Eur. J. Pediat. Dermatol.

30, 104-10, 2020

Congenital ichthyosis in newborns.

A case-series and review of the literature.
Pontello E.1,2, Battajon N.2, Tormena F.2, Giovannini M.2, Buffo M.2, Mainini N.2, Visintin G.2
Favero V.2, Vendramin S.2, Galeazzo B.2, Cutrone M.3, Lago P.2
1
Department of Woman’s and Child’s Health, University of Padova, Padova, Italy
2
Neonatal Intensive Care Unit, Women and Child Department, Ca’ Foncello Hospital, Treviso, Italy
3
Pediatric Unit, Ospedale San Bortolo, Vicenza, Italy

Summary Congenital ichthyosis (CI) constitutes a large etiologically and phenotypically hetero-
geneous group of infrequent genetic cornification disorders marked by impaired epider-
mal barrier function, with highly variable outcome and severity. In newborns with severe
ichthyosis, the consequence of this disrupted barrier can be particularly dangerous, at times
life-threatening, with increased susceptibility to respiratory failure, infection, and dramati-
cally increased metabolic demands due to increased epidermal turnover and transepidermal
water loss. We report five cases of congenital ichthyosis, admitted in the last 4 years to
our NICU. This article explores different neonatal presentations of ichthyoses, describes
potential complications and causes of morbidity and mortality, and discusses management
considerations relevant to the neonatal period. Case 1 and 2 are siblings suffering from Har-
lequin ichthyosis, successfully treated with acitretin with no significant side effects. Case
3 is a case of severe CI, called Netherton syndrome, with poor prognosis. Case 4 and 5 are
an example of collodion babies. All cases required NICU admission for intensive skin care
and hydration, and some requested respiratory support. Case three died due to necrotizing
enterocolitis and sepsis. Although congenital ichthyosis is fairly rare, it is important for the
neonatologist to be aware of this heterogeneous disorder, as the perinatal period represents a
particularly critical stage. Severe forms of CI require admission to a NICU and a thoughtful
interdisciplinary approach to improve prognosis and to successfully treat complications. An
early oral retinoid therapy should be considered in Harlequin ichthyosis.

Keywords Congenital ichthyosis, collodion baby, Harlequin ichthyosis, newborn, oral retinoids.

C
ongenital ichthyosis (CI), defined as ge-
netic disorders of cornification, is cha-
racterized by visible scaling or hyperke-
ratosis of the skin (4, 18). Clinical manifestations
are various, depending on the heterogeneous
group of genetic mutations implicated, such as
those involving keratinocyte differentiation and
epidermal barrier homeostasis (9, 17). In the ma-
jority of cases the congenital phenotypes tran-
sform into generalized scaling, the latter typically
persisting throughout life. The treatment of CI is
symptomatic rather than mechanism- or pathoge-
nesis-based (13, 14).
Harlequin ichthyosis (HI) is one of the most
severe forms of congenital ichthyosis, characteri-
zed by a typical clinical appearance. The affected
child has markedly impaired skin function and
a high risk of prematurity and life-threatening
complications, such as respiratory failure, in-
fections, fluid loss, and electrolyte abnormali-

104

Fig. 1
Fig. 3
Fig. 1, 2, 3, 4: Harlequin ichthyosis in two brothers (cases 1 e 2) at birth (Fig. 1, 3) and when aged 3 weeks (Fig. 2, 4).
ties (7, 8). Historically, infants with HI did not
survive beyond the neonatal period; however,
recent advances in neonatal intensive care, grea-
ter awareness of the condition, multidisciplinary
management, and early-stage retinoid treatment
have greatly improved survival in these patients.
Other forms of ichthyosis are less severe. How-
ever, they need to be recognized to undergo the
appropriate treatment (5, 6).
In this article, we report a case-series of conge-
nital ichthyosis with a wide range of manifesta-
tions, reviewing the clinical approach and treat-
ment as reported by the literature.
Cases series
Case 1. Male, born at 34 weeks to non-con-
sanguineous healthy parents. At birth, he had ar-
mored hyperkeratosis, severe ectropion and ecla-
bium, short and tapered fingers, flattened nose
and ears leading to the diagnosis of Harlequin
ichthyosis. He experienced severe respiratory
failure that required mechanical ventilation and
105
Congenital ichthyosis in newborns
Fig. 2
Fig. 4
administration of surfactants; he also presented
feeding difficulties that required parenteral nu-
trition, hypernatremic dehydration, electrolyte
imbalance and thermal instability; subsequently
the baby presented corneal lesions and late onset
Staphylococcus aureus-induced sepsis.
The treatment included oral administration of
acitretin at the initial dosage of 0.5 mg / kg / per
day, respiratory support, nutrition with nasoga-
stric tube, aggressive antibiotic therapy in case
of infection, and the administration of sedatives.
Moreover, monitoring of vital signs and hydro-
electrolyte balance, daily weight measurement,
humidification of the incubator (90%), reduction
of manual skills avoiding patches and adhesives,
application of emollients with modest content of
ceramides and daily bath were carried out.
The child was followed by the ophthalmolo-
gist who administered artificial tears and by the
audiologist.
In the following course, thanks to the treatment
with acitretin, the conditions of the skin and ec-
tropion improved, but corneal scars persisted.
The child was discharged at 2 months; however,
Pontello et Al.
Fig. 5
Fig. 7
Fig. 5, 6, 7, 8: Self-healing collodion baby (case 4) at birth (Fig. 5, 6) and when aged 2 weeks (Fig. 7, 8).
at 3 months he experienced severe hypernatre-
mic dehydration. The genetic investigation sho-
wed the presence of the same ABC12 mutations
(c.3270delT and c.3463 °> C) of which the pa-
rents were carriers.
Case 2. Male, brother of case 1, received a
prenatal genetic diagnosis of HI; he was born at
34 + 5 with clinical features superimposable to
those ones of his brother. Also the treatment was
similar; early administerd acitretin improved the
cutaneous signs and ectropion. The baby did not
developd corneal lesions and was discharged at
6 weeks.
Case 3. Male, born at 34 + 5 to non-consan-
guineous parents carrying in heterozygosity
an unknown mutation of SPINK5. The patient
presented at birth erythroderma prevalent in
the limbs with distal flaking; the hair was spar-
se and brittle showing trichorrhexis invaginata
on trichoscopic examination, thus confirming
106
Fig. 6
Fig. 8
the diagnosis of Netherton syndrome. The child
had temperature instability, weight loss, severe
hypernatremic dehydration and metabolic aci-
dosis, late-onset infection with Staphylococcus
aureus, low-molecular-weight heparin-treated
intracardiac thrombosis, severe necrotizing ente-
rocolitis that required surgery until fatal multior-
gan failure.
Case 4. Female, born at 37 weeks after a nor-
mal pregnancy. At birth a translucent membrane
covered the whole skin; ectropion and eclabium
were present (Fig. 5, 6). At the age of 3 days, the
skin was reminiscent of parchment paper with
scaling in some areas. The baby was treated with
emollients containing ceramides, acetaminophen
and artificial tears. She improved from the se-
cond week and was discharged whne aged 10
days; after 3 months the skin was almost normal,
leading to the diagnosis of self-healing collodion
baby.

Fig. 9
Fig. 9, 10: Epidermolytic hyperkeratosis (bullous erythrodermic ichthyosis) at birth (case 5).
Case 5. Male, born at 39 + 5 to consanguineous
parents, who were heterozygous carriers of an
unknown mutation of KRT10 (c.1155 + 5G> A).
At birth the baby presented modest erythroderma
with blisters and erosions in the area of minimal
trauma; the blisters decreased with months while
hyperkeratosis became more evident, with thick
scales and rippled appearance. He had no respira-
tory or food problems, but only oral candidiasis.
He was treated with hydration, acetaminophen,
antibiotics, emollients and discharged in the se-
cond week.
Discussion
Congenital ichthyosis constitutes a large etio-
logically and phenotypically heterogeneous
group of cornification disorders, with highly
variable outcome and severity (4, 18). Different
subtypes of congenital ichthyosis can be distin-
guished clinically by the quality and distribution
of scaling/hyperkeratosis, extracutaneous invol-
vement (syndromic vs. non-syndromic), onset,
and type of inheritance, using the consensus no-
menclature adopted by the 2009 Ichthyosis Con-
sensus Conference (15).
The diagnosis is usually based on clinical eva-
luation, including skin manifestations, presence
of a collodion membrane at birth, hair anomalies,
and signs of extracutaneous involvement, such as
ocular, ear, skeletal and neurological manifesta-
tions (11, 12, 15).
107
Congenital ichthyosis in newborns
Fig. 10
The five above presented cases confirm the
existence of a severe form of congenital ichthyo-
sis, with high complication and mortality rates
and an important impact on the quality of life. A
collodion baby is not a specific feature of certain
ichthyosis but a presenting phenotype; collodion
babies are born encased in a collodion membrane
that usually sheds in the first few weeks of life re-
vealing the definitive phenotype. In some cases,
it is self-healing, but requires the same daily skin
care routine to prevent complications, such as in
our fourth and fifth cases (16).
Harlequin ichthyosis is the most severe form of
autosomal recessive congenital ichthyosis caused
by a mutation in the ABCA12 gene, which codes
for an epidermal keratinocyte lipid transporter.
The loss of the normal lipid barrier results in the
typical clinical phenotype (so-called Harlequin
syndrome). Reverend Oliver described the first
case of HI in 1750. The incidence of HI has been
estimated to be about 1 in 300,000 births. Appro-
ximately 200 cases have been reported interna-
tionally (1, 8).
Prognosis is poor, but early treatment with oral
retinoids might improve survival. Prior reports
suggest that the mortality rate in the neonatal pe-
riod is approximately 50%, and most neonates
die shortly after delivery (4, 7) due to fulminant
sepsis (75% of deaths), heat loss, dehydration,
electrolytic disturbances, or respiratory distress
(25% of deaths).
Prenatal genetic diagnosis is possible and
should be offered to parents who had a previous
Pontello et Al.
child with HI (8). In some cases, prenatal ultra-
sonography might allow detection of signs sug-
gestive of HI after the second trimester (3, 8),
including eclabium, ectropion, rudimentary ears,
contractures, and dense floating particles in am-
niotic fluid (“snowflake sign”).
At birth, the neonate is encased in an “armor”
of thick yellowish scales separated by deep ery-
thematous fissures involving the entire body
surface. This finding can be easily differentiated
from the less severe collodion baby phenotype;
the latter presents as a thin membrane that splits
soon after birth and is lost in the first weeks of
life.
In HI there are also eversion of the superior
and inferior eyelids (ectropion) and both lips
(eclabium), absence of eyelashes and eyebrows,
sparse hair, abnormal flattened ears and broade-
ned, flat nose, abnormally fixed limbs and fin-
gers, and toes in rigid flexion due to the inability
of the skin to expand. Constricting bands around
the extremities can restrict movement and cause
digital necrosis and pain.
As the skin barrier is severely compromised,
neonates are more susceptible to sepsis, dehydra-
tion, impaired thermoregulation, and present
increased metabolic demands with consequent
growth failure. Sepsis susceptibility comes from
impaired skin barrier and decreased innate immu-
ne function related to impaired lamellar granule
transport and secretion of various antimicrobial
peptides.
The increase in knowledge about the patho-
physiology of ichthyosis has not led to curative
therapy, but only to clinical improvement. The
choice of treatment must be optimized for each
patient; it depends on the morphology, distribu-
tion, severity of disease, and the age of the pa-
tient. Usually, newborns with ichthyosis require
intensive monitoring in a high-level care center
and appropriate skin specific management.
The newborn with ichthyosis should initially
be placed in an incubator (humidity, ~80-90%;
temperature, ~35°C) to maintain optimal body
temperature and protect him/her from dehydra-
tion, with close monitoring of body temperature,
weight, electrolyte balance, and signs of infec-
tion. The incubator temperature requires a fine
touch to avoid heat intolerance, which could be
108
mistaken for fever. The babies should be bathed
daily with warmed sterile water and a mild cle-
anser, and lubricated with a thin, nonocclusive
washable emollient three to eight times daily
to restore the normal moisture and reduce scale
formation. Neither oil nor salt bath additives are
ideal; sodium bicarbonate is most effective. The
application technique of topical therapies should
avoid contamination with pathogenic microbes
(latex-free, sterile, single-use gloves). It is im-
portant to avoid products with potential toxicity,
such as sulfadiazine, salicylate, or topical calci-
neurin inhibitors, considering the increased risk
of transcutaneous absorption.
Skin is very fragile and more susceptible to in-
fection and injury from even minor trauma; it can
be a source of pain and discomfort, particularly in
cases of extensive fissuring or digital necrosis. To
minimize this risk of damage, careful handling
and avoidance of conventional adhesives are
recommended; a special protocol to secure cen-
tral venous umbilical lines and tubing should be
adopted.
For the clinician, it is more difficult to recogni-
ze signs and severity of pain, but it is mandatory
to provide adequate pain control with acetamino-
phen, non-steroidal anti-inflammatory medica-
tions, or opioids.
Some forms of ichthyosis benefit dramatical-
ly from systemic retinoids, thanks to their mo-
dulating effect on keratinocyte proliferation and
differentiation. Therefore, HI is no longer univer-
sally fatal because of the early use of acitretin, a
synthetic analog of retinoic acid, that increased
the survival possibility from 24% to 83% (8). The
first successful neonatal use of acitretin in HI was
reported in 2001.
Treatment initiation within the first 7 days of
life at the dose of 0.5 mg/kg once daily is re-
commended. The effect should be evaluated af-
ter a few weeks. The dosage might be gradually
increased until there is sufficient improvement
with tolerable side-effects (max 1 mg/kg body
weight), titrating acitretin to the lowest dose pos-
sible (8).
Adverse effects include mucocutaneous to-
xicities (e.g., xeroderma, xerophthalmia, chei-
litis, hair loss, and nail disease), hepatotoxicity,
increased liver enzymes, hypertriglyceridemia,

hypercholesterolemia, increased serum gluco-
se, and changes in blood counts. Long-term use
of systemic retinoids can induce toxic effects in
the bone tissue (hyperostosis), having a negative
impact on growth and requiring periodic evalua-
tion.
Surveillance laboratory data includes blood
tests at baseline and at 1- to 2-week intervals for
4 to 8 weeks, then as clinically indicated (8, 17).
Treatment should be continued for several years,
and it might be required indefinitely to prevent
relapse. In cases where oral retinoid therapy can-
not be tolerated, the use of topical retinoids has
proved beneficial (8).
The clinical course of CI in neonatal age might
have various complications, beyond issues that
result from prematurity. Respiratory failure can
be the result of several mechanisms, such as pre-
maturity, restricted chest expansion, nasal ob-
struction, infection, or pain. Surfactant secretion
deficiency was reported in one mouse model of
HI. Secondary cutaneous and systemic infections
are complications of many ichthyoses (2), espe-
cially in Netherton syndrome, such as in our third
case.
Classical signs and symptoms of systemic in-
fection are less specific. Consequently, it is im-
portant to maintain a high index of suspicion for
infection, as well as a low threshold for sepsis
workup and early administration of systemic an-
timicrobials. Prophylactic antibiotics are not re-
commended.
Eclabium and jaw constriction might interfere
with oral feeding. Nutrition through a nasogastric
tube should be initiated when the infant has diffi-
cult feeding and poor weight gain, to cover the in-
creased caloric need. An early nutritional assess-
ment and caloric supplementation is essential to
maximize growth (1, 8, 13, 14). Frequent emesis
has been observed, but the possibility of associa-
ted gastrointestinal dysmotility has not been stu-
died. Vitamin D deficiency and rickets have been
reported. Severely affected babies with failure to
thrive, as a result of chronic disease, had impro-
ved growth after starting retinoids.
The most common ocular abnormalities inclu-
de ectropion, corneal alterations, cataracts, and
retinal defects. Some of these can lead to visual
impairment and even blindness if not treated in
109
Congenital ichthyosis in newborns
a timely fashion (1, 8, 13, 14). Frequent ocular
lubricants as a first-line treatment are highly re-
commended for all patients. Topical retinoids ap-
plied to the eyelids might be useful to improve
ectropion.
Severe scaling in and around the ears might
result in occlusion of the external auditory canal.
Hearing loss is another issue and might interfere
with the development of language and commu-
nication. Early otolaryngology and audiology in-
tervention are recommended (1, 6, 8, 13, 14 16,
19).
Beyond the neonatal period, the severely ab-
normal keratotic epithelium marking HI at birth
gradually turns into a severe ichthyosiform
erythroderma. Affected children could have a
failure to grow, chronic pain, heat/cold intole-
rance, pruritus, and increased frequency of in-
fection or hospitalization. Motor developmental
delay due to hyperkeratotic skin and pain was
reported in almost one-third of the cases of HI.
Impaired cognitive and social functioning might
be present.
Ichthyosis is a stigma for every patient, lea-
ding to social rejection. Therefore, it requires
labor-intensive and time-consuming treatment.
These patients deserve social support and often
require professional psychologic care to improve
socialization, self-confidence, and quality of life
(5, 7, 10).
Parents facing ichthyosis in their newborn
child frequently experience considerable uncer-
tainty and fear. It is crucial to establish the cor-
rect diagnosis as early as possible and to offer
comprehensive information about the disease, in-
cluding prognosis and genetic counseling. Bond
formation between mother and infant has been
shown to be delayed in the NICU setting when
a neonate’s appearance was not compatible with
parent expectations. It is important to support the
family throughout the therapeutic process and
help to understand that the initial appearance is
transient, that pain can be controlled, and that the
underlying skin disorder can be treated. Touch
and breastfeeding should be encouraged (1, 8,
13, 14).
In conclusion ichthyosis, while fairly rare, is
a condition that requires significant attention in
the neonatal period. The genetic and phenotypic
Pontello et Al.
heterogeneity of this condition requires an indivi-
dualized treatment plan. Successful management
of ichthyosis in the newborn can be achieved
through a thoughtful, directed, and interdiscipli-
nary approach.
Address to:
Dr. Eleonora Pontello
Department of Woman’s and Child’s Health
University of Padova, Padova, Italy and
Neonatal Intensive Care Unit,
Ca’ Foncello Hospital, Treviso, Italy
e-mail address: eleonora.pontello1@gmail.com
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