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Publicly Available Published by De Gruyter March 28, 2017

A novel keratin 10 gene mutation causing epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma) in a term neonate

  • Satyaranjan Pegu ORCID logo EMAIL logo , Jaya. P. Bodani , Edmond G. Lemire and Karen I. Holfeld

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 autosomal 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 recessive inheritance. Furthermore, diagnosis was achieved by molecular genetic testing circumventing the need to perform a skin biopsy.

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 resolved 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 SSSS and epidermolysis bullosa were also considered in the differential diagnosis. Consultations with dermatology, 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 provided 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.
Figure 1:

Condition of the skin at the time of admission.

Figure 2: 
          Healing skin at the time of discharge.
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 responsible 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 carriers. Genetic counselling was provided to the family.

Discussion

Exfoliative skin disease manifests infrequently in neonates. EHK or bullous congenital ichthyosiform erythroderma (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 characteristic 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 hyperkeratosis and keratin 10 mutations in those without palmar/plantar involvement in those families [1, 3]. 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 causing 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 inheritance 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 Clinical and diagnostic features Onset
Staphylococcal scalded skin syndrome (SSSS) Abrupt onset of erythema followed 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. 2–30 days
Congenital herpes simplex virus infection Vesicles, blisters and bullae in groups leaving large denuded areas after rupture.Fever, poor feeding, hypothermia, lethargy. Positive viral cultures. First 20 days
Epidermolysis bullosa Blisters at sites of least trauma or pressure. Heals by scarring.Involves mucous membrane. Usually at birth
Epidermolytic hyperkeratosis (EHK), epidermolytic ichthyosis (EI) or bullous congenital ichthyosiform Blisters in crops which leave raw 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. At birth
Suction blisters One or few blisters on thumb, radial aspect of forearm, presumably due to sucking in utero. Absence of systemic symptoms.Spontaneous resolution without sequelae. At birth

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 homozygous KRT10 mutations consistent with autosomal recessive inheritance as in our patient. Knowledge of this 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.


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

Author’s statement

  1. Conflict of interest: Authors state no conflict of interest.

Material and methods

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

  2. Ethical approval: The research related to human subject use has complied with all the relevant national regulations, and institutional policies, and is in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.

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Article note:

Dr Satyaranjan Pegu and Dr Jaya. P. Bodani were involved in the patient management and preparing the manuscript. Dr Edmond G. Lemire and Dr Karen I. Holfeld were involved in the diagnosis and reviewing the manuscript.


Received: 2016-08-20
Accepted: 2017-02-09
Published Online: 2017-03-28
Published in Print: 2017-03-26

©2017 Walter de Gruyter GmbH, Berlin/Boston

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