121
C HA PTER 10
Differential Diagnosis of Neonatal
Erythroderma
Hagen Ott1 & Peter H. Hoeger2
1
Division of Pediatric Dermatology and Allergology, Epidermolysis bullosa Centre Hannover, Children’s Hospital AUF DER BULT, Hannover, Germany
2
Department of Paediatric Dermatology, Catholic Children’s Hospital Wilhelmstift, Hamburg, Germany
Introduction, 121 Adverse drug reactions, 129
Cutaneous disorders, 123 Immunological disorders, 130
Infections and toxicities, 128 Inborn errors of metabolism, 132
Abstract
Neonatal erythroderma occurs during the first 28 days of life and
is defined as a generalized erythema covering more than 90% of
body surface area. It can be the manifestation of various clinical
syndromes ranging from benign, transient skin diseases to poten-
tially fatal systemic disorders. The prognosis of affected patients
Key points
• Neonatal erythroderma is characterized by a generalized
erythema covering more than 90% of the neonate’s body
surface area.
• The underlying illnesses range from benign, erythematosquamous
disorders such as atopic dermatitis to fatal diseases such as
severe combined immunodeficiencies.
­Introduction
By definition, neonatal erythroderma has its onset during
the first 28 days of life and refers to a generalized ery­
thema with or without scaling that covers more than 90%
of the newborn’s body surface area [1]. Although reliable
epidemiological data are still not available, neonatal
erythroderma can be considered a rare disorder as dem­
onstrated by a single‐centre study of 19 000 paediatric
dermatology patients yielding a 0.11% incidence of eryth­
rodermic neonates and infants during a 6‐year period [2].
Neonatal erythroderma can be the manifestation of
various clinical syndromes ranging from benign, tran­
sient skin diseases to potentially fatal systemic disorders.
The prognosis of affected patients is serious due to a per­
sistence of severe skin symptoms in 70% after 3 years and,
more importantly, a mortality rate of up to 25%.
Irrespective of its cause, erythroderma per se is a life‐
threatening condition in neonates, mainly due to an
Harper’s Textbook of Pediatric Dermatology, Fourth Edition. Edited by Peter Hoeger, Veronica Kinsler and Albert Yan.
© 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.
SECTION 2: SKIN DISORDERS
OF NEONATES AND INFANTS
Diagnostic work‐up of neonatal
erythroderma, 133
critically depends on swift diagnosis and early therapeutic inter-
vention. Therefore, this chapter focuses on clinical clues and further
diagnostic steps that are helpful in the differentiation of conditions
regularly associated with neonatal erythroderma. For practical rea-
sons, these are classified into acquired and hereditary skin diseases,
infections, immunodeficiency disorders, drug reactions and inborn
errors of metabolism.
• Irrespective of its cause, neonatal erythroderma is associated
with complications due to impaired epidermal barrier function
such as hypothermia, dehydration or infection.
• To differentiate nonsyndromic forms with good prognosis from
more severe variants of neonatal erythroderma, a thorough
diagnostic work‐up is mandatory in every affected patient.
• Besides routine laboratory tests such as whole blood count, total
serum IgE and blood gas analysis, further molecular genetic and
other analyses are often required.
increased transcutaneous loss of fluid leading to hyper­
natraemic dehydration, increased energy consumption
and hypothermia.
Thus, in order to avoid a critical delay in diagnosis,
definitive identification of the underlying condition is
imperative and often requires further laboratory, histologi­
cal, microbiological or molecular genetic analyses [3–5]
(Fig. 10.1). The historical term ‘Leiner’s disease’ (synonyms:
erythrodermia desquamativa Leiner, Leiner–Moussous
syndrome) originally denoted infants with exfoliative
erythroderma, diarrhoea and failure to thrive. Because this
condition can be attributed to a wide range of different dis­
eases it is recommended that the term be abandoned.
Many of the diseases that need to be considered in this
context are discussed in detail elsewhere in this textbook.
Therefore, the focus of this chapter is on clinical clues and
further diagnostic steps that are helpful in the differentia­
tion of conditions regularly associated with neonatal
 122 Section 2 Skin Disorders of the Neonate and Young Infant

Basic diagnostic work-up

- Patient history
- Clinical examination Neonatal/infantile erythroderma
- Skin smear
- Capillary blood gas analysis
SECTION 2: SKIN DISORDERS
OF NEONATES AND INFANTS

CSF, blood, urine + Congenital cutaneous

Candida?
cultures candidiasis
no

Blood ammonia level, Molecular

Ketoacidosis? + + Holocarboxylase synthetase def.
HLCS-activity genetics (HLCS)
no

+ Re-exposure, if + Red man syndrome

Vancomycin? Discontinue
indicated

Ophthalmology, Molecular + Chondrodysplasia punctata II

+
no

BERA/audiometry genetics (EBP)

Immunohistochemistry, Mol. genetics

+ + Netherton syndrome
trichogram (SPINK5)
Ichthyosîs?
Mol. genetics
Electron microscopy + + NCIE/BCIE
(TGM1, K1/10)

Funduscopy, FALDH- Mol. genetics

no

+ + Sjögren–Larsson syndrome
activity (fibroblasts) (ALDH3A2)

Exfoliation? Histology (cleavage level) Subepidermal? Toxic epidermal necrolysis

no

Subcorneal? PCR
+ SSSS
(sea, seb)
no

Total lgE, Mol. genetics

+ + Omenn syndrome
lymphocyte typing (RAG1/2, others)
Dystrophy,
Alopecia?
Histology, Chimerism
+ + Maternofetal GvHD
lymphocyte typing analysis
no

Atopic dermatitis
Consider Psoriasis vulgaris
‘transient erythroderma’ Seborrheic dermatitis
Pityriasis rubra pilaris

Fig. 10.1 Proposal for a diagnostic algorithm to be followed in the management of neonatal and early infantile erythroderma. Source: Ott et al. 2008 [1].
Reproduced with permission of John Wiley & Sons. EBP, emopamil‐binding protein; FALDH, fatty aldehyde dehydrogenase; NCIE/BCIE, nonbullous
congenital ichthyosiform erythroderma/bullous congenital ichthyosiform erythroderma; PCR, polymerase chain reaction.
 Chapter 10 Differential Diagnosis of Neonatal Erythroderma 123

Box 10.1 Neonatal erythroderma: differential diagnosis

­Cutaneous disorders
Retrospective hospital‐based investigations have identified
Cutaneous disorders primary skin diseases as the most common cause of
Erythematosquamous skin diseases neonatal and infantile erythroderma, accounting for as
• Seborrhoeic dermatitis many as 80% of all cases. The underlying cutaneous
disorders comprise erythematosquamous diseases, geno­

SECTION 2: SKIN DISORDERS

• Atopic dermatitis

OF NEONATES AND INFANTS

• Psoriasis dermatoses and further skin diseases, particularly scabies
• Pityriasis rubra pilaris and generalized cutaneous mastocytosis [1–3].

Genodermatoses
• Nonsyndromic ichthyosis (nonbullous congenital ichthyosiform
erythroderma, epidermolytic ichthyosis)
• Syndromal ichthyosis (Chanarin–Dorfman syndrome, Conradi–
Hünermann–Happle syndrome, Sjögren–Larsson syndrome)
• Disorders of epidermal homeostasis (Netherton syndrome, peeling
skin syndrome type B, SAM syndrome)
• Ectodermal dysplasia
Other skin diseases
• Diffuse cutaneous mastocytosis
• Scabies
Infections and toxicities
• Staphylococcal scalded skin syndrome
• Congenital and neonatal candidiasis
Adverse drug reactions
• Stevens–Johnson syndrome, toxic epidermal necrolysis
• Red man syndrome
Immunological disorders
• Omenn syndrome
• Graft‐versus‐host disease
• Other primary immunodeficiencies (DiGeorge syndrome,
Wiskott–Aldrich syndrome, IPEX syndrome)
Inborn errors of metabolism
• Holocarboxylase synthetase deficiency
• Amino acid disorders (maple syrup urine disease, methylmalonic
acidaemia)
erythroderma. For practical reasons, these can be classified
into cutaneous disorders, infectious diseases, immunode­
ficiency disorders, drug reactions and inborn errors of
metabolism (Box 10.1).
­References
1 Ott H, Hutten M, Baron JM et al. Neonatal and infantile erythrodermas.
J Dtsch Dermatol Ges 2008;6:1070–85.
2 Sarkar R, Basu S, Sharma RC. Neonatal and infantile erythrodermas.
Arch Dermatol 2001;137:822–3.
3 Al‐Dhalimi MA. Neonatal and infantile erythroderma: a clinical and
follow‐up study of 42 cases. J Dermatol 2007;34:302–7.
4 El Euch D, Zeglaoui F, Benmously R et al. Erythroderma: a clinical
study of 127 cases and review of the literature. Exog Dermatol 2003;2:
234–9.
5 Pruszkowski A, Bodemer C, Fraitag S et al. Neonatal and infantile
erythrodermas: a retrospective study of 51 patients. Arch Dermatol
2000;136:875–80.
Erythematosquamous skin diseases
Seborrhoeic dermatitis (see Chapters 15 and 21)
Infantile seborrhoeic dermatitis (SD) represents a tran­
sient skin disease of good prognosis affecting up to 70%
of newborns and infants during the first months of life [4].
While pruritus is usually mild or completely absent, skin
lesions typically correspond to erythematous patches
with a yellowish hue and greasy scaling which are most
prominent on the scalp (cradle cap), the napkin (diaper)
area and other intertriginous zones [5]. In most patients,
skin symptoms respond rapidly to topical treatment with
low‐potency glucocorticoids or antifungal agents, but in
some cases neonatal and infantile SD may develop into
erythroderma.
As pathognomonic laboratory parameters or histological
features do not exist, the diagnosis of infantile SD is
established on clinical grounds. In contrast to atopic
­dermatitis, erythematous patches in SD are clearly demar­
cated, usually less pruritic, and tend to predominate in
the flexural folds including the anogenital area.
In patients with systemic symptoms such as diarrhoea
or failure to thrive, skin biopsy and further diagnostic
steps are warranted to rule out more severe conditions
such as immunodeficiencies or metabolic defects.
Atopic dermatitis (see Chapter 15)
Despite a period prevalence of up to 28% within the first
year of life, atopic dermatitis (AD) does not usually occur
in infants younger than 3 months of age and only very
rarely causes severe skin symptoms or even erythroderma
in neonates [6]. If present, however, acute lesions are char­
acterized by widespread pruritic erythematous papules
and patches, often with marked exudation. Infantile AD
typically involves the scalp, the face, the trunk and the
extensor surfaces of the extremities whereas, in contrast
to infantile psoriasis and seborrhoeic dermatitis, the nap­
kin area is frequently spared (Fig. 10.2) [7]. Moreover, in
contrast to more serious causes of neonatal erythroderma,
newborns affected by AD without concurrent food allergy
usually thrive well and do not exhibit persisting alopecia
or additional clinical signs of extracutaneous pathology
(e.g. lymphadenopathy, diarrhoea, atypical infections).
The lesions respond rapidly to topical therapy with cor­
ticosteroids, calcineurin inhibitors and emollients. Due to
a considerable clinical overlap and rather uncharacteristic
histological findings upon skin biopsy, differentiation of
erythrodermic AD from other causes of neonatal erythro­
derma is challenging. Although elevated total serum IgE
levels indicate early‐onset AD, they are nonspecific and
 124 Section 2 Skin Disorders of the Neonate and Young Infant
SECTION 2: SKIN DISORDERS
OF NEONATES AND INFANTS
Fig. 10.2 Erythroderma sparing the napkin (diaper) area in an otherwise
healthy male infant with atopic dermatitis.
may also be associated with more serious disorders such
as Omenn syndrome, Wiskott–Aldrich syndrome or
Netherton syndrome. Conversely, normal total serum IgE
levels do not rule out neonatal or infantile AD due to a
high prevalence of the intrinsic variant of AD in this age
group [8]. Likewise, recent prospective birth cohort
studies have disclosed that the presence of food‐specific
IgE is not a reliable indicator of infantile AD (as was
previously postulated), because it can be detected equally
often in affected and healthy children [9–11]. Hence, if
severe AD with concurrent cow’s milk allergy is sus­
pected in a non‐breastfed neonate with erythroderma, the
patient should first be fed with an extensively hydrolysed
milk‐ or amino acid‐based formula for a limited period of
time, e.g. 2 weeks. Likewise, in breastfed infants, maternal
avoidance of potential food allergens may be considered,
but only after adequate dietary counselling. If a clear
amelioration is achieved by allergen avoidance, the infant
should undergo an oral food challenge (OFC) with the
incriminated allergen. If symptoms recur upon OFC, the
diagnosis of food allergy in the context of severe AD is
highly probable.
Psoriasis (see Chapter 30)
Up to 37.5% of children suffering from plaque psoriasis
and up to 50% of children with pustular psoriasis develop
symptoms during the first year of life [12]. Neonatal or
congenital psoriasis is, however, very rare. Neonatal
erythroderma due to psoriasis is likely to evolve into
generalized pustular psoriasis (GPP). Erythrodermic
GPP requires a thorough diagnostic work‐up in order to
exclude other serious differential diagnoses, especially
infections with herpes simplex virus (HSV), varicella zoster
virus (VZV), Staphylococcus aureus or Candida spp. More­
over, GPP demands immediate treatment to avoid poten­
tially severe complications such as sterile lytic bone
lesions, bacterial superinfection or sepsis [13,14].
Infantile psoriasis often starts with an unusually severe
napkin rash that is better demarcated and brighter red than
that of seborrhoeic dermatitis (Fig. 10.3). Subse­ quently,
rapid dissemination leads to generalized erythemato­
squamous skin lesions, but in neonates and young infants
psoriatic erythroderma may also mimic nonbullous
Fig. 10.3 Noncongenital psoriasis with widespread lesions in the napkin
and abdominal area of a male infant revealing sharply demarcated,
infiltrated, bright red plaques.
ichthyosiform erythroderma, severe AD or Netherton
syndrome. Hence, correct diagnosis may require skin
biopsy that reveals a psoriasiform reaction pattern with
laminated parakeratosis, elongated rete ridges often con­
taining neutrophils and little or no dermal lymphocytic
infiltrate while LEKTI staining is negative [15]. Once the
diagnosis of psoriasis is safely established, systemic
treatment with acitretin (0.5–1 mg/kg/day) has proved to
be well‐tolerated and effective even in young infants and
children with GPP [16–18].
Pityriasis rubra pilaris (see Chapter 32)
Pityriasis rubra pilaris (PRP) represents a rare papulo­
squamous disorder of unknown origin which can mani­
fest at any age. In the first month of life, PRP is almost
exclusively encountered in those extremely rare patients
with congenital disease onset. These individuals may be
affected by familial PRP, which accounts for about 5% of
all PRP cases and has recently been shown to be due to
activating mutations in CARD14, the gene encoding
caspase recruitment domain family member 14, a known
activator of nuclear factor kappa B (NF‐κB) signalling [19].
Clinically resembling atypical juvenile PRP (Griffiths
classification type V), skin lesions consist of widespread
follicular, keratotic papules and erythematous patches
coalescing into erythroderma. As in typical juvenile PRP,
neonates display salmon‐coloured erythema with islands
of unaffected skin (‘nappes claires’) (Fig. 10.4) whereas
 Chapter 10
Fig. 10.4 Atypical juvenile pityriasis rubra pilaris in a male infant with
follicular, erythematous papules and patches coalescing into erythroderma.
Of note, the typically salmon‐coloured erythema reveals islands of
unaffected skin (‘nappes claires’) and marked palmar hyperkeratosis.
palmoplantar keratoderma is usually discrete or com­
pletely lacking. Histological features of neonatal PRP have
only been reported casuistically and consist of alternating
ortho‐ and parakeratosis with lipping of follicular ostia
and associated follicular plugging [20,21].
Genodermatoses
Neonatal erythroderma is a presenting sign of several
monogenic skin diseases, particularly ectodermal dyspla­
sia and hereditary disorders of keratinization. The latter
include nonsyndromic ichthyoses with exclusively cutane­
ous symptoms as well as syndromic ichthyoses associated
with potentially severe metabolic, neurological, ophthal­
mological or other abnormalities [22,23]. If suspicion arises,
skin biopsy is mandatory and further diagnostic steps
(e.g. molecular genetics, immunohistochemistry) should
optimally be coordinated in cooperation with national
reference centres such as the Network for Ichthyoses and
Related Keratinization Disorders: NIRK (https://www.
medizin.uni‐muenster.de/nirk/network‐for‐ichthyoses‐
and‐related‐keratinization‐disorders/willkommen/) or the
Centre de référence des maladies rares de la peau et des
muqueuses d’origine génétique, MAGEC (http://www.
maladiesrares‐necker.aphp.fr/magec/), for example.
Nonsyndromic ichthyoses (see Chapter 129)
Nonbullous congenital ichthyosiform erythroderma (NCIE,
OMIM #242100) is an autosomal recessive keratinization
disorder that is caused by mutations in various genes
(ABCA12, ALOXE3, ALOX12B, CERS3, CYP4F22, LIPN,
NIPAL4/ICHTHYIN, PNPLA1, TGM1) [22]. As a clinical
hallmark, up to 90% of affected patients present with a
collodion membrane directly post partum which is shed
during the neonatal period, revealing erythroderma with
generalized fine scaling (Fig. 10.5a and b) [24,25]. While
systemic symptoms are usually absent, further cutaneous
symptoms can include ectropion or eclabium, obstruction of
the external auditory canal, scarring alopecia or peripheral
Differential Diagnosis of Neonatal Erythroderma 125
SECTION 2: SKIN DISORDERS
OF NEONATES AND INFANTS
(a)
(b)
Fig. 10.5 (a) Collodion baby phenotype in a female neonate with
nonbullous congenital erythroderma.Source: Ott et al. 2008 [24].
Reproduced with permission of John Wiley & Sons. (b) Same patient as in
(a) who reveals ‘self‐improving’ ichthyosiform erythroderma with fine
scaling and discrete palmoplantar hyperkeratosis after shedding of the
collodion membrane.
ischaemia due to constricting skin bands [26]. At first
presentation, it is important to rule out syndromic
­differential diagnoses of the collodion baby phenotype
such as Sjögren–Larsson syndrome, Netherton syndrome,
trichothiodystrophy, Chanarin–Dorfman syndrome or
type 2 Gaucher disease [25].
Autosomal dominant epidermolytic ichthyosis (EI, OMIM
#113800), also designated as bullous congenital ichthy­
osiform erythroderma or epidermolytic hyperkeratosis,
belongs to the group of keratinopathic ichthyoses and is
caused by mutations in genes encoding the suprabasal
keratins 1 and 10 (KRT1, KRT10) [27]. Clinical presenta­
tion varies greatly, but affected patients usually suffer
from severe blistering immediately after birth, sometimes
with widespread erosions, accompanied by variously
severe ichthyosiform erythroderma. During the following
weeks, hystrix‐like hyperkeratoses appear. Interestingly,
marked palmoplantar hyperkeratosis is characteristically
encountered in patients with KRT1 mutations, although
individuals with EI due to KRT10 mutations may also be
affected. Initially, other bullous disorders of neonatal onset
have to be considered as possible differential diagnoses,
 126 Section 2 Skin Disorders of the Neonate and Young Infant

especially epidermolysis bullosa hereditaria, superficial
epidermolytic ichthyosis (formerly ichthyosis bullosa
Siemens), staphylococcal scalded skin syndrome and
diffuse cutaneous mastocytosis [28]. Affected family
members may also facilitate diagnosis, although a nega­
tive family history does not rule out EI because >50%
SECTION 2: SKIN DISORDERS
OF NEONATES AND INFANTS
oligodendrocytes, retinal cells), resulting in the character­
istic clinical triad of ichthyosis, psychomotor retardation
and spastic diplegia. In neonates and young infants, SLS
tends to manifest as ichthyosiform erythroderma while
the full clinical picture is usually not apparent until early
childhood. Definitive diagnosis can be established by the

of patients have spontaneous mutations that are readily assessment of FALDH activity in cultured fibroblasts,
detected in EDTA blood samples or skin biopsy specimens. the characteristic elevation of leukotriene B4 (LTB4) in
urine specimens and, finally, targeted sequencing of the
Syndromic ichthyoses (see Chapter 129) ALDH3A2 gene. Pathognomonic crystalline deposits
Autosomal recessive Chanarin–Dorfman syndrome (CDS, within the retina (‘glistening dots’) and reduced levels of
OMIM #275630), also referred to as neutral lipid storage mean foveal macular pigment are seen upon funduscopy
disease with ichthyosis, represents a multiorgan disorder and macular pigment reflectometry, respectively [33,34].
elicited by mutations in the CGI85 (ABDH5) gene. These
induce pathological alterations in the metabolism of Disorders of epidermal homeostasis
endogenous triglycerides leading to the accumulation of The autosomal recessive Netherton syndrome (NS, OMIM
neutral lipids in multiple cell types, particularly leuko­ #256500), a syndromic ichthyosis, is caused by inactivat­
cytes, myocytes, hepatocytes, fibroblasts and keratino­ ing mutations in the epidermal serine protease inhibitor
cytes. The resulting cutaneous phenotype resembles Kazal‐type 5 (SPINK5) gene which codes for the lym­
other forms of congenital ichthyosiform erythroderma phoepithelial Kazal‐type 5 related inhibitor (LEKTI). As a
only occasionally associated with the presenting sign of result, severe defects in epidermal barrier function and a
a collodion membrane. Systemic manifestations in neo­ persistent inflammatory reaction lead to severe neonatal
nates and infants may consist of liver involvement such erythroderma (Fig. 10.6) while the typical polycyclic, ser­
as hepatosteatosis or cirrhosis in 70% of patients, whereas piginous plaques with erythematous borders and double‐
ocular symptoms (e.g. cataract, nystagmus, myopia) and edged scaling (ichthyosis linearis circumflexa) usually do
sensorineural deafness can occur in about 40% and 25% of not manifest before early childhood. Affected neonates
patients, respectively. Additionally, developmental delay and infants often have bacterial skin infections which are
and growth retardation are frequently observed in CDS also due to an underlying immunodeficiency associated
patients. Lipid vacuoles are present in numerous organs
and can be seen in a skin biopsy specimen or in granulo­
cytes and monocytes of a peripheral blood smear on
Pappenheim staining (Jordan sign) [29,30].
Also known as Conradi–Hünermann–Happle syndrome,
type 2 chondrodysplasia punctata (CDPX2, OMIM #302960)
is an X‐linked dominant disorder caused by mutations in
the emopamil‐binding protein (EBP) gene. These entail
increased serum levels of pathological cholesterol metabo­
lites due to an impaired function of 8‐7‐sterol isomerase.
CDPX2 is nearly always fatal for male fetuses. In contrast,
affected female neonates suffer from severe ichthyosiform
erythroderma immediately post partum which is usually
associated with hyperkeratosis and scaling following
Blaschko’s lines. Extracutaneous features which may not
become apparent until later in childhood include short stat­
ure and kyphoscoliosis, hearing loss, sectorial cataracts,
punctate bone calcifications and mild‐to‐moderate mental
retardation. Moreover, asymmetrical shortening of the
limbs is observed in up to 80% of affected girls. While
elevated serum levels of 8‐dehydrocholesterol and a dimin­
ished stratum granulosum with cytoplasmic vacuoles upon
skin biopsy hint at CDPX2, definitive diagnosis is reached
by molecular genetic analysis of the EBP gene [31,32].
As a severe neurocutaneous disease, the autosomal
recessive Sjögren–Larsson syndrome (SLS, OMIM #270200)
is caused by mutations in the ALDH3A2 gene that codes
for fatty aldehyde dehydrogenase (FALDH), an enzyme
of crucial importance for cutaneous and extracutaneous
lipid metabolism. Diminished FALDH activity leads
to a pathological accumulation of essential fatty acids Fig. 10.6 Severe ichthyosiform erythroderma, hypotrichosis and failure
in the membrane of various cell types (keratinocytes, to thrive in an infant with Netherton syndrome.
 Chapter 10
with an immature natural killer cell phenotype and a
decrease of nonswitched memory B cells or CD27+ mem­
ory B cells [35]. The clinical distinction of NS from other
causes of ichthyosiform erythroderma is facilitated by
microscopy of hair shafts (scalp hair, eyebrows, eyelashes)
revealing trichorrhexis invaginata (‘bamboo hair’) and
hypotrichosis. Skin biopsy with immunohistochemical
staining reveals a psoriasiform epidermal hyperplasia
with absence of the stratum granulosum, a mixed perivas­
cular infiltrate and reduced or absent LEKTI expression.
Additionally, total and allergen‐specific IgE levels are fre­
quently elevated while other traits of atopic disease such
as bronchial asthma or allergic rhinitis do not become
apparent until late infancy or early childhood. Associated
systemic symptoms are subject to marked phenotypic
variability and include hypernatraemic dehydration, failure
to thrive and chronic diarrhoea which are responsible for
a fatality rate of up to 20% in the first year of life [35,36].
Peeling skin syndrome type B (PSS‐B, OMIM #270300), a
nonsyndromic ichthyosis, results from loss‐of‐function
mutations in CDSN, the gene encoding for corneodes­
mosin. Phenotypically, neonates and infants with PSS‐B
develop a clinical picture mimicking NS with ichthyosi­
form erythroderma, recurrent staphylococcal skin infec­
tions, severe pruritus and frequent food anaphylaxis in
the context of elevated total and food allergen‐specific
serum IgE levels. However, unlike in NS, hair shaft abnor­
malities are absent and, even more importantly, PSS‐B
patients show increased skin fragility and spontaneous
peeling (Fig. 10.7) corresponding to subcorneal cleavage
upon skin biopsy [37,38].
Fig. 10.7 Severe erythroderma and spontaneous, superficial exfoliation in
a newborn with peeling skin syndrome type B.
Differential Diagnosis of Neonatal Erythroderma 127
Severe dermatitis, multiple allergies and metabolic wasting
syndrome (SAM, OMIM #615508) has recently been shown
to be caused by homozygous mutations in DSG1, the
desmoglein‐1‐encoding gene (DSG1). These mutations
lead to desmosome dysfunction, impaired cell adhesion
and aberrant epidermal differentiation. As a consequence,
SECTION 2: SKIN DISORDERS
OF NEONATES AND INFANTS
affected neonates reveal early‐onset, ichthyosiform eryth­
roderma, multiple food allergies and a severe failure to
thrive. Additional clinical features consist of recurrent
skin or pulmonary infections, hypotrichosis and palmo­
plantar keratoderma, which may help to distinguish SAM
syndrome from NS and PSS‐B clinically. While histology
reveals subcorneal separation associated with acantholysis,
a definitive diagnosis can be established by DSG1
sequencing [38].
Ectodermal dysplasia (see Chapter 134)
Erythroderma can also be seen in neonates suffering from
ectodermal dysplasias, a heterogenous group of inherited
disorders involving absence or dysplasia of the ectodermal
appendages. In particular, neonates with ankyloblepha­
ron, ectodermal dysplasia and cleft lip/palate syndrome
(AEC, OMIM #106260), a very rare autosomal dominant
genodermatosis caused by TP63 mutations, may present
with widespread erythema. In these patients, neonatal
erythroderma with extensive erosions and diffuse depig­
mented patches in previously eroded areas can be observed
besides further clinical signs of ectodermal dysplasia such
as palmoplantar keratoderma, partial anhidrosis, nail
dystrophy, patchy alopecia and hypodontia [39,40].
Other skin diseases
Diffuse cutaneous mastocytosis (see Chapter 92)
As the rarest subtype of cutaneous mastocytosis (CM),
diffuse cutaneous mastocytosis (DCM) affects up to 5% of
CM patients and usually manifests with a peculiar type
of neonatal erythroderma either at birth or shortly there­
after. Characteristically, infiltration of mast cells through­
out the entire cutis leads to widespread, yellow‐reddish
erythema accompanied by extensive bulla formation.
Other skin manifestations attributable to mediator release
from mast cells comprise flushing, urticaria or pachyder­
mia. Extracutaneous symptoms occur in virtually all
affected patients and may consist of abdominal pain,
diarrhoea, headache or even anaphylaxis. Hence, erythro­
dermic neonates with DCM require interdisciplinary
management including bone marrow biopsy if suspicion
of systemic mastocytosis arises, as in patients with hepat­
osplenomegaly, lymphadenopathy, abnormal blood count
and/or serum tryptase levels above 100 ng/mL [41–43].
Scabies (see Chapter 59)
Neonatal erythroderma due to infestation with the mite
Sarcoptes scabiei hominis has only been very rarely reported.
In these cases, physical examination revealed scaly
erythroderma, multiple micropustules and papules on
the trunk, extremities, scalp, face and the palmoplantar
region with secondary eczematization and bacterial super­
infection. Peripheral blood cell counts showed marked
eosinophilia. In a recent multicentre trial, anamnestic
 128 Section 2 Skin Disorders of the Neonate and Young Infant
relapse, the presence of skin nodules and the involvement
of soles and scalp were found to be highly characteristic
signs of scabies infestation in infants and young children.
Extracutaneous features such as hepatosplenomegaly or
lymphadenopathy were not observed [44–46].
SECTION 2: SKIN DISORDERS
OF NEONATES AND INFANTS
­References
1 Al‐Dhalimi MA. Neonatal and infantile erythroderma: a clinical and
follow‐up study of 42 cases. J Dermatol 2007;34:302–7.
2 El Euch D, Zeglaoui F, Benmously R et al. Erythroderma: a clinical
study of 127 cases and review of the literature. Exog Dermatol
2003;2:234–9.
3 Pruszkowski A, Bodemer C, Fraitag S et al. Neonatal and infantile
erythrodermas: a retrospective study of 51 patients. Arch Dermatol
2000;136:875–80.
4 Foley P, Zuo Y, Plunkett A et al. The frequency of common skin condi­
tions in preschool‐aged children in Australia: seborrheic dermatitis
and pityriasis capitis (cradle cap). Arch Dermatol 2003;139:318–22.
5 Alexopoulos A, Kakourou T, Orfanou I et al. Retrospective analysis of
the relationship between infantile seborrheic dermatitis and atopic
dermatitis. Pediatr Dermatol 2014;31:125–30.
6 Draaisma E, Garcia‐Marcos L, Mallol J et al.; EISL Study Group. A
multinational study to compare prevalence of atopic dermatitis in the
first year of life. Pediatr Allergy Immunol 2015;26:359–66.
7 Deleuran M, Vestergaard C. Clinical heterogeneity and differential
diagnosis of atopic dermatitis. Br J Dermatol 2014;170(suppl 1):2–6.
8 Ott H, Stanzel S, Ocklenburg C et al. Total serum IgE as a parameter
to differentiate between intrinsic and extrinsic atopic dermatitis in
children. Acta Derm Venereol 2009;89:257–61.
9 Ballardini N, Bergström A, Wahlgren CF et al. IgE antibodies in
relation to prevalence and multimorbidity of eczema, asthma, and
rhinitis from birth to adolescence. Allergy 2016;71:342–9.
10 Eller E, Kjaer HF, Host A et al. Food allergy and food sensitization in
early childhood: results from the DARC cohort. Allergy 2009;64:1023–9.
11 Eigenmann PA. Clinical features and diagnostic criteria of atopic der­
matitis in relation to age. Pediatr Allergy Immunol 2001;12(Suppl
14):69–74.
12 Burden‐Teh E, Thomas KS, Ratib S et al. The epidemiology of child-
hood psoriasis: a scoping review. Br J Dermatol 2016;174:1242–57.
13 Lehman JS, Rahil AK. Congenital psoriasis: case report and literature
review. Pediatr Dermatol 2008;25:332–8.
14 de Oliveira ST, Maragno L, Arnone M et al. Generalized pustular pso­
riasis in childhood. Pediatr Dermatol 2010;27:349–54.
15 Leclerc‐Mercier S, Bodemer C, Bourdon‐Lanoy E et al. Early skin
biopsy is helpful for the diagnosis and management of neonatal and
infantile erythrodermas. J Cutan Pathol 2009;37:249–55.
16 Chao PH, Cheng YW, Chung MY. Generalized pustular psoriasis in a
6‐week‐old infant. Pediatr Dermatol 2009;26:352–4.
17 Haug V, Benoit S, Wohlleben M, Hamm H. Annular pustular psoriasis
in a 14‐month‐old girl: a therapeutic challenge. J Dermatolog Treat
2017:28:520–2.
18 Posso‐De Los Rios CJ, Pope E, Lara‐Corrales I. A systematic review of
systemic medications for pustular psoriasis in pediatrics. Pediatr
Dermatol 2014;31:430–9.
19 Fuchs‐Telem D, Sarig O, van Steensel MA et al. Familial pityriasis
rubra pilaris is caused by mutations in CARD14. Am J Hum Genet
2012;91:163–70.
20 Thomson MA, Moss C. Pityriasis rubra pilaris in a mother and two
daughters. Br J Dermatol 2007;157:202–4.
21 Allison DS, El‐Azhary RA, Calobrisi SD, Dicken CH. Pityriasis rubra
pilaris in children. J Am Acad Dermatol 2002;47:386–9.
22 Takeichi T, Akiyama M. Inherited ichthyosis: Non‐syndromic forms.
J Dermatol 2016;43:242–51.
23 Yoneda K. Inherited ichthyosis: Syndromic forms. J Dermatol 2016;
43:252–63.
24 Ott H, Hutten M, Baron JM et al. Neonatal and infantile erythroder­
mas. J Dtsch Dermatol Ges 2008;6:1070–85.
25 Prado R, Ellis LZ, Gamble R et al. Collodion baby: an update with a
focus on practical management. J Am Acad Dermatol 2012;67:
1362–74.
26 Craiglow BG. Ichthyosis in the newborn. Semin Perinatol 2013;37:
26–31.
27 Hotz A, Oji V, Bourrat E et al. Expanding the clinical and genetic spec­
trum of KRT1, KRT2 and KRT10 mutations in keratinopathic ichthyosis.
Acta Derm Venereol 2016;96:473–8.
28 Avril M, Riley C. Management of epidermolytic ichthyosis in the
newborn. Neonatal Netw 2016;35:19–28.
29 Emre S, Unver N, Evans SE et al. Molecular analysis of Chanarin‐
Dorfman syndrome (CDS) patients: Identification of novel mutations
in the ABHD5 gene. Eur J Med Genet 2010;53:141.
30 Nur BG, Gencpinar P, Yuzbasıoglu A et al. Chanarin‐Dorfman
syndrome: genotype‐phenotype correlation. Eur J Med Genet 2015;
58:238–42.
31 Kolb‐Maurer A, Grzeschik KH, Haas D et al. Conradi‐Hunermann‐
Happle syndrome (X‐linked dominant chondrodysplasia punctata)
confirmed by plasma sterol and mutation analysis. Acta Derm
Venereol 2008;88:47–51.
32 Cañueto J, Girós M, Ciria S et al. Clinical, molecular and biochemical
characterization of nine Spanish families with Conradi‐Hünermann‐
Happle syndrome: new insights into X‐linked dominant chondro­
dysplasia punctata with a comprehensive review of the literature.
Br J Dermatol 2012;166:830–8.
33 Nagappa M, Bindu PS, Chiplunkar S et al. Child Neurology: Sjögren‐
Larsson syndrome. Neurology 2017;88:e1–4.
34 Fuijkschot J, Theelen T, Seyger MM et al. Sjögren‐Larsson syndrome
in clinical practice. J Inherit Metab Dis 2012;35:955–62.
35 Hannula‐Jouppi K, Laasanen SL, Ilander M et al. Intrafamily and
interfamilial phenotype variation and immature immunity in
patients with Netherton Syndrome and Finnish SPINK5 Founder
Mutation. JAMA Dermatol 2016;152:435–42.
36 Renner ED, Hartl D, Rylaarsdam S et al. Comel‐Netherton syndrome
defined as primary immunodeficiency. J Allergy Clin Immunol
2009;124:536–43.
37 Oji V, Eckl KM, Aufenvenne K et al. Loss of corneodesmosin leads
to severe skin barrier defect, pruritus, and atopy: unraveling the
peeling skin disease. Am J Hum Genet 2010;87:274–81.
38 Samuelov L, Sprecher E. Peeling off the genetics of atopic dermatitis‐
like congenital disorders. J Allergy Clin Immunol 2014;134:808–15.
39 Berk DR, Crone K, Bayliss SJ. AEC syndrome caused by a novel p63
mutation and demonstrating erythroderma followed by extensive
depigmentation. Pediatr Dermatol 2009;26:617–18.
40 Yoo J, Berk DR, Fabre E et al. Ankyloblepharon‐ectodermal dyspla­
sia‐clefting (AEC) syndrome with neonatal erythroderma: report of
two cases. Int J Dermatol 2007;46:1196–7.
41 Méni C, Bruneau J, Georgin‐Lavialle S et al. Paediatric mastocytosis:
a systematic review of 1747 cases. Br J Dermatol 2015;172:642–51.
42 Heide R, Zuidema E, Beishuizen A et al. Clinical aspects of diffuse
cutaneous mastocytosis in children: two variants. Dermatology
2009;219:309–15.
43 Lange M, Niedoszytko M, Nedoszytko B et al. Diffuse cutaneous
mastocytosis: analysis of 10 cases and a brief review of the literature.
J Eur Acad Dermatol Venereol 2012;26:1565–71.
44 Haim A, Grunwald MH, Kapelushnik J et al. Hypereosinophilia in
red scaly infants with scabies. J Pediatr 2005;146:712.
45 Hortala M, Vicente A, Abellaneda C et al. Erythroderma in a 1‐
month‐old boy. Eur J Pediatr 2007;166:979–80.
46 Boralevi F, Diallo A, Miquel J et al; Groupe de Recherche Clinique
en Dermatologie Pédiatrique. Clinical phenotype of scabies by age.
Pediatrics 2014;133:e910–16.
­Infections and toxicities
Staphylococcal scalded skin syndrome
(see Chapter 37)
Staphylococcal scalded skin syndrome (SSSS), also known
as Ritter disease, staphylogenic Lyell syndrome or
pemphigus acutus neonatorum, is caused by phage group
2 staphylococci that produce the exfoliative toxins A or B
(ETA, ETB). As epidermotropic serine proteases, ETA and
ETB induce subcorneal cleavage by proteolysis of the
desmosomal adhesion protein desmoglein‐1, thereby
causing exfoliative dermatitis.
The disease tends to affect neonates, infants and young
children because of immature renal toxin clearance
and low serum levels of toxin‐neutralizing antibodies.
Following a superficial staphylococcal infection (e.g.
purulent conjunctivitis, omphalitis), patients exhibit
 Chapter 10
Fig. 10.8 Widespread erythema with flaccid, rapidly eroding bullae in a
male neonate with staphylococcal scalded skin syndrome (SSSS).
flexural and facial erythema which may eventually
coalesce into erythroderma. Other symptoms include
extremely tender skin, fever and a rapid decline of the
infant’s general condition. Sepsis‐like symptoms are not
uncommon in this initial erythematous stage of the
disease. Shortly thereafter, large, flaccid, rapidly eroding
bullae appear over the entire body (Fig. 10.8). A positive
Nikolsky sign can regularly be elicited in this exfoliative
stage of SSSS, whereas the mucous membranes are usually
spared.
Neonates and especially preterm infants with sus­
pected SSSS should be hospitalized, especially because
there is a reported mortality risk of about 2.5–11% in this
age group [1]. If exfoliation is extensive, affected neonates
and infants should be treated with nonadhesive, polyure­
thane wound dressings in analogy to burn care or epider­
molysis bullosa patients. In addition, after microbiological
samples have been obtained, systemic antibiotic treatment
is warranted, preferably consisting of penicillinase‐resistant
penicillins. For definitive diagnosis, isolated Staph. aureus
strains may be sent for molecular genetic analysis of the
genes sea and seb. If other blistering or exfoliative skin
disorders such as toxic epidermal necrolysis, epidermolysis
bullosa hereditaria or ichthyosis bullosa of Siemens cannot
be ruled out with certainty, a lesional skin biopsy should
be taken. Subcorneal acantholysis is the characteristic
feature of SSSS and distinguishes it from toxic epidermal
necrolysis with subepidermal blistering [1–3].
Congenital cutaneous candidiasis (see Chapter 7)
Candidal chorioamnionitis, which occurs more often in
pregnant women who have had cerclage or placement of
an intrauterine pessary, can manifest immediately post
partum as congenital cutaneous candidiasis (CCC).
Whitish macules appear on the placenta and umbilical
cord whereas the affected neonate has a maculopapular,
sometimes pustular or bullous exanthema that may rap­
idly evolve into exfoliative erythroderma (‘white dots on
the placenta, red dots on the baby’). Characteristically, the
palmoplantar and umbilical regions are involved initially;
Differential Diagnosis of Neonatal Erythroderma 129
paronychia has also frequently been reported. Unlike
neonatal candidiasis, which is acquired during passage
through the birth canal, the oral cavity and nappy area are
usually spared.
In neonates with CCC, further diagnostic and therapeu­
tic measures are determined by the patient’s gestational
SECTION 2: SKIN DISORDERS
OF NEONATES AND INFANTS
stage. In full‐term infants the disease is generally benign,
running a self‐limiting course without complications.
Oral fluconazole (3–6 mg/kg/day) is a safe option; in
milder cases, the condition can be treated with topical
agents alone (clotrimazole, miconazole) under careful
clinical surveillance. In contrast, premature infants with
CCC, especially those born before 27 weeks’ gestation
and/or a birthweight of <1000 g, may develop invasive
candidal infections that are associated with a mortality
rate of up to 40%. Therefore, a thorough diagnostic work‐up
should be performed in these high‐risk patients includ­
ing blood, urine and cerebrospinal fluid (CSF) cultures.
Depending on test results, systemic antimycotic therapy
with liposomal amphotericin B or fluconazole should be
initiated under close clinical surveillance. Moreover, vari­
ous transient and infectious pustular diseases of the new­
born must be considered as possible differential diagnoses
(see Chapters 6 and 11). In particular, Listeria monocytogenes
infection should be excluded as it may also present with
vesiculopustular eruptions in the n ­ eonate and whitish
macules on the umbilical cord and placenta [4,5].
­References
1 Handler MZ, Schwartz RA. Staphylococcal scalded skin syndrome:
diagnosis and management in children and adults. J Eur Acad
Dermatol Venereol 2014;28:1418–23.
2 Aalfs AS, Oktarina DM, Diercks GF et al. Staphylococcal scalded skin
syndrome: loss of desmoglein 1 in patient skin. Eur J Dermatol
2010;20:451–6.
3 Saida K, Kawasaki K, Hirabayashi K et al. Exfoliative toxin A staphy­
lococcal scalded skin syndrome in preterm infants. Eur J Pediatr
2015;174:551–5.
4 Darmstadt GL, Dinulos JG, Miller Z. Congenital cutaneous candidia­
sis: clinical presentation, pathogenesis, and management guidelines.
Pediatrics 2000;105:438–44.
5 Aguin TJ, Sobel JD. Vulvovaginal candidiasis in pregnancy. Curr Infect
Dis Rep. 2015;17:462.
­Adverse drug reactions
Stevens–Johnson syndrome and toxic epidermal
necrolysis (see Chapters 66 and 67)
Stevens–Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN) represent a spectrum of severe, usually
drug‐induced skin changes that arise from massive apop­
tosis of epidermal keratinocytes and an interaction of
additional pathogenetic factors which are discussed more
thoroughly in Chapters 66 and 67. Both entities are
extremely rare during the first 2 months of life and only a
few cases of neonatal or very early infantile TEN have
been published so far.
These neonates and young infants revealed irritability,
poor feeding and hypothermia as nonspecific prodromal
symptoms before the onset of cutaneous lesions. As in adults,
skin involvement consisted of rapidly coalescing, tender,
erythematous macules progressing to extensive exfoliative
erythroderma with pluriorificial mucosal involvement.
 130 Section 2 Skin Disorders of the Neonate and Young Infant
Histopathological analysis of lesional skin revealed
characteristic subepidermal blistering and complete
necrosis of the epidermis, whereas the main differential
diagnosis SSSS was ruled out by the absence of subcorneal
splitting. In contrast, concurrent systemic infection with
Klebsiella pneumoniae could be diagnosed in two individ­
SECTION 2: SKIN DISORDERS
OF NEONATES AND INFANTS
uals, whereas Candida albicans/dubliensis, Escherichia coli
and coagulase‐negative streptococci were found to be
relevant pathogens in other affected individuals. Thus,
the majority of patients had received multiple antimicro­
bial and other medications prior to the onset of blistering
which hampered the identification of a single culprit
drug. Unfortunately, all reported patients died despite
the limitation of applied medications to vitally indicated
drugs and intensive care support [1–4]. However, whether
neonatal TEN generally carries a fatal prognosis and
whether concurrent sepsis is a relevant co‐factor or even
the main prerequisite for TEN in newborns remains to be
elucidated.
Red man syndrome
Rapid intravenous administration (<60 min) of vancomy­
cin and other antimicrobial agents, such as rifampicin,
teicoplanin, ceftriaxone, amphotericin B or ciprofloxacin,
can lead to nonspecific histamine release in up to 14% of
treated patients. Within seconds to several minutes after
the initiation of therapy, patients of any age may develop
generalized flushing, with or without anaphylactoid
symptoms, and consecutive transient erythroderma giving
patients a ‘red man’ appearance. Studies of vancomycin
have also shown that the most severe reactions tend
to occur in younger patients, particularly children. Further­
more, concomitant application of further histamine liber­
ators such as opioid analgesics or radiological contrast
media may enhance the risk of vancomycin‐induced red
man syndrome.
The syndrome is easily recognizable, given the short
interval between drug administration and onset of initial
symptoms. As in other immediate‐type reactions, acute
therapy consists of intravenous administration of an
antihistamine and, if necessary, epinephrine in patients
with circulatory disturbances. As a preventive measure,
vancomycin should be given in an adequate dilution
and the infusion rate should be less than 10 mg/min. In
the absence of alternative agents and if vancomycin is
urgently indicated, desensitization with the culprit drug
is possible but requires close clinical surveillance [5,6].
­References
1 de Groot R, Oranje AP, Vuzevski VD, Mettau JW. Toxic epidermal
necrolysis probably due to Klebsiella pneumoniae sepsis. Dermatologica
1984;169:88–90.
2 Hawk RJ, Storer JS, Daum RS. Toxic epidermal necrolysis in a 6‐week‐
old infant. Pediatr Dermatol 1985;2:197–200.
3 Lohmeier K, Megahed M, Schulte KW et al. Toxic epidermal necrolysis
in a premature infant of 27 weeks’ gestational age. Br J Dermatol
2005;152:150–1.
4 Islam S, Singer M, Kulhanjian JA. Toxic epidermal necrolysis in a
neonate receiving fluconazole. J Perinatol 2014;34:792–4.
5 Myers AL, Gaedigk A, Dai H et al. Defining risk factors for red man
syndrome in children and adults. Pediatr Infect Dis J 2012;31:464–8.
6 Wazny LD, Daghigh B. Desensitization protocols for vancomycin
hypersensitivity. Ann Pharmacother 2001;35:1458–64.
­Immunological disorders (see Chapters
53 and 56)
Omenn syndrome
Omenn syndrome (OS, OMIM #603554) represents a
genetically heterogeneous, autosomal recessive primary
immunodeficiency characterized by lymphadenopathy,
hepatosplenomegaly, elevated serum IgE and eosinophilia.
It is caused predominantly by mutations in the recombi­
nation activating genes 1 and 2 (RAG‐1/RAG‐2), the
interleukin‐7Rα chain or the nonhomologous end‐joining
factor Artemis, which interfere with somatic diversifica­
tion of T‐ and B‐cell receptor‐encoding genes. This leads
to oligoclonal expansion of autoreactive T cells and a
marked reduction in circulating B cells (‘T+B‐ SCID’,
‘leaky SCID’).
Affected neonates and infants initially reveal severely
pruritic eczematous lesions resembling atopic dermatitis,
which can coalesce to form erythroderma, pachydermia,
onychodystrophy and alopecia while eyebrows and eye­
lashes may appear normal (Fig. 10.9a and b). Over the
course of the disease, the majority of patients develop
lymphadenopathy, hepatosplenomegaly, profuse diar­
rhoea and failure to thrive. Furthermore, patients often
present in a reduced general state with hypothermia,
hypernatraemic dehydration and clinical signs of bacte­
rial infection, particularly pneumonia, or even sepsis.
More than 90% of children show a massive increase in
total serum IgE levels and nearly all patients display
marked peripheral eosinophilia. Lesional skin biopsies
usually show epithelial hyperplasia, spongiosis, focal
basal vacuolation and parakeratosis as well as an inflam­
matory infiltrate in the upper dermis mainly consisting of
lymphocytes with few interspersed eosinophils.
OS is known to have a lethal outcome if left untreated,
mostly due to recurrent severe infections. In the presence
of the characteristic clinical triad of erythroderma, hepat­
osplenomegaly and lymphadenopathy in conjunction
with typical laboratory changes such as marked eosino­
philia and elevated total IgE levels, immunomodulatory
therapy with ciclosporin (cyclosporine) can be initiated
rapidly to suppress autoreactive T‐cell clones. This has
been shown to provide quick symptom relief, particularly
with regard to the often debilitating pruritus. Nevertheless,
curative therapy can only be achieved with bone marrow‐
or umbilical cord blood‐derived haematopoietic stem cell
transplantation yielding survival rates that range from
less than 50% (haploidentical donor) to 75% (HLA‐identical
donor) [2–5].
Graft‐versus‐host disease
Along with Omenn syndrome, there are several other
severe combined immunodeficiencies (SCID) that are
inherited in an autosomal recessive or X‐linked pattern
and are very rare with an estimated incidence of 1 in
50 000 to 1 in 500 000 live births. Owing to variable defects
in both T‐ and B‐cell immunity, classic symptoms such as
profuse diarrhoea, failure to thrive, mucocutaneous can­
didiasis and orogenital ulcerations can occur as early as
the first 4 weeks of life.
 Chapter 10
(a)
(b)
Fig. 10.9 (a) Ichthyosiform erythroderma, pachydermia and alopecia in a
female infant with Omenn syndrome. (b) Same patient as in (a) after
5 days of incubator care, intravenous rehydration and topical therapy with
panthenol ointment.Source: Ott et al. 2008 [1]. Reproduced with
permission of John Wiley & Sons.
In addition, up to 50% of patients with T‐ SCID have
maternal T cells in the peripheral blood leading to graft‐
versus‐host‐disease (GVHD) in nearly 60% of these cases.
Affected infants may develop alopecia and severe neona­
tal erythroderma with a scaly erythematous rash spread­
ing craniocaudally, often also affecting the palms and
soles [6,7].
If suspicion arises, a comprehensive immunological
work‐up including differential blood counts, lymphocyte
phenotyping and chimerism analysis should be performed.
Differential Diagnosis of Neonatal Erythroderma 131
Upon analysis of the affected baby’s peripheral blood,
the identification of accessory HLA haplotypes, high
numbers of maternal lymphocytes or an XX genotype in a
male neonate are highly suggestive of GVHD. Interest­
ingly, skin histopathology in neonates with SCID and
maternal engraftment has been reported to differ from
SECTION 2: SKIN DISORDERS
OF NEONATES AND INFANTS
that obtained in patients with SCID after bone marrow
transplantation or after transplant for other diseases.
Whereas a vacuolar interface pattern is usually observed
in the latter disorders, GVHD due to maternal engraft­
ment is characterized by psoriasiform epidermal hyper­
plasia, dermal lymphocytic infiltrates, parakeratosis and
variable spongiosis [8].
Given the otherwise grave prognosis, haematopoietic
stem cell transplantation should be performed promptly,
as it allows full recovery in 52% (HLA‐different, nonre­
lated donors) to 92% (HLA‐identical, related donors) of
patients [6].
Other primary immunodeficiencies
While OS and GVHD due to maternal engraftment are
regularly associated with neonatal erythroderma, other
primary immunodeficiencies only occasionally induce
widespread erythema in newborns or very young
infants.
For example, patients with DiGeorge syndrome (DGS,
OMIM #188400), which is caused by a hemizygous
deletion of chromosome 22q11.2, suffer from conotrun­
cal cardiac defects, hypoparathyroidism and immune
dysfunction due to thymic hypoplasia. Additionally,
affected infants and children frequently develop eczem­
atous skin lesions closely resembling those of atopic
dermatitis. Never­theless, generalized eczematous erup­
tions have only very rarely been observed in newborns
with DGS [9,10].
Wiskott–Aldrich syndrome (WAS, OMIM #301000), an
X‐linked immunodeficiency with thrombocytopenia,
recurrent infections and secondary autoimmune disorders,
is associated with recalcitrant eczematous dermatitis in
nearly 90% of affected patients. However, only very few
WAS cases have been reported to present with neonatal
erythroderma [11–13]. Besides inflammatory skin lesions
and recurrent cutaneous infections, petechiae and ecchy­
mosis in a boy with eczema should raise the suspicion
of WAS [14,15].
The immune dysregulation, polyendocrinopathy, enteropathy,
X‐linked syndrome (IPEX, OMIM #304790) represents a
very rare disorder caused by mutations in the FOXP3
gene, the master transcriptional regulator for the devel­
opment and function of CD4+ regulatory T cells. IPEX
patients reveal disrupted immune homeostasis resulting
in early‐onset autoimmunity with neonatal diabetes mel­
litus and hypothyroidism, recurrent infections, cytope­
nias and villous atrophy leading to enteropathy and
severe failure to thrive. Cutaneous symptoms include
eczematous skin lesions in up to 65% of patients that may
appear as severe and generalized ichthyosiform dermatitis.
Additionally, serum total IgE levels are clearly elevated in
the majority of neonates and infants with IPEX who also
have marked peripheral eosinophilia [16–18].
 132 Section 2 Skin Disorders of the Neonate and Young Infant
­References
1 Ott H, Hutten M, Baron JM et al. Neonatal and infantile erythroder­
mas. J Dtsch Dermatol Ges 2008;6:1070–85.
2 Cassani B, Poliani PL, Moratto D et al. Defect of regulatory T cells in
patients with Omenn syndrome. J Allergy Clin Immunol 2010;125:
209–16.
3 Bai X, Liu J, Zhang Z et al. Clinical, immunologic, and genetic charac­
teristics of RAG mutations in 15 Chinese patients with SCID and
SECTION 2: SKIN DISORDERS
OF NEONATES AND INFANTS
Omenn syndrome. Immunol Res 2016;64:497–507.
4 Caglayan Sozmen S, Isik S, Arikan Ayyildiz Z et al. Cyclosporin treat­
ment improves skin findings in omenn syndrome. Pediatr Dermatol
2015;32:e54–7.
5 Sharapova SO, Guryanova IE, Pashchenko OE et al. Molecular
Characteristics, Clinical and Immunologic Manifestations of 11
Children with Omenn Syndrome in East Slavs (Russia, Belarus,
Ukraine). J Clin Immunol 2016;36:46–55.
6 Muller SM, Ege M, Pottharst A et al. Transplacentally acquired mater­
nal T lymphocytes in severe combined immunodeficiency: a study of
121 patients. Blood 2001;98:1847–51.
7 Wahlstrom J, Patel K, Eckhert E et al. Transplacental maternal engraft­
ment and posttransplantation graft‐versus‐host disease in children
with severe combined immunodeficiency. J Allergy Clin Immunol
2017;139:628–33.
8 Leclerc‐Mercier S, Bodemer C, Bourdon‐Lanoy E et al. Early skin
biopsy is helpful for the diagnosis and management of neonatal and
infantile erythrodermas. J Cutan Pathol 2009;37:249–55.
9 Archer E, Chuang TY, Hong R. Severe eczema in a patient with
DiGeorge’s syndrome. Cutis 1990;45:455–9.
10 Minakawa S, Nakano H, Takeda H et al. Chromosome 22q11.2 dele­
tion syndrome associated with severe eczema. Clin Exp Dermatol
2009;34:410–11.
11 Sarkar R, Basu S, Sharma RC. Neonatal and infantile erythrodermas.
Arch Dermatol 2001;137:822–3.
12 Al‐Dhalimi MA. Neonatal and infantile erythroderma: a clinical and
follow‐up study of 42 cases. J Dermatol 2007;34:302–7.
13 Pruszkowski A, Bodemer C, Fraitag S et al. Neonatal and infantile
erythrodermas: a retrospective study of 51 patients. Arch Dermatol
2000;136:875–80.
14 Massaad MJ, Ramesh N, Geha RS. Wiskott‐Aldrich syndrome: a com­
prehensive review. Ann N Y Acad Sci 2013;1285:26–4.
15 Loyola Presa JG, de Carvalho VO, Morrisey LR et al. Cutaneous
manifestations in patients with Wiskott‐Aldrich syndrome submit­
ted to haematopoietic stem cell transplantation. Arch Dis Child
2013;98:304–7.
16 Chen CA, Chung WC, Chiou YY et al. Quantitative analysis of tissue
inflammation and responses to treatment in immune dysregulation,
polyendocrinopathy, enteropathy, X‐linked syndrome, and review of
literature. J Microbiol Immunol Infect 2016;49:775–82.
17 Bin Dhuban K, Piccirillo CA. The immunological and genetic basis
of immune dysregulation, polyendocrinopathy, enteropathy, X‐linked
syndrome. Curr Opin Allergy Clin Immunol 2015;15:525–32.
18 Xavier‐da‐Silva MM, Moreira‐Filho CA, Suzuki E et al. Fetal‐onset
IPEX: report of two families and review of literature. Clin Immunol
2015;156:131–40.
­Inborn errors of metabolism
(see Chapter 152)
Case studies have reported a number of hereditary meta­
bolic disorders that present with cutaneous symptoms in
neonates and infants. Of these, only holocarboxylase
synthetase deficiency, methylmalonic acidaemia and
maple syrup urine disease appear to be frequently asso­
ciated with neonatal erythroderma.
Holocarboxylase synthetase deficiency (HSD, OMIM
#253270) is a very rare autosomal recessive metabolic
disorder arising from a defect in incorporation of biotin
(vitamin B7 or H) as a prosthetic group in biotin‐dependent
enzymes such as acetyl‐CoA carboxylase and pyruvate
carboxylase. While the major clinical findings include
severe neurological symptoms such as lethargy and sei­
zures as well as potentially lethal ketoacidosis, infants
with the disease also have eczematous erythroderma with
marked periorificial involvement and alopecia. IF HSD is
not included in the neonatal screening programme, rapid
diagnosis and effective therapy may be missed unless
carboxylase activity is analysed in cultured fibroblasts.
On the other hand, if a high clinical index of suspicion is
supported by characteristic laboratory parameters such as
severe ketoacidosis, hyperammonaemia and hypoglycae­
mia, neonatal intensive care including biotin substitution
at an oral dose of 10 mg daily is mandatory [1–3].
Methylmalonic acidaemias (MMA, OMIM #251110,
#243500 and others) represent genetically heterogeneous
disorders of methylmalonate and cobalamin metabolism.
Patients affected by the infantile, non‐vitamin B12‐responsive
subtype may appear healthy at birth, but rapidly develop
severe symptoms such as muscular hypotonia, respira­
tory distress and encephalopathy which are associated
with marked metabolic ketoacidosis, hyperammonaemia
and hyperglycinaemia. Cutaneous symptoms are initially
similar to the rash observed in acrodermatitis enteropathica
comprising acrofacial, psoriasiform dermatitis and alope­
cia. However, untreated infants may develop widespread
erythema and, finally, exfoliative erythroderma [4–6].
Similar acrodermatitis‐like eruptions have been
encountered in newborns and infants suffering from
maple syrup urine disease (MSUD, OMIM #248600), another
organic aminoacidopathy elicited by an impaired
branched‐chain alpha‐keto acid dehydrogenase complex
(BCKD). MSUD is characterized by elevated tissue, blood
and urine concentrations of valine, leucine and isoleucine
which are responsible for potentially severe symptoms
such as respiratory distress, muscular hypotonia and
seizures. The only effective therapy currently consists of
restricted dietary intake of branched‐chain amino acids.
Interestingly, generalized erythematous eruptions have
only been described in treated neonates, so far, and have
been attributed to extremely low plasma levels of iso­
leucine. Accordingly, neonatal erythroderma resolved
after supplementation of the deficient amino acid in the
majority of affected patients [7,8].
­References
1 Donti TR, Blackburn PR, Atwal PS. Holocarboxylase synthetase
deficiency pre and post newborn screening. Mol Genet Metab Rep
2016;7:40–4.
2 Van Hove JL, Josefsberg S, Freehauf C et al. Management of a patient
with holocarboxylase synthetase deficiency. Mol Genet Metab 2008;95:
201–5.
3 Tammachote R, Janklat S, Tongkobpetch S et al. Holocarboxylase
synthetase deficiency: novel clinical and molecular findings. Clin
Genet 2010;78:88–93.
4 Fraser JL, Venditti CP. Methylmalonic and propionic acidemias: clinical
management update. Curr Opin Pediatr 2016;28:682–93.
5 Sasaki M, Aikoh H, Sugai K et al. Picture of the month. Cutaneous
lesions associated with isoleucine deficiency. Arch Pediatr Adolesc
Med 1998;152:707–8.
6 Bodemer C, De Prost Y, Bachollet B et al. Cutaneous manifestations
of methylmalonic and propionic acidaemia: a description based on
38 cases. Br J Dermatol 1994;131:93–8.
7 Koch SE, Packman S, Koch TK, Williams ML. Dermatitis in treated
maple syrup urine disease. J Am Acad Dermatol 1993;28:289–92.
8 Flores K, Chikowski R, Morrell DS. Acrodermatitis dysmetabolica
in an infant with maple syrup urine disease. Clin Exp Dermatol
2016;41:651–4.
 Chapter 10
­ iagnostic work‐up of neonatal
D (blood culture) should be performed to detect the exfo­
erythroderma
So far, no prospective multicentre studies of neonatal or
infantile erythroderma have been performed and, there­
fore, evidence‐based diagnostic algorithms are still not
available.
However, even in the case of a complex differential
diagnosis, a thoughtful stepwise approach to neonatal
erythroderma will lead to a straightforward clinical
diagnosis in most cases (see Fig. 10.1). The first step is to
determine whether the physical examination and history
are consistent with psoriasis, atopic or seborrhoeic der­
matitis and, if so, to treat appropriately. If the answer to
the first step is ‘no’ or there is no or insufficient response
to therapy, the next step is to consider alternative diagnoses,
i.e. pustules with candidiasis, periorificial distribution in
metabolic disorders. The third step is to assess whether
the patient is ill or exhibits failure to thrive. If so, the
patient is more likely to have an underlying infectious,
immunological or metabolic disorder.
Irrespective of the underlying disease, neonates and
young infants with erythroderma are at greater risk of
potential complications due to impaired epidermal barrier
function such as hypothermia, hypernatraemia, dehydra­
tion or hypoproteinaemia. Therefore, at the initial visit,
these patients need to undergo a thorough clinical paedi­
atric examination including neurological assessment and
measurement of bodyweight and core body temperature.
Initial capillary blood gas analysis and assessment of
serum electrolytes in combination with a limited number
of other screening tests such as differential blood count
and serum total IgE level are also advisable. In desquama­
tive and bullous erythrodermas affecting neonates, a skin
biopsy should be taken to locate the cleavage level and
exclude toxic epidermal necrolysis. If subcorneal blister­
ing is present, polymerase chain reaction (PCR) analysis
Differential Diagnosis of Neonatal Erythroderma 133
liative toxins A and B.
Whitish maculae on the placenta and umbilical cord
warrant mycological investigation for Candida. Very pre­
mature infants who are diagnosed with congenital cutane­
ous candidiasis should be tested for an invasive candidal
SECTION 2: SKIN DISORDERS
OF NEONATES AND INFANTS
infection (CSF/blood culture).
If a clearly elevated serum IgE level is observed in a
neonatal patient or a young infant with erythroderma,
lymphocyte phenotyping is warranted. In patients with
B‐lymphocytopenia, a mutation analysis, especially of
the RAG‐1/RAG‐2 gene loci, should be obtained; in T‐cell
immunodeficiency, a chimerism analysis should be per­
formed to detect engraftment of maternal T‐lymphocytes.
If the results of immunological tests are normal and
hair shaft anomalies such as trichorrhexis invaginata
are not present, epidermal LEKTI expression should be
determined by immunohistochemistry so as to exclude
Netherton syndrome.
A blood gas analysis showing ketoacidosis with con­
comitant hypoglycaemia and hyperammonaemia has to
be considered a metabolic emergency. Thus, patients
should be referred to a specialized centre for substitution
therapy or dietary counselling and further diagnostic
testing (holocarboxylase‐synthetase activity in cultured
fibroblasts, organic acids in urine).
Ichthyosiform erythroderma is particularly difficult
to distinguish from other diagnoses. The previously‐
mentioned molecular genetic and hair shaft analyses as
well as ophthalmological examinations, including fundus­
copy (glistening dots, sectoral cataract?), and if necessary,
assessment of sterol isomerase and fatty aldehyde dehy­
drogenase activity in cultured fibroblasts are needed.
­Reference
1 Ott H, Hutten M, Baron JM et al. Neonatal and infantile erythrodermas.
J Dtsch Dermatol Ges 2008;6:1070–85.