Available online at www.sciencedirect.com

www.elsevier.com/locate/semperi

S E M I N A R S I N P E R I N A T O L O G Y 3 7 ( 2 0 1 3 ) 3 2 – 3 9

0146-0005/13/$ - seehttp://dx.doi.org/10

nCorrespondenceNY 10016.

E-mail address:

Evaluation and treatment of the newborn withepidermolysis bullosa

Mercedes E. Gonzalez, MDn

The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY

a r t i c l e i n f o

Keywords:

Neonate

Newborn

Blistering

Congenital

Epidermolysis bullosa

Wound

front matter & 2013 Else.1053/j.semperi.2012.11.0

address. Department of

mercedes.e.gonzalez@gm

a b s t r a c t

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

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

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

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

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

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

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

Epidermolysis bullosa (EB) is an inherited mechanobullous

disorder characterized by skin fragility and blister formation,

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

passes many clinically distinctive phenotypes, all of which

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

extracutaneous manifestations and premature death. To

date, over 1000 different mutations involving 14 structural

genes within the skin have been documented to lead to the

clinical phenotype of EB.1 Mutations result in either abnor-

mal, absent or significantly reduced levels of a specific

protein that is important in epidermis to dermis adhesion,

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

ultrastructurally uniform cleavage planes. In general, the

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

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

ease severity, with complete absence of a protein resulting in

vier Inc. All rights reserv04

Dermatology, New York

ail.com

a more severe phenotype with involvement of extracuta-

neous tissues.

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

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

tural skin protein is located and the corresponding ultra-

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

simplex (EBS), cleavage and blister formation occurs within

the epidermis. This group has been further subdivided into

basilar (cleavage within the basal layer keratinocytes) and

suprabasilar (cleavage within the keratinocytes above the

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

junctional EB (JEB), blister formation occurs within the

lamina lucida, an electron-lucent region that contains

anchoring filaments that connect the basal keratinocytes to

the underlying lamina densa. In the dermolytic type, or

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

sublamina densa). The junctional and dermolytic groups of

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

ed.

University School of Medicine, 530 1st Avenue, #7R, New York,

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

EB Type EB Simplex (Epidermolytic)Junctional EB

(Lucidolytic)

Dystrophic EB

(Dermolytic) Mixed type

Level of skin

cleavage

Within the epidermis Within the lamina lucida Within the dermis Multiple

cleavage

points

Affected

proteins

Keratins 5 & 14, plectin, dystonin,

plakophillin-1, desmoplakin

Laminin-332, collagen

XVII, a6b4 integrin

Collagen VII Kindlin-1

Major

Subtypes

Basilar JEB, Herlitz RDEB Kindler

Syndrome

EBS-Localized JEB, other RDEB, severe

generalized

EBS-Generalized JEB-non-Herlitz, RDEB, generalized

other

EBS-Dowling-Meara generalized RDEB, puriginosaa

EBS with muscular dystrophy (MD) JEB-non-Herlitz, RDEB, dermolysis of

the newborna

EBS with pyloric atresia (PA)a localized RDEB, centripetalisa

EBS with mottled pigmentationa JEB with pyloric DDEB

atresia DDEB, generalized

Suprabasilar JEB-late onseta DDEB, pruriginosaa

EBS Superficialisa JEB-laryngo- DDEB, dermolysis of

the newborna

EBS Plakophillin deficiencya onycho- DDEB, pretibiala

Lethal acantholytic EBSa cutaneous (LOC) DDEB, acrala

syndromea DDEB, nails onlya

JEB, inversaa

Inheritance Most are AD, except for suprabasilar

types & EBS w MD and EBS w PA

AR 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.

S E M I N A R S I N P E R I N A T O L O G Y 3 7 ( 2 0 1 3 ) 3 2 – 3 9 33

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 pre-

valence of 0.9 per million, and the lowest incidence of 2.0 per

million live births.3 EB shows no geographic or racial pre-

dilection. This article reviews the clinical features of the four

major EB types, and the evaluation, diagnosis and manage-

ment of a newborn with EB.

Fig. 1 – Newborn boy with JEB-Herlitz and widespread

blistering localized to lower back and diaper region.

Courtesy of Dr. Karen Wiss.

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 blister-

ing 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)

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

S E M I N A R S I N P E R I N A T O L O G Y 3 7 ( 2 0 1 3 ) 3 2 – 3 934

clustered vesicles in an arcuate array (‘‘herpetiform’’ appear-

ance) and there is gradual development of diffuse palmo-

plantar 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.

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

generalized. Note the atrophic scarring, the syndactyly

and the absence of fingernails.

Junctional epidermolysis bullosa

In junctional EB (JEB) blisters form below the basal keratino-

cytes, at the level of the lamina lucida. All types of JEB are

inherited in an autosomal recessive manner. JEB-Herlitz (JEB-

H) 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-non-

Herlitz, 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, hydronephro-

sis/hydroureter, ureterocele, duplicated renal collecting sys-

tem, 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 Shabbir’s

syndrome) was added as a new variant of JEB due to its

clinical and molecular similarities. It is the result of muta-

tions 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.

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, chil-

dren with the dominantly inherited form (dominant dys-

trophic 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 involve-

ment 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 like-

lihood of developing aggressive squamous cell carcinoma

which is the main cause of early death in RDEB-severe general-

ized.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

S E M I N A R S I N P E R I N A T O L O G Y 3 7 ( 2 0 1 3 ) 3 2 – 3 9 35

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 cell–cell adhesion, in addition to cell

signaling, morphogenesis, differentiation and cell migra-

tion.10 Defective kindlin-1 results in blistering at multiple

cleavage planes including intraepidermal, junctional, and

sublamina densa.11 Initially there is trauma-induced blister-

ing 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 sun-

exposed 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 carci-

noma. 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 trauma-

induced blisters, infection related blisters such as herpes sim-

plex, bullous impetigo, staphylococcal scalded skin syn-

drome, neonatal candidiasis, neonatal varicella; maternal

autoimmune bullous conditions such as bullous pemphigoid

(can also appear de novo), pemphigoid gestationis or pem-

phigus vulgaris; others such as bullous aplasia cutis con-

genita, and bullous mastocytosis; and genetic disorders

including incontinentia pigmenti, ectodermal dysplasia, epi-

dermolytic 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 prog-

nosis of the neonate. Consultation with a pediatric derma-

tologist 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

medical history including a family history of inherited

blistering disorders and a maternal obstetrical history, a

complete physical examination, and microbial testing (bac-

terial, viral and fungal cultures) to rule out infectious etiol-

ogies.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 (perile-

sional) 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, includ-

ing 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, new-

borns with variants of EB simplex can present with extensive

blistering and mucosal involvement at birth but then ulti-

mately, 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 immunofluor-

escence, DIF) on a freshly induced blister is now recom-

mended 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., rhoda-

mine or fluorescein) are applied to skin sections and exam-

ined 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 blis-

tering (JEB-non-Herlitz, localized) will show reduced collagen

S E M I N A R S I N P E R I N A T O L O G Y 3 7 ( 2 0 1 3 ) 3 2 – 3 936

XVII reactivity on IFM whereas in patients with JEB-non-

Herlitz 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. Occa-

sionally, IFM fails to provide the exact subtype diagnosis.

This most commonly occurs in the less severe DDEB sub-

types 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 success-

ful IFM, the skin biopsy must be transported in normal saline

(if it will be delivered for processing within 24 h) or in a

specialized Michel’s 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 interpreta-

tion, the technique is readily available through most derma-

topathology 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 dermal–epidermal junction. It is the

only technique that can identify patients with EBS-Dowling-

Meara by visualizing the clumped keratin filaments within

the basal keratinocytes.2 EM requires expensive equipment,

and specialized expertise for specimen processing and inter-

pretation, 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 paraformalde-

hyde 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

order to appropriately guide and prepare the parents. In the

early 1990s, prenatal diagnosis was accomplished via elec-

tron 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 10–12 weeks, or amniotic

fluid samples taken at 12–15 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 6–7 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 candi-

date 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 pro-

gress 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 patient’s cultured

keratinocytes and then grafted back on to the patient’s own

skin, protein replacement by transfection of the corrected

protein into the patient’s cultured keratinocytes, and bone

marrow transplantation are all being vigorously investigated

as possible curative treatments.31–33 Until a safe and effective

corrective treatment becomes widely available, the manage-

ment of EB is based on several general principles: (1)

S E M I N A R S I N P E R I N A T O L O G Y 3 7 ( 2 0 1 3 ) 3 2 – 3 9 37

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 complica-

tions ; 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 well-

lubricated with vaseline or other bland ointment, and the

infant should be maintained in cool, air-conditioned envir-

onments as overheating can increase skin fragility. Babies

with EB should be lifted by placing one hand beneath the

child’s 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, prophy-

lactic wrapping is often used to prevent new blisters.34

In the hospitalized neonate, it is important that all indivi-

duals involved in the patient’s 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 dres-

sings 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 intraopera-

tive 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

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 dres-

sing 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, puru-

lence, 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 EBS-

DM, JEB-non-Herlitz and RDEB-generalized other.41 In infants

with EB, painful blistering in the mouth can prevent ade-

quate intake and specialized nipples and caloric supplemen-

tation of breast milk and/or formula may be required. Despite

caloric, vitamin and nutrient supplements and efforts to

increase intake, supplementary gastrostomy feeding is some-

times 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 child’s

nutritional status.

Surveillance for subtype-specific extracutaneous manifes-

tations is required beyond the neonatal period. The extra-

cutaneous 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 stric-

tures can be life-threatening if undetected. Patients with JEB

should also be monitored closely for external eye involve-

ment, 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 ten-

sion 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

S E M I N A R S I N P E R I N A T O L O G Y 3 7 ( 2 0 1 3 ) 3 2 – 3 938

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, gastroenterol-

ogy/nutrition specialist, pain management, physical and

occupational therapist, geneticist, psychologist, and dentist.

In some areas, specialized EB clinics allow for this compre-

hensive 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 dis-

tinctive 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 diag-

noses 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.

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