Journal of Neonatology Vol. 22, No. 1, Jan. - Mar.
2008
REVIEW ARTICLE
Blistering disorders: Clues to diagnosis
Vibhu Mehendiratta
Department of Dermatology and Venereology, Lady Hardinge Medical College, New Delhi 110 001
vibhumendiratta@rediffmail.com
Abstract
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Blistering diseases in neonates could be primary due to
either a genetic mutation or autoimmune response or they
may be secondary to infections, local injury of the skin or
passive transfer of maternal antibodies, resulting in fluid
accumulation within a specific layer of the skin. Some
diseases are characterized by self limiting lesions and are
considered benign.
Introduction
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A wide spectrum of diseases of the skin are manifested as
a blistering process. Blistering may occur as a secondary
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event associated with viral or bacterial infections of the skin,
eg, herpes simplex and impetigo, or with local injury of the
skin, eg, burns, ischemia, and dermatitis. In other diseases,
blistering of the skin occurs as a primary event and is
associated with tissue injury and fluid accumulation within
a specific layer of the skin: intraepidermal, dermal-epidermal
junction (DEJ), or subepidermal. Blister formation in this latter
group of diseases is due to either genetic mutation or an
autoimmune response. Genodermatoses associated with
blisters are typically manifested in the neonate, whereas the
autoimmune blistering disorders are acquired and usually
expressed later in life. Recent advances have uncovered the
relevance of the keratinocyte cytoskeleton, the desmosome,
the hemidesmosome, and extracellular matrix proteins in
blister formation1-4. This article reviews the neonatal
blistering eruptions and outlines a practical approach to
diagnosis and management.
Etiopathogenesis
There are three compartments in the skin where blisters
might arise: the epidermis (limited by the stratum corneum
on the outside and the basal cell layer on the inside), the DEJ
or lamina lucida (limited by the cell surface of basal
keratinocytes and the lamina densa), and the dermis (the
tissue located below the lamina densa). Blisters can be
classified, therefore, according to the location of the vesicle
into intraepidermal, junctional, and subepidermal (below
the lamina densa). The basal cell layer is anchored to the
dermis and remains undifferentiated, whereas suprabasal
keratinocytes adhere to each other and terminally
differentiate, forming the stratum corneum. The structural
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integrity of the epidermis (the mechanical scaffold) results
from a complex set of molecular interactions involving the
keratinocyte cytoskeleton and the desmosomal plaque, and
intercellular interactions between the transmembrane core
glycoproteins of adjacent cells.
Under normal circumstances, the molecular interactions
of the structural proteins of the epidermis, DEJ, and dermis
sustain and strengthen the scaffolding of the skin. Any defect
of these proteins (i.e, those introduced by genetic mutation
of a key domain of a molecule) weakens the mechanical
framework of the skin and gives rise to a potential site for
blister formation. The structural proteins of the skin might
also become the target of immunologic injury in a variety of
autoimmune diseases. Genetic mutation and a loss of
function of the respective protein might trigger blister
formation3,4.
Clinical features
General physical examination of the baby is of utmost
importance as physical signs such as fever, dyspnea,
hypotension may point towards serious systemic infection.
Poor feeding, lethargy and irritability in the neonate indicate
some serious disease.
Type of blisters and other associated lesions- vesicles
containing clear fluid (up to 0.5cm) are seen in viral infections
such as herpes, candida and infantile acropustulosis.
Umbilicated vesicles are seen in chicken pox and herpes
zoster. Fragile, superficial blisters signify an epidermal
pathology and are encountered in miliaria crystallina,
epidermolysis bullosa (simplex). Tense bullae are seen in
herpes gestationis and also in junctional and dermal variants
of epidermolysis bullosa. Associated scaling along with
pustular lesions are seen in congenital candidiasis. Erosions,
peeling of the skin on mechanical pressure (Nikolsky’s sign)
and scarring should also be looked for as their presence may
offer diagnostic clues for the diagnosis of pemphigus and
staphylococcal scalded skin syndrome.
Distribution of the lesions: Blisters are noticed over the
trauma prone sites in the mechanobullous disorders such as
epidermolysis bullosa. The sites commonly involved are the
shoulders, back, buttocks, elbows, knees, hands and feet.
Pustules localized over the acral areas such as the hands and
the feet are observed in infantile acropustulosis.
 Journal of Neonatology Vol. 22, No. 1, Jan. - Mar. 2008

Infectious vesiculobullous lesions in the Congenital candidiasis: The lesions are usually present at
birth but sometimes may be delayed. They are seen as diffuse
neonate
erythema with vesiculopustular lesions with a collarette of
scales and are distributed over the palms, soles and the groins.
Neonatal herpes: This condition is a medical emergency.
The infant is generally well. Diagnosis is established by KOH
The cutaneous lesions may be present at birth but can be
preparation from the vesicle or the scales. Topical antifungal
delayed upto 28 days after birth. Neonatal herpes presents
agents such as miconazole or clotrimazole are used for
with grouped vesicles and erosions over the back, lower
treatment. A close watch should be kept for signs of
limbs or the trunk which pass through stages of crusting.
disseminated infection which will require systemic
There can be keratoconjunctivitis . The infant may also
antifungals.
develop neurological signs. Diagnosis is based on the Tzanck
Congenital Varicella infection: The infant may develop
smear, electron microscopy and viral culture. Positive history
blisters ( in the form of dew drops on rose petals) if maternal
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of herpes infection in the mother should alert the

varicella occurred less than 17 days from the delivery.
neonatologist. Treatment is in the form of intravenous
Neonatal varicella is a serious condition, hence
acyclovir5.
administration of the zoster immunoglobulin to the neonate
Staphylococcal infections: Staphylococcal infections can
is mandatory even if the neonate is asymptomatic but there
be in the form of impetigo which presents as fragile bullae
is a positive history of maternal varicella 5 days before and 2
that contain pus. Some may erode to form crusts. The lesions
days after the delivery. Diagnosis is by Tzanck smear and
involve the neck, face, and the extremities in the neonate
viral culture. Intravenous acyclovir is given in the dose of
(Fig. 3.1a & Fig. 3.1b). Toxin producing strains of
500 mg/meter square 8 hourly for 7 days.
staphylococcus can cause staphylococcal skin syndrome
Congenital Syphilis: Snuffles, maculopapular or
which is characterized by the presence of diffuse blotchy
papulosquamous skin rash with osseous and musculoskeletal
erythema of the skin along with superficial blistering,
involvement are more common than bullae. If present, they
wrinkling and peeling of the skin. The neonate appears toxic
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are noted over the palms and the soles and are large blisters.
and unwell. Diagnosis of bullous impetigo can be
Blister fluid shows treponema pallidum on dark ground
ascertained by Gram stain of the blister fluid and culture of
examination. The baby is treated with parenteral penicillin.
the staphylococci. Culture is negative in Staphylococcal
Neonatal scabies: The infestation is generally acquired from
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Scalded Skin Syndrome (SSSS) (Fig. 3.2). Penicillinase resistant

an intrafamilial source. The lesions observed are papules
penicillin should be administered systemically6.
vesicles and pustules over the palms and soles, genitals and
the head and neck. Bullae are rare. Secondary
impetiginization is a frequent complication. Ten percent
Table 1: Causes of vesiculobullous conditions in neonate. crotamiton and sulphur ointment (6-10%) are safe for use
1. Non-infective in infants and the treatment should be provided to the whole
Erythema toxicum neonatorum (ETN) family and not just the infant.
Transient neonatal pustular melanosis (TNPN)
Milia Non infective blisters in the neonate
Miliaria crystallina
2. Infective Erythema toxicum neonatorum: The etiology of this
Impetigo neonatorum condition is unknown and it may be a response of the
Staphylococcal scalded skin syndrome (SSSS) neonatal skin to thermal or mechanical stimuli. The lesions
Herpes (neonatal) appear 1-2 days after birth and are accompanied with blotchy,
Chicken pox erythematous papules and vesicles along with pustules at
Herpes zoster places. Involvement of the face, trunk, limbs and the back is
Neonatal candidiasis common. Mucous membranes, palms and soles are spared.
Congenital syphilis The baby is afebrile. The blister fluid examination shows
Neonatal scabies presence of numerous eosinophils and no organisms. The
condition does not require any treatment (Fig. 3.3).
3. Genodermatoses Transient Neonatal Pustular melanosis: Lesions appear
Bullous icthyosiform erythroderma as papules which turn into vesicles and then into pustules.
Epidermolysis bullosa The site of distribution is the trunk, buttocks and the lower
Incontinentia pigmenti limbs. The pustules dry up and heal with macular
4. Autoimmune hyperpigmentation often with a collerette of scales in 2-3
Pemphigus neonatorum weeks. Grams stain of the blister fluid shows plenty of
Herpes gestationis neutrophils without any organism7.
Linear Ig A dermatosis (rare) Miliaria: It is a pathological process which arises as a result
5. Bullous mastocytosis of injury to the eccrine sweat duct due to heat, sweating,
maceration and occlusion. Immaturity of the sweat duct in
6. Suction blisters the neonate contributes to the sweat retention. The vesicles
7. Traumatic are 1-2 mm in size and contain clear fluid. Intertiginous areas
Burns (thermal, electrical, chemical) and the forehead are the common affected sites in the

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 Journal of Neonatology
neonates. The condition generally follows episodes of fever
in neonates and babies kept in warm conditions in the nursery.
Suction Blisters: These are quite common and are said to
occur in 1 in every 250 deliveries. The blisters are seen
commonly over the digit, hand or the arm and are caused by
the friction of sucking by the infant. They are benign. The
lesions are non progressive which helps in differentiating
them from epidermolysis bullosa.
Genodermatoses
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Epidermolysis bullosa: Epidermolysis bullosa is a group
of mechanobullous disorders and refers to a group of rare,
inherited skin diseases characterized by recurring painful
blisters and open sores, often in response to minor trauma,
as a result of the unusually fragile nature of the skin. Some
severe forms may involve the eyes, tongue, and esophagus,
and some may produce scarring and disabling
musculoskeletal deformities. There are three major forms:
Epidermolysis Bullosa Simplex (EB simplex), the most
common; Dystrophic Epidermolysis Bullosa (DEB), and
Junctional Epidermolysis Bullosa (JEB) (Fig. 3.4). The recessive
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forms of epidermolysis bullosa tend to be more severe.The
hallmark of these conditions is the formation of large, fluid-
filled blisters that develop in response to minor trauma. Some
infants may have large blisters at birth. Chafing (wearing
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away) of the skin, rubbing, or even increased room
temperature may cause blisters to form. In the severe forms,
scarring after blister formation may cause deformities, fusion
of the fingers and toes, and contracture deformities (for
example, at the fingers, elbows and knees). If the mouth and
esophagus are involved, blistering and scarring lead to
feeding and swallowing difficulties. Secondary infection is
common. Distribution of bullae is over the trauma prone
areas such as the buttocks, hands, feet and the back. Presence
of other features such as milia and scarring, loss of nail plate
further point towards the diagnosis of EB. Confirmation of
the diagnosis is based on the skin biopsy,
immunofluorescence and electron microscopy which would
determine the level of blistering.Treatment is mainly
supportive. Baby should be handled carefully and parents
are counseled about it8.
Bullous icthyosiform erythroderma: It is a disfiguring,
autosomal dominant disorder of keratinization which is
characterized by multiple erosions and bullae at the time of
birth in association with generalized erythema and scaling
of the skin. The disorder can be diagnosed antenatally.
Supportive treatment constitutes rehydration, skin care with
emollients and antibiotics. Oral retinoids especially etretinate
can be administered for controlling the keratinous scaling
and the bullae9,10 (Fig. 3.5).
Incontinentia pigmenti: It is an X- linked dominant disorder
and seen in girls. This neurocutaneous disorder has three
stages- vesicular, verrucous and the pigmentary stage.The
disorder can begin within 6 weeks of birth and in the
neonatal age presents with erythema and vesicles in a linear
distribution chiefly over the lower limbs. The disorder is
associated with multiple skeletal, neurological, eye and dental
anomalies which might develop over a period of time. Blister
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Vol. 22, No. 1, Jan. - Mar. 2008
fluid examination using Gram stain shows an eosinophilic
infiltrate.
Auto-immune blistering disorders
These are acquired disorders and generally seen in older
children. Transplacental passage of maternal autoantibodies
to the neonate can give rise to bullous lesions in the case of
maternal pemphigus vulgaris, pemphigus foliaceous and
herpes gestationis. The former two conditions present with
erosions and crusted lesions in the infant over the scalp,
neck and the upper trunk. Bullae are infrequent, whereas in
the herpes gestationis, large, tense bullae are encountered
over an erythematous skin on the trunk of the baby. Diagnosis
is suspected in view of a positive history of maternal disease
during pregnancy. Histopathology of the lesions and
immunofluorescence confirm the diagnosis. These blisters
are transitory and self limiting conditions11,12.
Iatrogenic and traumatic blisters
Neonate is exposed to a wide range of irritating chemicals
in the form of antiseptics, adhesives and dressings etc. some
of which can cause irritant dermatitis producing injury to
the skin which causes bulla formation. Therapeutic
interventions in the form of phototherapy can also cause
accidental burn and blister formation in the baby. Bullae can
also be produced secondary to the administration of various
drugs in the neonate.
Miscellaneous conditions
Bullae are seen in mastocytosis, which is a condition
characterized by infiltration of the skin by mast cells.
Degranulation of mast cells induces blisters along with
erythema and urticarial lesions in the neonate.
Histopathology of the skin shows diffuse infiltrates of mast
cells in the dermis.
Approach to the diagnosis
1. Maternal History: Some maternal infections such as herpes,
candida, syphilis etc. can be passed on to the neonate
and manifest as vesiculopustules or bullae. Similarly
certain autoimmune blistering disorders in the mother
such as pemphigus vulgaris , pemphigus foliaceus and
herpes gestationis can cause bullae in the neonate due to
the transplacental passage of the IgG. Hence history of
blistering condition should be taken in the mother.
2. Trauma: Trauma at the time of delivery, application of
suction apparatus, thermal burns or chemical burn or
electrical burn can cause localized bullous eruptions.
3. Friction: Sucking by the infant can result in friction blister
over the digit, arm or hand.
4. Family history: Genetic skin conditions such as the
epidermolysis bullosa and the bullous icthyosiform
 Journal of Neonatology
erythroderma run in families, hence family history of any
blistering condition must be sought in order to exclude
the above. Absence of family history, however does not
rule out a genetic condition. Presence of itchy,
papulovesicular lesions in the other family members
corroborates the diagnosis of neonatal scabies in an infant
who has papulovesicular lesions.
5. Drug administration: Some drugs such as antibiotics,
anticonvulsants etc. can give rise to blistering drug rashes.
Investigations
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1. Smear from the blister fluid- Gram’s stain, Giemsa stain
and the KOH preparation should be done to look for any
cocci, giant cells, acantholytic cells or budding yeast cells.
Type of inflammatory infiltrate can give useful clues
towards the diagnosis. An eosinophil rich fluid signifies
incontinentia pigmenti and erythema toxicum
neonatorum, where as predominantly neutrophilic
infiltrate is encountered in transient neonatal pustular
melanoses and bacterial infections.
2. Culture for bacteria and yeast
3. Skin biopsy-Histology of the skin and immunological
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investigations -immunofluorescence techniques electron
microscopic and immunoelectron microscopic
examination. Molecular biological techniques should be
used to make a precise diagnosis of any of the
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genodermatoses
4. Electron microscopy and viral culture.
Conclusions
Blistering conditions are encountered quite commonly in
the neonates and they range from benign, noninfective, self
limiting rashes, common infective dermatoses to severe,
genetic bullous disorders. Passive transfer of maternal auto
antibodies in autoimmune blistering disorders can also give
rise to transient blisters in the neonates. History, knowledge
of the common causes, familiarity with the type and
CONGRATULATIONS
Dr Ranjan Kumar Pejaver, President, NNF, Karnataka branch have been unanimously elected as the
President Elect (2010-2012) of the Federation of Asia Oceania Perinatal Societies. The first Indian to
occupy the post. He attended the biannual congress of FAOPS held in Nagoya, Japan and spoke on
‘Telemedicine in Perinatal health care’
18
Vol. 22, No. 1, Jan. - Mar. 2008
distribution of lesions, microbiological and cytological
evaluation of the blister fluid are useful aids to the diagnosis.
Histopathological examination coupled with immunological
and molecular techniques can be employed for the
confirmatory diagnosis.
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