Inherited epidermolysis bullosa: Updated recommendations on diagnosis and classification

doi:10.1016/j.jaad.2014.01.903

Journal of the American Academy of Dermatology

Volume 70, Issue 6, June 2014, Pages 1103-1126

, , , , , , , , , , , , , , , , , , , …

https://doi.org/10.1016/j.jaad.2014.01.903 Get rights and content

Background

Several new targeted genes and clinical subtypes have been identified since publication in 2008 of the report of the last international consensus meeting on diagnosis and classification of epidermolysis bullosa (EB). As a correlate, new clinical manifestations have been seen in several subtypes previously described.

Objective

We sought to arrive at an updated consensus on the classification of EB subtypes, based on newer data, both clinical and molecular.

Results

In this latest consensus report, we introduce a new approach to classification (“onion skinning”) that takes into account sequentially the major EB type present (based on identification of the level of skin cleavage), phenotypic characteristics (distribution and severity of disease activity; specific extracutaneous features; other), mode of inheritance, targeted protein and its relative expression in skin, gene involved and type(s) of mutation present, and–when possible–specific mutation(s) and their location(s).

Limitations

This classification scheme critically takes into account all published data through June 2013. Further modifications are likely in the future, as more is learned about this group of diseases.

Conclusion

The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and molecular features of each EB subtype, and has sufficient flexibility incorporated in its structure to permit further modifications in the future.

Section snippets

Major EB types

We recommend that the currently used names for the 4 major EB types–EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler–be retained, so as to maintain continuity with decades of clinical and basic scientific literature and to prevent any confusion or ambiguity arising among patients; EB support organizations; medical, nursing, and other clinical colleagues; governmental agencies; and third-party insurers. Changing those names would add little or no value and might prove

Diagnostic testing in EB

Diagnostic testing and classification in EB begin with the identification of the level of skin cleavage via immunofluorescence antigen mapping (IFM) and/or transmission electron microscopy on preferably newly induced blisters. The use of monoclonal antibodies directed against components of the skin BMZ and epidermal antigens can further facilitate subclassification, because skin samples from most of the EB subtypes vary in the intensity of antigen staining (if even present) of specific

“Onion skin” approach to classification

Initial attempts at the classification of patients with EB at the bedside are based on personal and family history and the presence or absence of specific clinical features, both cutaneous and extracutaneous. Only later, once more sophisticated laboratory testing has been performed, is it possible to subclassify these patients more accurately. As with any other disease, a physician sees, listens to, and examines a patient suspected of having EB; generates a differential diagnosis; and then

Elimination of eponyms and other proposed name changes

Since the first description of EB in 1886, as new EB phenotypes were recognized it became a common practice to attach the name(s) of the clinician(s) who first reported them. A similar tradition has existed in many medical and surgical specialties in the naming of rare syndromes and surgical procedures. Unfortunately, although some eponyms immediately bring to mind specific phenotypic features, and their use honors those who astutely first recognized these conditions, eponyms have no immediate

Updated summaries of the clinical and laboratory findings in EB subtypes

Table X, Table XI, Table XII, Table XIII summarize the clinical findings on each of the major EB subtypes. Similar tables on the minor or rarer subtypes may be found in Table XIV, Table XIX, Table XV, Table XVI, Table XVII, Table XVIII, Table XX, Table XXI, Table XXII, Table XXIII, Table XXIV, Table XXV, Table XXVI. Although we have made every effort to ensure that the descriptions are correct for each subtype, we recognize that new clinical findings or associations may be reported in the

Other reported but not yet adopted EB subtypes

The recent literature contains several case reports, based on the findings in 1 or only a small number of patients, proposing the existence of other EB subtypes. We critically reviewed each of these reports and have incorporated as new entities those that presented sufficient documentation to merit inclusion at this time. Others must await more rigorous confirmation. As an example, 2 children reported as having pretibial EB and renal disease were shown to have mutations in the gene encoding for

Summary

This revised classification of EB incorporates several new genetic subtypes. Where possible we have replaced eponyms with descriptive terms. We hope our proposed systematic onion skin approach using successive layers of clinical, immunohistochemical, and molecular findings will prove useful to both clinicians and researchers, and adaptable to future discoveries.

References (32)

J.-D. Fine et al.
The classification of inherited epidermolysis bullosa (EB): report of the third international consensus meeting on diagnosis and classification of EB
J Am Acad Dermatol
(2008)
R.W. Pearson
Studies on the pathogenesis of epidermolysis bullosa
J Invest Dermatol
(1962)
V. Karamatic Crew et al.
CD151, the first member of the tetraspan (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin
Blood
(2004)
M. Ayub et al.
A homozygous nonsense mutation in the human desmocollin-3 (DSC3) gene underlies hereditary hypotrichosis and recurrent skin vesicles
Am J Hum Genet
(2009)
A.S. Payne
No evidence of skin blisters with human desmocollin-3 gene mutation
Am J Hum Genet
(2010)
D.C. Blaydon et al.
Mutations in CSTA, encoding cystatin A, underlie exfoliative ichthyosis and reveal a role for this protease inhibitor in cell-cell adhesion
Am J Hum Genet
(2011)
R.M. Cabral et al.
Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome
Genomics
(2012)
N.J. Wilson et al.
Keratin K6c mutations cause focal palmoplantar keratoderma
J Invest Dermatol
(2010)
D. Kiritsi et al.
Acral peeling skin syndrome with TGM5 gene mutations may resemble epidermolysis bullosa simplex in young individuals
J Invest Dermatol
(2010)
R.P. Hobbs et al.
Insights from a desmoplakin mutation identified in lethal acantholytic epidermolysis bullosa
J Invest Dermatol
(2010)

M. Pigors et al.

TGM5 mutations impact epidermal differentiation in acral peeling skin syndrome

J Invest Dermatol

(2012)

J.A. McGrath et al.

Ectodermal dysplasia-skin fragility syndrome

Dermatol Clin

(2010)

J.A. McGrath et al.

Germline mutation in EXPH5 implicates the Rab27B effector protein Slac2-b in inherited skin fragility

Am J Hum Genet

(2012)

M. Pigors et al.

Molecular heterogeneity of epidermolysis bullosa simplex: contribution of EXPH5 mutations

J Invest Dermatol

(2014)

R.W. Groves et al.

A homogeneous 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

J Invest Dermatol

(2010)

J.-D. Fine et al.

Inherited epidermolysis bullosa (EB) and the risk of life-threatening skin-derived cancers: experience of the National EB Registry, 1986-2006

J Am Acad Dermatol

(2009)

Cited by (688)

Allele-specific CRISPR-Cas9 editing of dominant epidermolysis bullosa simplex in human epidermal stem cells
2024, Molecular Therapy
Epidermolysis bullosa simplex (EBS) is a rare skin disease inherited mostly in an autosomal dominant manner. Patients display a skin fragility that leads to blisters and erosions caused by minor mechanical trauma. EBS phenotypic and genotypic variants are caused by genetic defects in intracellular proteins whose function is to provide the attachment of basal keratinocytes to the basement membrane zone and most EBS cases display mutations in keratin 5 (KRT5) and keratin 14 (KRT14) genes. Besides palliative treatments, there is still no long-lasting effective cure to correct the mutant gene and abolish the dominant negative effect of the pathogenic protein over its wild-type counterpart. Here, we propose a molecular strategy for EBS01 patient’s keratinocytes carrying a monoallelic c.475/495del21 mutation in KRT14 exon 1. Through the CRISPR-Cas9 system, we perform a specific cleavage only on the mutant allele and restore a normal cellular phenotype and a correct intermediate filament network, without affecting the epidermal stem cell, referred to as holoclones, which play a crucial role in epidermal regeneration.
Beyond the Surface: A Narrative Review Examining the Systemic Impacts of Recessive Dystrophic Epidermolysis Bullosa
2024, Journal of Investigative Dermatology
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease resulting from inadequate type VII collagen (C7). Although recurrent skin blisters and wounds are the most apparent disease features, the impact of C7 loss is not confined to the skin and mucous membranes. RDEB is a systemic disease marred by chronic inflammation, fibrotic changes, pain, itch, and anemia, significantly impacting QOL and survival. In this narrative review, we summarize these systemic features of RDEB and promising research avenues to address them.
Highly Efficient Ex Vivo Correction of COL7A1 through Ribonucleoprotein-Based CRISPR/Cas9 and Homology-Directed Repair to Treat Recessive Dystrophic Epidermolysis Bullosa
2024, Journal of Investigative Dermatology
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and severe genetic skin disease responsible for blistering of the skin and mucosa after minor trauma. RDEB is caused by a wide variety of variants in COL7A1 encoding type VII Collagen, the major component of anchoring fibrils that form key attachment structures for dermal–epidermal adherence. In this study, we achieved highly efficient COL7A1 editing in primary RDEB keratinocytes and fibroblasts from 2 patients homozygous for the c.6508C>T (p.Gln2170∗) variant through CRISPR/Cas9-mediated homology-directed repair. Three guide RNAs targeting the c.6508C>T variant or harboring sequences were delivered together with high-fidelity Cas9 as a ribonucleoprotein complex. Among them, one achieved 73% cleavage activity in primary RDEB keratinocytes and RDEB fibroblasts. Then, we treated RDEB keratinocytes and RDEB fibroblasts with this specific ribonucleoprotein complex and the corresponding donor template delivered as single-stranded oligodeoxynucleotide and achieved up to 58% of genetic correction as well as type VII Collagen rescue. Finally, grafting of corrected 3-dimensional skin onto nude mice induced re-expression and normal localization of type VII Collagen as well as anchoring fibril formation at the dermal–epidermal junction 5 and 10 weeks after grafting. With this promising nonviral approach, we achieved therapeutically relevant specific gene editing that could be applicable to all variants in exon 80 of COL7A1 in primary RDEB cells.
Genotype–Phenotype Correlation in Junctional Epidermolysis Bullosa: Signposts to Severity
2024, Journal of Investigative Dermatology
Junctional epidermolysis bullosa (JEB) is a rare autosomal recessive genodermatosis with a broad spectrum of phenotypes. Current genotype–phenotype paradigms are insufficient to accurately predict JEB subtype and characteristics from genotype, particularly for splice site variants, which account for over a fifth of disease-causing variants in JEB. This study evaluated the genetic and clinical findings from a JEB cohort, investigating genotype–phenotype correlations through bioinformatic analyses and comparison with previously reported variants. Eighteen unique variants in LAMB3, LAMA3, LAMC2, or COL17A1 were identified from 17 individuals. Seven had severe JEB, 9 had intermediate JEB, and 1 had laryngo–onycho–cutaneous syndrome. Seven variants were previously unreported. Deep phenotyping was completed for all intermediate JEB cases and demonstrated substantial variation between individuals. Splice site variants underwent analysis with SpliceAI, a state-of-the-art artificial intelligence tool, to predict resultant transcripts. Predicted functional effects included exon skipping and cryptic splice site activation, which provided potential explanations for disease severity and in most cases correlated with laminin-332 immunofluorescence. RT-PCR was performed for 1 case to investigate resultant transcripts produced from the splice site variant. This study expands the JEB genomic and phenotypic landscape. Artificial intelligence tools show potential for predicting the functional effects of splice site variants and may identify candidates for confirmatory laboratory investigation. Investigation of RNA transcripts will help to further elucidate genotype–phenotype correlations for novel variants.
Type VII Collagen Deficiency in the Oncogenesis of Cutaneous Squamous Cell Carcinoma in Dystrophic Epidermolysis Bullosa
2023, Journal of Investigative Dermatology
Dystrophic epidermolysis bullosa is a rare genetic skin disorder caused by COL7A1 sequence variations that result in type VII collagen deficits and cutaneous and extracutaneous manifestations. One serious complication of dystrophic epidermolysis bullosa is cutaneous squamous cell carcinoma, a leading driver of morbidity and mortality, especially among patients with recessive dystrophic epidermolysis bullosa. Type VII collagen deficits alter TGFβ signaling and evoke multiple other cutaneous squamous cell carcinoma progression–promoting activities within epidermal microenvironments. This review examines cutaneous squamous cell carcinoma pathophysiology in dystrophic epidermolysis bullosa with a focus on known oncogenesis pathways at play and explores the idea that therapeutic type VII collagen replacement may reduce cutaneous squamous cell carcinoma risk.
Extracellular matrix in skin diseases: The road to new therapies
2023, Journal of Advanced Research
Citation Excerpt :
Epidermolysis bullosa (EB) forms another group of genetic disorders yet characterized by skin blistering. Blisters result from dermal-epidermal separation after minor trauma due to mutations in proteins composing the or associated with BM [6]. Up to now, EB has been linked to mutations in 18 distinct genes and classified into four major types according to the ultrastructural level of skin blistering: above (epidermolysis bullosa simplex- EBS), at (junctional EB - JEB), below (dystrophic EB - DEB), or at multiple sites of (Kindler EB) the BM [6].
The extracellular matrix (ECM) is a vital structure with a dynamic and complex organization that plays an essential role in tissue homeostasis. In the skin, the ECM is arranged into two types of compartments: interstitial dermal matrix and basement membrane (BM). All evidence in the literature supports the notion that direct dysregulation of the composition, abundance or structure of one of these types of ECM, or indirect modifications in proteins that interact with them is linked to a wide range of human skin pathologies, including hereditary, autoimmune, and neoplastic diseases. Even though the ECM’s key role in these pathologies has been widely documented, its potential as a therapeutic target has been overlooked.
This review discusses the molecular mechanisms involved in three groups of skin ECM-related diseases - genetic, autoimmune, and neoplastic – and the recent therapeutic progress and opportunities targeting ECM.
This article describes the implications of alterations in ECM components and in BM-associated molecules that are determinant for guaranteeing its function in different skin disorders. Also, ongoing clinical trials on ECM-targeted therapies are discussed together with future opportunities that may open new avenues for treating ECM-associated skin diseases.

View all citing articles on Scopus

: Funding sources: None. (Although the authors have acknowledged in other unrelated publications their extramural support for their own epidermolysis bullosa–related research programs, none of these has provided funding for the Consensus Conference or the generation of this report.)

: Conflicts of interest: None declared.

: Reprints not available from the authors.

View full text

ReviewInherited epidermolysis bullosa: Updated recommendations on diagnosis and classification

Background

Objective

Results

Limitations

Conclusion

Section snippets

Major EB types

Diagnostic testing in EB

“Onion skin” approach to classification

Elimination of eponyms and other proposed name changes

Updated summaries of the clinical and laboratory findings in EB subtypes

Other reported but not yet adopted EB subtypes

Summary

J Am Acad Dermatol

J Invest Dermatol

Blood

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Genomics

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

Dermatol Clin

Am J Hum Genet

J Invest Dermatol

J Invest Dermatol

J Am Acad Dermatol

Review
Inherited epidermolysis bullosa: Updated recommendations on diagnosis and classification