SE

M I N A R S I N

PE

R I N AT O L O G Y

37 (2013) 3239

Available online at www.sciencedirect.com

www.elsevier.com/locate/semperi

Evaluation and treatment of the newborn with

epidermolysis bullosa
Mercedes E. Gonzalez, MDn
The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY

article info

a bs t r a c t

Keywords:

Epidermolysis bullosa (EB) is a heterogeneous group of inherited skin diseases character-

Neonate

ized by increased skin fragility and variable degrees of extracutaneous involvement. The

Newborn

clinical spectrum ranges from localized skin disease to a life-threatening and disabling

Blistering

disease with extensive extracutaneous involvement. All four major types of EB, namely EB

Congenital

simplex, Junctional EB, Dystrophic EB and Kindler syndrome, can present with blistering

Epidermolysis bullosa

and erosions at birth and cannot be distinguished clinically in the newborn period. The

Wound

extensive differential diagnosis of blistering and erosions in the neonate must be

considered and common etiologies ruled out. The diagnosis of EB can be confirmed via
a skin biopsy for immunoflourescence mapping. This review discusses the four major
subtypes of EB and their associated extracutaneous features. The evaluation of a newborn
suspected of having EB, including diagnosis and management, is also reviewed.
& 2013 Elsevier Inc. All rights reserved.

Introduction

a more severe phenotype with involvement of extracuta-

Epidermolysis bullosa (EB) is an inherited mechanobullous

neous tissues.
In 2008, EB was re-classified into four major types, based on

disorder characterized by skin fragility and blister formation,

the level in the skin where the missing or abnormal struc-

following minor trauma or traction on the skin. EB encom-

tural skin protein is located and the corresponding ultra-

passes many clinically distinctive phenotypes, all of which

structural level of cleavage.2 In the epidermolytic type, or EB

have skin blistering as a major feature, but variable risks of

simplex (EBS), cleavage and blister formation occurs within

extracutaneous manifestations and premature death. To

the epidermis. This group has been further subdivided into

date, over 1000 different mutations involving 14 structural

basilar (cleavage within the basal layer keratinocytes) and

genes within the skin have been documented to lead to the

suprabasilar (cleavage within the keratinocytes above the

clinical phenotype of EB. Mutations result in either abnor-

basal layer). In the junctional or lucidolytic type, called

mal, absent or significantly reduced levels of a specific

junctional EB (JEB), blister formation occurs within the

protein that is important in epidermis to dermis adhesion,

lamina lucida, an electron-lucent region that contains

and the result is shearing of the skin, or blistering, with

anchoring filaments that connect the basal keratinocytes to

ultrastructurally uniform cleavage planes. In general, the

the underlying lamina densa. In the dermolytic type, or

precise protein affected, and the degree to which it is altered

dystrophic EB (DEB), blistering occurs in the dermis (or

(abnormal, slightly reduced, or absent) determines the dis-

sublamina densa). The junctional and dermolytic groups of

ease severity, with complete absence of a protein resulting in

EB are further subdivided into major and minor types. Lastly,

n
Correspondence address. Department of Dermatology, New York University School of Medicine, 530 1st Avenue, #7R, New York,
NY 10016.
E-mail address: mercedes.e.gonzalez@gmail.com

0146-0005/13/$ - see front matter & 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1053/j.semperi.2012.11.004

SE

M I N A R S I N

PE

R I N AT O L O G Y

33

37 (2013) 3239

Table 1 The Four Major EB Types, with Corresponding Level of Skin Cleavage, Affected Proteins, Major and Rare
Subtypes, and Mode of Inheritance.2
EB Type

EB Simplex (Epidermolytic)

Junctional EB
(Lucidolytic)

Dystrophic EB
(Dermolytic)

Level of skin
cleavage

Within the epidermis

Within the lamina lucida

Within the dermis

Affected
proteins
Major
Subtypes

Keratins 5 & 14, plectin, dystonin,

plakophillin-1, desmoplakin
Basilar

Laminin-332, collagen
XVII, a6b4 integrin
JEB, Herlitz

Collagen VII

EBS-Localized

JEB, other

EBS-Generalized

JEB-non-Herlitz,

EBS-Dowling-Meara
EBS with muscular dystrophy (MD)

generalized
JEB-non-Herlitz,

EBS with pyloric atresia (PA)a

EBS with mottled pigmentationa

localized
JEB with pyloric
atresia
JEB-late onseta
JEB-laryngo-

Suprabasilar
EBS Superficialisa
EBS Plakophillin deficiencya
Lethal acantholytic EBSa

Inheritance

Most are AD, except for suprabasilar

types & EBS w MD and EBS w PA

onychocutaneous (LOC)
syndromea
JEB, inversaa
AR

RDEB

Mixed type
Multiple
cleavage
points
Kindlin-1
Kindler
Syndrome

RDEB, severe
generalized
RDEB, generalized
other
RDEB, puriginosaa
RDEB, dermolysis of
the newborna
RDEB, centripetalisa
DDEB
DDEB, generalized
DDEB, pruriginosaa
DDEB, dermolysis of
the newborna
DDEB, pretibiala
DDEB, acrala
DDEB, nails onlya
RDEB-AR

AR

DDEB-AD
Abbreviations: JEB, Junctional EB; RDEB, recessive dystrophic EB; DDEB, dominant dystrophic EB; AD, autosomal dominant; AR, autosomal
recessive.
a
denotes rare subtypes. Reference: Fine et al.5 2008.

the mixed type is called Kindler syndrome and exhibits

multiple cleavage planes (Table 1).
Based on work derived from the national United States (US)
EB registry, the estimated EB prevalence in the US is 8.22 per 1
million and the incidence over a 5-year period was 19.6 per 1
million live births. EB simplex is the most common type with
a prevalence of 4.6 per million and an incidence of 10.8 per
million. Recessive dystrophic EB (RDEB) has the lowest prevalence of 0.9 per million, and the lowest incidence of 2.0 per
million live births.3 EB shows no geographic or racial predilection. This article reviews the clinical features of the four
major EB types, and the evaluation, diagnosis and management of a newborn with EB.

can present with blistering at birth that heals with variable

amounts of postinflammatory changes, although they rarely
scar. In EBS-DM, blistering characteristically appears as small

Epidermolysis bullosa simplex

In EB simplex blistering occurs within the epidermis. The
localized subtype of EB simplex (EBS), EBS-localized, is the
most common type of EB worldwide.3 EBS-localized presents
with trauma-induced blisters primarily on acral surfaces in
childhood. Bullae typically heal without scarring and blistering tends to improve with age, although focal keratoderma
may develop. There is mild to no mucosal involvement and
affected individuals have a normal lifespan. The more severe
forms of EBS, EBS-generalized and EBS-Dowling-Meara (DM)

Fig. 1 Newborn boy with JEB-Herlitz and widespread

blistering localized to lower back and diaper region.
Courtesy of Dr. Karen Wiss.

34

E M I N A R S I N

E R I N AT O L O G Y

37 (2013) 3239

clustered vesicles in an arcuate array (herpetiform appearance) and there is gradual development of diffuse palmoplantar keratoderma with variable amounts of nail dystrophy
and oral involvement. This subtype of EBS is best diagnosed
by electron microscopy showing clumped keratin filaments.
Most forms of EBS are inherited in an autosomal dominant
manner except for the rarer subtypes, including lethal
acantholytic EBS, plakophilin deficiency, autosomal recessive
EBS, EBS with pyloric atresia, EBS with muscular dystrophy.
Overall EBS has a good prognosis and a relatively good quality
of life with adequate wound care. The less common subtypes
such as EBS with muscular dystrophy, EBS with pyloric
atresia and lethal acantholytic EBS have a worse prognosis
and are associated with early death.

Junctional epidermolysis bullosa

In junctional EB (JEB) blisters form below the basal keratinocytes, at the level of the lamina lucida. All types of JEB are
inherited in an autosomal recessive manner. JEB-Herlitz (JEBH) represents the most severe form of EB and is the result of
complete absence of laminin-332 expression. Patients with
JEB-H will present with widespread blistering at birth and the
development of excessive non-healing, granulation tissue in
areas of blistering especially on the periorificial skin and upper
back (Fig. 1). Blisters heal with atrophic scarring and milia, and
nails are often dystrophic or absent. Airway involvement
occurs in greater than 25% of patients with JEB, with a
cumulative risk of 40% by 6 years of age.4 Involvement of
the eyes, and the gastrointestinal and genitourinary systems
is also common. JEB-H is associated with high mortality
within the first 2 years of life, with a cumulative risk of death
from all causes of 44.7% by 1 year of age, rising to 61.8% by 15
years of age.5 The most common causes of death in JEB-H are
failure to thrive, sepsis and respiratory failure.5
JEB-non-Herlitz (JEB,Other) type is associated with partial
or abnormal laminin-332 or collagen XVII and presents with
blistering in infancy that heals with scarring. The course and
prognosis depend on how severely affected the target protein
is, with some patients having a mild phenotype and a normal
life span (JEB-non-Herlitz, localized) while others have a
severe disease and an increased risk of death (JEB-nonHerlitz, generalized).6 Involvement of hair, nails and teeth
is common. In fact, enamel hypoplasia is a unifying feature
in all forms of JEB.
JEB with pyloric atresia (JEB-PA) presents with blistering at
birth and symptoms of pyloric atresia and/or ureteral and
renal anomalies (dysplastic/multicystic kidney, hydronephrosis/hydroureter, ureterocele, duplicated renal collecting system, absent bladder) become apparent shortly after birth.
JEB-PA is usually severe and often lethal in the neonatal
period.
Laryngo-onycho-cutaneous syndrome (also called Shabbirs
syndrome) was added as a new variant of JEB due to its
clinical and molecular similarities. It is the result of mutations in the alpha chain of laminin-332 and presents with
blisters and erosions at birth that are most prominent on the
face and neck.7 Extracutaneous involvement and early death
is common.

Fig. 2 Right hand of a young child with RDEB-severe

generalized. Note the atrophic scarring, the syndactyly
and the absence of fingernails.

Dystrophic epidermolysis bullosa

Dystrophic EB is the result of mutations in collagen VII, an
anchoring fibril located below the basement membrane in
the upper dermis. As a result of defective or absent anchoring
fibrils, blisters form, deep, below the epidermis and thus heal
with significant scarring and milia (Fig. 2). In general, children with the dominantly inherited form (dominant dystrophic EB (DDEB) have reduced expression of collagen VII
and have a milder phenotype, whereas the recessively
inherited form (recessive dystrophic EB (RDEB) is associated
with complete absence of collagen VII and a more severe
phenotype, poor quality of life and shortened life span.5 In
both major types of DEB, nails are dystrophic or absent and
the mucous membranes are frequently involved, including
those of the mouth, gastrointestinal tract and eyes.
In RDEB-severe generalized, the classic severe form of DEB,
widespread blistering is present from birth. Oral mucosal
involvement may lead to difficulty in feeding during the
neonatal period. RDEB-severe generalized is associated with
numerous extracutaneous manifestations including involvement of the eyes, gastrointestinal tract, genitourinary tract,
kidneys and heart. Children with RDEB-severe generalized, are
at an increased risk of glomerulonephritis, renal amyloidosis,
IgA nephropathy and cardiomyopathy.8 Recurrent, chronic
wounds and scarring on the hands and feet can lead to
syndactyly of the fingers and toes that can render the hands
non-functional (Fig. 2). In addition, patients have a high likelihood of developing aggressive squamous cell carcinoma
which is the main cause of early death in RDEB-severe generalized.9 In contrast, the blistering in RDEB-generalized other, is
localized to hands, feet, knees, and elbows without the severe,
mutilating scarring seen in classic RDEB-severe generalized.
In DDEB, blistering is often mild and limited to hands, feet,
knees, and elbows, but nonetheless, heals with scarring.
Dystrophic nails, especially toenails, are common and may
be the only manifestation of DDEB (DDEB-nails only). Bullous
dermolysis of the newborn (BDN) is a less common variant of
DEB that can be inherited in an autosomal dominant or
recessive manner (DDEB, bullous dermolysis of the newborn

SE

M I N A R S I N

PE

R I N AT O L O G Y

or RDEB, bullous dermolysis of the newborn). BDN presents

with generalized, spontaneous or trauma-induced blistering
at birth that spontaneously regresses in the first year of life.

Kindler syndrome
Kindler syndrome (KS) is the result of mutations in the
fermitin family member 1 (FERMT1) gene, which encodes
for kindlin-1 (also called fermitin family homolog 1 protein,
FFH1). Kindlin-1 is a part of the connection between the actin
cytoskeleton of basal keratinocytes to the extracellular matrix
and plays a role in cellcell adhesion, in addition to cell
signaling, morphogenesis, differentiation and cell migration.10 Defective kindlin-1 results in blistering at multiple
cleavage planes including intraepidermal, junctional, and
sublamina densa.11 Initially there is trauma-induced blistering at birth, or shortly thereafter, that improves with time and
can disappear altogether. Blistering is most common on acral
sites. Later in life, there is progressive poikiloderma on sunexposed skin. Poikiloderma and exquisite photosensitivity
distinguish KS from all other types of EB.11 Extracutaneous
features include gingivitis, colitis (can be severe), mucosal
stenoses (e.g., esophageal, urethral) and acquired syndactyly.
Patients also have an increased risk of squamous cell carcinoma. KS is inherited in an autosomal recessive manner and
is associated with normal lifespan.

The neonate with EB

The newborn infant with EB may present with localized or
widespread blistering at birth, or within the first few days of
life, and it is not possible to determine EB type by clinical
examination. However, EB should be one, among many other
diagnostic considerations, when evaluating a newborn with
blisters and/or erosions. The differential diagnosis for blisters
in a neonate is extensive and includes common acquired
etiologies such as sucking blisters or other birth traumainduced blisters, infection related blisters such as herpes simplex, bullous impetigo, staphylococcal scalded skin syndrome, neonatal candidiasis, neonatal varicella; maternal
autoimmune bullous conditions such as bullous pemphigoid
(can also appear de novo), pemphigoid gestationis or pemphigus vulgaris; others such as bullous aplasia cutis congenita, and bullous mastocytosis; and genetic disorders
including incontinentia pigmenti, ectodermal dysplasia, epidermolytic hyperkeratosis (bullous congenital ichtyosiform
erythroderma), pachyonychia congenita, congenital erosive
dermatosis with reticulate supple scarring and epidermolysis
bullosa (all subtypes). The diagnostic possibilities range from
benign and self-limited to severe and life-threatening; and
thus a timely and accurate diagnosis within the first few
weeks of life is essential for proper management and prognosis of the neonate. Consultation with a pediatric dermatologist can be helpful in establishing a diagnosis, as often
subtle differences in the clinical appearance of blisters can
help to narrow down the differential diagnosis.
In the assessment of a neonate with blisters, Nischler et al.,
recommend an algorithmic approach that includes a detailed

37 (2013) 3239

35

medical history including a family history of inherited

blistering disorders and a maternal obstetrical history, a
complete physical examination, and microbial testing (bacterial, viral and fungal cultures) to rule out infectious etiologies.12 If infectious etiologies and exogenous causes
(perinatal trauma-induced blisters) have been ruled out, a
skin biopsy is warranted for histologic and ultrastructural
assessment. If an immunobullous disorder is suspected, a
biopsy of uninvolved skin just adjacent to a blister (perilesional) is optimal in order to avoid the appearance of
secondary changes that may occur in established blisters. If
EB is suspected, a skin biopsy should be taken from the edge
of a fresh blister (1/2 blister and 1/2 uninvolved skin) that is
o12 h old.13 Ideally, a fresh blister should be induced by
firmly applying a pencil eraser to an area of skin nearby the
blistered skin, and rotating it laterally back and forth until
mild erythema appears.13 It is recommended to wait at least
5 min for a blister to develop microscopically before taking
the biopsy.13
As described above, many different subtypes of EB, including mild and severe variants, can present with blistering at
birth. In addition, the various subtypes of EB can have
overlapping clinical features during the neonatal period,
rendering a clinical diagnosis unreliable. For example, newborns with variants of EB simplex can present with extensive
blistering and mucosal involvement at birth but then ultimately, have localized, mild disease as children.12 Caution
must be taken not to provide the family with a presumptive
diagnosis of EB prior to a full diagnostic evaluation, as this
can lead to unnecessary anxiety and worry. A skin biopsy
from a freshly induced blister sent in proper fixative for IFM
is the first-line diagnostic test to determine the subtype of EB.
This information must then be combined with a thorough
family history before subtype and prognosis is discussed
with the family. In cases where an initial biopsy and IFM is
unable to delineate the diagnosis, a second and/or third
biopsy for repeat IFM and electron microscopy should be
performed. EB subtype should be determined expeditiously,
given its implications for long-term prognosis including risk
of extracutaneous manifestations and premature death.

Diagnosis of EB
Immunofluorescence mapping (IFM) (or direct immunofluorescence, DIF) on a freshly induced blister is now recommended as the primary method for the diagnosis of EB.2
Routine light microscopy can identify the level of the split as
intraepidermal versus subepidermal but is not very helpful in
delineating the specific subtype of EB, as both junctional and
dystrophic subtypes will show subepidermal blistering. In
IFM, antibodies conjugated with fluorochromes (i.e., rhodamine or fluorescein) are applied to skin sections and examined using ultraviolet light microscopy. IFM provides
information as to the precise level of tissue separation, and
the relative expression and distribution of the various protein
antigens at the basement membrane zone.14 In the majority
of patients with EB, IFM allows for subtype classification and
prognosis. For example, JEB-non-Herlitz with localized blistering (JEB-non-Herlitz, localized) will show reduced collagen

36

E M I N A R S I N

E R I N AT O L O G Y

XVII reactivity on IFM whereas in patients with JEB-nonHerlitz with generalized blistering collagen XVII is absent.15
In addition, certain subtypes of EB will have characteristic
IFM findings such as the intraepidermal granules of type VII
collagen seen in bullous dermolysis of the newborn. Occasionally, IFM fails to provide the exact subtype diagnosis.
This most commonly occurs in the less severe DDEB subtypes where collagen VII is only slightly reduced and the IFM
can appear as normal skin. In these situations, repeat
biopsies for IFM and electron microscopy and genetic testing
can be considered for a definitive diagnosis.
In order to ensure proper antigen preservation for successful IFM, the skin biopsy must be transported in normal saline
(if it will be delivered for processing within 24 h) or in a
specialized Michels media that can preserve target antigens
for 24 h to 6 weeks until testing.16,17 Although, IFM for the
diagnosis of EB requires specialized expertise for interpretation, the technique is readily available through most dermatopathology laboratories and is the preferred initial
diagnostic test for EB. For IFM laboratories inexperienced in
testing for EB, an updated list of antibodies and their
suppliers is available through the Dystrophic epidermolysis
bullosa Research Association (DebRA) website (http://www.
debra-international.org).
Electron microscopy (EM) uses beams of electrons focused
by magnetic lenses to create a two-dimensional image with a
resolution and magnification 1000 times greater than a light
microscope. EM is an additional diagnostic technique that
can be utilized for the diagnosis of EB. The advantages of EM
are that it allows for direct visualization and provides
morphologic and semiquantitative information of important
skin structures at the dermalepidermal junction. It is the
only technique that can identify patients with EBS-DowlingMeara by visualizing the clumped keratin filaments within
the basal keratinocytes.2 EM requires expensive equipment,
and specialized expertise for specimen processing and interpretation, and is only available in a few labs worldwide,
making it impractical for use in routine clinical diagnosis.2
Nonetheless, EM continues to be important in EB research
and for cases where IFM has failed to establish a diagnosis. In
a comparative study, IFM was shown to be more sensitive
and specific than EM in the diagnosis of EB.18 For proper
preparation, tissue for EM needs to be fixed in paraformaldehyde or glutaraldehyde.
Genetic testing can determine the precise site and type of
mutation present, and provide a definitive diagnosis of EB
subtype and mode of inheritance. Currently, the cost and lack
of widespread availability precludes it from being a first line
diagnostic test for EB. In the United States, few insurers will
pay for genetic testing. Nonetheless, a list of laboratories that
provide testing for EB can be found at http://www.ncbi.nlm.
nih.gov/sites/GeneTests. It is important that IFM be per
formed prior to pursuing mutational analysis in order to
focus the testing on a specific gene.

Prenatal and preimplantation diagnosis

In families with EB or those at risk for having a child with EB,
prenatal and now preimplantation diagnosis is possible in

37 (2013) 3239

order to appropriately guide and prepare the parents. In the

early 1990s, prenatal diagnosis was accomplished via electron microscopy and/or IFM of a fetal skin biopsy performed
after the 17th week of gestation.19 The major downsides to
this technique were the possibility of sampling error, the risk
of miscarriage and the emotional distress associated with
terminations of affected fetuses at an older gestational age.20
More recently, numerous groups have demonstrated the
successful prenatal diagnosis of EB using DNA isolated from
chorionic villus samples taken at 1012 weeks, or amniotic
fluid samples taken at 1215 weeks gestation in at-risk
pregnancies.21,22 In one report of 144 at-risk pregnancies,
including families with EBS, JEB, JEB with pyloric atresia, and
DEB, prenatal genetic testing on DNA from chorionic villi or
amniotic fluid predicted postnatal EB diagnosis with greater
than 98% accuracy.23
Prenatal diagnosis of EB via the assessment of fetal DNA in
the maternal circulation is an area of active investigation.24
Although fetal cells in the maternal circulation have been
detected as early as 4 weeks, their isolation is very difficult
because of their low density. Successful implementation of
this technique would allow for prenatal diagnosis of EB from
a maternal blood sample as early as 67 weeks.25
Preimplantation genetic diagnosis is a newer option for
families at high risk for EB that avoids the need to consider
termination of an established pregnancy. This method uses
in vitro fertilization and involves testing of DNA extracted
from the preimplanted embryo for mutations in the candidate gene. If testing reveals a normal or a carrier genotype,
the embryo is implanted. At present, the clinical pregnancy
rate after this procedure is 25% per embryo transfer.26
Advances in molecular genetics, which have shortened the
time for mutation detection, have improved success rates
and several successful unaffected pregnancies have been
reported after preimplantation genetic diagnosis for JEB,27,28
RDEB,29 and EBS.30 Preimplantation genetic testing is a highly
specialized procedure that is currently available in relatively
few centers worldwide, however, continued technologic progress will widen its availability and accessibility.
A crucial prerequisite for prenatal or preimplantation
mutation analysis is the identification of the candidate gene
in the affected family member(s). This requires a thorough
family history, detailed clinical phenotype information and
knowledge of the level of skin cleavage or affected protein as
determined by IFM. Prenatal testing and appropriate genetic
counseling are an integral part of the management of
patients with EB and families at risk of EB.

Management of the neonate with EB

At present, there is no cure for EB. Gene therapy, whereby the
necessary gene is introduced into the patients cultured
keratinocytes and then grafted back on to the patients own
skin, protein replacement by transfection of the corrected
protein into the patients cultured keratinocytes, and bone
marrow transplantation are all being vigorously investigated
as possible curative treatments.3133 Until a safe and effective
corrective treatment becomes widely available, the management of EB is based on several general principles: (1)

SE

M I N A R S I N

PE

R I N AT O L O G Y

prevention of skin trauma to avoid new blister formation; (2)

meticulous wound care with appropriate wound dressings to
ensure timely healing of wounds and prevention of infection;
(3) maintenance of good nutrition to maximize growth and
wound healing; (4) surveillance for extracutaneous complications ; and (5) ongoing psychosocial support. In the neonatal
period, prevention of new blisters and wound care are the
most important aspects of treatment. Psychosocial support is
also especially important at this time when diagnosis and
prognosis are being investigated. In the neonatal period,
prevention of new blisters is attempted by gentle handling
of the infant, using loose-fitting clothing, padding bony
prominences, and avoiding adhesives or direct rubbing (use
patting instead) of the skin. The skin should be welllubricated with vaseline or other bland ointment, and the
infant should be maintained in cool, air-conditioned environments as overheating can increase skin fragility. Babies
with EB should be lifted by placing one hand beneath the
childs bottom and one hand behind the neck, rather than
from under the arms, so as to minimize friction and blister
development in this area. As the infant gets older, prophylactic wrapping is often used to prevent new blisters.34
In the hospitalized neonate, it is important that all individuals involved in the patients care are familiar with how to
handle an infant with EB. No tape or adhesives should be
applied directly on the skin, instead non-stick wound dressings should be placed under pulse oximeter probes, EKG
leads and around IV sites. Regular gauze can then be applied
over the non-stick dressings and tape can then be used to
secure the lead or IV to the gauze wrap. Patients should be
transferred by gentle lifting, rather than sliding. Gauze or
loose-fitting clothing should be left in place under a blood
pressure cuff or a tourniquet. Extra padding of beds and
operating room tables can prevent accidental injury to the
skin. Tubes that need to be introduced into mucosal surfaces
or that come in contact with the skin should be heavily
lubricated. If surgery is needed, patients with EB require
special preoperative evaluation, preparation and intraoperative management, which will vary according to the EB
subtype. In general, avoiding unnecessary trauma to the
skin, eyes and mucosa is key. When appropriate precautions
are taken, surgical procedures can be uneventful in children
with EB. Perioperative guidelines for children with EB were
thoroughly reviewed by Goldschneider et al. in 2010.35 In
addition, general information about the routine and hospital
care of infants with EB is available online at http://www.
debra.org/understanding and at http://dermatology.stanford.
edu/gsdc/eb_clinic and printable anesthetic guidelines are
available at: http://pedsanesthesia.stanford.edu/downloads/
guideline-eb.pdf. If questions arise that are not answered
online, a nurse educator is also available via telephone,
weekdays 9 am to 5 pm through DebRA.36
Despite careful precautions, it is impossible to prevent all
blister formation in children with EB. When blisters form,
proper wound care can help assure timely healing and
prevention of infection. Skin should be cleansed daily and
caregivers should wash hands prior to dressing changes. New
blisters should be drained as soon as possible with sterile
large-bore needles at two sites, in order to prevent extension.
The blister roof should be left in place as it acts as a natural

37 (2013) 3239

37

wound dressing. Vaseline or other bland healing ointment

should first be applied to a non-stick dressing (e.g. Mepitels,
Mepilexs, Vaseline gauzes, or Telfas), then the coated dressing is applied to the site. Next, a rolled gauze is wrapped
around the non-adherent dressing and secured in place with
a stretch netting or by cutting the tail of the rolled gauze
down the middle and tying the two ends in place.37 If
necessary, tape should only be used to secure gauze to gauze.
Dressings should be changed daily after gentle skin cleansing.
Topical antibiotics and antimicrobial dressings should be
used judiciously in patients with EB. Bacterial colonization of
wounds is inevitable and often does not interfere with
healing.38 Due to the increased risk of bacterial resistance,
topical antibiotic ointments and antimicrobial dressings
should be reserved for those wounds that are colonized with
bacteria and fail to heal, referred to as critically colonized.38
Frank wound infection (increased erythema, swelling, purulence, odor and pain) often requires systemic antibiotics. In
some cases, topical antibiotics are used on a rotational basis
in children with chronic and/or critically colonized wounds.
Children with EB have increased caloric and protein needs
due to the increased energy expenditure for wound healing,
similar to burn patients.39 At the same time, involvement of
the oropharyngeal, esophageal and gastrointestinal mucosa
in some patients may limit intake and decrease absorption of
nutrients making it difficult to satisfy the high-caloric needs.
Maximizing nutrition is of vital importance in order to
promote growth and development, optimize wound healing
and improve quality of life.40
The risk of malnutrition is more prevalent in the severe
forms of EB, most notably in RDEB-severe generalized and
JEB-Herlitz, although it is also observed in children with EBSDM, JEB-non-Herlitz and RDEB-generalized other.41 In infants
with EB, painful blistering in the mouth can prevent adequate intake and specialized nipples and caloric supplementation of breast milk and/or formula may be required. Despite
caloric, vitamin and nutrient supplements and efforts to
increase intake, supplementary gastrostomy feeding is sometimes necessary. Gastrostomy feedings have been shown to
improve both growth and nutrition in EB patients.42 Growth
charts must be closely monitored. A nutritionist or dietitian
who is experienced with EB can help to optimize the childs
nutritional status.
Surveillance for subtype-specific extracutaneous manifestations is required beyond the neonatal period. The extracutaneous features associated with the different subtypes of
EB and their relative frequency was reviewed by Fine et al. in
2009.42 In patients with JEB-Herlitz, tracheal-laryngeal strictures can be life-threatening if undetected. Patients with JEB
should also be monitored closely for external eye involvement, excessive dental caries and failure to thrive. Children
with DEB are at an increased risk of esophageal strictures and
malabsorption.42 Syndactyly of the fingers and toes from
repeated scarring is one of the most debilitating sequelae of
RDEB. Preventative wrapping of individual fingers with tension in the web space, beginning in infancy is recommended
in an attempt to preserve function for as long as possible.34
Metastatic-squamous cell carcinoma (SCC) is the leading
cause of death in patients with RDEB-severe generalized,
thus surveillance for SCC with frequent complete skin

38

E M I N A R S I N

E R I N AT O L O G Y

examinations is required in this population, beginning at age

10.9 SCC and basal cell carcinoma also occur with increased
frequency in patients with JEB-Herlitz and EBS-Dowling
Meara, respectively.9
Lastly, ongoing psychosocial support for both the child and
the family is critical as they manage this devastating disease
that can isolate the child and family. This is often best
accomplished via a multi-disciplinary approach where the
mental health professional is part of the management team
and is aware of all medical issues. The complete care of
patients with EB requires a multi-disciplinary team that
includes a dermatologist, EB nurse specialist, gastroenterology/nutrition specialist, pain management, physical and
occupational therapist, geneticist, psychologist, and dentist.
In some areas, specialized EB clinics allow for this comprehensive care in one visit. If such a clinic is not available a
dermatologist or pediatrician should coordinate with the
various specialists via consultation. It is important to seek
specialists who are familiar with the specific needs of
children with EB.

Conclusions
Epidermolysis bullosa encompasses over 30 clinically distinctive phenotypes that are all characterized by increased
skin fragility. The clinical spectrum ranges from localized
skin disease with a normal lifespan as in the most prevalent
subtype, EBS-localized; to a debilitating disease, associated
with numerous extracutaneous complications and early
death, as in RDEB-severe generalized. A reliable clinical
diagnosis is not possible in the neonatal period and
an extensive differential diagnosis must be considered in a
newborn with blistering. A skin biopsy for IFM is the first-line
diagnostic test for EB. Prenatal and preimplantation diagnoses now allow at risk families to make informed decisions.
No curative therapy exists for EB, and thus current treatment
centers around multi-disciplinary care with an emphasis on
meticulous wound care, and surveillance and treatment of
extracutaneous complications. Exciting ongoing research
into curative treatments, provides hope for children with
EB. Information on EB, EB care centers, ongoing clinical trials
and support groups is available online at http://www.Debra.
org and http://www.Debra-international.org.

ref e ren ces

1. Fine JD. Inherited epidermolysis bullosa: recent basic and

clinical advances. Curr Opin Pediatr. 2010;22:453458.
2. Fine JD, Eady RAJ, Bauer EA, 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;58:931950.
3. Fine JD, Johnson LB, Suchindran C, et al. The epidemiology of
inherited EB: findings within American, Canadian, and European study populations. In: Fine JD, Bauer EA, McGuire J,
Moshell A, Epidermolysis Bullosa: Clinical, Epidemiologic, and
Laboratory Advances, and the Findings of the National Epidermolysis Bullosa Registry Baltimore. MD: Johns Hopkins University
Press; 1999. p. 101113.

37 (2013) 3239

4. Fine JD, Johnson LB, Weiner M, et al. Tracheolaryngeal

complications of inherited epidermolysis bullosa: cumulative
experience of the national epidermolysis bullosa registry.
Laryngoscope. 2007;117:16521660.
5. Fine JD, Johnson LB, Weiner M, et al. Cause-specific risks of
childhood death in inherited epidermolysis bullosa. J Pediatr.
2008;152:276280.
6. Kiritsi D, Kern JS, Schumann H, et al. Molecular mechanisms
of phenotypic variability in junctional epidermolysis bullosa.
48:450-457, 2011.
7. McLean WH, Irvine AD, Hamill KJ, et al. An unusual Nterminal deletion of the laminin alpha3a isoform leads to
the chronic granulation tissue disorder laryngo-onychocutaneous syndrome. Hum Mol Genet. 2003;12:23952409.
8. Lara-Corrales I, Mellerio JE, Martinez AE, et al. Dilated
cardiomyopathy in epidermolysis bullosa: a retrospective,
multicenter study. Pediatr Dermatol. 2010;27:238243.
9. Fine JD, Johnson LB, Weiner M, et al. Epidermolysis bullosa
and the risk of life-threatening cancers: The National EB
registry experience, 19862006. J Am Acad Dermatol.
2009;60:203211.
10. DSouza MA, Kimble RM, McMillan JR. Kindler syndrome
pathogenesis and fermitin family homologue 1 (kindlin-1)
function. Dermatol Clin. 2010;28:115118.
11. Yazdanfar A, et al. Kindler syndrome. Int J Dermatol.
2009;48:145149.
12. Nischler E, Lausegger A, Huttner C, et al. Diagnostic pitfalls in
newborns and babies with blisters and erosions. Dermatol Res
Pract. 2009;2009:320403.
13. Intong LRA, Murrell DF. How to take skin biopsies for
epidermolysis bullosa. Dermatol Clin. 2010;28:197200.
14. Huligol SC, Bhogal BS, Black MM. Immumofluorescence of the
immunobullous disorders: Part One: Methodology. Indian J
Dermatol Venereol Leprol. 1995;61:187195.
15. Pasmooij AM, Pas HH, Jansen GH, et al. Localized and
generalized forms of blistering in junctional epidermolysis
bullosa due to COL17A1 mutations in the Netherlands. Br J
Dermatol. 2007;156:861870.
16. Fischer EG. To fix or not to fix; Michels is the solution. Int J
Surg Pathol. 2006;14:108.
17. Vodegel RM, de Jong MC, Meijer HJ, et al. Enhanced diagnostic
immunofluorescence using biopsies transported in saline.
BMC Dermatol. 2004;4:10.
18. Yiasemides E, Walton J, Marr P, et al. A comparative study
between transmission electron microscopy and immunofluorescence mapping in the diagnosis of epidermolysis
bullosa. Am J Dermatopathol. 2006;28:387394.
19. Holbrook KA, Smith LT, Elias S. Prenatal diagnosis of genetic
skin disease using fetal skin biopsy samples. Arch Dermatol.
1993;129:14371454.
20. Broen AN, Moum T, Bodtker AS, et al. The course of mental
health after miscarriage and induced abortion: a longitudinal, five-year follow-up study. BMC Med. 2005;3:18.
21. Fassihi H, Eady RA, Mellerio JE, et al. Prenatal diagnosis for
severe inherited skin disorders: 25 years experience. Br J
Dermatol. 2006;154:106113.
22. McGrath JA, Dunnill MG, Christiano AM, et al. First trimester
DNA-based exclusion of recessive dystrophic epidermolysis
bullosa from chorionic villus sampling. Br J Dermatol.
1996;134:734739.
23. Pfender EG, Nakano A, Pulkkien L, et al. Prenatal diagnosis for
epidermolysis bullosa: a study of 144 consecutive pregnancies at risk. Prenat Diagn. 2003;23:447456.
24. IFu XH, Chen HP. Advances on circulating fetal DNA in
maternal plasma. Chin Med J. 2007;120:12561259.
25. Uitto J, Pfender E, Jackson LC. Probing the fetal genome:
progress towards non-invasive prenatal diagnosis. Trends Mol
Med. 2003;9:339343.

SE

M I N A R S I N

PE

R I N AT O L O G Y

26. Fassihi H, McGrath JA. Prenatal Diagnosis of Epidermolysis

Bullosa. Dermatol Clin. 2010;28:231237.
27. Fassihi H, Liu L, Renwick PJ, et al. Development and successful clinical application of preimplantation genetic haplotyping for Herlitz junctional epidermolysis bullosa. Br J Dermatol.
2010;162(6):13301336.
28. Ozge A, Safak H, Ebru H, et al. First successful preimplantation genetic diagnosis of epidermolysis bullosa with pyloric
atresia: case study of a novel c.45054508insACTC mutation. J
Assist Reprod. 2012;29(4):347352.
29. Vendrell X, Bautista-Llacer R, Alberola TM, et al. Pregnancy
after PGD for recessive dystrophic epidermolysis bullosa
inversa: genetics and preimplantation genetics. Assist Reprod
Genet. 2011;28(9):825832.
30. Fassihi H, Grace J, Lashwood A, et al. Preimplantation genetic
diagnosis of skin fragility-ectodermal dysplasia syndrome. Br
J Dermatol. 2006;154:546550.
31. Siprashvilli Z, Nguyen NT, Bezchinsky MY, et al. Long-term
type VII collagen restoration to human epidermolysis bullosa
skin tissue. Hum Gene Ther. 2010;21:12991310.
32. Igoucheva O, Kelly A, Uitto J, et al. Protein therapeutics for
junctional epidermolysis bullosa: incorporation of recombinant b3 chain into laminin 332 in b3-/-keratinocytes in vitro. J
Invest Dermatol. 2008;128:14761486.

37 (2013) 3239

39

33. Wagner JE, Ishida-Yamamoto A, McGrath JA, et al. Bone

marrow transplantation for recessive dystrophic epidermolysis bullosa. N Engl J Med. 2010;363(7):629639.
34. /http://dermatology.stanford.edu/gsdc/eb_clinic/eb-videos.
htmlS; Accessed 9.10.12.
35. Goldschneider K, Lucky AW, Mellerio JE, et al. Perioperative
Icare of patients with epidermolysis bullosa: proceedings of
the 5th international symposium on epidermolysis bullosa,
Santiago Chile, December 46, 2008. Pediatr Anesth. 2010;
20:797804.
36. /http://www.debra.org/nurseS Accessed 9.10.12.
37. /http://dermatology.stanford.edu/downloads/
EB%20care%20tips.pdfS Accessed 9.10.12.
38. Mellerio JE. Infection and colonization in epidermolysis
bullosa. Dermatol Clin. 2010;28:267269.
39. Gamelli RL. Nutritional problems of the acute and chronic
burn patient. Relevance to epidermolysis bullosa. Arch Dermatol. 1988;124:756759.
40. Haynes L. Nutrition for children with epidermolysis bullosa.
Dermatol Clin. 2010;28:289301.
41. Freeman EB, Koglemeier J, Martinez AE, et al. Gastrointestinal
complications of epidermolysis bullosa in children. Br J
Dermatol. 2008;158:13081314.
42. Fine JD, Mellerio JE. Exracutaneous manifestations and complications of inherited epidermolysis bullosa. Part I. Epithelial
associated tissues. J Am Acad Dermatol. 2009;61:367384.