Pediatric Epidermolysis Bullosa 

  • Author: Surasak Puvabanditsin, MD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Aug 17, 2011
 

Background

Epidermolysis bullosa (EB) is a rare group of inherited disorders that manifests as blistering or erosion of the skin and, in some cases, the epithelial lining of other organs, in response to little or no apparent trauma.

Categorizations of the types of epidermolysis bullosa were once controversial and often confusing because more than 20 types of epidermolysis bullosa have been described. The following major types of epidermolysis bullosa have been identified:

  • Epidermolytic - Epidermolysis bullosa simplex (EBS)
  • Lucidolytic - Junctional epidermolysis bullosa (JEB)
  • Dermolytic - Dystrophic epidermolysis bullosa (DEB)

These major types were based on the precise ultrastructural level at which the split responsible for blistering occurs.

The 3 main types of epidermolysis bullosa were clinically and histologically delineated by the 1960s.[1] In the 1970s, electron microscopy revealed abnormal epidermal keratin filaments in epidermolysis bullosa simplex, disordered dermal anchoring fibrils in dystrophic epidermolysis bullosa, and defective hemidesmosomes in junctional epidermolysis bullosa. Antigens identified with immunohistochemistry in the 1980s[2, 3] led to discovery of the major epidermolysis bullosa genes in the 1990s.[4, 5, 6]

The identified genes include those that encode keratins 5 and 14 in epidermolysis bullosa simplex, collagen VII in dystrophic epidermolysis bullosa, and laminin 5 in Herlitz junctional epidermolysis bullosa. Toward the end of millennium, as the complex structure of desmosomes and hemidesmosomes was unraveled, the genes responsible for the rare subtypes were found, including those that encode α6β4 integrin in epidermolysis bullosa with pyloric atresia, plectin in epidermolysis bullosa with muscular dystrophy, and plakophilin in epidermolysis bullosa with ectodermal dysplasia.

During the past few years, systemic data collection and analysis have been performed on several thousands of patients with epidermolysis bullosa worldwide, and more than 1000 mutations, encompassing more than 10 structural genes, have now been documented. More has been learned about the molecular basis of epidermolysis bullosa, this group of diseases shares clinical or molecular features with several other genodermatoses. The leading authority on epidermolysis bullosa has included Kindler syndrome as the fourth major epidermolysis bullosa type.[7]

Eponyms associated with different forms of epidermolysis bullosa include the following:

  • Dowling-Meara
  • Köebner
  • Weber-Cockayne
  • Kallin
  • Mendes de Costa
  • Herlitz
  • Ogna
  • Carmi
  • Cockayne-Touraine
  • Pasini
  • Hallopeau-Siemens
  • Shabbir
  • Laryngoonychocutaneous (LOC)
  • Kindler
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Pathophysiology

Cytolysis causes blisters in the epidermis or basement membrane zone of the skin. In epidermolysis bullosa simplex, cytolysis causes blisters in the basal or spinous layers of the epidermis, and keratinocytes often have abnormal density and organization of keratin filaments. In junctional epidermolysis bullosa, the epidermis separates from the basal lamina, forming a blister cavity in the plane of the lamina lucida, where hemidesmosome structure and density are frequently diminished. In dystrophic epidermolysis bullosa, the basal lamina remains attached to the epidermis, but the blister cavity forms beneath the lamina densa of dermoepidermal junction, and anchoring fibrils may appear abnormal, reduced in number, or altogether absent.

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Epidemiology

Frequency

United States

The exact prevalence of epidermolysis bullosa is unknown. Mild variants have been estimated to occur as frequently as 1 per 50,000 births. The more severe varieties are believed to occur in 1 per 500,000 births annually.

Between 1986-2002 the National Institutes of Health (NIH) funded the National EB Registry (NEBR), a cross-sectional and longitudinal epidemiological study of EB patients across the entire continental United States. Nearly 3300 EB patients were identified, enrolled, classified, clinically characterized, and followed for outcomes. The prevalence and incidence of EB was estimated as approximately 8 cases per 1 million population and 19 cases per 1 million live births, in 1990 and 1986-1990, respectively.[8] These data were then used to estimate carrier frequencies for EB within the United States.

International

The point prevalence of all forms of EB in Scotland was 49.0 cases per million, comprising EB simplex at 28.6 cases per million and dystrophic EB at 20.4 cases per million population.[9]

The incidence rate of new cases of EB diagnosed per year in Northern Ireland during a 23-year period (1962-84) is 1.4 cases per million and the prevalence of all forms estimated at 32 cases per million population. The prevalence of simplex, junctional, and dystrophic forms is 28 cases, 0.7 cases, and 3 cases per million population, respectively.[10]

The estimated prevalence of each type of EB in Japan was as follows: simplex type, 2.9-4 cases per million population; junctional type, 0.15-0.20 cases per million population; dominant dystrophic type, 1.1-1.5 cases per million population; and recessive dystrophic type, 1.5-2.1 cases per million population.[11]

The prevalence of EB in Croatia, Yugoslavia, from 1960-1987 is 9.5 cases per million population.[12]

Mortality/Morbidity

Depending on the type of epidermolysis bullosa, disease severity may range from occasional mild blistering of the hands and feet to severe and widespread formation of bullae. These lesions may result in nonhealing erosions, infection, scarring, and joint contracture. Death may occur during infancy or early childhood, due to sepsis, renal failure, upper airway occlusion, or failure to thrive.[13, 14] Mortality is also related to the abnormalities or anomalies associated with epidermolysis bullosa. The most significant morbidity in adults with epidermolysis bullosa, especially recessive dystrophic epidermolysis bullosa, is cutaneous squamous cell carcinoma (SCC). By mid adulthood, nearly all individuals with dystrophic epidermolysis bullosa have had one SCC, and nearly 80% die of metastatic SCC.[15]

Healing of dystrophic epidermolysis bullosa results in dystrophic or scarring change. In epidermolysis bullosa simplex, when blisters cleave in the epidermis, healing occurs without scarring. In junctional epidermolysis bullosa, when blisters cleave below the epidermis but above the basal lamina, blistering leads to mild atrophic changes.

Race

The epidermolysis bullosa simplex Ogna variant has been described in Norwegian individuals.

Sex

Epidermolysis bullosa is an autosomal inherited disorder. The incidence does not differ by sex.

Age

The onset of epidermolysis bullosa simplex is at birth or early infancy. The onset of junctional epidermolysis bullosa is at birth. The onset of dystrophic epidermolysis bullosa is at birth or early childhood. The onset of Kindler syndrome is usually within the first year of life.

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Contributor Information and Disclosures
Author

Surasak Puvabanditsin, MD  Assistant Professor of Pediatrics, UMDNJ-New Jersey Medical School; Associate Professor of Pediatrics, St George's University School of Medicine, Grenada; Associate Professor of Pediatrics, Seton Hall University School of Graduate Medical Education

Surasak Puvabanditsin, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Coauthor(s)

Erik Brandsma, MD  Fellow, Division of Neonatology, Department of Peditrics, UMDNJ-Robert Wood Johnson Medical School

Disclosure: Nothing to disclose.

Nisha Patel, MD  Resident Physician, Westchester Medical Center, Maria Ferrari Children's Hospital

Nisha Patel, MD is a member of the following medical societies: American Medical Student Association/Foundation and Phi Beta Kappa

Disclosure: Nothing to disclose.

Rungtiwa Weerasethsiri, MD  General Pediatrician, Merced Facuty Associates, California

Rungtiwa Weerasethsiri, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Alexis A D'Elia, MD  Resident Physician, Department of Internal Medicine, Winthrop University Hospital

Alexis A D'Elia, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Specialty Editor Board

Kevin P Connelly, DO  Clinical Assistant Professor, Department of Pediatrics, Division of General Pediatrics and Emergency Care, Virginia Commonwealth University School of Medicine; Medical Director, Paws for Health Pet Visitation Program of the Richmond SPCA; Pediatric Emergency Physician, Emergency Consultants Inc, Chippenham Medical Center

Kevin P Connelly, DO is a member of the following medical societies: American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Merrily P M Poth, MD  Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Acknowledgments

The authors thank Judy Wilkinson, librarian at the Jersey City Medical Center, for her assistance. The authors also thank Sylvia Sutton-Thorpe Chrystal Puvabandistin and Christina Puvabanditsin for supporting this effort and preparing the manuscript.

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous coauthor Eugene Garrow, MD, to the original writing and development of this article.

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Ruptured bulla and newly erupted bulla of the leg in a newborn with epidermolysis bullosa simplex (EBS).
Dystrophic epidermolysis bullosa (DEB) with multiple blisters and erosions.
Dystrophic epidermolysis bullosa (DEB) with generalized blistering and erosion.
Dystrophic epidermolysis bullosa (DEB) that subsequently healed, with scarring.
Junctional epidermolysis bullosa (JEB). Image shows a newborn with bulla of the finger, the usual site of blistering secondary to trauma.
Junctional epidermolysis bullosa (JEB) with an associated defect of a congenital absence of the skin.
Junctional epidermolysis bullosa (JEB) with an associated defect of a congenital absence of the skin and an ear anomaly.
Contrast-enhanced radiograph of the abdomen suggestive of pyloric atresia (PA) in a patient with junctional epidermolysis bullosa (JEB). The association between PA and EB is a distinct entity and is now referred to as PA-EB syndrome.
Electron micrograph of a skin sample shows cleavage in the intralaminar lucida in a neonate with junctional epidermolysis bullosa (JEB).
Dystrophic nails in a neonate with junctional epidermolysis bullosa (EB).
Congenital localized absence of skin, nose, in a neonate with junctional epidermolysis bullosa (JEB).
Ruptured bullae on the abdomen in a neonate with junctional epidermolysis bullosa (JEB).
A large bullae on the elbow in a neonate with junctional epidermolysis bullosa (JEB).
Congenital localized absence of skin on the scrotum in a neonate with junctional epidermolysis bullosa (JEB). Absence of the foreskin was also noted.
Severe right hydronephrosis in a neonate with junctional epidermolysis bullosa (JEB).
Genitourinary obstruction in a fetus with junctional epidermolysis bullosa (JEB). Prenatal ultrasonography reveals severe right hydronephrosis.
Ruptured bulla of the hand in a newborn with epidermolysis bullosa simplex (EBS).
Abdominal radiography revealing a single gastric bubble in a neonate with pyloric atresia (PA) and junctional epidermolysis bullosa (JEB).
Table 1. Ultrastructural Findings of Major Types and Subtypes of Epidermolysis Bullosa
Type or SubtypeUltrastructural Site of Skin FindingsOther Ultrastructural Findings
Epidermolysis bullosa simplex
LocalizedBasal layerSplit may spread to suprabasilar layer
Dowling-MearaBasal layer in subnuclear cytoplasmDense, circumscribed clumps of keratin Filaments
Muscular dystrophyPredominantly in basal layer, above level of hemidesmosome attachment plaqueReduced integration of keratin filaments with hemidesmosome
Autosomal recessiveBasal keratinocytesAbsent or reduced keratin filaments within basal keratinocytes
SuperficialisSplit usually at interface between granular and cornified cell layers...
Lethal acantholyticSuprabasal cleavage and acantholysisPerinuclear retraction of keratin filaments
Plakophillin-1 deficiencyMid epidermal cell-cell separationDiminutive suprabasal desmosomes, perinuclear retraction of keratin filaments
Pyloric atresia (PA)Lower basal layer, above level of hemidesmosome plaqueReduced integration of keratin filaments with hemidesmosome
Junctional epidermolysis bullosa
HerlitzLamina lucidaMarkedly reduced or absent hemidesmosome, absent sub-basal dense plate
Non-HerlitzLamina lucidaHemidesmosome may be normal or reduced in size and number
Pyloric atresiaLamina lucidaSmall hemidesmosome plaques often with attenuated sub-basal dense plate
Dominant dystrophic epidermolysis bullosa
GeneralizedSub-lamina densaNormal or decreased numbers of anchoring fibrils
Bullous dermolysis of the newbornSub-lamina densaElectron-dense stellate bodies within basal layer, reduced anchoring fibrils
Recessive dystrophic epidermolysis bullosa
Severe generalizedSub-lamina densaAbsent or rudimentary anchoring fibrils
Generalized otherSub-lamina densaReduced or rudimentary-appearing anchoring fibrils
Bullous dermolysis of the newbornSub-lamina densaElectron-dense stellate bodies within basal layer, reduced anchoring fibrils
Table 2. Major Types of Epidermolysis Bullosa
level of Skin CleavageMajor TypeKnown Targeted Protein
Intraepidermal (epidermolytic)Epidermolysis bullosa simplexKeratins 4 and 14; plectin; α6β4 integrin; plakophillin-1 desmoplakin
Intra-lamina lucida (lamina lucidolytic)Junctional epidermolysis bullosaLaminin-332(laminin 5); type XVII collagen; α6β4 integrin
Sub-lamina densa (dermolytic)Dystrophic epidermolysis bullosaType VII collagen
MixedKindler syndromeKindlin-1
Table 3. Mutational Analyses and Inherited Epidermolysis Bullosa
Epidermolysis Bullosa SubtypeTarget Gene(Protein)Types of Known Mutations
Epidermolysis bullosa simplex - SuprabasalPKP1 (plakophilin1)Splice site, deletion, nonsense
DSP (desmoplakin)Nonsense, deletion
Epidermolysis bullosa simplex - BasalKRT5 (keratin-5)Missense, nonsense, deletion, splice site
KRT14 (keratin-14)Missense, nonsense, deletion, insertion, splice site, in-frame deletion/insertion
PLEC1 (plectin)Missense, nonsense, deletion, insertion, in-frame deletion/insertion
ITGA6, ITGB4 (α6β4 integrin)missense, nonsense, deletion, insertion, splice site
Junctional epidermolysis bullosa - HerlitzLAMA3, LAMB3, LAMC2 (laminin-332)Nonsense, deletion, insertion, splice site
Junctional epidermolysis bullosa - OtherLAMA3, LAMB3, LAMC2 (laminin-332)Missense, nonsense, deletion, insertion, splice site
COL17A1 (type XVII collagen)Missense, nonsense, deletion, insertion, splice site
ITGA6, ITGB4 (α6β4 integrin)Missense, nonsense, deletion, insertion, splice site
Dystrophic epidermolysis bullosa - DominantCOL17A1 (type VII collagenMissense, splice site
Dystrophic epidermolysis bullosa - RecessiveCOL17A1 (type VII collagenMissense, nonsense, deletion, insertion, splice site
Kindler syndromeKIND1 (kindling-1)Nonsense, deletion, insertion, splice site
Table 4. Major EB Subtypes and Their Targeted Proteins (2008 International Consensus Report[18] )
Major EB TypeMajor EB SubtypesTargeted Protein(s)
EB simplex (EBS)suprabasal subtypes
lethal acantholytic EBSdesmoplakin
plakophilin-1 deficiencyplakophilin-1
EBS superficialis (EBSS)?
basal subtypes
EBS, localized (EBS-loc)K5, K14
EBS, Dowling-Meara (EBS-DM)K5, K14
EBS, other generalized (EBS,-gen nDM)K5, K14
EBS with mottled pigmentation (EBS-MP)K5
EBS with muscular dystrophy (EBS-MD)plectin
EBS with pyloric atresia (EBS-PA)plectin; α6β4 integrin
EBS, autosomal recessive (EBS-AR)K14
EBS, Ogna (EBS-Og)plectin
EBS, migratory circinate (EBS-migr)K5
Junctional EB (JEB)JEB, Herlitz (JEB-H)laminin-332
JEB, generalized non-Herlitz (JEB-nH gen)laminin-332; type XVII collagen
JEB, localized non-Herlitz (JEB-nH loc)type XVII collagen
JEB with pyloric atresia (JEB-PA)α6β4 integrin
JEB, inversa (JEB-I)laminin-332
JEB, late onset (JEB-lo)?
LOC syndromelaminin-332 α3 chain
Dominant dystrophic EB (DDEB)DDEB, generalized (DDEB-gen)type VII collagen
DDEB, acral (DDEB-ac)type VII collagen
DDEB, pretibial (DDEB-Pt)type VII collagen
DDEB, pruriginosa (DDEB-Pr)type VII collagen
DDEB, nails only (DDEB-na)type VII collagen
DDEB, bullous dermolysis of newborn (DDEB-BDN)type VII collagen
Recessive dystrophic EB (RDEB)RDEB, severe generalized (RDEB-sev gen)type VII collagen
RDEB, generalized other (RDEB, generalized mitis (RDEB-O)type VII collagen
RDEB, inversa (RDEB-I)type VII collagen
RDEB, pretibial (RDEB-Pt)type VII collagen
RDEB, pruriginosa (RDEB-Pr)type VII collagen
RDEB, centripetalis (RDEB-Ce)type VII collagen
RDEB, bullous dermolysis of newborn (RDEB-BDN)type VII collagen
Kindler syndromekindlin-1
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