DE GRUYTER Case Reports in Perinatal Medicine.

2017; 20160050

Satyaranjan Pegu1 / Jaya. P. Bodani1 / Edmond G. Lemire2 / Karen I. Holfeld3

A novel keratin 10 gene mutation causing

epidermolytic hyperkeratosis (bullous
congenital ichthyosiform erythroderma) in a
term neonate
1
Division of Neonatology, Department of Pediatrics, Regina Qu’Appelle Health Region, Regina, SK, Canada, E-mail:
satyapegu@gmail.com. http://orcid.org/0000-0002-7699-9864.
2
Division of Medical Genetics, Department of Pediatrics, University of Saskatchewan, Saskatoon, SK, Canada
3
Division of Dermatology, Regina Qu’Appelle Health Region, Regina, SK, Canada

Abstract:
Epidermolytic hyperkeratosis (EHK) is a rare skin condition characterized by erythroderma and blistering at
birth, leading to generalized hyperkeratosis of varying severity in adulthood. EHK is frequently mistaken for
staphylococcal scalded skin syndrome (SSSS) or epidermolysis bullosa. EHK is usually inherited in an autoso-
mal dominant fashion, but very rare autosomal recessive families have been reported. Molecular genetic testing
in this patient identified a novel homozygous keratin-10 gene (KRT10) mutation consistent with autosomal re-
cessive inheritance. Furthermore, diagnosis was achieved by molecular genetic testing circumventing the need
to perform a skin biopsy.
Keywords: Bullous congenital ichthyosiform erythroderma (BCIE), epidermolytic hyperkeratosis (EHK), epider-
molytic ichthyosis (EI), molecular genetics, staphylococcal scalded skin syndrome (SSSS)
DOI: 10.1515/crpm-2016-0050
Received: August 20, 2016; Accepted: February 9, 2017

Introduction
Many neonatal infectious diseases are associated with a skin eruption; however, only very few manifest as
erythroderma. Epidermolytic hyperkeratosis (EHK) or bullous congenital ichthyosiform erythroderma (BCIE)
is frequently mistaken for staphylococcal scalded skin syndrome (SSSS) or epidermolysis bullosa. EHK should
be considered in the differential diagnosis along with other common conditions like sepsis, when neonates
present with erythema and widespread formation of epidermal blisters at birth. This would help anticipate the
complications, plan management properly and also provide genetic counseling to the parents.

Presentation of the case

This term baby boy weighing 5.15 kg, was born by elective cesarean section to a 37-year-old female. The mother
was a known diabetic on metformin. The pregnancy was otherwise uncomplicated. The parents were non-
consanguineous and of First Nations descent. Apgar scores at 1 min and 5 min were 8, 9, respectively, and the
infant did not require active resuscitation. Shortly thereafter, the baby was found to have extensive peeling of
the skin over the entire body. The referring pediatrician transferred the baby to the neonatal unit on suspicion
of SSSS.
The infant was alert, responsive, in sinus tachycardia and hemodynamically stable. Sinus tachycardia re-
solved with the administration of analgesics. There was extensive denudation of the skin leaving an underlying
erythematous layer (Figure 1). There was no involvement of the mucous membranes. EHK was suspected, but

Satyaranjan Pegu is the corresponding author.

Corresponding author: Doctor Satyaranjan Pegu, MD, 2C 19.04, Division of Neonatology, Department of Pediatrics, Regina General Hospital, 1440 14th Avenue,
Regina, S4P 0W5, Saskatchewan, Canada, Tel.: +306-766-0699, Fax: 306-766-4149
©2017 Walter de Gruyter GmbH, Berlin/Boston.

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SSSS and epidermolysis bullosa were also considered in the differential diagnosis. Consultations with derma-
tology, plastic surgery and medical genetics were initiated to assist with the diagnosis and management. Initial
management included umbilical venous catheterization for secure intravenous access, screening for sepsis and
coverage with intravenous and topical antibiotics. Fluid intake was liberalized and the baby was nursed in
high humidity for the first few days to minimize fluid loss. Intermittent morphine was used for analgesia. The
wounds were cleaned with sterile water and dressed under analgesia twice weekly. Nutrition was initially pro-
vided through total parenteral nutrition with extra protein supplementation. By discharge at 4 weeks of age,
the baby was exclusively breast-feeding on demand and most of the skin lesions had healed (Figure 2). During
hospitalization, the infant did not have any complications such as dehydration, electrolyte imbalance or sepsis.

Figure 1: Condition of the skin at the time of admission.

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Figure 2: Healing skin at the time of discharge.

The baby had few episodes of supraventricular tachycardia (SVT) on 5th day of life. Echocardiogram did not
reveal any structural abnormality and electrocardiogram (ECG) was not suggestive of Wolff-Parkinson-White
(WPW) syndrome. SVT episodes were managed with vagal maneuvers and intravenous adenosine. Propranolol
was added for long-term prophylaxis.
For diagnostic confirmation, sequencing of the keratin-1 gene (KRT1) and keratin-10 gene (KRT10) genes re-
sponsible for EHK was initiated. No disease-associated mutation was identified in KRT1. A novel homozygous
4 base deletion (c.875_878delAAGA) was identified in the KRT10 gene that results in a prematurely truncated
protein (p.Lys292ThrfsX10). Further testing confirmed that the parents are heterozygous KRT10 mutation car-
riers. Genetic counselling was provided to the family.

Discussion
Exfoliative skin disease manifests infrequently in neonates. EHK or bullous congenital ichthyosiform erythro-
derma (BCIE), currently known as epidermolytic ichthyosis (EI) is a rare disease that is usually inherited as
autosomal dominant. Up to 50% of the cases have no apparent family history and result from new mutations
in the KRT1 or KRT10 genes. Some rare cases of EHK can result from homozygous KRT10 mutations consistent
with autosomal recessive inheritance as in our family. Whether autosomal dominant or recessive, the charac-
teristic clinical presentation is erythema and widespread formation of epidermal blisters developing at birth.
Progressive hyperkeratosis, causing thickening of the cornified layer of the epidermis presents later in life [1,
2].
The incidence of EHK is 1 case per 100,000–300,000 births. No racial or sex predilection is apparent for this
condition. EHK is a lifelong condition with an onset at birth or in the neonatal period. EHK patients have also
been classified into two clinical groups based on the distinctive characteristic presence or absence of severe
palmoplantar hyperkeratosis. Keratin 1 mutations were found in individuals with severe palmar plantar hy-
perkeratosis and keratin 10 mutations in those without palmar/plantar involvement in those families [1, 3].

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However, some KRT10 mutation patients may also have palmoplantar hyperkeratosis. In autosomal dominant
EHK, heterozygous mutations in the KRT1 and KRT10 genes disrupt the keratin filament network causing skin
cell collapse and blistering. Genetic studies have identified a mutational hot spot within the 1A alpha-helical
segment of K10 where different substitutions of amino acids take place at residue 10 of the rod domain [4].
With autosomal dominant EHK, there may be a positive family history. However, up to 50% of the cases are
the results of new KRT1 or KRT10 gene mutations. In autosomal recessive EHK, the KRT10 mutation leads to
transcript instability and degradation. Heterozygous individuals are clinically unaffected, while homozygotes
have no epidermal keratin K10. A severe non-lethal case of EHK of autosomal recessive inheritance has been
reported in the literature. Affected family members carried a homozygous nonsense mutation in KRT10 caus-
ing complete loss of epidermal K10 expression. The existence of rare autosomal recessive cases, impacts genetic
counseling. A new case of EHK without any family history may either result from a new autosomal dominant
mutation, in which case the recurrence risk is <1% barring gonadal mosaicism, or autosomal recessive inheri-
tance with a 25% chance of recurrence. In our case, the parents are not reported to be consanguineous, but are
from ethnically similar populations. The parents may be distantly related or the KRT10 mutation may represent
a founder effect, though there is no other evidence to support this hypothesis. Parental testing was important
to confirm the mode of inheritance and to provide accurate recurrence risks [1, 5].
EHK is frequently mistaken for some of the more common conditions like SSSS and epidermolysis bullosa
[6, 7]. Being a rare condition, diagnosis can be missed in the neonatal period unless considered in the differential
diagnosis of neonatal blistering skin conditions (Table 1).

Table 1: Neonatal blistering conditions.

Clinical condition
Staphylococcal scalded skin
syndrome (SSSS)
Congenital herpes simplex virus
infection
Epidermolysis bullosa
Epidermolytic hyperkeratosis (EHK),
epidermolytic ichthyosis (EI) or
bullous congenital ichthyosiform
Suction blisters
Clinical and diagnostic features Onset
Abrupt onset of erythema followed 2–30 days
by blistering and exfoliation.
Generally begins with localized
infection of the conjunctivae, nares,
peri-oral region, perineum, or
umbilicus.Associated with fever,
poor feeding, and thermal instability.
Vesicles, blisters and bullae in groups First 20 days
leaving large denuded areas after
rupture.Fever, poor feeding,
hypothermia, lethargy. Positive viral
cultures.
Blisters at sites of least trauma or Usually at birth
pressure. Heals by scarring.Involves
mucous membrane.
Blisters in crops which leave raw At birth
erythematous areas when
ruptured.No mucous membrane or
nail involvement. Secondary bacterial
infections with Staphylococcus aureus
may occur.Thick, grayish brown
scales after the age of 3 months.
One or few blisters on thumb, radial At birth
aspect of forearm, presumably due to
sucking in utero. Absence of systemic
symptoms.Spontaneous resolution
without sequelae.

Review of the literature did not reveal any association between EHK and SVT and are likely unrelated.

Take home message

• EHK, though rare may manifest as an exfoliative skin disease in neonates.
• EHK is usually inherited in an autosomal dominant fashion; but some rare cases can result from homozy-
gous KRT10 mutations consistent with autosomal recessive inheritance as in our patient. Knowledge of this

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heterogeneity would be important for guiding genetic counseling of patients and their families. In addition,
this may have an impact for possible gene-therapy in the future.
• EHK is frequently mistaken for SSSS or epidermolysis bullosa and can be missed in the neonatal period. It
should be considered as a possible diagnosis when neonates present with such a clinical picture.
• Diagnosis is achieved by molecular genetic testing circumventing the need to perform a skin biopsy.

Author’s statement

Conflict of interest: Authors state no conflict of interest.

Material and methods

Informed consent: Informed consent has been obtained from all individuals included in this study.

Ethical approval: The research related to human use has been done in compliance with all the relevant na-
tional regulations, institutional policies and in accordance the tenets of the Helsinki Declaration, and has been
approved by the authors’ institutional review board or equivalent committee.
Article note: Dr Satyaranjan Pegu and Dr Jaya. P. Bodani were involved in the patient management and prepar-
ing the manuscript. Dr Edmond G. Lemire and Dr Karen I. Holfeld were involved in the diagnosis and review-
ing the manuscript.

References
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sults of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010;63:607–41.
[3] DiGiovanna JJ, Bale SJ. Clinical heterogeneity in epidermolytic hyperkeratosis. Arch Dermatol. 1994;130:1026–35.
[4] Rothnagel JA, Fisher MP, Axtell SM, Pittelkow MR, Anton-Lamprecht I, Huber M, et al. A mutational hot spot in keratin 10 (KRT 10) in pa-
tients with epidermolytic hyperkeratosis. Hum Mol Genet. 1993;2:2147–50.
[5] Betlloch I, Lucas Costa A, Mataix J, Pérez-Crespo M, Ballester I. Bullous congenital ichthyosiform erythroderma: a sporadic case produced
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