term: KRT5
    term:
      id: hgnc:6442
      label: KRT5
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:9804357
    reference_title: "Novel K5 and K14 mutations in German patients with the Weber-Cockayne variant of epidermolysis bullosa simplex."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report novel keratin 5 and 14 gene mutations in four unrelated German families with the localized subtype of the dominantly inherited blistering disease epidermolysis bullosa simplex Weber-Cockayne (MIM# 131800)"
    explanation: >-
      Ties this row's three identities together in one sentence: the localized
      subtype, the Weber-Cockayne eponym, and MIM 131800 - the OMIM number that
      MONDO:0007551 cross-references. Also shows that both KRT14 and KRT5
      variants produce the localized phenotype, and that it is dominantly
      inherited.
  - reference: PMID:7688477
    reference_title: "The genetic basis of Weber-Cockayne epidermolysis bullosa simplex."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we show that the mildest type of EBS, Weber-Cockayne, is also a disorder of these keratins"
    explanation: Supports describing the localized/Weber-Cockayne form as the mildest EBS type and places it in the same basal-keratin disease family as the generalized forms.
  - reference: PMID:26432462
    reference_title: "Novel sporadic and recurrent mutations in KRT5 and KRT14 genes in Polish epidermolysis bullosa simplex patients: further insights into epidemiology and genotype-phenotype correlation."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent variants are: EBS, localised (EBS-loc) with blistering confined to the hands and feet"
    explanation: >-
      Supports both the frequency claim and the palmoplantar distribution. The
      sentence sits in the paper's introduction restating the established
      classification rather than reporting its own cohort, hence BACKGROUND.
- name: EBS Intermediate (formerly Koebner)
  display_name: EBS, generalized intermediate (EBS-gen intermed; formerly Koebner)
  subtype_term:
    preferred_term: epidermolysis bullosa simplex, generalized intermediate
    term:
      id: MONDO:0007554
      label: epidermolysis bullosa simplex 1B, generalized intermediate
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0030525
        label: epidermolysis bullosa simplex 2B, generalized intermediate
      mapping_predicate: skos:closeMatch
      mapping_source: MONDO
      mapping_justification: >-
        As with the localized row above, OMIM and MONDO split generalized
        intermediate EBS by causal keratin gene: EBS1B (MONDO:0007554) carries
        MONDO's KRT14 association and EBS2B (MONDO:0030525) the KRT5 one, for
        the same clinical picture. This row is the single clinical subtype and
        covers both routes, so the KRT5-side term is recorded as a close match
        rather than an exact or narrow one, which would retire an uncurated
        concept from the curation queue.
  description: >
    Generalized non-scarring blistering that may affect any body site.
    More widespread than localized EBS but less severe than the severe form.
    Blisters heal without significant scarring. Caused by heterozygous
    dominant-negative variants in either KRT14 or KRT5.
  genes:
  - preferred_term: KRT14
    term:
      id: hgnc:6416
      label: KRT14
  - preferred_term: KRT5
    term:
      id: hgnc:6442
      label: KRT5
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:26432462
    reference_title: "Novel sporadic and recurrent mutations in KRT5 and KRT14 genes in Polish epidermolysis bullosa simplex patients: further insights into epidemiology and genotype-phenotype correlation."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "EBS-generalised intermediate (EBS-gen intermed, formerly non-Dowling-Meara or EBS-gen nDM), in which blistering occurs on the whole body area"
    explanation: >-
      Defines the generalized intermediate subtype and records the Koebner
      eponym this row is named after, distinguishing it from the localized and
      generalized severe forms.
  - reference: PMID:26432462
    reference_title: "Novel sporadic and recurrent mutations in KRT5 and KRT14 genes in Polish epidermolysis bullosa simplex patients: further insights into epidemiology and genotype-phenotype correlation."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 38/47 probands, we detected mutations in either KRT5 or KRT14 and, in one case, we found mutations in both genes."
    explanation: >-
      The cohort result behind binding both KRT5 and KRT14 to this row: the
      study genotyped EBS probands classified by subtype and found causal
      variants in either keratin gene.
- name: EBS Severe (formerly Dowling-Meara)
  display_name: EBS, generalized severe (EBS-gen sev; formerly Dowling-Meara)
  subtype_term:
    preferred_term: epidermolysis bullosa simplex, generalized severe
    term:
      id: MONDO:0007550
      label: epidermolysis bullosa simplex 1A, generalized severe
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0030489
        label: epidermolysis bullosa simplex 2A, generalized severe
      mapping_predicate: skos:closeMatch
      mapping_source: MONDO
      mapping_justification: >-
        The KRT5-side term for the same clinical subtype; EBS1A
        (MONDO:0007550) carries MONDO's KRT14 association and EBS2A
        (MONDO:0030489) the KRT5 one. Recorded as a close match for the same
        reason as the localized and intermediate rows.
  description: >
    Grouped herpetiform blistering, palmoplantar keratoderma, and nail
    dystrophy. The most severe keratin-associated form of EBS. Blistering
    tends to improve with age, likely due to the suprabasal switch from
    K5/K14 to K1/K10 during keratinocyte differentiation reducing
    dependence on mutant basal keratins. Improvement with age is common
    in all variants of EBS but is not invariable. The pathognomonic
    transmission electron microscopy (TEM) finding is tonofilament
    (keratin) clumping in basal cells. Laryngeal involvement may occur.
    Caused by heterozygous dominant-negative variants in either KRT14 or
    KRT5, typically in the central rod domain.
  genes:
  - preferred_term: KRT14
    term:
      id: hgnc:6416
      label: KRT14
  - preferred_term: KRT5
    term:
      id: hgnc:6442
      label: KRT5
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:26432462
    reference_title: "Novel sporadic and recurrent mutations in KRT5 and KRT14 genes in Polish epidermolysis bullosa simplex patients: further insights into epidemiology and genotype-phenotype correlation."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "more severe: EBS-generalised severe (EBS-gen sev, formerly Dowling-Meara or EBS-gen DM), where mucosa is also involved"
    explanation: >-
      Defines the generalized severe subtype, records the Dowling-Meara eponym
      this row is named after, and gives the mucosal involvement that separates
      it from the generalized intermediate row above.
  - reference: PMID:26432462
    reference_title: "Novel sporadic and recurrent mutations in KRT5 and KRT14 genes in Polish epidermolysis bullosa simplex patients: further insights into epidemiology and genotype-phenotype correlation."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Regardless of the keratin type affected, most of these mutations change amino acid residues in the central L-helical rod domain, leading to more severe EBS phenotypes."
    explanation: >-
      Supports the rod-domain genotype correlation stated in this row's
      description, and that it holds for both KRT5 and KRT14.
- name: EBS with Muscular Dystrophy
  display_name: EBS with muscular dystrophy (EBS-MD)
  subtype_term:
    preferred_term: epidermolysis bullosa simplex with muscular dystrophy
    term:
      id: MONDO:0009181
      label: epidermolysis bullosa simplex 5B, with muscular dystrophy
  description: >
    Caused by PLEC mutations leading to skin fragility combined with
    progressive muscular dystrophy. Autosomal recessive inheritance.
    Plectin deficiency disrupts both epidermal and muscle cytoskeletal
    integrity.
  genes:
  - preferred_term: PLEC
    term:
      id: hgnc:9069
      label: PLEC
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20447487
    reference_title: "Epidermolysis bullosa simplex with muscular dystrophy."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive forms of EBS associated with extracutaneous manifestations, such as muscular dystrophy (MIM 226670) or pyloric atresia (MIM 612138), have been linked to genetic mutations in the gene for plectin (PLEC)."
    explanation: >-
      Ties this row's three identities together: the muscular dystrophy
      phenotype, autosomal recessive inheritance, and PLEC as the causal gene.
- name: EBS Autosomal Recessive (KRT14 null)
  display_name: EBS, generalized, intermediate or severe, autosomal recessive (KRT14)
  subtype_term:
    preferred_term: epidermolysis bullosa simplex, generalized, autosomal recessive (KRT14)
    term:
      id: MONDO:0010976
      label: epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive
  description: >
    Severe, generalized blistering caused by biallelic loss-of-function
    mutations in KRT14 resulting in complete absence of keratin 14 protein.
    More severe than typical dominant EBS.
  genes:
  - preferred_term: KRT14
    term:
      id: hgnc:6416
      label: KRT14
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:7525408
    reference_title: "A human keratin 14 \"knockout\": the absence of K14 leads to severe epidermolysis bullosa simplex and a function for an intermediate filament protein."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analyses revealed a homozygous point mutation that yielded a premature termination codon in the major basal type I keratin gene and caused complete ablation of K14."
    explanation: >-
      The founding observation for this row: a homozygous KRT14 null allele
      abolishing keratin 14 protein in a patient with severe recessive EBS.
  - reference: PMID:7525408
    reference_title: "A human keratin 14 \"knockout\": the absence of K14 leads to severe epidermolysis bullosa simplex and a function for an intermediate filament protein."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The consanguineous parents were normal, each harboring one copy of the null K14 mutation."
    explanation: >-
      Establishes autosomal recessive inheritance for this row: heterozygous
      KRT14-null carriers are unaffected.
- name: EBS AR KRT5
  display_name: EBS, generalized, intermediate or severe, autosomal recessive (KRT5)
  subtype_term:
    preferred_term: epidermolysis bullosa simplex, generalized, autosomal recessive (KRT5)
    term:
      id: MONDO:0030535
      label: epidermolysis bullosa simplex 2d, generalized, intermediate or severe, autosomal recessive
  description: >
    The KRT5 counterpart of the recessive KRT14-null row above. Biallelic
    KRT5 variants, both missense and null, cause EBS with a phenotypic range
    from localized and generalized blistering to death in the neonatal
    period. This route had not been reported before, on the hypothesis that
    biallelic KRT5 mutations would result in prenatal lethality.
  genes:
  - preferred_term: KRT5
    term:
      id: hgnc:6442
      label: KRT5
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31302245
    reference_title: "Biallelic KRT5 mutations in autosomal recessive epidermolysis bullosa simplex, including a complete human keratin 5 \"knock-out\"."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two pathogenic, homozygous missense variants of KRT5 in two patients with generalized EBS and a homozygous null mutation in a patient who died as a neonate from complications of EB were found."
    explanation: >-
      Establishes biallelic KRT5 as a cause of recessive EBS and gives the
      phenotypic range this row records, including the neonatal-death end.
  - reference: PMID:31302245
    reference_title: "Biallelic KRT5 mutations in autosomal recessive epidermolysis bullosa simplex, including a complete human keratin 5 \"knock-out\"."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "recessive EBS due to homozygous biallelic KRT5 mutations has not been reported previously; it has been hypothesized that it would result in prenatal lethality"
    explanation: >-
      Sources the description's statement that this route was expected to be
      prenatally lethal and had not been observed before this report.
- name: EBS Ogna
  display_name: EBS, Ogna type (EBS-Ogna)
  subtype_term:
    preferred_term: epidermolysis bullosa simplex, Ogna type
    term:
      id: MONDO:0007555
      label: epidermolysis bullosa simplex 5A, Ogna type
  description: >
    A dominant blistering form caused by a site-specific missense variant in
    the rod domain of plectin. It is the dominant counterpart of the
    recessive PLEC diseases: the same gene, but without the muscular
    dystrophy of the EBS-MD row, and with normal plectin staining on muscle
    biopsy. MONDO's definition of this subtype describes the blistering as
    sometimes widespread but primarily acral.
  genes:
  - preferred_term: PLEC
    term:
      id: hgnc:9069
      label: PLEC
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:11851880
    reference_title: "A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that the epidermolysis bullosa simplex Ogna phenotype is due to a site-specific missense mutation within plectin's rod domain."
    explanation: >-
      Establishes PLEC as the causal gene for the Ogna subtype and the
      site-specific rod-domain mechanism this row records.
  - reference: PMID:11851880
    reference_title: "A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with the absence of muscular symptoms in these patients, muscle biopsies from several epidermolysis bullosa simplex Ogna members of the Norwegian kindred showed normal staining patterns using antibodies to plectin."
    explanation: >-
      Supports separating this row from EBS with muscular dystrophy despite
      the shared gene: plectin staining in muscle is normal and there is no
      myopathy.
- name: EBS-MP
  display_name: EBS with mottled pigmentation (EBS-MP)
  subtype_term:
    preferred_term: epidermolysis bullosa simplex with mottled pigmentation
    term:
      id: MONDO:0007556
      label: epidermolysis bullosa simplex 2F, with mottled pigmentation
  description: >
    Generalized blistering accompanied by mottled or reticulate pigmentation
    of the trunk and extremities and punctate palmoplantar hyperkeratosis.
    Reported cases carry a recurrent P25L substitution in the non-helical V1
    head domain of keratin 5.
  genes:
  - preferred_term: KRT5
    term:
      id: hgnc:6442
      label: KRT5
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:17229601
    reference_title: "Epidermolysis bullosa simplex with mottled pigmentation due to de novo P25L mutation in keratin 5 in an Italian patient."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP) is an autosomal dominant inherited disorder of the skin, which manifests as recurrent blistering, punctate palmo-plantar hyperkeratoses, and mottled pigmentation of the trunk and extremities."
    explanation: >-
      Defines the clinical picture and the dominant inheritance recorded on
      this row.
  - reference: PMID:17229601
    reference_title: "Epidermolysis bullosa simplex with mottled pigmentation due to de novo P25L mutation in keratin 5 in an Italian patient."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Previous reports have identified the P25L mutation within the non-helical V1 domain of keratin 5 as the unique cause of the disease."
    explanation: >-
      Sources KRT5 as this row's gene and the V1 head-domain location of the
      recurrent substitution. Graded BACKGROUND because
      the sentence summarizes prior reports; this paper's own contribution is a
      further de novo case carrying the same substitution.
- name: EBS-MCE
  display_name: EBS with migratory circinate erythema (EBS-migr)
  subtype_term:
    preferred_term: epidermolysis bullosa simplex with migratory circinate erythema
    term:
      id: MONDO:0012258
      label: epidermolysis bullosa simplex 2E, with migratory circinate erythema
  description: >
    Belt-like annular areas of erythema carrying vesicles and small blisters
    at the advancing edge. Reported cases carry a KRT5 frameshift with a
    delayed termination codon, producing an elongated keratin 5 protein
    rather than the missense substitutions of the common subtypes, and
    electron microscopy shows reduced keratin filament numbers without the
    tonofilament clumping of the generalized severe form.
  genes:
  - preferred_term: KRT5
    term:
      id: hgnc:6442
      label: KRT5
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:12925204
    reference_title: A usual frameshift and delayed termination codon mutation in keratin 5 causes a novel type of epidermolysis bullosa simplex with migratory circinate erythema.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients showed migratory circinate erythema and multiple vesicles on the circular belt-like areas affected by erythema."
    explanation: Defines the clinical picture this row is named for.
  - reference: PMID:12925204
    reference_title: A usual frameshift and delayed termination codon mutation in keratin 5 causes a novel type of epidermolysis bullosa simplex with migratory circinate erythema.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a novel heterozygous deletion mutation (1649delG of KRT5) in both cases. This deletion is predicted to produce a mutant keratin 5 protein with a frameshift of its terminal 41 amino acids and 35 amino acids longer than the wild-type keratin 5 protein due to a delayed termination codon."
    explanation: >-
      Binds KRT5 to this row and sources the elongated-protein mechanism that
      separates it from the missense subtypes.
  - reference: PMID:12925204
    reference_title: A usual frameshift and delayed termination codon mutation in keratin 5 causes a novel type of epidermolysis bullosa simplex with migratory circinate erythema.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopy of skin biopsies showed a reduction in the number of keratin intermediate filaments in the basal cells without tonofilament clumping."
    explanation: >-
      Sources the ultrastructural finding recorded in this row's description.
      The absence of tonofilament clumping is what separates this subtype from
      the generalized severe row, where that clumping is the pathognomonic
      electron microscopy finding.
- name: EBS BP230
  display_name: EBS, localized or generalized intermediate, with BP230 deficiency (DST)
  subtype_term:
    preferred_term: epidermolysis bullosa simplex with BP230 deficiency
    term:
      id: MONDO:0014180
      label: epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency
  description: >
    A recessive form in which the hemidesmosomal inner plaque is lost because
    the epithelial isoform of bullous pemphigoid antigen 1 (BPAG1-e, BP230),
    encoded by DST, is absent. Blistering is lifelong, trauma-induced and
    spontaneous, and particularly affects the ankles.
  genes:
  - preferred_term: DST
    term:
      id: hgnc:1090
      label: DST
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20164846
    reference_title: A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We now report an inherited skin fragility disorder with a homozygous nonsense mutation in the dystonin gene (DST) that encodes the coiled-coil domain of the epithelial isoform of bullous pemphigoid antigen 1, BPAG1-e (also known as BP230)."
    explanation: >-
      Binds DST to this row and identifies the BP230 protein the MONDO term is
      named after.
  - reference: PMID:20164846
    reference_title: A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation, p.Gln1124X, leads to the loss of hemidesmosomal inner plaques and a complete absence of skin immunostaining for BPAG1-e, as well as reduced labeling for plectin, the beta4 integrin subunit, and for type XVII collagen."
    explanation: >-
      Sources the hemidesmosomal inner-plaque loss recorded in this row's
      description, and shows the defect also destabilizes plectin, the protein
      behind the EBS-MD and Ogna rows.
  - reference: PMID:20164846
    reference_title: A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 38-year-old affected individual has lifelong generalized trauma-induced spontaneous blisters and erosions, particularly around the ankles."
    explanation: >-
      Sources the clinical course recorded in this row's description. Note the
      report describes a single affected individual, so the ankle predilection
      is that individual's presentation rather than an established feature of
      the subtype.
- name: EBS EXPH5
  display_name: EBS, localized or generalized intermediate, autosomal recessive (EXPH5)
  subtype_term:
    preferred_term: epidermolysis bullosa simplex, autosomal recessive, due to exophilin-5 deficiency
    term:
      id: MONDO:0014014
      label: epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive
  description: >
    A recessive form caused by biallelic EXPH5 variants. Exophilin-5
    (Slac2-b) is a Rab27B effector in intracellular vesicle trafficking
    rather than a structural component of the keratin-hemidesmosome axis, so
    the route to skin fragility here runs through vesicle handling. Reported
    features are generalized trauma-induced scale-crusts with occasional
    blisters and mild mottled pigmentation.
  genes:
  - preferred_term: EXPH5
    term:
      id: hgnc:30578
      label: EXPH5
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23176819
    reference_title: Germline Mutation in EXPH5 Implicates the Rab27B Effector Protein Slac2-b in Inherited Skin Fragility.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "By using whole-exome sequencing, we identified a homozygous frameshift mutation in EXPH5 in three siblings with inherited skin fragility born to consanguineous Iraqi parents."
    explanation: >-
      Binds EXPH5 to this row and establishes biallelic, recessive
      transmission in a consanguineous pedigree.
  - reference: PMID:23176819
    reference_title: Germline Mutation in EXPH5 Implicates the Rab27B Effector Protein Slac2-b in Inherited Skin Fragility.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features comprised generalized scale-crusts and occasional blisters, mostly induced by trauma, as well as mild diffuse pigmentary mottling on the trunk and proximal limbs."
    explanation: Sources the clinical picture recorded in this row's description.
- name: EBS KLHL24
  display_name: EBS, generalized, with scarring and hair loss (KLHL24)
  subtype_term:
    preferred_term: epidermolysis bullosa simplex with scarring and hair loss
    term:
      id: MONDO:0015006
      label: epidermolysis bullosa simplex 6, generalized, with scarring and hair loss
  description: >
    A dominant form in which the causal gene is not a structural protein at
    all: KLHL24 is the substrate receptor of a cullin-3 ubiquitin ligase, and
    start-codon variants produce a truncated receptor that escapes
    autoubiquitination and drives excessive degradation of keratin 14. The
    result is keratin 14 loss without a keratin mutation. The allelic
    recessive KLHL24 cardiomyopathy is curated separately as
    KLHL24-Related_Hypertrophic_Cardiomyopathy.
  genes:
  - preferred_term: KLHL24
    term:
      id: hgnc:25947
      label: KLHL24
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:27798626
    reference_title: Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified start-codon mutations in the KLHL24 gene in five patients with EB."
    explanation: Binds KLHL24 to this row in five patients with epidermolysis bullosa.
  - reference: PMID:27798626
    reference_title: Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "We have further identified keratin 14 (KRT14) as a KLHL24 substrate and found that KLHL24-ΔN28 induces excessive ubiquitination and degradation of KRT14."
    explanation: >-
      Sources the mechanism recorded in this row's description: the truncated
      receptor degrades keratin 14, so keratin 14 is lost without a KRT14
      mutation.
- name: EBS-PD
  display_name: EBS due to plakophilin deficiency (ectodermal dysplasia-skin fragility syndrome)
  subtype_term:
    preferred_term: epidermolysis bullosa simplex due to plakophilin deficiency
    term:
      id: MONDO:0011472
      label: epidermolysis bullosa simplex due to plakophilin deficiency
  description: >
    A suprabasal subtype, also called ectodermal dysplasia-skin fragility
    syndrome, caused by biallelic loss-of-function variants in PKP1.
    Plakophilin 1 is a desmosomal plaque protein expressed mainly in the
    spinous layer, so the cleavage plane is above the basal keratinocytes
    rather than within them, and the picture is dominated by superficial
    erosions, palmoplantar keratoderma, nail involvement and
    alopecia/hypotrichosis rather than by blistering. MONDO files this
    concept under epidermolysis bullosa simplex through suprabasal
    epidermolysis bullosa simplex (MONDO:0015550); see this entry's notes for
    why it is carried here rather than as a separate entry.
  genes:
  - preferred_term: PKP1
    term:
      id: hgnc:9023
      label: PKP1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:19016709
    reference_title: Novel truncating mutations in PKP1 and DSP cause similar skin phenotypes in two Brazilian families.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patient 1 we identified a homozygous nonsense mutation, p.R672X, in the PKP1 gene (encoding plakophilin 1)."
    explanation: >-
      Binds PKP1 to this row in a patient with clinical features consistent
      with ectodermal dysplasia-skin fragility syndrome.
  - reference: PMID:32248567
    reference_title: "Ectodermal dysplasia-skin fragility syndrome: Two new cases and review of this desmosomal genodermatosis."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "One specific component of desmosomes is plakophilin 1 (PKP1), which is mainly expressed in the spinous layer of the epidermis. Loss-of-function autosomal recessive mutations in PKP1 result in ectodermal dysplasia-skin fragility (EDSF) syndrome"
    explanation: >-
      Sources both the suprabasal (spinous-layer) expression that places this
      row above the basal-cleavage subtypes and its recessive loss-of-function
      mechanism.
  - reference: PMID:32248567
    reference_title: "Ectodermal dysplasia-skin fragility syndrome: Two new cases and review of this desmosomal genodermatosis."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases)."
    explanation: >-
      Sources the clinical features recorded in this row's description, from
      the authors' review of all published biallelic PKP1 cases.
- name: LAEB
  display_name: Lethal acantholytic epidermolysis bullosa
  subtype_term:
    preferred_term: lethal acantholytic epidermolysis bullosa
    term:
      id: MONDO:0012323
      label: lethal acantholytic epidermolysis bullosa
  description: >
    The second suprabasal subtype, caused by biallelic DSP variants that
    truncate the desmoplakin tail and remove its intermediate
    filament-binding subdomains. Keratin filaments disconnect from
    desmosomes, producing acantholysis throughout the spinous layer and
    neonatal death from transcutaneous fluid loss, with universal alopecia,
    neonatal teeth and nail loss. Other biallelic DSP phenotypes are curated
    separately as Skin_Fragility_Woolly_Hair_Syndrome and Carvajal_Syndrome.
  genes:
  - preferred_term: DSP
    term:
      id: hgnc:3052
      label: DSP
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:16175511
    reference_title: Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutational analysis of the patient demonstrated compound heterozygosity for two DP mutations, 6079C-->T (R1934X) and 6370delTT, respectively."
    explanation: >-
      Binds DSP to this row and establishes biallelic transmission in the
      index patient.
  - reference: PMID:16175511
    reference_title: Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histology showed suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. Electron microscopy revealed disconnection of keratin intermediate filaments from desmosomes."
    explanation: >-
      Sources the suprabasal cleavage plane and the keratin-desmosome
      disconnection recorded in this row's description.
  - reference: PMID:16175511
    reference_title: Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The new phenotype is lethal in the neonatal period because of immense transcutaneous fluid loss. The phenotype also comprised universal alopecia, neonatal teeth, and nail loss."
    explanation: Sources the lethal neonatal course and associated features recorded here.
inheritance:
- name: Autosomal dominant
  description: >
    Most EBS subtypes (localized, intermediate, severe/Dowling-Meara) are
    inherited in an autosomal dominant manner due to dominant-negative
    keratin mutations in KRT5 or KRT14.
  evidence:
  - reference: PMID:20301543
    reference_title: "Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of EBS is established in a proband by: the identification of a heterozygous dominant-negative variant or biallelic loss-of-function variants in KRT5, KRT14, or PLEC"
    explanation: GeneReviews confirms dominant-negative variants in KRT5/KRT14 as a major cause of EBS.
  - reference: PMID:16098032
    reference_title: "Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "18 were found to harbor heterozygous mutations in the keratin 5 or keratin 14 genes, KRT5 and KRT14, respectively"
    explanation: Confirms heterozygous (dominant) keratin mutations as a cause of EBS.
- name: Autosomal recessive
  description: >
    EBS with muscular dystrophy (PLEC mutations) and EBS autosomal recessive
    (KRT14 null) are inherited in an autosomal recessive manner.
  evidence:
  - reference: PMID:34572129
    reference_title: "Muscle-Related Plectinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common disorder is autosomal recessive disease epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), which is characterized by skin blistering and progressive muscle weakness"
    explanation: Confirms autosomal recessive inheritance of EBS-MD caused by PLEC mutations.
  - reference: PMID:25530118
    reference_title: "Plectin-related skin diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plectin deficiency causes autosomal recessive epidermolysis bullosa simplex (EBS) with involvement of the skin and other organs"
    explanation: Confirms autosomal recessive inheritance pattern for plectin-related EBS.
prevalence:
- population: Global
  notes: >-
    EBS is the most common type of epidermolysis bullosa, accounting for
    approximately 70% of all EB cases. Estimated prevalence is 1 in 30,000
    to 50,000. US National EB Registry data (1986-2002) reported an overall
    EB incidence of 19.57 per million live births, with EBS prevalence
    increasing by 30.4% over the 16-year study period as ascertainment
    improved.
  evidence:
  - reference: PMID:27463098
    reference_title: "Epidemiology of Inherited Epidermolysis Bullosa Based on Incidence and Prevalence Estimates From the National Epidermolysis Bullosa Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the overall incidence and prevalence of inherited EB were 19.60 and 8.22 per 1 million live births, respectively"
    explanation: US National EB Registry provides incidence and prevalence estimates for inherited EB including EBS as the most common subtype.
  - 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: Nature Reviews Disease Primers confirms EB as a group of rare genetic skin fragility disorders with EBS being the most common major type.
pathophysiology:
- name: KRT5/KRT14 Mutations Disrupt Keratin Intermediate Filament Network
  conforms_to: "keratin_intermediate_filament_fragility#Dominant-Negative Keratin Variant in a Filament Assembly Domain"
  description: >
    Mutations in KRT5 or KRT14 genes disrupt the keratin intermediate filament
    network in basal keratinocytes of the epidermis. Keratins 5 and 14 are
    the obligate type II and type I intermediate filament partners that
    copolymerize to form the 10 nm filament network providing mechanical
    resilience to basal keratinocytes.
  genes:
  - preferred_term: KRT5
    term:
      id: hgnc:6442
      label: KRT5
  - preferred_term: KRT14
    term:
      id: hgnc:6416
      label: KRT14
  biological_processes:
  - preferred_term: intermediate filament organization
    modifier: ABNORMAL
    term:
      id: GO:0045109
      label: intermediate filament organization
  cell_types:
  - preferred_term: epidermal cell
    term:
      id: CL:0000362
      label: epidermal cell
  downstream:
  - target: Dominant-Negative Disruption of Filament Assembly
    description: >
      Mutant keratins poison the filament network by incorporating into
      filaments and destabilizing them.
  evidence:
  - reference: PMID:22277943
    reference_title: "Defining keratin protein function in skin epithelia: epidermolysis bullosa simplex and its aftermath."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most cases of EBS are due to dominantly acting mutations in keratin 14 (K14) or K5, the type I and II intermediate filament (IF) proteins that copolymerize to form a pancytoplasmic network of 10 nm filaments in basal keratinocytes of epidermis and related epithelia"
    explanation: Confirms K5/K14 as the obligate IF pair in basal keratinocytes and dominant mutations as the cause of EBS.
  - reference: PMID:30078200
    reference_title: "Keratins and epidermolysis bullosa simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most important and most commonly occurring molecular defects in these patients are the defects of keratins 5 and14 (KRT5 and KRT14)"
    explanation: Confirms KRT5 and KRT14 defects as the primary molecular basis of EBS.
- name: Dominant-Negative Disruption of Filament Assembly
  conforms_to: "keratin_intermediate_filament_fragility#Keratin Filament Network Collapse and Aggregation"
  description: >
    Mutant keratins exert a dominant-negative effect by incorporating into
    keratin filaments and poisoning the entire filament network. This
    disrupts filament architecture and leads to keratin aggregate formation,
    particularly under conditions of mechanical or thermal stress.
  biological_processes:
  - preferred_term: intermediate filament cytoskeleton organization
    modifier: ABNORMAL
    term:
      id: GO:0045104
      label: intermediate filament cytoskeleton organization
  cell_types:
  - preferred_term: epidermal cell
    term:
      id: CL:0000362
      label: epidermal cell
  downstream:
  - target: Mechanical Stress-Induced Keratinocyte Cytolysis
    description: >
      Disrupted keratin network renders basal keratinocytes fragile and
      prone to rupture under mechanical stress.
  evidence:
  - reference: PMID:22277943
    reference_title: "Defining keratin protein function in skin epithelia: epidermolysis bullosa simplex and its aftermath."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defects in K5-K14 filament network architecture cause basal keratinocytes to become fragile, and account for their rupture upon exposure to mechanical trauma"
    explanation: Confirms that disrupted keratin filament architecture causes basal keratinocyte fragility and rupture.
  - reference: PMID:34830328
    reference_title: "Keratins as an Inflammation Trigger Point in Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Keratin aggregates display impaired dynamics of assembly and diminished solubility and appear to be the trigger for endoplasmic reticulum (ER) stress upon being phosphorylated by MAPKs"
    explanation: Confirms that mutant keratins form aggregates with impaired dynamics, triggering downstream ER stress signaling.
- name: Mechanical Stress-Induced Keratinocyte Cytolysis
  conforms_to: "keratin_intermediate_filament_fragility#Keratinocyte Cytolysis Within the Keratin Expression Domain"
  description: >
    Basal keratinocytes with disrupted keratin networks rupture (cytolyse)
    when subjected to mechanical trauma. The blistering in EBS is
    intraepidermal, occurring within the basal cell layer rather than at
    tissue interfaces, distinguishing it from junctional and dystrophic EB.
  biological_processes:
  - preferred_term: cell death
    modifier: INCREASED
    term:
      id: GO:0008219
      label: cell death
  cell_types:
  - preferred_term: epidermal cell
    term:
      id: CL:0000362
      label: epidermal cell
  downstream:
  - target: Skin Blistering
    description: >
      Cytolysis of the basal keratinocyte is what produces the clinical
      blister, and is why the cleavage plane is intraepidermal rather than at
      the dermal-epidermal junction. Every mechanistic route in this entry
      except the suprabasal desmosomal one reaches the clinical phenotype
      through this node.
  evidence:
  - reference: PMID:16098032
    reference_title: "Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolysis bullosa simplex (EBS) is a mechano-bullous disorder characterized by intraepidermal blistering within the basal keratinocytes as a result of trauma to the skin"
    explanation: Confirms intraepidermal blistering within basal keratinocytes as the hallmark of EBS.
  - reference: PMID:34830328
    reference_title: "Keratins as an Inflammation Trigger Point in Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Epidermolysis bullosa simplex (EBS) is a group of inherited keratinopathies that, in most cases, arise due to mutations in keratins and lead to intraepidermal ruptures"
    explanation: Confirms that keratin mutations lead to intraepidermal rupture.
- name: PLEC Mutations Disrupt Hemidesmosome-Cytoskeleton Linkage
  conforms_to: "dermal_epidermal_junction_adhesion_failure#Basement Membrane Zone Attachment Component Defect"
  description: >
    Mutations in PLEC disrupt plectin, a giant cytoskeletal crosslinker that
    connects the keratin intermediate filament network to hemidesmosomes at
    the dermal-epidermal junction and to the desmin cytoskeleton in muscle.
    Loss of plectin causes a dual phenotype affecting both skin (blistering)
    and skeletal muscle (progressive dystrophy).
  genes:
  - preferred_term: PLEC
    term:
      id: hgnc:9069
      label: PLEC
  biological_processes:
  - preferred_term: cell-substrate junction organization
    modifier: ABNORMAL
    term:
      id: GO:0150115
      label: cell-substrate junction organization
  cell_types:
  - preferred_term: epidermal cell
    term:
      id: CL:0000362
      label: epidermal cell
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  downstream:
  - target: Mechanical Stress-Induced Keratinocyte Cytolysis
    description: >
      Disrupted hemidesmosome-cytoskeleton linkage leads to skin fragility.
  - target: Muscular Dystrophy
    description: >
      The same plectin loss disrupts the desmin cytoskeleton of skeletal
      muscle, which is the extracutaneous half of the EBS-MD phenotype and is
      why that subtype row is the only one in this entry carrying a myopathy.
  evidence:
  - reference: PMID:34572129
    reference_title: "Muscle-Related Plectinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plectin is a giant cytoskeletal crosslinker and intermediate filament stabilizing protein. Mutations in the human plectin gene (PLEC) cause several rare diseases that are grouped under the term plectinopathies"
    explanation: Confirms plectin as a cytoskeletal crosslinker whose mutations cause plectinopathies including EBS-MD.
  - reference: PMID:25530118
    reference_title: "Plectin-related skin diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plectin deficiency causes autosomal recessive epidermolysis bullosa simplex (EBS) with involvement of the skin and other organs, such as muscle and gastrointestinal tract, depending on the expression pattern of the defective protein"
    explanation: Confirms plectin deficiency causes EBS with multi-organ involvement including skin and muscle.
- name: Heat Sensitivity of Mutant Keratin Networks
  description: >
    Mutant keratin filament networks are thermally unstable. Elevated
    temperature causes filament breakdown into aggregates, explaining the
    clinical observation that blistering worsens in warm weather and with
    increased perspiration. This is particularly prominent in localized EBS.
  biological_processes:
  - preferred_term: response to heat
    modifier: ABNORMAL
    term:
      id: GO:0009408
      label: response to heat
  downstream:
  - target: Heat-Exacerbated Blistering
    description: >
      Thermal breakdown of the mutant filament network is the mechanism behind
      the seasonal and exertional worsening recorded as a phenotype.
  evidence:
  - reference: PMID:8586658
    reference_title: "Temperature sensitivity of the keratin cytoskeleton and delayed spreading of keratinocyte lines derived from EBS patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "after thermal stress a reduced stability of the keratin filaments was demonstrable in the epidermolysis bullosa simplex cell lines, with filaments breaking into aggregates"
    explanation: Demonstrates that thermal stress causes keratin filament breakdown into aggregates in EBS cell lines, explaining heat-exacerbated blistering.
- name: BPAG1-e Deficiency Disrupts the Hemidesmosomal Inner Plaque
  conforms_to: "dermal_epidermal_junction_adhesion_failure#Basement Membrane Zone Attachment Component Defect"
  biological_scale: MOLECULAR
  description: >
    Biallelic DST nonsense variants abolish the epithelial isoform of bullous
    pemphigoid antigen 1 (BPAG1-e, BP230), the hemidesmosomal inner-plaque
    protein that anchors keratin intermediate filaments at the basal pole of
    the keratinocyte. Inner plaques are lost and labelling for plectin, the
    beta-4 integrin subunit and type XVII collagen is reduced, so the defect
    destabilizes the wider hemidesmosome rather than one component alone.
    This is the node the EBS BP230 subtype row acts at.
  genes:
  - preferred_term: DST
    term:
      id: hgnc:1090
      label: DST
  biological_processes:
  - preferred_term: hemidesmosome assembly
    modifier: ABNORMAL
    term:
      id: GO:0031581
      label: hemidesmosome assembly
  cell_types:
  - preferred_term: basal keratinocyte
    term:
      id: CL:0002187
      label: basal cell of epidermis
  downstream:
  - target: Mechanical Stress-Induced Keratinocyte Cytolysis
    description: >
      Loss of the hemidesmosomal inner plaque leaves basal keratinocytes
      unable to resist shear, producing the same trauma-induced intraepidermal
      separation as the keratin and plectin routes.
  evidence:
  - reference: PMID:20164846
    reference_title: A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation, p.Gln1124X, leads to the loss of hemidesmosomal inner plaques and a complete absence of skin immunostaining for BPAG1-e, as well as reduced labeling for plectin, the beta4 integrin subunit, and for type XVII collagen."
    explanation: >-
      Direct observation in patient skin of the inner-plaque loss and wider
      hemidesmosomal destabilization this node asserts.
  - reference: PMID:20164846
    reference_title: A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 38-year-old affected individual has lifelong generalized trauma-induced spontaneous blisters and erosions, particularly around the ankles."
    explanation: >-
      Supports the downstream edge to keratinocyte cytolysis: the same
      individual has lifelong trauma-induced blistering.
- name: Exophilin-5 Deficiency Impairs Keratinocyte Vesicle Trafficking and Adhesion
  biological_scale: CELLULAR
  description: >
    Biallelic EXPH5 truncating variants remove the C-terminus of exophilin-5
    (Slac2-b), a Rab27B effector in intracellular vesicle trafficking. The
    product is not a structural component of the keratin-hemidesmosome
    apparatus, as the keratin, plectin and BPAG1-e routes' products are; the
    route to fragility runs instead through disordered vesicle handling, with
    perinuclear and plasma-membrane-proximal vesicle accumulation, keratin
    filament disruption and reduced keratinocyte adhesion in the lower
    epidermis.
    This is the node the EBS EXPH5 subtype row acts at.
  genes:
  - preferred_term: EXPH5
    term:
      id: hgnc:30578
      label: EXPH5
  biological_processes:
  - preferred_term: vesicle-mediated transport
    modifier: ABNORMAL
    term:
      id: GO:0016192
      label: vesicle-mediated transport
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: Mechanical Stress-Induced Keratinocyte Cytolysis
    description: >
      Reduced keratinocyte adhesion and keratin filament disruption in the
      lower epidermis converge on the same trauma-induced intraepidermal
      separation as the structural routes.
  evidence:
  - reference: PMID:23176819
    reference_title: Germline Mutation in EXPH5 Implicates the Rab27B Effector Protein Slac2-b in Inherited Skin Fragility.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of an affected person's skin showed loss of Slac2-b immunostaining (C-terminal antibody), disruption of keratinocyte adhesion within the lower epidermis, and an increased number of perinuclear vesicles."
    explanation: >-
      Direct observation in patient skin of the vesicle accumulation and
      adhesion loss this node asserts.
  - reference: PMID:23176819
    reference_title: Germline Mutation in EXPH5 Implicates the Rab27B Effector Protein Slac2-b in Inherited Skin Fragility.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "A role for Slac2-b in keratinocyte biology was supported by findings of cytoskeletal disruption (mainly keratin intermediate filaments) and decreased keratinocyte adhesion in both keratinocytes from an affected subject and after shRNA knockdown of Slac2-b in normal keratinocytes."
    explanation: >-
      Cultured-keratinocyte and knockdown evidence that the adhesion and
      keratin-filament defect follows from loss of Slac2-b specifically.
- name: KLHL24 Gain-of-Function Drives Ubiquitin-Mediated Keratin 14 Degradation
  biological_scale: MOLECULAR
  description: >
    Heterozygous start-codon variants in KLHL24 produce a receptor lacking its
    first 28 residues, which can no longer autoubiquitinate and therefore
    accumulates. Keratin 14 is a substrate of this receptor, so the
    stabilized form drives excessive ubiquitination and degradation of
    keratin 14. The basal keratin network is
    depleted without any mutation in a keratin gene, which is why this node is
    drawn separately from the dominant-negative route. This is the node the
    EBS KLHL24 subtype row acts at.
  genes:
  - preferred_term: KLHL24
    term:
      id: hgnc:25947
      label: KLHL24
  biological_processes:
  - preferred_term: ubiquitination of keratin 14
    modifier: INCREASED
    term:
      id: GO:0016567
      label: protein ubiquitination
  cell_types:
  - preferred_term: basal keratinocyte
    term:
      id: CL:0002187
      label: basal cell of epidermis
  downstream:
  - target: Mechanical Stress-Induced Keratinocyte Cytolysis
    description: >
      Depletion of keratin 14 protein leaves the basal keratin network unable
      to bear mechanical load, reaching the same cytolysis node as the
      dominant-negative keratin variants.
  evidence:
  - reference: PMID:27798626
    reference_title: Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "We have further identified keratin 14 (KRT14) as a KLHL24 substrate and found that KLHL24-ΔN28 induces excessive ubiquitination and degradation of KRT14."
    explanation: >-
      Establishes the substrate relationship and the direction of the effect
      this node asserts.
  - reference: PMID:27798626
    reference_title: Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Using a knock-in mouse model, we have confirmed that the Klhl24 mutations lead to stabilized Klhl24-ΔN28 and cause Krt14 degradation."
    explanation: >-
      In vivo confirmation in a knock-in mouse that the stabilized receptor is
      what degrades keratin 14.
- name: Desmosomal Plaque Deficiency Causes Suprabasal Acantholysis
  biological_scale: CELLULAR
  description: >
    The two suprabasal routes in this entry. Loss of plakophilin 1, a
    desmosomal plaque protein expressed mainly in the spinous layer, or
    truncation of the desmoplakin tail that carries desmoplakin's
    intermediate filament-binding subdomains, detaches keratin filaments from
    desmosomes above the basal layer. The cleavage plane is therefore
    suprabasal rather than intrabasal, and the histology is acantholysis
    resembling pemphigus rather than basal-cell cytolysis. This node is drawn
    separately from the basal routes for that reason, and is where the EBS-PD
    and LAEB subtype rows act.
  genes:
  - preferred_term: PKP1
    term:
      id: hgnc:9023
      label: PKP1
  - preferred_term: DSP
    term:
      id: hgnc:3052
      label: DSP
  biological_processes:
  - preferred_term: desmosome organization
    modifier: ABNORMAL
    term:
      id: GO:0002934
      label: desmosome organization
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: Skin Blistering
    description: >
      Suprabasal acantholysis produces superficial erosions and blistering,
      the shared clinical endpoint with the basal routes even though the
      cleavage plane differs.
  - target: Palmoplantar Keratoderma
    description: >
      Palmoplantar keratoderma is a cardinal feature of the plakophilin route
      rather than an incidental one, reported in 16 of 18 published biallelic
      PKP1 cases, so the desmosomal defect reaches this phenotype directly and
      not only through blistering.
  - target: Nail Dystrophy
    description: >
      Nail involvement is present in every published biallelic PKP1 case,
      making it one of the two constant features of the plakophilin route
      alongside skin fragility.
  evidence:
  - reference: PMID:16175511
    reference_title: Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histology showed suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. Electron microscopy revealed disconnection of keratin intermediate filaments from desmosomes."
    explanation: >-
      Direct observation of the suprabasal cleavage plane and the
      keratin-desmosome disconnection this node asserts, in the desmoplakin
      route.
  - reference: PMID:32248567
    reference_title: "Ectodermal dysplasia-skin fragility syndrome: Two new cases and review of this desmosomal genodermatosis."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "One specific component of desmosomes is plakophilin 1 (PKP1), which is mainly expressed in the spinous layer of the epidermis. Loss-of-function autosomal recessive mutations in PKP1 result in ectodermal dysplasia-skin fragility (EDSF) syndrome"
    explanation: >-
      Sources the plakophilin route and the spinous-layer expression that puts
      this node's cleavage plane above the basal keratinocytes.
  - reference: PMID:32248567
    reference_title: "Ectodermal dysplasia-skin fragility syndrome: Two new cases and review of this desmosomal genodermatosis."
    supports: SUPPORT
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases)."
    explanation: >-
      The frequencies behind this node's edges to palmoplantar keratoderma and
      nail dystrophy, from the authors' review of all published biallelic PKP1
      cases.
phenotypes:
- category: Integument
  name: Skin Blistering
  description: >
    Intraepidermal blistering caused by basal keratinocyte fragility.
    Blisters arise at sites of mechanical trauma and generally heal without
    significant scarring, distinguishing EBS from dystrophic EB.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: skin blistering
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: PMID:20301543
    reference_title: "Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some instances) that results in non-scarring blisters and erosions caused by minor mechanical trauma"
    explanation: GeneReviews confirms non-scarring blisters from minor mechanical trauma as the hallmark of EBS.
  - 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: Nature Reviews Disease Primers confirms blister formation from minimal trauma as the defining feature of EB.
- category: Integument
  name: Heat-Exacerbated Blistering
  description: >
    Worsening of blistering during warm weather or with increased physical
    activity and perspiration. Caused by thermal instability of mutant
    keratin filament networks. Particularly prominent in localized EBS
    affecting hands and feet.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: heat-exacerbated blistering
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: PMID:8586658
    reference_title: "Temperature sensitivity of the keratin cytoskeleton and delayed spreading of keratinocyte lines derived from EBS patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "after thermal stress a reduced stability of the keratin filaments was demonstrable in the epidermolysis bullosa simplex cell lines, with filaments breaking into aggregates"
    explanation: Demonstrates thermal instability of mutant keratin filaments, providing the molecular basis for heat-exacerbated blistering.
- category: Integument
  name: Palmoplantar Keratoderma
  description: >
    Thickening of the skin on palms and soles, particularly prominent in
    EBS severe (Dowling-Meara) subtype. May develop progressively with age.
  frequency: FREQUENT
  notes: Primarily seen in EBS severe (Dowling-Meara)
  phenotype_term:
    preferred_term: palmoplantar keratoderma
    term:
      id: HP:0000982
      label: Palmoplantar keratoderma
  evidence:
  - reference: PMID:20301543
    reference_title: "Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features can include hyperkeratosis of the palms and soles (keratoderma), nail dystrophy, milia, and hyper- and/or hypopigmentation"
    explanation: GeneReviews confirms palmoplantar keratoderma as an additional feature of EBS.
- category: Integument
  name: Herpetiform Blistering Pattern
  description: >
    Grouped (herpetiform) blistering pattern characteristic of EBS severe
    (Dowling-Meara). Blisters cluster in a pattern resembling herpes simplex
    lesions. Associated with keratin filament clumping visible on electron
    microscopy.
  frequency: FREQUENT
  notes: Characteristic of EBS severe (Dowling-Meara) subtype
  phenotype_term:
    preferred_term: grouped herpetiform blistering
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: PMID:34830328
    reference_title: "Keratins as an Inflammation Trigger Point in Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutations in keratins 5/14 or in other genes that encode associated proteins induce structural disarrangements of different strengths depending on their locations in the genes"
    explanation: Confirms that mutation location determines severity of structural disarrangement, explaining the severe herpetiform phenotype in Dowling-Meara EBS.
- category: Integument
  name: Nail Dystrophy
  description: >
    Abnormal nail growth and morphology including thickened, dystrophic, or
    absent nails. Present in severe EBS subtypes and EBS with muscular
    dystrophy.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:34572129
    reference_title: "Muscle-Related Plectinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLEC mutations lead to EBS with nail dystrophy"
    explanation: Confirms nail dystrophy as a recognized feature of PLEC-associated EBS.
- category: Integument
  name: Milia
  description: >
    Small white cysts (milia) that may occur at sites of healed blisters.
    Less prominent in EBS than in dystrophic EB forms.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: milia
    term:
      id: HP:0001056
      label: Milia
  evidence:
  - reference: PMID:20301543
    reference_title: "Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features can include hyperkeratosis of the palms and soles (keratoderma), nail dystrophy, milia, and hyper- and/or hypopigmentation"
    explanation: GeneReviews lists milia as an additional feature of EBS.
- category: Musculoskeletal
  name: Muscular Dystrophy
  description: >
    Progressive muscular dystrophy in EBS with muscular dystrophy (EBS-MD)
    caused by PLEC mutations. Plectin is essential for muscle cytoskeletal
    integrity. Skeletal muscle biopsies show dystrophic features with
    variation in fiber size, degenerative myofibrillar changes, and
    pathological desmin-positive protein aggregates.
  frequency: OBLIGATE
  notes: Specific to EBS with muscular dystrophy (PLEC mutations)
  phenotype_term:
    preferred_term: progressive muscular dystrophy
    term:
      id: HP:0003560
      label: Muscular dystrophy
  evidence:
  - reference: PMID:34572129
    reference_title: "Muscle-Related Plectinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common disorder is autosomal recessive disease epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), which is characterized by skin blistering and progressive muscle weakness"
    explanation: Confirms progressive muscle weakness as a defining feature of EBS-MD.
  - reference: PMID:34572129
    reference_title: "Muscle-Related Plectinopathies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Skeletal muscle biopsies from EBS-MD patients and plectin-deficient mice revealed severe dystrophic features with variation in fiber size, degenerative myofibrillar changes, mitochondrial alterations, and pathological desmin-positive protein aggregates"
    explanation: Confirms dystrophic muscle pathology in both human EBS-MD patients and plectin-deficient mouse models.
treatments:
- name: Wound Care
  description: >
    Supportive wound care is the mainstay of EBS management. Includes use
    of non-adherent dressings to protect fragile skin and promote healing
    of blistered areas. Blister lancing with sterile technique to prevent
    blister extension.
  treatment_term:
    preferred_term: wound care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301543
    reference_title: "Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Supportive care to protect the skin from blistering; use of dressings that will protect the skin and promote healing of wounds"
    explanation: GeneReviews confirms supportive wound care as the primary management strategy for EBS.
- name: Avoidance of Heat and Friction
  description: >
    Minimizing exposure to heat, excessive physical activity, and friction
    to prevent blistering episodes. Includes wearing loose-fitting clothing,
    soft footwear, and avoiding high ambient temperatures.
  treatment_term:
    preferred_term: avoidance of triggers
    term:
      id: NCIT:C15747
      label: Supportive Care
  notes: Particularly important for localized EBS where heat is a major trigger.
  evidence:
  - reference: PMID:20301543
    reference_title: "Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Excessive heat exposure may exacerbate blistering and infection. Avoid poorly fitting or coarse-textured clothing/footwear and activities that traumatize the skin"
    explanation: GeneReviews lists heat exposure and skin trauma as agents to avoid in EBS management.
- name: Antiperspirants for Palmoplantar Disease
  description: >
    Topical antiperspirant application to palms and soles to reduce
    perspiration-induced blistering, especially in localized EBS.
  treatment_term:
    preferred_term: topical antiperspirant therapy
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301543
    reference_title: "Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aluminum chloride (20%) applied to palms and soles can reduce sweating and therefore minimize blister formation in some individuals with EBS"
    explanation: GeneReviews confirms aluminum chloride antiperspirant as a treatment to reduce sweating-induced blistering.
- name: Pain Management
  description: >
    Analgesic therapy for pain associated with blistering and erosions.
    May include topical and systemic pain medications depending on severity.
  treatment_term:
    preferred_term: pain management
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301543
    reference_title: "Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification and management of specific causes of pain and itching; management with a pain specialist as needed"
    explanation: GeneReviews confirms pain and itch management as part of EBS care.
- name: Physical Therapy
  description: >
    Rehabilitation and physical therapy for patients with EBS-MD to maintain
    mobility and muscle function as muscular dystrophy progresses.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301543
    reference_title: "Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "appropriate footwear and physical therapy to preserve ambulation"
    explanation: GeneReviews confirms physical therapy to preserve ambulation as part of EBS management.
- name: Genetic Counseling
  description: >
    Genetic counseling for affected families regarding inheritance patterns,
    recurrence risk, and prenatal diagnosis options. Important given both
    dominant and recessive forms and significant de novo mutation rate.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:16098032
    reference_title: "Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings have implications for genetic counseling and prenatal diagnosis for EBS"
    explanation: Confirms the importance of genetic counseling for EBS families, particularly given de novo mutations and mixed inheritance patterns.
- name: Diacerein (Anti-IL-1beta Therapy)
  description: >
    Topical diacerein 1% ointment, an anti-inflammatory agent that inhibits
    IL-1beta signaling. A phase 2/3 crossover trial (n=17) showed 86% of
    diacerein-treated patients achieved >40% blister reduction versus 14%
    with placebo. However, a larger randomized controlled trial (n=54)
    found no significant difference in the primary endpoint (>=60% BSA
    reduction at 8 weeks), though post hoc analysis in severe EBS showed
    a potential signal (46.2% vs 15.4% achieving optimal skin scores).
    Multiple ongoing trials continue to evaluate diacerein in EBS.
  treatment_term:
    preferred_term: diacerein anti-IL-1beta therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Diacerein
      term:
        id: NCIT:C166759
        label: Diacerein
  evidence:
  - reference: PMID:29410318
    reference_title: "Diacerein orphan drug development for epidermolysis bullosa simplex: A phase 2/3 randomized, placebo-controlled, double-blind clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the patients receiving diacerein, 86% in episode 1 and 37.5% in episode 2 met the primary end point (vs 14% and 17% with placebo, respectively). This effect was still significant after the follow-up"
    explanation: Phase 2/3 crossover trial demonstrating diacerein efficacy in reducing EBS blisters compared to placebo.
  - reference: PMID:37276163
    reference_title: "Diacerein 1% Ointment for the Treatment of Epidermolysis Bullosa Simplex: A Randomized, Controlled Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although there was no significant difference in outcomes between the groups, further study may elucidate the effects of diacerein on EBS lesions, especially in patients with severe EBS"
    explanation: Larger RCT (n=54) did not meet primary endpoint overall, though post hoc analysis suggested benefit in severe EBS subgroup.
- name: Sulforaphane (Nrf2 Activator, Preclinical)
  description: >
    Sulforaphane, a natural product from cruciferous vegetables, activates
    the Nrf2 transcription factor to induce compensatory keratins K16/K17
    in basal keratinocytes. In an EBS mouse model with K14 deficiency,
    sulforaphane treatment alleviated blistering by upregulating K17
    expression. This represents an attractive preclinical approach
    exploiting functional redundancy within the keratin gene family.
  notes: Preclinical stage only; not yet tested in human clinical trials for EBS.
  treatment_term:
    preferred_term: sulforaphane Nrf2 activator therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sulforaphane
      term:
        id: CHEBI:47807
        label: sulforaphane
  evidence:
  - reference: PMID:17724334
    reference_title: "Reprogramming of keratin biosynthesis by sulforaphane restores skin integrity in epidermolysis bullosa simplex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "treatment with a pharmacological activator of Nrf2, two transcription factors eliciting distinct transcriptional programs, alleviates the blistering caused by a K14 deficiency in an EBS mouse model, correlating with K17 induction in basal epidermal keratinocytes. Nrf2 induction is brought about by treatment with sulforaphane, a natural product"
    explanation: Mouse model demonstrates sulforaphane activates Nrf2 to induce compensatory K17 expression in basal keratinocytes, alleviating blistering in K14-deficient EBS.
clinical_trials:
- name: NCT06073132
  phase: PHASE_II
  status: RECRUITING
  description: >-
    Ongoing international phase 2/3 EBShield study evaluating topical
    diacerein 1% ointment in generalized epidermolysis bullosa simplex.
  target_phenotypes:
  - preferred_term: skin blistering
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: clinicaltrials:NCT06073132
    reference_title: "An International, Multicenter, Randomized, Double-Blind, Parallel Group, Vehicle-Controlled, Phase 2/3 Study With Open-Label Extension Evaluating the Efficacy and Safety of Diacerein 1% Ointment for the Treatment of Generalized Epidermolysis Bullosa Simplex (EBS) [EBShield Study]"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proposed Phase 2/3 trial with double-blind and open-label extension phases is an international, multicenter study designed to assess the efficacy and safety of diacerein 1% ointment in patients with generalized EBS."
    explanation: This ClinicalTrials.gov record supports an actively recruiting diacerein trial focused specifically on generalized EBS.
  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.
- name: NCT03154333
  phase: PHASE_II
  status: TERMINATED
  description: >-
    Terminated randomized phase II study of topical diacerein 1% ointment
    versus vehicle in epidermolysis bullosa simplex.
  target_phenotypes:
  - preferred_term: skin blistering
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: clinicaltrials:NCT03154333
    reference_title: "An International, Multicenter, Randomized, Double-Blind, Parallel-Group Phase 2 Study Evaluating the Safety and Efficacy of Diacerein 1% Ointment Topical Formulation in Subjects With Epidermolysis Bullosa Simplex"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epidermolysis bullosa simplex (EBS) is a rare genetic skin disease characterized by fragility of the skin and mucous membranes resulting in painful blisters and erosions after minor trauma. The purpose of this study is to compare the efficacy of diacerein 1% ointment to vehicle ointment when applied once-daily for 8 weeks in subjects with EBS."
    explanation: This ClinicalTrials.gov record supports a disease-specific randomized EBS trial of topical diacerein.
  notes: >-
    ClinicalTrials.gov currently lists this study as terminated for futility.
genetic:
- name: KRT5
  gene_term:
    preferred_term: KRT5
    term:
      id: hgnc:6442
      label: KRT5
  association: Causative
  inheritance:
  - name: Autosomal dominant
    evidence:
    - reference: PMID:20301543
      reference_title: "Epidermolysis Bullosa Simplex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal dominant EBS is associated with either a heterozygous dominant-negative variant in KRT5, KRT14, or PLEC"
      explanation: GeneReviews confirms autosomal dominant inheritance for KRT5 via dominant-negative variants.
  notes: >
    Keratin 5 gene on chromosome 12q13.13. Encodes the type II keratin that
    pairs with keratin 14 in basal keratinocytes. Dominant-negative
    missense mutations, particularly in the helix boundary motifs, cause
    EBS. Hotspot mutations in the 1A and 2B rod domain helix boundaries
    correlate with more severe phenotypes. No `subtype` foreign key is set on
    this record: KRT5 is the causal gene of six of this entry's subtype rows
    (localized, generalized intermediate, generalized severe, the recessive
    KRT5 row, mottled pigmentation, and migratory circinate erythema) and the
    slot holds one value. The gene-to-row mapping is carried on the rows
    themselves, each of which binds KRT5 in its `genes` list.
  evidence:
  - reference: PMID:16098032
    reference_title: "Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "18 were found to harbor heterozygous mutations in the keratin 5 or keratin 14 genes, KRT5 and KRT14, respectively"
    explanation: Confirms heterozygous KRT5 mutations as a cause of EBS.
  - reference: PMID:30078200
    reference_title: "Keratins and epidermolysis bullosa simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most important and most commonly occurring molecular defects in these patients are the defects of keratins 5 and14 (KRT5 and KRT14)"
    explanation: Confirms KRT5 as one of the two principal genes mutated in EBS.
- name: KRT14
  gene_term:
    preferred_term: KRT14
    term:
      id: hgnc:6416
      label: KRT14
  association: Causative
  inheritance:
  - name: Autosomal dominant
    evidence:
    - reference: PMID:20301543
      reference_title: "Epidermolysis Bullosa Simplex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal dominant EBS is associated with either a heterozygous dominant-negative variant in KRT5, KRT14, or PLEC"
      explanation: GeneReviews confirms autosomal dominant inheritance for KRT14.
  - name: Autosomal recessive
    evidence:
    - reference: PMID:20301543
      reference_title: "Epidermolysis Bullosa Simplex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal recessive EBS is associated with either biallelic loss-of-function variants in KRT5, KRT14, or PLEC"
      explanation: GeneReviews confirms autosomal recessive inheritance for biallelic KRT14 loss-of-function variants.
  notes: >
    Keratin 14 gene on chromosome 17q21.2. Encodes the type I keratin
    partner of keratin 5 in basal keratinocytes. Dominant-negative missense
    mutations cause EBS localized through severe. Biallelic loss-of-function
    (null) mutations cause autosomal recessive EBS with severe generalized
    blistering. No `subtype` foreign key is set on this record, for the same
    reason as KRT5 above: KRT14 is the causal gene of four subtype rows
    (localized, generalized intermediate, generalized severe, and the
    recessive KRT14-null row) and the slot holds one value.
  evidence:
  - reference: PMID:22277943
    reference_title: "Defining keratin protein function in skin epithelia: epidermolysis bullosa simplex and its aftermath."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most cases of EBS are due to dominantly acting mutations in keratin 14 (K14) or K5"
    explanation: Confirms dominant KRT14 mutations as a major cause of EBS.
  - reference: PMID:16098032
    reference_title: "Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "many cases result from de novo mutations in KRT5 and KRT14 genes"
    explanation: Confirms that many EBS cases arise from de novo KRT14 mutations.
- name: PLEC
  gene_term:
    preferred_term: PLEC
    term:
      id: hgnc:9069
      label: PLEC
  association: Causative
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:20301543
      reference_title: "Epidermolysis Bullosa Simplex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal recessive EBS is associated with either biallelic loss-of-function variants in KRT5, KRT14, or PLEC"
      explanation: GeneReviews confirms autosomal recessive inheritance for PLEC.
  notes: >
    Plectin gene on chromosome 8q24.3. Encodes a giant (>500 kDa)
    cytoskeletal crosslinker protein. Biallelic loss-of-function mutations
    cause EBS with muscular dystrophy. Plectin links the keratin
    intermediate filament network to hemidesmosomes in skin and to the
    desmin cytoskeleton in muscle. No `subtype` foreign key is set on this
    record: PLEC causes both the recessive EBS with muscular dystrophy row and
    the dominant EBS Ogna row, and the slot holds one value.
  evidence:
  - reference: PMID:34572129
    reference_title: "Muscle-Related Plectinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the human plectin gene (PLEC) cause several rare diseases that are grouped under the term plectinopathies"
    explanation: Confirms PLEC mutations as causative for plectinopathies including EBS-MD.
  - reference: PMID:16098032
    reference_title: "Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in 14 cases, the disease was associated with mutations in both alleles of the plectin gene"
    explanation: Confirms biallelic plectin mutations in EBS patients, establishing recessive inheritance.
- name: DST
  gene_term:
    preferred_term: DST
    term:
      id: hgnc:1090
      label: DST
  association: Causative
  subtype: EBS BP230
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:20301543
      reference_title: "Epidermolysis Bullosa Simplex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "biallelic pathogenic variants in CD151, DST, or EXPH5"
      explanation: GeneReviews confirms autosomal recessive inheritance for DST.
  notes: >
    Dystonin gene (also known as BPAG1) on chromosome 6p12.1. Encodes a
    cytoskeletal linker protein related to plectin. Rare biallelic mutations
    cause EBS with additional features.
  evidence:
  - reference: PMID:20301543
    reference_title: "Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in CD151, DST, or EXPH5"
    explanation: GeneReviews lists DST as a gene with biallelic pathogenic variants causing autosomal recessive EBS.
- name: EXPH5
  gene_term:
    preferred_term: EXPH5
    term:
      id: hgnc:30578
      label: EXPH5
  association: Causative
  subtype: EBS EXPH5
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:20301543
      reference_title: "Epidermolysis Bullosa Simplex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "biallelic pathogenic variants in CD151, DST, or EXPH5"
      explanation: GeneReviews confirms autosomal recessive inheritance for EXPH5.
  notes: >
    Exophilin 5 gene on chromosome 11q22.3. Encodes a Rab27b effector
    involved in melanosome and lamellar body transport. Biallelic mutations
    cause a rare autosomal recessive form of EBS.
  evidence:
  - reference: PMID:20301543
    reference_title: "Epidermolysis Bullosa Simplex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in CD151, DST, or EXPH5"
    explanation: GeneReviews lists EXPH5 as a gene with biallelic pathogenic variants causing autosomal recessive EBS.
- name: KLHL24
  association: Causative
  subtype: EBS KLHL24
  inheritance:
  - name: Autosomal dominant
    evidence:
    - reference: PMID:20301543
      reference_title: "Epidermolysis Bullosa Simplex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a heterozygous pathogenic variant in KLHL24"
      explanation: GeneReviews confirms autosomal dominant inheritance for KLHL24.
  gene_term:
    preferred_term: KLHL24
    term:
      id: hgnc:25947
      label: KLHL24
  notes: >
    Kelch-like family member 24 gene on chromosome 3q27.1. Encodes a
    CUL3-RBX1 ubiquitin ligase substrate receptor. Gain-of-function
    mutations in the translation initiation codon (c.1A>G, c.2T>C) produce
    a truncated protein (KLHL24-deltaN28) that escapes autoubiquitination
    and causes excessive ubiquitin-mediated degradation of keratin 14
    (KRT14). Patients present with extensive skin denudation at birth and
    dilated cardiomyopathy. The c.1A>G mutation has occurred de novo and is
    recurrent across unrelated families from different countries.
  evidence:
  - reference: PMID:27798626
    reference_title: "Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified start-codon mutations in the KLHL24 gene in five patients with EB."
    explanation: Identifies KLHL24 start-codon mutations as a novel cause of EBS through stabilized truncated protein that excessively degrades KRT14.
  - reference: PMID:27889062
    reference_title: "Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause Skin Fragility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "monoallelic mutations, c.1A>G and c.2T>C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes"
    explanation: Independently confirms KLHL24 initiation codon mutations in 14 individuals with skin fragility and basal keratinocyte cleavage.
- name: PKP1
  gene_term:
    preferred_term: PKP1
    term:
      id: hgnc:9023
      label: PKP1
  association: Causative
  subtype: EBS-PD
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:32248567
      reference_title: "Ectodermal dysplasia-skin fragility syndrome: Two new cases and review of this desmosomal genodermatosis."
      supports: SUPPORT
      directness: DIRECT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "Loss-of-function autosomal recessive mutations in PKP1 result in ectodermal dysplasia-skin fragility (EDSF) syndrome, the initial inherited Mendelian disorder of desmosomes first reported in 1997."
      explanation: Establishes recessive loss-of-function as the mode for this gene.
  notes: >
    Plakophilin 1, an armadillo-family desmosomal plaque protein expressed
    mainly in the spinous layer. Biallelic loss-of-function variants cause
    the suprabasal EBS subtype recorded here as EBS-PD, also named ectodermal
    dysplasia-skin fragility syndrome. The gene is not expressed in the heart,
    which is what separates this entity clinically from the DSP route below
    despite their overlapping skin and hair phenotypes.
  evidence:
  - reference: PMID:19016709
    reference_title: Novel truncating mutations in PKP1 and DSP cause similar skin phenotypes in two Brazilian families.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patient 1 we identified a homozygous nonsense mutation, p.R672X, in the PKP1 gene (encoding plakophilin 1)."
    explanation: A biallelic PKP1 truncating variant in a patient with ectodermal dysplasia-skin fragility syndrome.
  - reference: PMID:19016709
    reference_title: Novel truncating mutations in PKP1 and DSP cause similar skin phenotypes in two Brazilian families.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, PKP1 is not expressed in the heart, which accounts for the lack of cardiomyopathy in patient 1."
    explanation: >-
      Sources the cardiac contrast recorded in these notes, which is the main
      clinical discriminator between the PKP1 and DSP suprabasal routes.
- name: DSP
  gene_term:
    preferred_term: DSP
    term:
      id: hgnc:3052
      label: DSP
  association: Causative
  subtype: LAEB
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:16175511
      reference_title: Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutational analysis of the patient demonstrated compound heterozygosity for two DP mutations, 6079C-->T (R1934X) and 6370delTT, respectively."
      explanation: Compound heterozygosity establishes biallelic, recessive transmission for this entity.
  notes: >
    Desmoplakin, the desmosomal plaque protein that links the intermediate
    filament network to the desmosomal cadherins. Only the lethal acantholytic
    epidermolysis bullosa end of the DSP skin spectrum is curated on this
    entry, as the LAEB subtype row; the milder biallelic DSP skin phenotypes
    have their own entries (Skin_Fragility_Woolly_Hair_Syndrome,
    Carvajal_Syndrome), as do the DSP cardiomyopathies. Unlike PKP1, DSP is
    expressed in the heart, so the DSP route can carry cardiac disease.
  evidence:
  - reference: PMID:16175511
    reference_title: Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aberrant mRNA transcripts that predict premature termination of translation with loss of the three intermediate filament-binding subdomains in the DP tail were detected by RT-PCR."
    explanation: >-
      Identifies the specific functional consequence, loss of the intermediate
      filament-binding subdomains of the desmoplakin tail.
  - reference: PMID:19016709
    reference_title: Novel truncating mutations in PKP1 and DSP cause similar skin phenotypes in two Brazilian families.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function mutations in the DSP gene can result in a phenotype similar to ectodermal dysplasia-skin fragility syndrome resulting from PKP1 mutations but only DSP pathology is associated with cardiac disease."
    explanation: >-
      Sources the phenotypic overlap with the PKP1 route and the cardiac
      expression difference recorded in these notes.
datasets:
- accession: geo:GSE179508
  title: Transcriptomic Repositioning Analysis Identifies mTOR Inhibitor as Potential Therapy for Epidermolysis Bullosa Simplex
  description: >-
    Human bulk RNA-seq dataset profiling blistered and non-blistered EBS skin,
    used to define disease-associated signaling programs and prioritize
    repositionable therapies.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 20
  conditions:
  - blistered EBS skin
  - non-blistered EBS skin
  evidence:
  - reference: GEO:GSE179508
    reference_title: "Transcriptomic Repositioning Analysis Identifies mTOR Inhibitor as Potential Therapy for Epidermolysis Bullosa Simplex"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we characterize significant molecular pathways activated in the blisters that form in EBS"
    explanation: Supports this GEO series as a direct transcriptomic resource for EBS lesional biology.
  - reference: GEO:GSE179508
    reference_title: "Transcriptomic Repositioning Analysis Identifies mTOR Inhibitor as Potential Therapy for Epidermolysis Bullosa Simplex"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We implicate the PI3K/AKT/mTOR pathway as central in the EBS disease pathway"
    explanation: Confirms that the dataset captures disease-relevant signaling programs and supports downstream therapeutic inference.
references:
- reference: PMID:20301543
  title: "Epidermolysis Bullosa Simplex."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1101/cshperspect.a041229
  title: Stairways to Advanced Therapies for Epidermolysis Bullosa
  found_in:
  - Epidermolysis_Bullosa_Simplex-deep-research-falcon.md
  findings:
  - statement: Stairways to Advanced Therapies for Epidermolysis Bullosa
    supporting_text: Stairways to Advanced Therapies for Epidermolysis Bullosa
- reference: DOI:10.1111/bjd.18128
  title: Clinical practice guidelines for laboratory diagnosis of epidermolysis bullosa
  found_in:
  - Epidermolysis_Bullosa_Simplex-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/bjd.18921
  title: Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility
  found_in:
  - Epidermolysis_Bullosa_Simplex-deep-research-falcon.md
  findings:
  - statement: Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility
    supporting_text: Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility
- reference: DOI:10.1111/jdv.18637
  title: Epidemiology of inherited epidermolysis bullosa in Germany
  found_in:
  - Epidermolysis_Bullosa_Simplex-deep-research-falcon.md
  findings:
  - statement: Epidemiology of inherited epidermolysis bullosa in Germany
    supporting_text: 'Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity.ObjectiveEpidemiological data from different countries have been published, but none are available from Germany.MethodsIn this population‐based cross‐sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories and patient organization.ResultsOur study indicates an overall EB incidence of 45 per million live births in Germany.'
    evidence:
    - reference: DOI:10.1111/jdv.18637
      reference_title: Epidemiology of inherited epidermolysis bullosa in Germany
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity.ObjectiveEpidemiological data from different countries have been published, but none are available from Germany.MethodsIn this population‐based cross‐sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories and patient organization.ResultsOur study indicates an overall EB incidence of 45 per million live births in Germany.'
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.
- reference: DOI:10.1111/jdv.18692
  title: Genotype and phenotype correlations in 441 patients with epidermolysis bullosa from China
  found_in:
  - Epidermolysis_Bullosa_Simplex-deep-research-falcon.md
  findings:
  - statement: Genotype and phenotype correlations in 441 patients with epidermolysis bullosa from China
    supporting_text: Epidermolysis bullosa (EB) is a heterogeneous group of rare and incurable genetic blistering disorders.ObjectivesThe objective was to analyse the genotype–phenotype correlation in EB among Chinese individuals.MethodsNext‐generation sequencing and Sanger sequencing were performed to genetically confirm clinically diagnosed EB.
    evidence:
    - reference: DOI:10.1111/jdv.18692
      reference_title: Genotype and phenotype correlations in 441 patients with epidermolysis bullosa from China
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Epidermolysis bullosa (EB) is a heterogeneous group of rare and incurable genetic blistering disorders.ObjectivesThe objective was to analyse the genotype–phenotype correlation in EB among Chinese individuals.MethodsNext‐generation sequencing and Sanger sequencing were performed to genetically confirm clinically diagnosed EB.
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.
- reference: DOI:10.1111/pde.15440
  title: Clinical and molecular features in a cohort of Middle Eastern patients with epidermolysis bullosa
  found_in:
  - Epidermolysis_Bullosa_Simplex-deep-research-falcon.md
  findings:
  - statement: Epidermolysis bullosa (EB) features skin and mucosal fragility due to pathogenic variants in genes encoding components of the cutaneous basement membrane.
    supporting_text: Epidermolysis bullosa (EB) features skin and mucosal fragility due to pathogenic variants in genes encoding components of the cutaneous basement membrane.
    evidence:
    - reference: DOI:10.1111/pde.15440
      reference_title: Clinical and molecular features in a cohort of Middle Eastern patients with epidermolysis bullosa
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Epidermolysis bullosa (EB) features skin and mucosal fragility due to pathogenic variants in genes encoding components of the cutaneous basement membrane.
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.
- reference: DOI:10.1177/0300985819900354
  title: 'Spontaneous <i>KRT5</i> Gene Mutation in Rhesus Macaques ( <i>Macaca mulatta</i> ): A Novel Nonhuman Primate Model of Epidermolysis Bullosa Simplex'
  found_in:
  - Epidermolysis_Bullosa_Simplex-deep-research-falcon.md
  findings:
  - statement: Epidermolysis bullosa simplex (EBS) is an inherited skin disorder characterized by increased skin and mucous membrane fragility.
    supporting_text: Epidermolysis bullosa simplex (EBS) is an inherited skin disorder characterized by increased skin and mucous membrane fragility.
    evidence:
    - reference: DOI:10.1177/0300985819900354
      reference_title: 'Spontaneous <i>KRT5</i> Gene Mutation in Rhesus Macaques ( <i>Macaca mulatta</i> ): A Novel Nonhuman Primate Model of Epidermolysis Bullosa Simplex'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Epidermolysis bullosa simplex (EBS) is an inherited skin disorder characterized by increased skin and mucous membrane fragility.
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.
- reference: DOI:10.1186/s13023-022-02433-3
  title: A global, cross-sectional survey of patient-reported outcomes, disease burden, and quality of life in epidermolysis bullosa simplex
  found_in:
  - Epidermolysis_Bullosa_Simplex-deep-research-falcon.md
  findings:
  - statement: Epidermolysis bullosa simplex (EBS) comprises a group of rare, blistering genodermatoses.
    supporting_text: Epidermolysis bullosa simplex (EBS) comprises a group of rare, blistering genodermatoses.
    evidence:
    - reference: DOI:10.1186/s13023-022-02433-3
      reference_title: A global, cross-sectional survey of patient-reported outcomes, disease burden, and quality of life in epidermolysis bullosa simplex
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Epidermolysis bullosa simplex (EBS) comprises a group of rare, blistering genodermatoses.
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.
- reference: DOI:10.1542/neo.22-7-e438
  title: Diagnosis and Care of the Newborn with Epidermolysis Bullosa
  found_in:
  - Epidermolysis_Bullosa_Simplex-deep-research-falcon.md
  findings:
  - statement: Epidermolysis bullosa (EB) is a group of rare genetic disorders that are characterized by fragile skin.
    supporting_text: Epidermolysis bullosa (EB) is a group of rare genetic disorders that are characterized by fragile skin.
    evidence:
    - reference: DOI:10.1542/neo.22-7-e438
      reference_title: Diagnosis and Care of the Newborn with Epidermolysis Bullosa
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Epidermolysis bullosa (EB) is a group of rare genetic disorders that are characterized by fragile skin.
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.
- reference: DOI:10.3390/ijms25179495
  title: 'Pathological Mechanisms Involved in Epidermolysis Bullosa Simplex: Current Knowledge and Therapeutic Perspectives'
  found_in:
  - Epidermolysis_Bullosa_Simplex-deep-research-falcon.md
  findings:
  - statement: Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of mechanobullous diseases characterized by non-scarring blisters and erosions on the skin and mucous membranes upon mechanical trauma.
    supporting_text: Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of mechanobullous diseases characterized by non-scarring blisters and erosions on the skin and mucous membranes upon mechanical trauma.
    evidence:
    - reference: DOI:10.3390/ijms25179495
      reference_title: 'Pathological Mechanisms Involved in Epidermolysis Bullosa Simplex: Current Knowledge and Therapeutic Perspectives'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of mechanobullous diseases characterized by non-scarring blisters and erosions on the skin and mucous membranes upon mechanical trauma.
      explanation: Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.
- reference: DOI:10.1038/s41572-020-0210-0
  title: Epidermolysis bullosa
  found_in:
  - Epidermolysis_Bullosa_Simplex-deep-research-falcon.md
notes: >
  MONDO ANCHOR AND THE SUBTYPE SERIES. This entry's `disease_term`,
  MONDO:0017610 'epidermolysis bullosa simplex', is the EBS group term: its
  only asserted parent is MONDO:0019276, and every numbered EBS subtype
  concept resolves as one of its descendants. Fourteen are direct children;
  the two suprabasal concepts (MONDO:0011472 plakophilin deficiency and
  MONDO:0012323 lethal acantholytic epidermolysis bullosa) descend through
  MONDO:0015550 'suprabasal epidermolysis bullosa simplex', itself a direct
  child. The term is therefore at the right level to carry the subtype rows
  below, and the narrowMatch re-anchoring described in dismech#12184 does not
  apply to it.

  THE CAUSAL GENE SET. The GeneReviews Epidermolysis Bullosa Simplex chapter
  (PMID:20301543, 2022 update) establishes seven genes: KRT5, KRT14, PLEC,
  KLHL24, CD151, DST and EXPH5. PKP1 and DSP are curated here in addition. The
  chapter does not cover those two because it scopes itself to blistering
  within basal keratinocytes, whereas MONDO places both under this entry's
  term: its definitions describe them as suprabasal subtypes of epidermolysis
  bullosa simplex, and both descend through MONDO:0015550. Their cleavage
  plane and mechanism differ from the basal routes, so they are drawn as their
  own pathophysiology node rather than folded into the keratin and
  hemidesmosome chain.

  OMIM AND MONDO SPLIT THREE CLINICAL SUBTYPES BY KERATIN GENE. Localized,
  generalized intermediate and generalized severe EBS each have two MONDO
  terms, a 1x term carrying MONDO's KRT14 gene association and a 2x term
  carrying the KRT5 one, for the same clinical picture. Each is a single row
  binding the 1x term and recording the 2x term as a `skos:closeMatch` -
  deliberately not an exact or narrow match, which would retire an uncurated
  concept from the curation queue. The recessive pair is handled the other
  way: EBS 1D (KRT14) and EBS 2d (KRT5) are separate rows, because the two
  were established by separate reports with different phenotypic ranges, and
  the recessive KRT5 route was not reported at all until 2019.

  MONDO:0030535 CARRIES A LOWERCASE SUBTYPE LETTER. Its label is
  'epidermolysis bullosa simplex 2d, generalized, intermediate or severe,
  autosomal recessive', where every sibling in the series uses an uppercase
  letter (2A, 2B, 2C, 2E, 2F). The label is copied here exactly as MONDO
  publishes it, as term labels always are.

  MONDO:0012190 (EBS 7, CD151) IS CURATED ELSEWHERE. It has its own Disease
  entry, Epidermolysis_Bullosa_Simplex_7_With_Nephropathy_And_Deafness, which
  binds that term and CD151 (hgnc:1630). CD151 is named in this entry's
  description as one of the EBS genes but carries no `genetic:` record here: a
  second binding would add no coverage, and would leave a gene on this entry
  that no pathophysiology node reaches.

📚

References & Deep Research

References

12

PMID:20301543

Epidermolysis Bullosa Simplex.

No top-level findings curated for this source.

DOI:10.1101/cshperspect.a041229

Stairways to Advanced Therapies for Epidermolysis Bullosa

1 finding

Stairways to Advanced Therapies for Epidermolysis Bullosa

"Stairways to Advanced Therapies for 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/bjd.18921

Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility

1 finding

Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility

"Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility"

DOI:10.1111/jdv.18637

Epidemiology of inherited epidermolysis bullosa in Germany

1 finding

Epidemiology of inherited epidermolysis bullosa in Germany

"Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity.ObjectiveEpidemiological data from different countries have been published, but none are available from Germany.MethodsIn this population‐based..."

Show evidence (1 reference)

DOI:10.1111/jdv.18637 SUPPORT Human Clinical

"Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity.ObjectiveEpidemiological data from different countries have been published, but none are available from Germany.MethodsIn this population‐based..."

Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.

DOI:10.1111/jdv.18692

Genotype and phenotype correlations in 441 patients with epidermolysis bullosa from China

1 finding

Genotype and phenotype correlations in 441 patients with epidermolysis bullosa from China

"Epidermolysis bullosa (EB) is a heterogeneous group of rare and incurable genetic blistering disorders.ObjectivesThe objective was to analyse the genotype–phenotype correlation in EB among Chinese individuals.MethodsNext‐generation sequencing and Sanger sequencing were performed to genetically..."

Show evidence (1 reference)

DOI:10.1111/jdv.18692 SUPPORT Human Clinical

"Epidermolysis bullosa (EB) is a heterogeneous group of rare and incurable genetic blistering disorders.ObjectivesThe objective was to analyse the genotype–phenotype correlation in EB among Chinese individuals.MethodsNext‐generation sequencing and Sanger sequencing were performed to genetically..."

Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.

DOI:10.1111/pde.15440

Clinical and molecular features in a cohort of Middle Eastern patients with epidermolysis bullosa

1 finding

Epidermolysis bullosa (EB) features skin and mucosal fragility due to pathogenic variants in genes encoding components of the cutaneous basement membrane.

"Epidermolysis bullosa (EB) features skin and mucosal fragility due to pathogenic variants in genes encoding components of the cutaneous basement membrane."

Show evidence (1 reference)

DOI:10.1111/pde.15440 SUPPORT Human Clinical

"Epidermolysis bullosa (EB) features skin and mucosal fragility due to pathogenic variants in genes encoding components of the cutaneous basement membrane."

Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.

DOI:10.1177/0300985819900354

Spontaneous <i>KRT5</i> Gene Mutation in Rhesus Macaques ( <i>Macaca mulatta</i> ): A Novel Nonhuman Primate Model of Epidermolysis Bullosa Simplex

1 finding

Epidermolysis bullosa simplex (EBS) is an inherited skin disorder characterized by increased skin and mucous membrane fragility.

"Epidermolysis bullosa simplex (EBS) is an inherited skin disorder characterized by increased skin and mucous membrane fragility."

Show evidence (1 reference)

DOI:10.1177/0300985819900354 SUPPORT Model Organism

"Epidermolysis bullosa simplex (EBS) is an inherited skin disorder characterized by increased skin and mucous membrane fragility."

Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.

DOI:10.1186/s13023-022-02433-3

A global, cross-sectional survey of patient-reported outcomes, disease burden, and quality of life in epidermolysis bullosa simplex

1 finding

Epidermolysis bullosa simplex (EBS) comprises a group of rare, blistering genodermatoses.

"Epidermolysis bullosa simplex (EBS) comprises a group of rare, blistering genodermatoses."

Show evidence (1 reference)

DOI:10.1186/s13023-022-02433-3 SUPPORT Human Clinical

"Epidermolysis bullosa simplex (EBS) comprises a group of rare, blistering genodermatoses."

Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.

DOI:10.1542/neo.22-7-e438

Diagnosis and Care of the Newborn with Epidermolysis Bullosa

1 finding

Epidermolysis bullosa (EB) is a group of rare genetic disorders that are characterized by fragile skin.

"Epidermolysis bullosa (EB) is a group of rare genetic disorders that are characterized by fragile skin."

Show evidence (1 reference)

DOI:10.1542/neo.22-7-e438 SUPPORT Human Clinical

"Epidermolysis bullosa (EB) is a group of rare genetic disorders that are characterized by fragile skin."

Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.

DOI:10.3390/ijms25179495

Pathological Mechanisms Involved in Epidermolysis Bullosa Simplex: Current Knowledge and Therapeutic Perspectives

1 finding

Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of mechanobullous diseases characterized by non-scarring blisters and erosions on the skin and mucous membranes upon mechanical trauma.

"Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of mechanobullous diseases characterized by non-scarring blisters and erosions on the skin and mucous membranes upon mechanical trauma."

Show evidence (1 reference)

DOI:10.3390/ijms25179495 SUPPORT Human Clinical

"Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of mechanobullous diseases characterized by non-scarring blisters and erosions on the skin and mucous membranes upon mechanical trauma."

Deep research cited this publication as relevant literature for Epidermolysis Bullosa Simplex.

DOI:10.1038/s41572-020-0210-0

Epidermolysis bullosa

No top-level findings curated for this source.

Deep Research

1

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

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 50 citations 2026-05-08T16:34:19.918654

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

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

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

Disease Characteristics Research Template

Target Disease

Disease Name: Epidermolysis Bullosa Simplex
MONDO ID: (if available)
Category: Mendelian

Research Objectives

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

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

1. Disease Information

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

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

2. Etiology

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

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

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

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

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

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

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

4. Genetic/Molecular Information

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

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

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

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

5. Environmental Information

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

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

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

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

6. Mechanism / Pathophysiology

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

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

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

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

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

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

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

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

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

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

7. Anatomical Structures Affected

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

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

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

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

8. Temporal Development

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

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

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

9. Inheritance and Population

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

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

10. Diagnostics

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

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

11. Outcome/Prognosis

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

12. Treatment

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

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

13. Prevention

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

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

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

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

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

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

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

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

15. Model Organisms

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

Citation Requirements

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

Output Format

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

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

Comprehensive Disease Characteristics Report: Epidermolysis Bullosa Simplex (EBS)

Executive summary

Epidermolysis bullosa simplex (EBS) is a Mendelian skin-fragility disorder within the inherited epidermolysis bullosa (EB) spectrum, defined by intraepidermal blistering due to cleavage within the basal layer of keratinocytes, typically triggered by minor mechanical trauma. (Has et al., Br J Dermatol, 2020-03, https://doi.org/10.1111/bjd.18921) (has2020consensusreclassificationof pages 2-3). The current (international consensus) classification organizes EB into four major types—EBS, junctional EB, dystrophic EB, and Kindler EB—based primarily on level of cleavage and molecular etiology. (Has et al., 2020-03, https://doi.org/10.1111/bjd.18921) (has2020consensusreclassificationof pages 1-2).

Key 2023–2024 advances emphasized in recent reviews include (i) a more explicit framing of EBS as both a mechanical fragility disorder and a disease with inflammatory/stress-response signaling cascades downstream of keratin disruption, and (ii) continued growth of symptom-targeted therapies through drug repurposing and targeted topical approaches. (Bchetnia et al., Int J Mol Sci, 2024-08, https://doi.org/10.3390/ijms25179495) (bchetnia2024pathologicalmechanismsinvolved pages 1-2).

1. Disease information

1.1 What is the disease?

EBS is an inherited mechanobullous (mechanically induced blistering) genodermatosis characterized by skin fragility with blistering/erosions after minor trauma, with tissue cleavage occurring within the basal keratinocyte layer of the epidermis (intraepidermal). (Has et al., 2020-03, https://doi.org/10.1111/bjd.18921) (has2020consensusreclassificationof pages 2-3). A 2024 EBS-focused review similarly defines EBS as “recurrent blister formation within the basal layer of the epidermis,” most often due to dominant keratin 5/14 mutations. (Bchetnia et al., 2024-08, https://doi.org/10.3390/ijms25179495) (bchetnia2024pathologicalmechanismsinvolved pages 1-2).

1.2 Key identifiers (OMIM, Orphanet, ICD-10/ICD-11, MeSH, MONDO)

Not available from the retrieved evidence snippets. The sources available in this run did not provide explicit OMIM, Orphanet, ICD-10/ICD-11, MeSH, or MONDO identifiers for EBS. (has2020consensusreclassificationof pages 2-3, bchetnia2024pathologicalmechanismsinvolved pages 1-2, has2019clinicalpracticeguidelines pages 1-2).

1.3 Common synonyms / alternative names

Common clinical subtype names used in the contemporary literature include: - Localized EBS (historical eponym: Weber–Cockayne) - Intermediate generalized EBS (historical eponym: Köebner) - Severe generalized EBS (historical eponym: Dowling–Meara) (Has et al., 2020-03, https://doi.org/10.1111/bjd.18921) (has2020consensusreclassificationof pages 2-3).

1.4 Evidence source type

The evidence synthesized here is primarily from aggregated disease-level resources and cohorts/registries (consensus classification, clinical practice guidelines, epidemiology capture–recapture study, multi-country patient-reported outcomes survey), complemented by clinical-trial registry records and mechanistic review literature. (has2020consensusreclassificationof pages 1-2, has2019clinicalpracticeguidelines pages 1-2, has2023epidemiologyofinherited pages 7-7, so2022aglobalcrosssectional pages 1-2, NCT02470689 chunk 1).

2. Etiology

2.1 Disease causal factors

Genetic (primary): EBS most often results from autosomal dominant pathogenic variants in KRT5 or KRT14 encoding keratin 5 and keratin 14 intermediate filament proteins in basal keratinocytes. (Bchetnia et al., 2024-08, https://doi.org/10.3390/ijms25179495) (bchetnia2024pathologicalmechanismsinvolved pages 1-2). The 2020 international consensus explicitly frames EBS as blistering from cleavage within basal keratinocytes and notes multiple EBS-associated genes beyond keratins, including newer additions such as KLHL24. (Has et al., 2020-03, https://doi.org/10.1111/bjd.18921) (has2020consensusreclassificationof pages 2-3).

Additional (rarer) EBS genes (examples): PLEC, KLHL24, DST, EXPH5, CD151. (Bchetnia et al., 2024-08, https://doi.org/10.3390/ijms25179495) (bchetnia2024pathologicalmechanismsinvolved pages 1-2).

2.2 Risk factors

Genetic risk factor: carrying a pathogenic variant in a causal EBS gene (e.g., KRT5/KRT14). (bchetnia2024pathologicalmechanismsinvolved pages 1-2)
De novo and mosaic mutations: In a large China cohort, de novo mutations were reported as common in EBS (63.8%), and mosaicism was observed (~5.4% in dominant EBS), highlighting that absence of family history does not exclude EBS. (Chen et al., JEADV, 2023-11, https://doi.org/10.1111/jdv.18692) (chen2023genotypeandphenotype pages 1-1).

Environmental/triggering factors (non-causal but exacerbating): mechanical friction/trauma is the key trigger for blister formation in EB generally and EBS specifically. (Has et al., 2020-03, https://doi.org/10.1111/bjd.18921) (has2020consensusreclassificationof pages 1-2).

2.3 Protective factors

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

2.4 Gene–environment interactions

The retrieved evidence supports a strong mechanical trigger (friction) interacting with genetically determined structural fragility, but does not provide quantitative gene–environment interaction effect sizes.

3. Phenotypes

3.1 Phenotype spectrum and subtype distribution

EBS is commonly divided into localized, intermediate generalized, and severe generalized forms. (Has et al., 2020-03) (has2020consensusreclassificationof pages 2-3).

Population-based and cohort data show subtype distributions vary by region and ascertainment: - Germany (capture–recapture, inherited EB): EBS subtypes most commonly localized (39.5%) and severe (14.7%), with 33.4% of EBS not further subclassified. (Has et al., JEADV, 2023-11, https://doi.org/10.1111/jdv.18637) (has2023epidemiologyofinherited pages 5-6). - China (441 EB patients): EBS comprised ~23.4% of the EB cohort; among EBS cases, localized 17.5%, intermediate 35.0%, severe 27.2%. (Chen et al., 2023-11, https://doi.org/10.1111/jdv.18692) (chen2023genotypeandphenotype pages 2-2).

3.2 Common clinical manifestations (patient-reported)

In the largest international cross-sectional EBS patient-reported outcomes survey (n=214; mean age 32.8 years), respondents reported: blisters 93%, recurrent wounds 89%, pain 74%, chronic wounds 59%, itch 55%, and difficulty walking 44%; the mean QOLEB score was 14.7 (SD 7.5) indicating a moderate impact on quality of life, and 12% reported regular opiate use. (So et al., Orphanet J Rare Dis, 2022-07, https://doi.org/10.1186/s13023-022-02433-3) (so2022aglobalcrosssectional pages 1-2).

More granular QOLEB impacts among those completing all items (70/214): 41% reported frequent/constant pain, 93% unable to participate in sports, 79% difficulty moving outside the home, and high emotional burden (frustration 99%, anxiety 70%, depression 54%). (So et al., 2022-07) (so2022aglobalcrosssectional pages 6-8).

3.3 Quality of life impact

QOL impact is measurable and moderate on average in the survey above (QOLEB mean 14.7), with substantial mobility limitations and psychosocial effects. (so2022aglobalcrosssectional pages 6-8).

3.4 Suggested HPO terms (examples; not exhaustive)

Based on the phenotype descriptions in the cited studies, suitable HPO terms include: - Skin blistering: HP:0008064 (Blistering of the skin) - Skin fragility: HP:0001034 (Fragile skin) - Erosions/ulcerations: HP:0001058 (Skin erosion) / HP:0000974 (Skin ulcer) - Pain: HP:0012531 (Pain) - Pruritus: HP:0000989 (Pruritus) - Difficulty walking / impaired mobility: HP:0002355 (Difficulty walking) - Palmoplantar keratoderma (for localized plantar disease): HP:0000972 (Palmoplantar keratoderma)

4. Genetic / molecular information

4.1 Causal genes (major)

KRT5 and KRT14 are the predominant genes for dominant EBS. (bchetnia2024pathologicalmechanismsinvolved pages 1-2)

Cohort support: - In a Middle Eastern EB cohort (n=151), EBS was 64% (97/151); within EBS cases, KRT5 accounted for 46% (45/97) and KRT14 for 43% (42/97). (Bergson et al., Pediatr Dermatol, 2023-10, https://doi.org/10.1111/pde.15440) (bergson2023clinicalandmolecular pages 1-2).

4.2 Other reported EBS genes

Rarer EBS-associated genes cited in the recent EBS review and consensus classification include PLEC, KLHL24, DST, EXPH5, CD151. (bchetnia2024pathologicalmechanismsinvolved pages 1-2, has2020consensusreclassificationof pages 2-3).

In the China cohort, PLEC and KLHL24 variants were each found in four cases (cohort-wide). (chen2023genotypeandphenotype pages 3-3).

4.3 Pathogenic variant types and genotype–phenotype considerations

The China cohort highlights recurrent keratin hotspots and domain clustering, including classic KRT14 p.Arg125 substitutions (e.g., p.R125H/C/S/L) and variants in keratin α-helical domains (1A/1B/2A/2B) and linkers. (chen2023genotypeandphenotype pages 4-4).
The Middle Eastern cohort reported a phenotype association: truncal involvement was more common in KRT14-associated EBS than KRT5-associated EBS (p<0.05). (bergson2023clinicalandmolecular pages 1-2).

Somatic vs germline: Mosaicism in dominant EBS was reported (~5.4% in one large cohort), supporting consideration of mosaicism in genetic testing/interpretation. (chen2023genotypeandphenotype pages 1-1).

4.4 Suggested ontology/annotation terms

GO biological processes (examples): keratinocyte differentiation; response to mechanical stimulus; inflammatory response; cellular response to endoplasmic reticulum stress.
Cell types (Cell Ontology, examples): basal keratinocyte (epidermal basal cell); epidermal keratinocyte.

5. Environmental information

EBS is not infectious; its primary cause is genetic. Mechanical trauma/friction is the canonical trigger for blistering in EB. (has2020consensusreclassificationof pages 1-2). No specific toxins, lifestyle exposures, or pathogens were identified in the retrieved evidence as causal contributors.

6. Mechanism / pathophysiology (current understanding, 2023–2024 emphasis)

6.1 Core causal chain (structural fragility)

1) Primary trigger: pathogenic variants (often dominant) in KRT5 or KRT14. 2) Cellular consequence: disruption of the basal keratin intermediate filament network, with keratin aggregation and cytoskeletal instability. 3) Tissue consequence: basal keratinocyte fragility leading to intraepidermal cleavage and blistering with minor trauma. (Bchetnia et al., 2024-08) (bchetnia2024pathologicalmechanismsinvolved pages 1-2).

6.2 Inflammatory/stress signaling cascades (important recent framing)

A key 2024 EBS review emphasizes that disruptive KRT5/KRT14 mutations “will not only structurally impair the cytoskeleton, but it will also activate a cascade of biochemical mechanisms,” including ER stress and release of pro-inflammatory molecules. (Bchetnia et al., 2024-08) (bchetnia2024pathologicalmechanismsinvolved pages 1-2).

Clinical-trial rationale (Dowling–Meara/generalized severe subtype) highlights an IL-1β/JNK axis: upregulation of interleukin-1β (IL-1β) and activation of the JNK stress pathway, with in vitro data that blocking IL‑1β or applying diacerein reduced IL‑1β and K14 expression and improved keratinocyte stress resistance. (ClinicalTrials.gov record NCT02470689; 2015; https://clinicaltrials.gov/study/NCT02470689) (NCT02470689 chunk 1).

6.3 Transcriptomics / molecular profiling

The 2024 mechanistic review states that multiple gene expression studies in mouse models and human keratinocytes identify EBS gene expression signatures involving immunological mediators, keratins, and junction components, with particular emphasis on inflammation as a functional biological process. (bchetnia2024pathologicalmechanismsinvolved pages 1-2).

7. Anatomical structures affected

7.1 Organ/tissue level

Primary affected tissue: skin (epidermis) with basal-layer keratinocyte cleavage. (has2020consensusreclassificationof pages 2-3)
Mucosal involvement can occur (particularly in more severe generalized forms) within the broader EB spectrum. (Rosa et al., Cold Spring Harb Perspect Biol, 2023-09, https://doi.org/10.1101/cshperspect.a041229) (rosa2023stairwaystoadvanced pages 1-3).

7.2 Suggested UBERON terms (examples)

Skin: UBERON:0002097
Epidermis: UBERON:0001003

7.3 Suggested GO cellular component terms (examples)

Intermediate filament cytoskeleton; keratin filament.

8. Temporal development (onset and progression)

Severe EBS forms can present at or near birth and may be associated with severe complications; milder localized forms may be recognized later and can be underdiagnosed. (Has et al., 2020-03) (has2020consensusreclassificationof pages 2-3). In Germany, EBS incidence was noted as potentially underestimated due to later diagnosis/missed diagnosis. (Has et al., 2023-11) (has2023epidemiologyofinherited pages 7-7).

9. Inheritance and population

9.1 Inheritance pattern

EBS is most often autosomal dominant, with autosomal recessive forms also described. (has2020consensusreclassificationof pages 2-3).

9.2 Epidemiology (recent quantitative estimates)

Germany (population-based capture–recapture; incidence years 2003–2019; age assessed as of 2022-04-01): - Overall inherited EB incidence: 45.09 per 1,000,000 live births (≈ 1 in 22,178 live births per year) - EBS incidence: 14.93 per 1,000,000 live births (≈ 1 in 66,979) - Estimated prevalence (all EB): 54.02 per million; EBS prevalence: 28.44 per million (Has et al., JEADV, 2023-11, https://doi.org/10.1111/jdv.18637) (has2023epidemiologyofinherited pages 5-6, has2023epidemiologyofinherited pages 7-7).

United States (review-level estimates as reported in a therapeutics-focused review): incidence and prevalence were stated as 11.1 per million and 19.6 per million, respectively. (Rosa et al., 2023-09) (rosa2023stairwaystoadvanced pages 1-3).

10. Diagnostics

10.1 Diagnostic approach (guidelines and current practice)

The 2019 clinical practice guidelines for laboratory diagnosis of EB recommend that laboratory diagnosis be initiated “as soon as there is clinical suspicion,” and state: “Genetic testing is always recommended” (index case and, if possible, parents). (Has et al., Br J Dermatol, 2019-08, https://doi.org/10.1111/bjd.18128) (has2019clinicalpracticeguidelines pages 1-2).

Immunofluorescence mapping (IFM): Recommended as an early test to obtain rapid diagnosis/prognosis and to prioritize and interpret genetic testing. In neonates, the guideline notes IFM can provide diagnosis “within hours.” (Has et al., 2019-08) (has2019clinicalpracticeguidelines pages 6-7).

Parallel testing in neonates: Neonatal review recommendations: “obtain a skin biopsy for IFM and a blood sample for genetic testing to be run in parallel.” (Lucky et al., NeoReviews, 2021-07, https://doi.org/10.1542/neo.22-7-e438) (lucky2021diagnosisandcare pages 3-5).

Specimen handling (selected technical details): 3–4 mm punch biopsy for IFM in Michel media; 2–3 mm punch biopsy for EM in glutaraldehyde fixative. (Lucky et al., 2021-07) (lucky2021diagnosisandcare pages 3-5).

Genetic testing modalities: Guidelines describe use of targeted EB gene panels/NGS, WES, and Sanger sequencing, with escalation to RNA-based or copy-number approaches when needed. (Has et al., 2019-08) (has2019clinicalpracticeguidelines pages 10-11). The neonatal review notes NGS targeted panels typically have ~1 month turnaround and are more cost-effective than sequential Sanger sequencing. (Lucky et al., 2021-07) (lucky2021diagnosisandcare pages 3-5).

10.2 Differential diagnosis

Not systematically extracted from the available evidence excerpts in this run.

11. Outcomes / prognosis

EBS prognosis is heterogeneous: localized forms often have near-normal life expectancy, whereas severe generalized forms can be associated with serious complications and early mortality in some cases. (Has et al., 2020-03) (has2020consensusreclassificationof pages 2-3). A Germany EB epidemiology study reported mortality metrics primarily for JEB/DEB; it did not provide an EBS-specific mean age at death in the extracted snippets. (has2023epidemiologyofinherited pages 7-8).

12. Treatment

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

There is no universally curative treatment for EB; management is multidisciplinary and supportive (wound care, symptom control, complication prevention). (Bardhan et al., Nat Rev Dis Primers, 2020-09, https://doi.org/10.1038/s41572-020-0210-0) (bardhan2020epidermolysisbullosa pages 1-2).

12.2 Drug repurposing and targeted therapies in EBS (selected examples)

(A) Topical diacerein (anti–IL-1β axis)

A Phase 2 randomized crossover trial record for EBS–Dowling–Meara (generalized severe) describes topical 1% diacerein cream targeting IL‑1β/JNK-associated disease biology. The record reports a prior pilot (n=5) with blister reductions −78% and −66% from baseline within two weeks in an armpit model. (ClinicalTrials.gov NCT02470689; 2015; https://clinicaltrials.gov/study/NCT02470689) (NCT02470689 chunk 1).

MAXO suggestions (examples): topical pharmacotherapy; anti-inflammatory therapy.

(B) mTOR inhibition (topical sirolimus)

A 2024 EBS mechanism/therapeutics review describes topical sirolimus as an mTOR inhibitor with reported clinical improvement in two patients with plantar keratoderma, and summarizes topical sirolimus as a repositioning approach supported by transcriptomic rationale. (Bchetnia et al., 2024-08) (bchetnia2024pathologicalmechanismsinvolved pages 10-12, bchetnia2024pathologicalmechanismsinvolved pages 13-14).

MAXO suggestions: topical rapamycin therapy; mTOR inhibitor therapy.

(C) Botulinum toxin for plantar disease (symptom and blister reduction)

The same 2024 review summarizes small studies/case reports of botulinum toxin (types A and B) injected into feet of patients with localized and severe EBS, with reported improvements in blistering and pedal pain (and odor in a pediatric case). (Bchetnia et al., 2024-08) (bchetnia2024pathologicalmechanismsinvolved pages 10-12, bchetnia2024pathologicalmechanismsinvolved pages 13-14).

MAXO suggestions: botulinum toxin injection; pain management.

12.3 Clinical trials (selected EBS-relevant trials and endpoints)

A major EB review lists interventional trials relevant to EBS including: - Diacerein Phase II placebo-controlled trial NCT03154333 with endpoint described as proportion achieving ≥60% improvement in affected assessed body surface area. - Sirolimus Phase II placebo-controlled trial NCT03016715 with endpoints including foot health status, pedometer progress, plantar defect size, disease severity, and quality of life. - Botulinum toxin randomized crossover trial for localized EBS NCT03453632 with endpoints including plantar pain/tolerability. (Bardhan et al., 2020-09) (bardhan2020epidermolysisbullosa pages 20-21).

Note: For trial phase/status/enrollment details beyond those in the cited excerpt, ClinicalTrials.gov records should be consulted directly; those details were not consistently present in the extracted evidence snippets for all listed NCTs.

13. Prevention

Primary prevention of genetically determined EBS is not currently feasible, but genetic counseling and prenatal diagnosis are discussed in diagnostic guidelines: DNA-based prenatal diagnosis is technically feasible for EB subtypes once familial pathogenic variants are known, subject to national regulations and family preference. (Has et al., 2019-08) (has2019clinicalpracticeguidelines pages 1-2).

14. Other species / natural disease

A spontaneous KRT5 insertion variant has been reported as a novel nonhuman primate model of EBS in rhesus macaques (Macaca mulatta). Two stillborn homozygous animals had widespread epidermal loss, intraepidermal clefts above the basement membrane, absent cytokeratin-5 immunoreactivity in epidermis, and a 34-bp insertion in exon 5 of KRT5 (HGVS-like c.1087_1088ins...). (Johnson et al., Vet Pathol, 2020-02, https://doi.org/10.1177/0300985819900354) (johnson2020spontaneouskrt5gene pages 1-3).

15. Model organisms

The rhesus macaque KRT5 model above provides a spontaneous large-animal model with histologic and molecular features consistent with basal-layer cleavage. (johnson2020spontaneouskrt5gene pages 1-3). Additional model systems (mouse models; zebrafish transgenesis) were referenced in retrieved literature but were not extracted into evidence snippets sufficient for detailed annotation in this run. (bchetnia2024pathologicalmechanismsinvolved pages 1-2).

Evidence table (knowledge-base ready)

The following table consolidates key, evidence-supported facts.

Category	Specific data points (with numbers)	Best supporting citation IDs
Identifiers/Classification	EBS is 1 of the 4 classical EB types; cleavage occurs within the basal layer of keratinocytes/intraepidermally. The 2020 consensus notes 7 genes associated with EBS.	(has2020consensusreclassificationof pages 2-3, has2020consensusreclassificationof pages 1-2, bchetnia2024pathologicalmechanismsinvolved pages 1-2)
Core definition	EBS is the most common EB subtype; one review cites ~70% of all EB, while a Dutch source cited in a patient-perspective review reports 45.7% of Dutch EB cases.	(bardhan2020epidermolysisbullosa pages 1-2, stock2024thepatientsperspective pages 4-7)
Major subtypes	Main clinical subtypes are localized, intermediate, and severe/generalized severe (historically Weber-Cockayne, Köebner, Dowling-Meara). In the German dataset, EBS subtypes were localized 39.5% and severe 14.7%; 33.4% lacked subclassification. In the China cohort, EBS cases were localized 17.5%, intermediate 35.0%, severe 27.2%.	(has2020consensusreclassificationof pages 2-3, bchetnia2024pathologicalmechanismsinvolved pages 1-2, has2023epidemiologyofinherited pages 5-6, chen2023genotypeandphenotype pages 2-2)
Key genes	Core genes: KRT5 and KRT14 are predominant; additional EBS genes include PLEC, KLHL24, DST, EXPH5, CD151. In a Middle Eastern cohort of 97 EBS patients, KRT5 accounted for 46% and KRT14 for 43% of EBS cases. In the China cohort, PLEC and KLHL24 were each mutated in 4 cases.	(bchetnia2024pathologicalmechanismsinvolved pages 1-2, bergson2023clinicalandmolecular pages 1-2, chen2023genotypeandphenotype pages 3-3)
Inheritance	Usually autosomal dominant; autosomal recessive forms also occur. In the German EB registry overall, inheritance counts were AD 222, AR 275, both 1, unavailable 53. In the China EB cohort, de novo mutations were high in EBS (63.8%) and mosaicism was reported in ~5.4% of dominant EBS.	(has2020consensusreclassificationof pages 2-3, bchetnia2024pathologicalmechanismsinvolved pages 1-2, has2023epidemiologyofinherited pages 5-6, chen2023genotypeandphenotype pages 1-1)
Epidemiology	Germany: overall EB incidence 45.09 per 1,000,000 live births (1 in 22,178); EBS incidence 14.93 per 1,000,000 live births (1:66,979). Germany prevalence estimates: overall EB 54.02/million; EBS 28.44/million. United States figures cited in reviews include incidence 8.2/million live births/year in newborn review, 11.1/million and prevalence 19.6/million in another review.	(has2023epidemiologyofinherited pages 5-6, has2023epidemiologyofinherited pages 7-7, lucky2021diagnosisandcare pages 1-2, rosa2023stairwaystoadvanced pages 1-3)
Diagnostics	Recommended neonatal workflow: skin biopsy for IFM plus blood for genetic testing in parallel. IFM can provide diagnosis within hours; biopsy sizes noted were 3-4 mm punch for IFM and 2-3 mm for EM. NGS-targeted EB panels typically have ~1 month turnaround. Genetic testing is always recommended; TEM is mainly for limited/inconclusive cases.	(lucky2021diagnosisandcare pages 3-5, has2019clinicalpracticeguidelines pages 1-2, has2019clinicalpracticeguidelines pages 6-7, has2019clinicalpracticeguidelines pages 4-6)
Mechanisms	Dominant KRT5/KRT14 mutations disrupt basal keratin intermediate filaments, causing keratin aggregates, ER stress, and pro-inflammatory signaling. Mechanistic pathways include IL-1β upregulation and JNK stress signaling; transcriptomic studies implicate inflammation, altered proliferation, differentiation, migration, and barrier homeostasis.	(NCT02470689 chunk 1, bchetnia2024pathologicalmechanismsinvolved pages 1-2, bchetnia2024pathologicalmechanismsinvolved pages 8-10)
Treatments/Trials	Diacerein: Phase 2 crossover trial NCT02470689 planned enrollment 50, ages 6-19, primary endpoint blister number at 4 weeks; prior pilot (n=5) reported blister reductions of -78% and -66% from baseline within 2 weeks. Long-term topical diacerein study NCT03389308 enrolled 51. TolaSure: Phase 1 NCT05062070 enrolled 6; Phase 2 NCT07027345 recruiting, enrollment 40. Sirolimus trial NCT03016715 enrolled 8. Botulinum toxin trials: NCT00936533 enrollment 40; NCT03453632 enrollment 25. Erythromycin Phase 3 NCT01340235 enrollment 8.	(NCT02470689 chunk 1, bardhan2020epidermolysisbullosa pages 20-21, bchetnia2024pathologicalmechanismsinvolved pages 10-12, bchetnia2024pathologicalmechanismsinvolved pages 13-14)
QoL burden	Global EBS survey: n=214, mean age 32.8 years. Reported blisters 93%, recurrent wounds 89%, pain 74%, chronic wounds 59%, itch 55%, difficulty walking 44%. Mean QOLEB score 14.7 (SD 7.5), indicating moderate impact; 12% required regular opiates.	(so2022aglobalcrosssectional pages 10-12)
Models/other species	Natural/experimental models include rhesus macaques with a 34-bp KRT5 insertion; 2 homozygous animals were stillborn with widespread epidermal loss, compared with 6 phenotypically normal heterozygotes. Other model systems referenced in retrieved literature include zebrafish transgenesis and mouse models of EBS-like disease.	(so2022aglobalcrosssectional pages 1-2)

Table: This table compiles core disease knowledge-base facts for epidermolysis bullosa simplex, including classification, epidemiology, genetics, diagnostics, mechanisms, therapies, and patient burden. Each row is limited to information supported by gathered evidence and linked to the best available context IDs.

Limitations of this report (evidence availability)

Disease identifiers (OMIM/Orphanet/ICD/MeSH/MONDO): not retrievable from the evidence excerpts available in this run; therefore, this section is incomplete.
Differential diagnosis and comprehensive subtype-specific prognostic statistics: not fully extractable from the retrieved snippets.
ClinicalTrials.gov metadata for every EBS trial (status/enrollment/endpoints): only partially extractable from available excerpts; one EBS diacerein trial record (NCT02470689) was captured in detail. (NCT02470689 chunk 1).

References

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(has2020consensusreclassificationof pages 1-2): C. Has, J.W. Bauer, C. Bodemer, M.C. Bolling, L. Bruckner‐Tuderman, A. Diem, J.‐D. Fine, A. Heagerty, A. Hovnanian, M.P. Marinkovich, A.E. Martinez, J.A. McGrath, C. Moss, D.F. Murrell, F. Palisson, A. Schwieger‐Briel, E. Sprecher, K. Tamai, J. Uitto, D.T. Woodley, G. Zambruno, and J.E. Mellerio. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. British Journal of Dermatology, 183:614-627, Mar 2020. URL: https://doi.org/10.1111/bjd.18921, doi:10.1111/bjd.18921. This article has 905 citations and is from a highest quality peer-reviewed journal.
(bchetnia2024pathologicalmechanismsinvolved pages 1-2): Mbarka Bchetnia, Julie Powell, Catherine McCuaig, Anne-Marie Boucher-Lafleur, Charles Morin, Audrey Dupéré, and Catherine Laprise. Pathological mechanisms involved in epidermolysis bullosa simplex: current knowledge and therapeutic perspectives. International Journal of Molecular Sciences, 25:9495, Aug 2024. URL: https://doi.org/10.3390/ijms25179495, doi:10.3390/ijms25179495. This article has 11 citations.
(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.
(has2023epidemiologyofinherited pages 7-7): Cristina Has, Moritz Hess, Waltraud Anemüller, Ulrike Blume‐Peytavi, Steffen Emmert, Regina Fölster‐Holst, Jorge Frank, Kathrin Giehl, Claudia Günther, Johanna Hammersen, Kathrin Hillmann, Bettina Höflein, Peter H. Hoeger, Alrun Hotz, Thuy Anh Mai, Vinzenz Oji, Holm Schneider, Kira Süßmuth, Iliana Tantcheva‐Póor, Frederieke Thielking, Birgit Zirn, Judith Fischer, and Antonia Reimer‐Taschenbrecker. Epidemiology of inherited epidermolysis bullosa in germany. Journal of the European Academy of Dermatology and Venereology, 37:402-410, Nov 2023. URL: https://doi.org/10.1111/jdv.18637, doi:10.1111/jdv.18637. This article has 56 citations and is from a domain leading peer-reviewed journal.
(so2022aglobalcrosssectional pages 1-2): Jodi Y. So, Shivali Fulchand, Christine Y. Wong, Shufeng Li, Jaron Nazaroff, Emily S. Gorell, Mark P. de Souza, Dedee F. Murrell, Joyce M. Teng, Albert S. Chiou, and Jean Y. Tang. A global, cross-sectional survey of patient-reported outcomes, disease burden, and quality of life in epidermolysis bullosa simplex. Orphanet Journal of Rare Diseases, Jul 2022. URL: https://doi.org/10.1186/s13023-022-02433-3, doi:10.1186/s13023-022-02433-3. This article has 21 citations and is from a peer-reviewed journal.
(NCT02470689 chunk 1): michal roll. Diacerin for the Treatment of Epidermolysis Bullosa Simplex. Tel-Aviv Sourasky Medical Center. 2015. ClinicalTrials.gov Identifier: NCT02470689
(chen2023genotypeandphenotype pages 1-1): Fuying Chen, Ruoqu Wei, Dan Deng, Xue Zhang, Yu Cao, Chaolan Pan, Yumeng Wang, Qiaoyu Cao, Jianbo Wang, Ming Zeng, Linting Huang, Yan Gu, Zhirong Yao, and Ming Li. Genotype and phenotype correlations in 441 patients with epidermolysis bullosa from china. Journal of the European Academy of Dermatology and Venereology, 37:411-419, Nov 2023. URL: https://doi.org/10.1111/jdv.18692, doi:10.1111/jdv.18692. This article has 26 citations and is from a domain leading peer-reviewed journal.
(has2023epidemiologyofinherited pages 5-6): Cristina Has, Moritz Hess, Waltraud Anemüller, Ulrike Blume‐Peytavi, Steffen Emmert, Regina Fölster‐Holst, Jorge Frank, Kathrin Giehl, Claudia Günther, Johanna Hammersen, Kathrin Hillmann, Bettina Höflein, Peter H. Hoeger, Alrun Hotz, Thuy Anh Mai, Vinzenz Oji, Holm Schneider, Kira Süßmuth, Iliana Tantcheva‐Póor, Frederieke Thielking, Birgit Zirn, Judith Fischer, and Antonia Reimer‐Taschenbrecker. Epidemiology of inherited epidermolysis bullosa in germany. Journal of the European Academy of Dermatology and Venereology, 37:402-410, Nov 2023. URL: https://doi.org/10.1111/jdv.18637, doi:10.1111/jdv.18637. This article has 56 citations and is from a domain leading peer-reviewed journal.
(chen2023genotypeandphenotype pages 2-2): Fuying Chen, Ruoqu Wei, Dan Deng, Xue Zhang, Yu Cao, Chaolan Pan, Yumeng Wang, Qiaoyu Cao, Jianbo Wang, Ming Zeng, Linting Huang, Yan Gu, Zhirong Yao, and Ming Li. Genotype and phenotype correlations in 441 patients with epidermolysis bullosa from china. Journal of the European Academy of Dermatology and Venereology, 37:411-419, Nov 2023. URL: https://doi.org/10.1111/jdv.18692, doi:10.1111/jdv.18692. This article has 26 citations and is from a domain leading peer-reviewed journal.
(so2022aglobalcrosssectional pages 6-8): Jodi Y. So, Shivali Fulchand, Christine Y. Wong, Shufeng Li, Jaron Nazaroff, Emily S. Gorell, Mark P. de Souza, Dedee F. Murrell, Joyce M. Teng, Albert S. Chiou, and Jean Y. Tang. A global, cross-sectional survey of patient-reported outcomes, disease burden, and quality of life in epidermolysis bullosa simplex. Orphanet Journal of Rare Diseases, Jul 2022. URL: https://doi.org/10.1186/s13023-022-02433-3, doi:10.1186/s13023-022-02433-3. This article has 21 citations and is from a peer-reviewed journal.
(bergson2023clinicalandmolecular pages 1-2): Shir Bergson, Daniel Daniely, David Bomze, Janan Mohamad, Kiril Malovitski, Odile Meijers, Valeria Briskin, Ofer Bihari, Natalia Malchin, Shirli Israeli, Jacob Mashiah, Tzipora Falik‐Zaccai, Emily Avitan‐Hersh, Marina Eskin‐Schwartz, Stavit Allon‐Shalev, Ofer Sarig, Eli Sprecher, and Liat Samuelov. Clinical and molecular features in a cohort of middle eastern patients with epidermolysis bullosa. Pediatric Dermatology, 40:1021-1027, Oct 2023. URL: https://doi.org/10.1111/pde.15440, doi:10.1111/pde.15440. This article has 6 citations and is from a peer-reviewed journal.
(chen2023genotypeandphenotype pages 3-3): Fuying Chen, Ruoqu Wei, Dan Deng, Xue Zhang, Yu Cao, Chaolan Pan, Yumeng Wang, Qiaoyu Cao, Jianbo Wang, Ming Zeng, Linting Huang, Yan Gu, Zhirong Yao, and Ming Li. Genotype and phenotype correlations in 441 patients with epidermolysis bullosa from china. Journal of the European Academy of Dermatology and Venereology, 37:411-419, Nov 2023. URL: https://doi.org/10.1111/jdv.18692, doi:10.1111/jdv.18692. This article has 26 citations and is from a domain leading peer-reviewed journal.
(chen2023genotypeandphenotype pages 4-4): Fuying Chen, Ruoqu Wei, Dan Deng, Xue Zhang, Yu Cao, Chaolan Pan, Yumeng Wang, Qiaoyu Cao, Jianbo Wang, Ming Zeng, Linting Huang, Yan Gu, Zhirong Yao, and Ming Li. Genotype and phenotype correlations in 441 patients with epidermolysis bullosa from china. Journal of the European Academy of Dermatology and Venereology, 37:411-419, Nov 2023. URL: https://doi.org/10.1111/jdv.18692, doi:10.1111/jdv.18692. This article has 26 citations and is from a domain leading peer-reviewed journal.
(rosa2023stairwaystoadvanced pages 1-3): Laura De Rosa, Elena Enzo, Michele Palamenghi, Laura Sercia, and Michele De Luca. Stairways to advanced therapies for epidermolysis bullosa. Cold Spring Harbor perspectives in biology, 15:a041229, Sep 2023. URL: https://doi.org/10.1101/cshperspect.a041229, doi:10.1101/cshperspect.a041229. This article has 14 citations and is from a peer-reviewed journal.
(has2019clinicalpracticeguidelines pages 6-7): 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.
(lucky2021diagnosisandcare pages 3-5): Anne W. Lucky, Jean Whalen, Susan Rowe, Kalyani S. Marathe, and Emily Gorell. Diagnosis and care of the newborn with epidermolysis bullosa. NeoReviews, 22 7:e438-e451, Jul 2021. URL: https://doi.org/10.1542/neo.22-7-e438, doi:10.1542/neo.22-7-e438. This article has 44 citations.
(has2019clinicalpracticeguidelines pages 10-11): 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.
(has2023epidemiologyofinherited pages 7-8): Cristina Has, Moritz Hess, Waltraud Anemüller, Ulrike Blume‐Peytavi, Steffen Emmert, Regina Fölster‐Holst, Jorge Frank, Kathrin Giehl, Claudia Günther, Johanna Hammersen, Kathrin Hillmann, Bettina Höflein, Peter H. Hoeger, Alrun Hotz, Thuy Anh Mai, Vinzenz Oji, Holm Schneider, Kira Süßmuth, Iliana Tantcheva‐Póor, Frederieke Thielking, Birgit Zirn, Judith Fischer, and Antonia Reimer‐Taschenbrecker. Epidemiology of inherited epidermolysis bullosa in germany. Journal of the European Academy of Dermatology and Venereology, 37:402-410, Nov 2023. URL: https://doi.org/10.1111/jdv.18637, doi:10.1111/jdv.18637. This article has 56 citations and is from a domain leading peer-reviewed journal.
(bardhan2020epidermolysisbullosa pages 1-2): Ajoy Bardhan, Leena Bruckner-Tuderman, Iain L. C. Chapple, Jo-David Fine, Natasha Harper, Cristina Has, Thomas M. Magin, M. Peter Marinkovich, John F. Marshall, John A. McGrath, Jemima E. Mellerio, Rex Polson, and Adrian H. Heagerty. Epidermolysis bullosa. Nature Reviews Disease Primers, 6:1-27, Sep 2020. URL: https://doi.org/10.1038/s41572-020-0210-0, doi:10.1038/s41572-020-0210-0. This article has 551 citations.
(bchetnia2024pathologicalmechanismsinvolved pages 10-12): Mbarka Bchetnia, Julie Powell, Catherine McCuaig, Anne-Marie Boucher-Lafleur, Charles Morin, Audrey Dupéré, and Catherine Laprise. Pathological mechanisms involved in epidermolysis bullosa simplex: current knowledge and therapeutic perspectives. International Journal of Molecular Sciences, 25:9495, Aug 2024. URL: https://doi.org/10.3390/ijms25179495, doi:10.3390/ijms25179495. This article has 11 citations.
(bchetnia2024pathologicalmechanismsinvolved pages 13-14): Mbarka Bchetnia, Julie Powell, Catherine McCuaig, Anne-Marie Boucher-Lafleur, Charles Morin, Audrey Dupéré, and Catherine Laprise. Pathological mechanisms involved in epidermolysis bullosa simplex: current knowledge and therapeutic perspectives. International Journal of Molecular Sciences, 25:9495, Aug 2024. URL: https://doi.org/10.3390/ijms25179495, doi:10.3390/ijms25179495. This article has 11 citations.
(bardhan2020epidermolysisbullosa pages 20-21): Ajoy Bardhan, Leena Bruckner-Tuderman, Iain L. C. Chapple, Jo-David Fine, Natasha Harper, Cristina Has, Thomas M. Magin, M. Peter Marinkovich, John F. Marshall, John A. McGrath, Jemima E. Mellerio, Rex Polson, and Adrian H. Heagerty. Epidermolysis bullosa. Nature Reviews Disease Primers, 6:1-27, Sep 2020. URL: https://doi.org/10.1038/s41572-020-0210-0, doi:10.1038/s41572-020-0210-0. This article has 551 citations.
(johnson2020spontaneouskrt5gene pages 1-3): Amanda L. Johnson, Samuel M. Peterson, Margaret M. L. Terry, Betsy Ferguson, Lois M. Colgin, and Anne D. Lewis. Spontaneous krt5 gene mutation in rhesus macaques (macaca mulatta): a novel nonhuman primate model of epidermolysis bullosa simplex. Veterinary Pathology, 57:344-348, Feb 2020. URL: https://doi.org/10.1177/0300985819900354, doi:10.1177/0300985819900354. This article has 8 citations and is from a domain leading peer-reviewed journal.
(stock2024thepatientsperspective pages 4-7): C Stock. The patient's perspective: a review on epidermolysis bullosa patients' needs as input towards harmonization of outcomes. Unknown journal, 2024.
(lucky2021diagnosisandcare pages 1-2): Anne W. Lucky, Jean Whalen, Susan Rowe, Kalyani S. Marathe, and Emily Gorell. Diagnosis and care of the newborn with epidermolysis bullosa. NeoReviews, 22 7:e438-e451, Jul 2021. URL: https://doi.org/10.1542/neo.22-7-e438, doi:10.1542/neo.22-7-e438. This article has 44 citations.
(has2019clinicalpracticeguidelines pages 4-6): 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.
(bchetnia2024pathologicalmechanismsinvolved pages 8-10): Mbarka Bchetnia, Julie Powell, Catherine McCuaig, Anne-Marie Boucher-Lafleur, Charles Morin, Audrey Dupéré, and Catherine Laprise. Pathological mechanisms involved in epidermolysis bullosa simplex: current knowledge and therapeutic perspectives. International Journal of Molecular Sciences, 25:9495, Aug 2024. URL: https://doi.org/10.3390/ijms25179495, doi:10.3390/ijms25179495. This article has 11 citations.
(so2022aglobalcrosssectional pages 10-12): Jodi Y. So, Shivali Fulchand, Christine Y. Wong, Shufeng Li, Jaron Nazaroff, Emily S. Gorell, Mark P. de Souza, Dedee F. Murrell, Joyce M. Teng, Albert S. Chiou, and Jean Y. Tang. A global, cross-sectional survey of patient-reported outcomes, disease burden, and quality of life in epidermolysis bullosa simplex. Orphanet Journal of Rare Diseases, Jul 2022. URL: https://doi.org/10.1186/s13023-022-02433-3, doi:10.1186/s13023-022-02433-3. This article has 21 citations and is from a peer-reviewed journal.

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OpenScientist Report

Classifications

Mappings

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Prevalence

Related Datasets

Clinical Trials

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Comprehensive Disease Characteristics Report: Epidermolysis Bullosa Simplex (EBS)

Executive summary

1. Disease information

1.1 What is the disease?

1.2 Key identifiers (OMIM, Orphanet, ICD-10/ICD-11, MeSH, MONDO)

1.3 Common synonyms / alternative names

1.4 Evidence source type

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Phenotype spectrum and subtype distribution

3.2 Common clinical manifestations (patient-reported)

3.3 Quality of life impact

3.4 Suggested HPO terms (examples; not exhaustive)

4. Genetic / molecular information

4.1 Causal genes (major)

4.2 Other reported EBS genes

4.3 Pathogenic variant types and genotype–phenotype considerations

4.4 Suggested ontology/annotation terms

5. Environmental information

6. Mechanism / pathophysiology (current understanding, 2023–2024 emphasis)

6.1 Core causal chain (structural fragility)

6.2 Inflammatory/stress signaling cascades (important recent framing)

6.3 Transcriptomics / molecular profiling

7. Anatomical structures affected

7.1 Organ/tissue level

7.2 Suggested UBERON terms (examples)

7.3 Suggested GO cellular component terms (examples)

8. Temporal development (onset and progression)

9. Inheritance and population

9.1 Inheritance pattern

9.2 Epidemiology (recent quantitative estimates)

10. Diagnostics

10.1 Diagnostic approach (guidelines and current practice)

10.2 Differential diagnosis

11. Outcomes / prognosis

12. Treatment

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

12.2 Drug repurposing and targeted therapies in EBS (selected examples)