University of California Davis Department of Dermatology. email@example.com
A 13-year-old boy presented to the dermatology clinic for treatment of a congenital ichthyosis with a history of generalized erythroderma and trauma related blistering at the time of birth. At the time of presentation he was noted to have red corrugated hyperkeratotic plaques involving the joint flexures, dorsal hands, and neck. Epidermolytic hyperkeratosis is a rare autosomal dominant genodermatosis that presents at birth with generalized erythema, blisters and erosions. In the subsequent months after birth erythema and blistering improves but patients go on to develop hyperkeratotic scaling that is especially prominent along the joint flexures, neck, hands and feet. The disease is caused by mutations in either keratin 1 or keratin 10. Treatment options include urea or alpha-hydroxy acid containing creams as well as topical and systemic retinoids. Epidermolytic hyperkeratosis is also known as bullous congenital ichthyosiform erythroderma (of Brocq) and disorder of cornification type 3.
A 13-year-old boy presented to the University of California Davis department of dermatology for treatment of a congenital ichthyosis that presented at birth with generalized erythroderma and trauma related blistering. By age 2, he had developed red corrugated hyperkeratotic plaques distributed over his joint flexures, dorsum of hands, and neck. Palms and soles were not affected. Although he continued to develop erythema and blisters, such episodes had decreased in severity and frequency. As the hyperkeratosis became more prominent, the skin developed a foul odor resembling rotten eggs. Physical examination revealed thickened red hyperkeratotic corrugated plaques distributed over the neck, back and flexural surfaces of his arms and legs affecting approximately 25 percent of his body surface area (Fig. 1). Areas of mild erythema with minimal scaling were evident on his back with complete sparing of the palms, soles and face.
The patient underwent treatment with a variety of topical therapies, the most effective being 40 percent urea cream, which he used as tolerated. In addition to topical therapy with 40 percent urea cream, isotretinoin 20 mg once daily was added to his treatment regimen. In an attempt to cut down the bacterial colonization of his skin and improve its odor, the patient was instructed to add one half cup of bleach to his nightly bath and to use an antibacterial soap. Although the patient improved on this therapy, isotretinoin had to be discontinued because of persistently elevated liver function tests. The patient is currently being managed with topical retinoids and 40 percent urea cream.
Epidermolytic hyperkeratosis (EHK) is a form of congenital ichthyosis with a prevalence of 1 in 200,000-300,000 people . The first clinical description of EHK was made by Brocq in 1902. He coined the term bullous ichthyosiform erythroderma, which he distinguished from the non-blistering condition, congenital ichthyotic erythroderma . Epidermolytic hyperkeratosis presents at birth with generalized erythroderma. Skin fragility causes blisters and peeling, even with mild trauma. Superficial ulcerations develop on the flexural surfaces. Because of the disruption of the epithelial barrier, neonates with EHK are at risk of developing severe infection, electrolyte imbalances, and sepsis. Gradually, the erythroderma and blisters improve, although they can persist throughout life. After a few months verrucous hyperkeratotic plaques become more prominent in the joint flexures, but can also appear on the scalp, neck and infragluteal folds. Bacterial colonization of the macerated scales causes a distinct foul odor, which can be partially responsive to topical antimicrobial cleansers.
Several phenotypes of EHK have been identified. Involvement of the palms and soles occurs in about 60 percent of patients with EHK, resulting in recurrent painful fissures and contractures that can lead to functional impairment. In 1994 DiGiovanna and Bale described two main clinical categories of EHK. The first type involves the palms and soles (PS) and the second type spares the palms and soles (NPS) . The PS type of EHK, has three subtypes: PS-1, PS-2, PS-3. These subtypes present with hyperkeratosis of the palmar and plantar surfaces and varying degrees of erythroderma, blistering and truncal involvement. NPS type EHK is subdivided into three subtypes: NPS-1, NPS-2 and NPS-3, all of which have normal or minimally involved, palmar and plantar surfaces and varying degrees of erythroderma, scaling, and blistering.
Epidermolytic hyperkeratosis is inherited as an autosomal dominant trait, but 50 percent of cases result from spontaneous mutations. Defects in keratin are responsible for EHK. Keratins, the major gene product of keratinocytes, are intermediate filaments. Mutations have been identified in approximately 18 keratins, all of which produce fragile cell phenotypes [4, 5]. Keratin mutations that are passed as autosomal dominant traits generally encode proteins that disrupt the keratin cytoskeleton or produce abnormal clumping of keratin filaments. As a result, the epithelial cells create skin that is less resilient and more disposed to blister formation, even with slight trauma. Basal layer keratinocytes express keratin 5 and 14. As these keratinocytes differentiate and migrate through the epidermis keratin 5 and 14 expression is down-regulated and keratin 1 and 10 expression is upregulated. It was discovered that mutations of keratin 1 on chromosome 12 is associated with EHK [5,6]. Subsequently mutations in keratin 10, the co-expressed partner of keratin 1, are also associated with EHK. The gene coding keratin 10 is located on chromosome 17. Keratin 1 and 10 proteins interact to secure the epithelial cell cytoskeleton. Defects of this protein network cause structural instability and weakness of keratinocytes that subsequently lead to blistering, hyperproliferation, and hyperkeratosis.
A diagnosis of EHK can usually be made clinically but at times may also require laboratory investigation. Skin biopsy of the involved areas can be submitted for immunohistochemistry as well as for light and electron microscopy. Keratin defect studies can be useful for prenatal diagnosis of EHK in families. In addition, prenatal diagnosis can be obtained via chorionic villus sampling, amniocentesis, and fetal skin biopsy . Interestingly, individuals with verrucous epidermal nevi may be at risk of having offspring with EHK; in these cases the epidermal nevus represents a somatic mosaicism for a keratin gene mutation.
Nikolski first described the histopathologic features of EHK in 1897. Typically, there is acanthosis, marked hyperkeratosis, coarse keratohyaline granules, and multiple perinuclear vacuoles present in the upper spinous layer. Electron microscopy shows clumping of keratin intermediate filaments at the suprabasilar level. Immunohistochemistry can show a defect in the expression of keratin 1 or 10.
Management for EHK is primarily targeted for symptom control and relief. Improved neonatal care has decreased morbidity secondary to sepsis, dehydration and electrolyte imbalances. In childhood and adulthood, malodor associated with bacterial overgrowth can be moderately controlled by antibacterial cleansers and, when necessary to control infection, systemic antibiotics. Topical emollients such as creams containing glycerin, lactic acid, urea, and α-hydroxy acids have been demonstrated to improve the appearance and feeling of hyperkeratotic scaly skin . For more severe cases, oral and topical retinoids have also shown to improve patients with EHK, although retinoids may promote desquamation and exacerbate blistering . Apparently, individuals with keratin 10 mutations, as opposed to those with keratin 1 mutations, respond better to topical or systemic retinoid therapy.
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