ARTICLE

Diagnosis and Care of the Newborn with

Epidermolysis Bullosa
Anne W. Lucky, MD,*† Jean Whalen, RN,* Susan Rowe, RN,* Kalyani S. Marathe, MD, MPH,*† and
Emily Gorell, DO, MS†
*Cincinnati Children’s Epidermolysis Bullosa (EB) Center, Division of Dermatology, Cincinnati Children’s Hospital, Cincinnati, OH, and
†
Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, OH

PRACTICE GAPS
Epidermolysis bullosa (EB) is a group of rare genetic disorders
occurring in only 8.2 per million live births per year in the United
States. Thus, many neonatologists have not had substantial clinical
experience to feel comfortable diagnosing and caring for neonates
who present with fragile skin suggestive of EB. In addition, recent
updates in the classification of EB have been based more on genetic
mutation analysis than solely on clinical presentation. Preferred
diagnostic methods and clinical care practices are also rapidly
changing.

OBJECTIVES After reading this review, readers will be able to:

1. Summarize how to accurately diagnose epidermolysis bullosa (EB) in

an infant with fragile skin and to recognize associated complications.
AUTHOR DISCLOSURE Drs Lucky,
Marathe, and Gorell and Mss Whalen and 2. Describe basic care of neonates with EB, including skin care, as well
Rowe have disclosed no financial as treatment of associated disorders of other systems.
relationships relevant to this article. This
commentary does contain a discussion of 3. Explain how to appropriately guide the family of an infant with EB
an unapproved/investigative use of a
through the child’s diagnosis, treatment, and prognosis.
commercial product/device. This research
was funded by the Epidermolysis Bullosa
Research Partnership (EBRP) and The
Cooperative (COOP) Society of Cincinnati
ABSTRACT
Children’s Hospital Epidermolysis bullosa (EB) is a group of rare genetic disorders that are
characterized by fragile skin. Because of its rarity, many neonatologists
ABBREVIATIONS may not be familiar with the current diagnosis and treatment
DDEB dominant dystrophic recommendations for EB. The classification of EB was updated in 2020.
epidermolysis bullosa The diagnosis of EB is now more heavily based on genetic rather than
DEB dystrophic epidermolysis clinical or histologic features. In this review, we summarize the basic
bullosa
DEBRA Dystrophic Epidermolysis classification of EB, the preferred methods of diagnosis including a
Bullosa Research Association panel of next-generation sequencing for all types of EB, as well as
EB epidermolysis bullosa specific immunofluorescence and electron microscopy of skin biopsies
EBS epidermolysis bullosa simplex
EM electron microscopy
in special circumstances. We also review the principles of skin care for
IFM immunofluorescence mapping the newborn with EB and discuss the possible associated
JEB junctional epidermolysis bullosa comorbidities including infectious, gastrointestinal, respiratory, and
NGS next-generation sequencing
genitourinary complications. Lastly, we discuss the approach to
RDEB recessive dystrophic
epidermolysis bullosa educating the family about the diagnosis, prognosis, and care of an
SS Sanger sequencing

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 infant with EB and describe resources for the successful transition of
the infant from the hospital to the home.

INTRODUCTION for all types of EB, as well as specific immunofluores-

cence mapping (IFM) and electron microscopy (EM) of
Epidermolysis bullosa (EB) is a group of rare genetic
skin biopsies in special circumstances. We will also re-
disorders that are characterized by fragile skin. Because
view the principles of skin care in the newborn and dis-
of its rarity, with an incidence of 8.2 per million live
cuss the possible associated comorbidities including
births in the United States, (1) many neonatologists may
infectious, gastrointestinal, respiratory, and genitouri-
not be familiar with the current diagnosis and treatment
nary complications. Lastly, we will discuss the approach
recommendations for EB. The classification of EB has
of educating the family about the diagnosis, prognosis,
been updated frequently, most recently in 2020, (2) as
and care of the infant and describe resources for the
new genes associated with fragile skin are discovered.
successful transition of the infant from the hospital to
The diagnosis of EB is now more heavily based on ge-
the home.
netic rather than clinical features. When an infant pre-
sents with blisters and/or erosions of the skin and
mucous membranes, it is imperative to consider fragile CLASSIFICATION OF EB
skin as part of the differential diagnosis. If EB is consid- According to the 2020 classification of EB, there are now 16
ered, elucidation of the molecular type is critical for di- genes associated with classical types of EB: EBS (7 genes),
agnostic and prognostic purposes. In this review, we JEB (7 genes), DEB (1 gene) and KEB (1 gene). Other disor-
will summarize the basic classification of EB and the ders associated with skin fragility, some of which were previ-
preferred methods of diagnosis including the next-gen- ously classified with EB, including peeling skin disorders (9
eration sequencing (NGS) method of genetic screening genes), erosive disorders (5 genes) and hyperkeratotic skin

Table 1. Molecular and Genetic Classification of EB

Type Inheritance Gene Protein
EB simplex (Intra-epidermal) Autosomal dominant KRT5 Keratin 5
KRT14 Keratin 14
PLEC Plectin
KLHL24 Kelch-like
protein 24
Autosomal recessive KRT5 Keratin 5
KRT14 Keratin 14
DST BP230 (BPAG1e,
dystonin)
EXPH5 (SLAC2B) Exophilin-5
(synaptotagmin-
like protein,
homolog lacking
C2 domains b,
Slac 2b)
CD151 (TSPAN24) CD151 antigen
(tetraspanin 24)
Junctional EB (junctional) Autosomal recessive LAMA3, LAMB3, Laminin 332
LAMC2
COL17A1 Type XVII
collagen
ITGA6, ITGB4 Integrin α6β4
ITGA3 Integrin α3
subunit
Dystrophic EB (dermal) Autosomal dominant COL7A1 Type VII collagen
Autosomal recessive COL7A1 Type VII collagen
Kindler EB (mixed) Mixed FERMT1 (KIND1) Fermitin family
homolog 1
(Kindlin-1)

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 disorders with skin fragility (10 genes), are now considered genetic mutations. One exception is a diagnosis of JEB-se-
separate from EB (Table 1): vere that has a nearly uniformly poor prognosis with an
average expected lifespan of 5 months. (5)(6) An important
• EB simplex (EBS): Proteins located in the epidermis (7 unmet need is to correlate the EB genotype with the phe-
genes) notype and prognosis.
• Junctional EB (JEB): Proteins located in the basement
membrane between the epidermis and the dermis (7 DIAGNOSIS OF EB
genes) Physical Findings
• Dystrophic EB (DEB): Recessive (RDEB) and dominant The subtypes of EB are usually clinically indistinguish-
(DDEB), COL7A1 (1 gene) located in the anchoring fi- able in the neonatal period. (7)(8) Common to all sub-
brils of the dermis. types of EB are findings of skin fragility, blisters, and
• Kindler EB: Located in several layers of the skin, erosions that may develop shortly after birth as well as
FERMT1 (1 gene) aplasia cutis congenita (missing skin at birth) (Fig 1).
The other 6 genes are associated with disorders of ero- Blisters and erosions can be widespread or localized to
sive skin fragility. sites of mechanical trauma. It is usually not possible to
EB is also classified into subtypes that are determined determine the EB subtype and thus, a prognosis cannot
largely by the clinical manifestations and severity of each be established based solely on the affected neonate’s
case and vary in clinical presentation and prognosis as physical examination findings.
well as location of mutations. (2)(3) Blistering of the skin However, several subtle clues in the newborn exami-
in a neonate is most commonly seen in the most severe nation may hint at a diagnosis of the EB subtype before
cases such as RDEB-severe, JEB-severe, and EBS-severe, definitive testing results are obtained. For example, lack
as well as EB with pyloric atresia (caused by PLEC1 and of lingual papillae may be seen in RDEB (9) and the
a6b4 integrin mutations and classified as EBS and JEB, presence of granulation tissue around the nails is a
respectively). However, it is impossible to determine a spe- sign of severe JEB (Fig 2). (10) Involvement of the air-
cific diagnosis by clinical observation alone, especially in way, because of granulation tissue or structural abnor-
the newborn period. (4) Thus, immediate treatment is the malities, with some infants requiring a tracheostomy,
same for all infants based on clinical needs. Unfortunate- can be found in patients with severe JEB. (11) Pyloric
ly, in most cases, it is not possible to determine the prog- atresia is observed in patients with JEB who have muta-
nosis of affected infants because of significant variation in tions in a6b4 integrin and in patients with EBS who
disease severity, even among patients with the same have plectin deficiency. These patients typically also
have ureter and renal abnormalities, often with a severe
and lethal outcome. (12) Other extracutaneous manifes-
tations of EB such as anemia and pseudosyndactyly pre-
sent later in life.

Differential Diagnosis
The differential diagnosis of EB is based on the findings
of skin fragility and blistering. Infections such as staphylo-
coccal scalded skin syndrome, bullous impetigo, candidia-
sis, and herpes simplex may be ruled out with bacterial,
fungal and viral cultures as well as potassium hydroxide
preparations. Bullous mastocytosis and neonatal lupus can
be diagnosed with a skin biopsy, including IFM. Neonatal
pemphigus and pemphigoid can be present in infants
born to mothers with these autoimmune conditions. In-
continentia pigmenti can present with blistering in the
Figure 1. Aplasia cutis congenita (ACC) in a neonate with EB. ACC affects newborn period. Epidermolytic ichthyosis can mimic both
most of the dorsal surface of the hand in this neonate with recessive dys-
trophic EB. ACC usually occurs on the extremities and is found in all sub-
staphylococcal scalded skin syndrome and EB and can be
types of EB. diagnosed with a skin biopsy and/or genetic analysis.

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 Figure 2. Physical clues to EB diagnosis. A. The absence of lingual papillae is a clue to the diagnosis of recessive dystrophic EB. B. Granulation tissue in
and around the nail bed can be seen in severe junctional EB caused by mutations in laminin 332.

Sucking blisters are common on the radial forearm, wrist, in practice, many clinicians are now first performing ge-
hands, and fingers. (13) netic testing, reserving biopsies only to clarify subtypes.
(17) For example, 2 mutations in 1 of the laminin 332
Family History genes is consistent with a diagnosis of JEB, and a com-
The diagnosis of EB and elucidation of the EB subtype are plete absence of laminin 332 on IFM predicts a usually fa-
aided by obtaining a detailed family history. It is crucial to tal outcome in early life. (18)
ask about family members who carry a diagnosis of EB as
well, because those individuals who tend to blister easily GENETIC TESTING. Genetic testing is recommended to
or have nail abnormalities may have gone undiagnosed, as definitively establish the diagnosis of EB and should be
these can signal mild forms of DDEB. (14) A family with a performed by laboratories with expertise in the identifica-
known history of a dominant condition such as EBS or tion of EB genes. (7) As noted before, genetic testing is
DDEB will not be surprised by the same diagnosis in their quickly becoming the new standard for EB diagnosis.
newborn and will not have a steep learning curve to care (17)(19) Samples for genetic testing may be obtained via
for their child’s skin condition. Lack of family history is blood, saliva, or tissue. Each of the methods described
also a clue to a diagnosis of either a recessive type of EB herein can be used to identify pathogenic EB mutations.
or a de novo mutation. Genetic counseling is recommended for all families who
have a child with EB.
Diagnostic Studies Sanger sequencing (SS) for mutations within specific
A definitive diagnosis of EB and the EB subtype is ob- genes was the first method used to identify pathogenic
tained via genetic mutation analysis or skin biopsy for mutations that caused EB. SS uses polymerase chain reac-
IFM and EM. It is imperative to establish an accurate diag- tion amplification to evaluate the coding regions and the
nosis as there are extreme differences in the care and out- exon/intron boundaries of a specific gene. SS may fail to
comes of patients along the spectrum of EB: from severe detect mutations in nonexamined genes, as well as muta-
generalized disease with a poor prognosis to mild local- tions causing large deletions, and mutations within in-
ized disease. However, a diagnosis of the type of EB does trons. SS for EB diagnosis is now typically used to
not always predict the prognosis. It is important to set ex- confirm genetic mutations identified via NGS of targeted
pectations with an affected family, and in severe cases, as- EB panels. (7)(20)
sist the family in decision-making about the extent of care NGS allows for parallel sequencing of multiple genes
to be provided. (6)(15)(16) using a single sample and can be performed using tar-
Current published recommendations for neonatal diag- geted gene panels, (20)(21)(22) whole-exome sequencing,
nosis are to obtain a skin biopsy for IFM and a blood sam- (23)(24)(25) or transcriptosome analysis (RNA-Seq). NGS-
ple for genetic testing to be run in parallel. (7) However, targeted gene panels typically have a turnaround time of 1

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 month, are more cost-effective than SS, and are able to as- skin. Typically, a 3- to 4-mm punch biopsy specimen is ob-
sess multiple potentially causative genes at once. Specific tained for IFM, and the sample is placed in Michel media.
individual mutations are subsequently confirmed via SS. The sample should be sent for processing as soon as pos-
If mutations are not identified via NGS or SS, whole- sible. A 2- to 3-mm punch biopsy sample may also be ob-
exome sequencing may be performed. Whole-exome se- tained for EM and placed in EM fixative, which contains
quencing is more expensive than NGS but may identify glutaraldehyde. Samples should be sent to laboratories
novel genes with mutations resulting in EB. However, it with expertise in the diagnosis of EB. (7)(8)(13)
may be difficult to determine which identified mutations IFM helps determine the level of blister formation as
are indeed causative versus so-called “noise.” (7) well as quantification of the various proteins that may be
Ultra-rapid targeted genomic sequencing and whole ge- decreased or absent in EB. (31) However, samples must be
nome sequencing are new techniques that can be used to sent to a pathology laboratory capable of measuring all of
screen for over 1,700 genes related to genetic conditions,
the EB-related proteins (Table 1). This type of mapping is
with results available in as few as 3 days. (26) The most
only done in a few institutions and must be specified, be-
common genes affected in EB are included in these com-
cause it is not the same as the immunofluorescence tech-
mercially available panels. (27)(28)
nique used routinely for autoimmune blistering diseases.
RNA-Seq is a technique that allows for quantification of
EM allows for visualization of the blister level and also
the transcribed RNA and is useful for evaluating the out-
the ultrastructural components of the skin. EM can be
comes of splice site mutations or variants of unknown sig-
useful when IFM and/or genetic testing are inconclusive.
nificance. (7)(29)(30) This technique is currently available
For example, absent anchoring fibrils are characteristic of
only in certain specialized academic centers and not cur-
severe RDEB whereas clumped keratin within the basal
rently available commercially.
Once a genetic diagnosis has been established, carrier layer is seen in the severe subtype of EBS. (7)(32) EM is
testing in which the mutation is confirmed can be per- expensive and requires expertise in both sample prepara-
formed in the biological parents. Parental testing is useful tion and interpretation.
to fully understand the inheritance pattern, particularly to
elucidate de novo cases, and to assess risks for future preg- SKIN CARE OF THE INFANT WITH EB
nancies. Carrier testing is typically performed using SS. The unexpected and presumed diagnosis of EB in a neo-
nate presents a challenge on multiple levels for everyone
SKIN BIOPSIES. Analysis of skin biopsies via IFM and/or involved in the initial care of the infant. Although there
EM was previously the gold standard for diagnosis of EB
are published guidelines for general skin care in EB,
and EB subtypes. (7) Biopsies carry the advantage of ob-
(33)(34) none are focused solely on the newborn period.
taining results faster than traditional genetic testing,
Consideration must be given to the potentially overwhelm-
which may be helpful for providing guidance and progno-
ing nature of this care and the need to modify/simplify
sis to an anxious family. (31) However, skin biopsies can
the routine. With this in mind, basic and safe recommen-
be tricky to perform, and the usefulness of the results de-
dations should be considered when developing an individ-
pends on the biopsy technique. Furthermore, skin biopsy
ualized care plan for an infant.
results are frequently equivocal. (17) Hematoxylin-eosin
Wound care in EB has 3 main components: a contact
staining is not recommended to diagnose EB but may be
layer, a secondary layer, and securement of the dressings.
used to diagnose other conditions that remain in the dif-
ferential for blistering diseases of the newborn. (7)(8) As Fig 3 shows, products for each layer may overlap in
Skin biopsy specimens should be obtained from non- their intended functions. Individualization of the dressing
blistered, nonacral skin, which is rubbed with a pencil process is critical to success and effectiveness of the care
eraser just until erythema results, but not so much as to as well as promoting confidence in the caregivers’ ability
tear the skin. This can be achieved by placing the eraser to apply appropriate dressings on their child’s skin.
against the skin with firm pressure, then rotating 180 de- Contact layer dressing products have direct contact with
grees in each direction 3 to 10 or more times. This tech- the skin and wounds. They are often silicone-based and
nique induces a microscopic blister, which will allow for nonadherent and can be used with or without emollient or
evaluation of the level of dermal-epidermal separation. topical antibacterial agents. Secondary layer dressing prod-
The biopsy specimen should include about half of this in- ucts are placed over the contact layer to absorb drainage,
duced blister, with the remaining portion on uninvolved promote movement of drainage away from the wound, or

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 Figure 3. Venn diagram of dressings for patients with EB. Layers required for EB wound dressings are depicted. As illustrated in the image, some prod-
ucts have “overlap” and can be used effectively for multiple purposes.

add padding for protection. Securement dressing products modifications to the dressing regimen should be made as
are used to hold the contact and secondary layers in place. indicated. Potential responses that should prompt a revi-
A contact layer of 1  36” strips of petrolatum-impreg- sion to the routine could include increased blistering at
nated gauze cut into shorter strips with added petrolatum the edges of the dressing, wound maceration, increased
or AquaphorV is applied to the affected areas, wrapping
R
blistering in general, worsening exudate, infection, or
from the distal to proximal skin. If the petrolatum-impreg- poor healing. In addition, some infants respond poorly to
nated gauze starts to fray at the edges or consistently ad- any dressing or excessive application of emollients, often
heres to wounds, a thin foam silicone dressing can be seen in EBS, which would lead to care modifications and
substituted as the contact layer. This foam dressing should changes in wound management.
be cut into long strips and applied as a roll gauze. Other Emollients used in routine dressing changes may in-
appropriate dressing products are also promoted as con- clude Aquaphor, petrolatum, coconut oil, or other nonme-
tact layer choices, though some lack the necessary flexibili- dicated lubricants. These products should be smeared in a
ty for an infant’s small frame. thin layer onto the contact layer, rather than directly onto the
The secondary layer consists of a 1” soft roll gauze for wound. This technique prevents shearing of the surface of
extremities and a 2” soft roll gauze for the torso and scalp, the skin/wound. At each dressing change, it is important to
which is placed over the contact layer. The contact layer assess both the efficacy of the amount used and frequency of
should be left slightly visible at the ends of the dressing, application. Many caregivers have a tendency to overlubri-
because roll gauze in direct contact with the skin may cate, which can lead to maceration, increased blistering, and
cause blisters or wounds. It is desirable for the roll gauze movement of the dressings. Nonprescription strength oint-
to be soft, conforming, and free from strings, which is a ments are used as medically necessary and may include topi-
common characteristic in burn care products. cal antibiotics (eg, PolysporinV R bacitracin), and medical-

Securement is the third essential dressing layer. Secure- grade honey. Prescription strength topical antibiotics such as
ment of the contact and secondary layers prevents these gentamicin, silver products, mupirocin, or retapamulin may
dressings from sliding and shearing the skin, subsequently be considered for infections.
causing more blisters and wounds. Choice of securement Blisters of at least pencil eraser size (5 mm) should be
layer product includes soft fabric or elasticized mesh tubu- lanced and drained as they develop. A needle or lancet
lar dressings. may be used, puncturing the blister and gently decom-
When caring for an infant, the response to the dress- pressing it with gauze. The roof of the blister should not
ings must be evaluated during each dressing change and be removed. (35)

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 Typically, dressing changes are recommended every other NUTRITION
day, though daily changes may be necessary initially. All an- Adequate nutrition in the newborn period is essential. In-
ticipated dressing products should be precut, lubricated, and fants with EB not only have baseline nutritional needs of a
arranged on a work surface before old dressings are removed newborn, but also require extra calories for adequate
from the infant’s skin. The dressing change is best complet- wound healing. However, there are several barriers to ade-
ed 1 limb at a time, because of the tendency for movement quate nutrition. First, mucosal fragility leads to oral blis-
and the potential for self-damage. Initially, an affected infant ters and erosions. If these are painful, infants will refuse
can have a sponge bath, rinsing gently using a syringe. Even- to suck and may not learn to suck appropriately if they are
tually, the infant can be safely immersed in a bath (before a unable to feed for prolonged periods. Second, many in-
dressing change) with proper care to prevent self-damage fants with EB develop gastrointestinal reflux disease,
from moving arms and legs. which can cause painful damage to the epiglottis and pos-
Diapers may lead to blistering and wounds or the in- terior pharyngeal mucosa. Third, as a result of pain as
fant may have an innately severely affected diaper area. well as anemia from chronic blistering, some infants be-
Aquaphor or petrolatum should be applied to the diaper come too weak to sustain adequate oral nutrition. Solu-
edges. Alternatively, a thin foam product may be cut to tions include coating of the oral mucosa with sucralfate,
shape and used as a liner. This liner should be well-lubri- which can be soothing, and more rapid-flow, soft nipples
cated with an emollient. Often the diaper elastic around (such as the Haberman nipple).
the legs is cut out from the diaper. Cloth diapers have not If oral feeding becomes inadequate, other nutritional
been found to be more beneficial. (36) Commercial wipes options include total parenteral nutrition using peripheral-
should not be used. Rather, it is recommended to gently ly inserted central catheters, or in young neonates, umbili-
cleanse the skin of the diaper area with soft gauze or cot- cal catheters for a temporary period. Such catheters must
ton balls, moistened with water or mineral oil. be placed and secured carefully using a special fragile skin
The occipital scalp may require special care, as the in- secure dressing. It is imperative to refrain from applying
fant’s natural movement can create extensive wounds. Ad- adhesive materials, which can tear the fragile skin when
ditional lubrication and placement of a foam dressing removed, causing further cutaneous injury (Fig 4). The ba-
product on the bedding for the head to rest on, may be sic dressing should have a nonadherent thin pad (such as
necessary for wound protection of this area. a silicone-based product like MepiformV R ) applied directly

Affected newborns require modification of their bedding on the skin to which the line can be securely taped. Use of
to provide them with cushioning and decrease pressure on a silicone-based tape such as MepitacV R is helpful. If possi-

their fragile skin. This varies institutionally and products ble, orogastric and nasogastric tubes should be avoided;
such as “Z-Flo mattresses,” sheepskin, and air mattresses these tubes may cause further oral and pharyngeal erosions
can be used. Areas of skin in contact with the bedding sur- and esophageal trauma, which can accelerate the develop-
face may require emollient application to reduce friction ment of esophageal strictures later in life in dystrophic
and decrease potential damage. Temperature regulation is forms of EB. (37)(38) Feeding tubes are also difficult to se-
driven by medical need with the consideration that heat cure because of skin fragility. Gastrostomy placement is an-
may increase blistering. Modification of dressings and other solution that can be lifesaving, but it is associated with
emollient may be needed. Infants in isolettes or under ther- risks inherent to surgery under anesthesia at a young age
apeutic lights need special monitoring to assess for worsen- and difficulty maintaining intact skin around the stoma site.
ing skin findings. These infants can, and should, be held
by their caregivers if deemed medically appropriate. INFECTION
Families should be encouraged to dress newborns with Any areas of denuded skin will inevitably become colonized
EB. Clothing should be made of soft material and may be with bacteria. It is impossible to “sterilize” such erosions, and
turned inside out so that seams do not rub against the skin. as long as they are asymptomatic, treatment is not necessary.
Some specialized clothing with seams on the outside is avail- Overuse of topical antibiotics may result in selection of resis-
able. The infant’s tolerance for clothing should be observed, tant organisms. (39) Thus, bland emollients such as white
and changes should be implemented as appropriate. petrolatum, or ointments such as Aquaphor or DermaphorV R,

Parents are an integral part of the care team. As wound and antimicrobials such as or silver-impregnated dressings or
care routines change, sometimes daily, they must be as- topical applications of medications (eg, medical-grade silver
sessed for understanding, comfort, and confidence. gels or honey), are preferred. When wounds become

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 Figure 4. Securing lines in patients with EB. A. Diagram shows an appropriate method to secure lines in patients with fragile skin using silicone-based
dressings instead of adhesives. B. This photograph shows a secured central venous catheter on the chest of a neonate with severe junctional EB. This
very sick infant required gastrostomy and tracheostomy tubes and, unfortunately, did not survive.

erythematous and tender or have increased exudate, especially in appetite, or lethargy should be addressed rapidly. Growing
if accompanied by fever in the newborn, treatment with ap- evidence suggests that thymic development is compromised
propriate topical or systemic antibiotics is warranted. In older in patients with JEB because of absence of laminin 332. (40)
children with EB, the most common colonizing organisms Rapid and often fatal sepsis is not uncommon.
are Staphylococcus aureus (both methicillin resistant and meth-
icillin sensitive), Streptococcus pyogenes, and Pseudomonas aeru- AIRWAY
ginosa. (39) There has not been a microbiome study to date Airway compromise can be a life-threatening feature of
in neonates with EB. During hospitalization, we highly rec- EB, especially in patients with JEB-severe. Other subtypes
ommend surveillance cultures with sensitivities in affected in- of EB can also manifest with airway dysfunction with typ-
fants every few days so that if and when signs/symptoms of ical symptoms of stridor, a hoarse or weak cry, and ulti-
infection appear, treatment choice can be optimized. mately hypoxemia. Causes include excess granulation
In severe forms of EB, especially JEB (although any type tissue (in JEB), tracheomalacia, “floppy” arytenoids, or
can be affected), typical signs of sepsis such as fever, change blister formation in the upper airway. (41)(42) In all types

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 of EB, acid from gastrointestinal reflux disease can affect not heard of this diagnosis. EB is often referred to as “The
the epiglottis and posterior pharynx, resulting in respira- Worst Disease You Have Never Heard Of.” (44) Searching
tory compromise. Evaluation of the airway requires an ex- the internet usually confronts families with frightening pho-
perienced otolaryngologist and must be performed with tos and descriptions of the worst outcomes for children with
caution because of the inherent fragility of the mucosa. EB. Many parents blame events that may have occurred dur-
Radiographic imaging is a safe way to evaluate the air- ing pregnancy and, when they are informed that this condi-
way. Monitoring for hypoxemia can be a challenge, and tion is genetic, bear an undeserved burden of guilt. Taking
any adhesive material must be removed from pulse oxi- the time to listen to a family’s questions and feelings about
meters; instead, oximeters can be secured via nonadher- the diagnosis of EB is important so that parents can feel re-
ent methods by using VelcroV R or Mepitac.
assured that their child’s condition is not caused by anything
that they did or did not do and was not preventable.
PAIN MANAGEMENT It is important to note that although it is necessary to
Infants can experience significant pain from eroded establish a genetic diagnosis to better predict future issues
skin, particularly during dressing changes. Pain control that might arise, it is usually not possible to predict the se-
often requires narcotics, but with time, infants can be verity of each individual case. Because it may take several
weaned to nonsteroidal anti-inflammatory drugs or weeks to receive a molecular genetic diagnosis, it is imper-
acetaminophen. Simple measures such as sucking on a ative to reassure families that routine care during this
sugar water–sweetened nipple may afford some relief. waiting time is not dependent on diagnosis. Prenatal test-
(43) It should be noted that because of oral blisters, the ing can be discussed with parents for purposes of future
use of a soft nipple, such as a nipple made for prema- family planning at a later date.
ture infants or the Haberman nipple, for administra- In this era of social media, many supportive parent
tion of sugar syrup is crucial. groups exist online. Families will be confronted with un-
solicited advice of varying degrees of benefit and some-
CARE OF THE FAMILY times harm. Building trust with families to assure them
The immediate reaction of most families confronted with a that as an informed medical professional, you will be
child diagnosed with EB is usually shock and guilt. If there available to discuss what they encounter online is vital at
is no previously affected family member, most people have this stage.

Table 2. Interdisciplinary Specialties Caring for the Newborn with EB

Specialty EB Sequelae Management
Dermatology Wound care, skin/wound infections, overall EB care coordination
Neonatology Overall care when hospitalized
Primary care Overall care as outpatient
Ancillary services
Nursing Dressings and feeding
Nutrition Adequate calories, micronutrients, vitamins
Social services Access to care and financial resources
Occupational therapy Feeding education
Physical therapy Contracture prevention
Medical specialties
Gastroenterology Gastroesophageal reflux disease, gastrostomy tube management
Pathology Diagnosis of EB
Hematology Anemia
Ophthalmology Corneal abrasions
Infectious diseases Wound infections, sepsis
Radiology Diagnosis of pyloric atresia, infections, line placement
Anesthesiology Advanced airway placement
Pain management Pain, itch management
Palliative care End of life care, decision-making for gastrostomy tube/tracheostomy placement
Surgical specialties
General pediatric surgery Tracheostomy or gastrostomy tube placement
Plastic surgery Skin grafting for aplasia cutis
Otolaryngology Tracheostomy/airway stenosis evaluation and management

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 Finally, in some cases, such as extensive aplasia cutis con- able for home care of their infant, and reports of clinical and
genita or a diagnosis of JEB with evidence of complete ab- scientific meetings and publications. In particular, DEBRA
sence of laminin 332, a rapidly progressive course involving International has sponsored a series of “Guidelines of Care”
respiratory failure or inability to sustain adequate nutrition, prepared by international teams. (46) These organizations
difficult discussions about the extent of life support and com- sponsor national and international meetings, some of which
fort care may be needed. Common dilemmas also include welcome families to participate. In addition, many have ro-
whether to place a tracheostomy and/or feeding gastrostomy. bust development programs that are intended to fund EB re-
In these situations, collaboration with a palliative care team search. With rapid advances in research on EB, clinical trials
and/or hospital chaplain are invaluable. of several wound-care treatments are currently ongoing, as
well as topical, parenteral, and transplant molecular and gene
ROLE OF EB CENTERS AND RESOURCES therapies for EB. (47)(48)(49)
Although in mild cases most NICUs can handle the medi-
cal needs of infants with EB, EB centers across the United Summary
States see large numbers of such patients. Transfer of af- EB is a group of rare genetic disorders that lead to
fected infants to 1 of these centers may be appropriate in fragile skin. Because of the skin blistering and oth-
some cases. However, most EB centers can also provide er complications of EB, affected infants are often re-
remote advice and education to physicians and staff, as it ferred to NICUs. Familiarity with the genetic
can be quite disruptive to transfer families away from classification and characteristics of the different
their home support systems. The EB centers usually em- types of EB; understanding the basic principles of
ploy specialists in all areas likely to be called upon for EB wound care; and being aware of the potentially as-
care. These specialists are familiar with how to handle the sociated complications such as poor nutrition, in-
special needs of infants with EB. The specialties usually fection, airway obstruction, and pain are essential
involved are listed in Table 2. for the neonatologist treating these patients. Caring
Teaching families to be comfortable with all aspects of for all the emotional and financial consequences of
their newborn’s EB care before discharge from the hospital EB with the family is necessary for a successful
is essential. This work may include helping families to se- transition home. Collaboration with EB centers and
cure home health care, connecting families to appropriate other resources in the local, national, and interna-
durable medical equipment providers to obtain the financial tional community can be very helpful in the care of
coverage of their bandage and/or feeding supplies. (45) Se- these infants and their families.
curing available state (eg, Medicaid or state-supported pro-
grams for handicapped children) as well as federal financial
support (eg, Social Security) can be lifesaving. Referral for
ongoing visits to an EB center after discharge is an ideal so-
lution to complement routine medical care.
American Board of Pediatrics
In addition to EB centers, online resources are available, Neonatal-Perinatal Content
such as the many country-specific Dystrophic Epidermolysis Specifications
Bullosa Research Association (DEBRA) groups. These include • Know the inheritance patterns, cutaneous and
DEBRA of America (www.debra.org) and DEBRA Interna- laboratory manifestations, management, and outcome
tional (www.debra-international.org). These sites contain ex- of epidermolysis bullosa.
cellent supportive material to educate families and medical • Know the management of bullous skin lesions in the
professionals, help for families to navigate the resources avail- newborn infant.

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 19. Feinstein JA, Jambal P, Peoples K, et al. Assessment of the timing
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1. Fine JD. Epidemiology of inherited epidermolysis bullosa based on from North America. JAMA Dermatol. 2019;155(2):196–203
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Bullosa Registry. JAMA Dermatol. 2016;152(11):1231–1238 A comprehensive next-generation sequencing assay for the diagnosis
2. Has C, Bauer JW, Bodemer C, et al. Consensus re-classification of of epidermolysis bullosa. Pediatr Dermatol. 2018;35(2):188–197
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37. Colomb V, Bourdon-Lannoy E, Lambe C, et al. Nutritional outcome www.debra.org. Accessed December 13, 2020
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39. Levin LE, Shayegan LH, Lucky AW, et al. Characterization of wound 47. ClinicalTrials.gov. Results of search for epidermolysis bullosa
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Dermatol. 202038(1):119–124 48. Eichstadt S, Barriga M, Ponakala A, et al. Phase 1/2a clinical trial of
40. Kim MG, Lee G, Lee SK, et al. Epithelial cell-specific laminin 5 is gene-corrected autologous cell therapy for recessive dystrophic
required for survival of early thymocytes. J Immunol. 2000;165(1): epidermolysis bullosa. JCI Insight. 2019;4(19):130554
192–201 49. Epidermolysis Bullosa Research Partnership Clinical Trials. VIITAL
41. Ida JB, Livshitz I, Azizkhan RG, Lucky AW, Elluru RG. Upper Study: Pivotal Phase 3 Clinical Trial of EB-101 for RDEB. Available
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 NEOREVIEWS QUIZ

NEO
QUIZ
1. A male term infant is noted to have multiple blisters and fragile skin 1 day
after birth. Epidermolysis bullosa (EB) is suspected. Which of the following
statements regarding classification of EB is correct?

A. The most current classification of EB is based solely on clinical features.

B. EB simplex is the subtype characterized by abnormal or missing
proteins located in the epidermis.
C. Junctional EB is characterized by abnormal proteins below the dermis.
D. The main classification is based on whether the inheritance pattern is
dominant (dominant EB) or recessive (recessive EB).
E. The 5 subtypes of EB are named after each of the 5 geneticists who
discovered the primary gene responsible for each subtype.
REQUIREMENTS: Learners can
2. A newborn male term infant is noted to have blistering of the skin and also take NeoReviews quizzes and
found to have emesis and feeding intolerance soon after birth. Which of the claim credit online only at:
following conditions is found in EB caused by PLEC1 or a6b4 integrin http://neoreviews.org.
mutations?
To successfully complete 2021
A. Hirschprung disease. NeoReviews articles for AMA PRA
B. Lactose intolerance. Category 1 Credit™, learners
must demonstrate a minimum
C. Annular pancreas.
performance level of 60% or
D. Necrotizing enterocolitis. higher on this assessment. If
E. Pyloric atresia. you score less than 60% on the
assessment, you will be given
3. A newborn female has skin fragility, blisters, and skin erosions that appear
additional opportunities to
during the first few days after birth. There are signs that this may be a answer questions until an
severe case of EB. Which of the following physical findings or signs in the overall 60% or greater score is
newborn period would indicate a stronger likelihood of recessive dystrophic achieved.
EB?
This journal-based CME activity
A. Anemia and thrombocytopenia. is available through Dec. 31,
B. Absence of any fingernails or toenails. 2023, however, credit will be
C. Lack of lingual papillae. recorded in the year in which
the learner completes the quiz.
D Presence of granulation tissue around the nails.
E. Involvement of airway leading to tracheostomy requirement.
4. A 5-day old infant who has been diagnosed with EB is being cared for in the
NICU. Which of the following aspects of care would be most appropriate?
A. The optimal wound care in EB involves air exposure with avoidance of
any emollients or dressings. 2021 NeoReviews is approved
for a total of 30 Maintenance of
B. Contact layer dressing products are best when adherent and always
Certification (MOC) Part 2
have a broad-spectrum antibiotic component. credits by the American Board
C. When skin wound dressings are applied, securement should be of Pediatrics (ABP) through the
avoided as dressings should be easily maneuverable without inhibition. AAP MOC Portfolio Program.
D. When emollients are used, they should not be applied directly onto NeoReviews subscribers can
the wound, but rather smeared into a thin layer onto the contact claim up to 30 ABP MOC Part 2
points upon passing 30 quizzes
layer.
(and claiming full credit for
E. The main anti-infective agent to be applied for an infection is each quiz) per year. Subscribers
metronidazole. can start claiming MOC credits
as early as October 2021. To
5. Nutrition is a critical component of caring for newborns with EB because of
learn how to claim MOC points,
their increased caloric and other nutritional needs. Which of the following go to: https://
statements most appropriately describes supplemental nutrition for patients www.aappublications.org/
with EB when oral feeding is inadequate? content/moc-credit.

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 A. Parenteral nutrition is contraindicated in all cases of EB because of the
potential for adverse events.
B. If catheters are placed, it is imperative to refrain from applying
adhesive materials, which can tear the fragile skin when removed.
C. Because almost all patients with EB will have inadequate feeding, an
orogastric tube should be placed immediately after diagnosis or
suspicion of diagnosis.
D. Umbilical catheters can be kept in infants with EB for a prolonged
period, up to 1 month, compared with other infants without risk of
infection.
E. Infants with EB should be fed soy-based formula to minimize their risk
of later developing other skin disorders such as eczema.

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