NORD is very grateful to Maurice A.M. van Steensel, MD, PhD, Professor of Genetic Dermatology, Department of Dermatology, Maastricht University Medical Center, The Netherlands, for assistance in the preparation of this report.
Synonyms of Epidermolytic Ichthyosis
- bullous congenital CIE
- bullous congenital ichthyosiform erythroderma (of Brocq)
- epidermolytic hyperkeratosis
- No subdivisions found.
Epidermolytic ichthyosis (EI) specifically refers to a hereditary skin disorder that is characterized by varying degrees of blistering and subsequent reactive scaling of the skin. The underlying histopathology shows mid-epidermal splitting and hyperkeratosis, together referred to as epidermolytic hyperkeratosis (EHK). Depending on the nature of the causative mutation, the symptoms may vary from mild blistering upon friction to severe erosions or widespread warty scaling ("porcupine man"). A palmoplantar keratoderma (excessive callus formation on palms and soles) and/or hair abnormalities may be present in some forms of the disorder.
The term epidermolytic ichthyosis was agreed upon by the International Ichthyosis Consensus Group in 2009 and replaces the older, confusing labels of bullous congenital ichthyosiform erythroderma (Brocq) and epidermolytic hyperkeratosis.
A number of disorders show epidermolytic hyperkeratosis, including EI, superficial epidermolytic ichthyosis bullosa and desmosomal disorders such as McGrath ectodermal dysplasia-skin fragility syndrome. Much confusion has resulted from use of the term EHK to refer to the disorder now known as epidermolytic ichthyosis.
Infants with EI may be born with red, blistering and denuded skin with visible areas of skin thickening. Over time, there is a gradual decrease in blistering, but an increase in the severity of the scaling and skin thickening. Scales tend to form in parallel rows of spines or ridges. A generalized erythroderma (redness of the skin) may be present in some individuals. Skin infections with common bacteria can be a problem. Heat intolerance is common. A palmoplantar keratodermia may be present and can be so severe as to limit ambulation and hand function. Surgical intervention may then be required. On the other end of the scale, there are individuals who have only minimal blistering in areas subject to friction, or have only a palmoplantar keratoderma. Rarely patients are covered in brown-grey hyperkeratotic spines. This is called ichthyosis hystrix (Curth-Macklin).
EI is caused by a mutation in the genes coding for the proteins keratin 1 or 10 (KRT1/KRT10). These are cytoskeletal proteins that are normally expressed in the outer nucleated cell layer (the spinous layer) of the skin. The mutant keratin pairs with a normal keratin, which interferes with the normal function of the keratin network in the cell. Normally, these keratins form protein filaments (cables) that loop between the cell membrane and nucleus. Disruption of these cables produces a cell that is poorly resistant to mechanical trauma and therefore susceptible to trauma or blistering. There are indications that cell growth may also be affected by the mutations. The severity of the disease depends on the location of the mutation in the protein. If keratin 1 is affected, the patient has a palmoplantar keratoderma. Keratin 10 is not expressed in the palmoplantar skin.
EI is an autosomal dominant genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. Some cases of EI are caused by a spontaneous mutation.
Somatic mosaicism for KRT1 and KRT10 mutations causes epidermolytic epidermal nevi, which are blistering and hyperkeratotic lesions limited to certain areas of the skin, and often following Blaschko's lines (inear epidermolytic hyperkeratotic nevus). In somatic mosaicism, the mutation of the gene occurs after fertilization and is not inherited. The mutation is found in some of the cells of the body, but not in others. The severity of the disease in these cases depends on the percentage of cells affected, and it is less severe than in individuals who have the mutation in all of their cells.
EI occurs in approximately 1 in 100,000 individuals. It affects males and females in equal numbers.
Symptoms of the following disorders may be similar to those of EI. Comparisons can be useful for a differential diagnosis.
Clinically it is usually not too difficult to distinguish EI from the other ichtyoses based on presentation or history. Blistering is notably absent in most of the other ichthyoses and inheritance in most of them is either X-linked recessive or autosomal recessive. When in doubt, light or electron microscopic examination of a skin biopsy followed by mutation analysis will help to establish the diagnosis.
Superficial epidermolytic ichthyosis (SEI, formerly known as ichthyosis bullosa Siemens) is caused by mutations in keratin 2e. The Sorèze classification has grouped this disorder, together with EI, under the keratinopathic ichthyoses (KPI). Autosomal dominantly inherited, SEI is characterized by very superficial blistering with greyish scaling limited mostly to the knees and elbows. It can sometimes mimic EI, but its limited distribution and more superficial blistering will differentiate it. It shows an excellent response to oral retinoids.
Erythrokeratodermia variabilis (EKV) and keratitis-ichthyosis-deafness (KID) like disorders are caused by mutations in genes coding for gap junction proteins (GJB3/4 and GJB2, respectively). These disorders can cause hystrix-like scaling that can cover a considerable area. In EKV, there are additionally migratory red patches and this disorder can then mimic cyclic ichthyosis with epidermolytic hyperkeratosis, which is a rare manifestation of EHK. A biopsy will help to differentiate. KID-like phenotypes are always associated with sensory hearing loss of varying severity. In addition, they can feature keratitis and sometimes severe mucosal inflammation. Again, biopsy can differentiate. Mutation analysis should always be performed and will settle the matter.
The hystrix presentation of EI must be distinguished from Lelis syndrome, which is a very rare hyperkeratotic presentation of X-linked hypohidrotic ectodermal dysplasia (XHED). A biopsy will differentiate. XHED is an X-linked recessive trait and affected males have distinguishing dysmorphic traits that are absent in EI.
Psoriasis is a common chronic and recurrent disorder characterized by dry, well-circumscribed silvery-gray scaling spots (papules) or plaques which usually appear on the scalp, elbows, or knees. This differential diagnosis will usually present no problems, but palmoplantar psoriasis can sometimes be difficult to distinguish from a palmoplantar keratoderma caused by a KRT1 mutation. In contrast to EI, psoriasis does not show simple autosomal dominant inheritance.
EI is diagnosed by physical signs and symptoms. Molecular genetic testing for mutations in the KRT1 and KRT10 genes is available to confirm the diagnosis.
Treating EI is a challenge. The medications that help to remove the excess thickened skin layers (topical keratolytics or oral retinoids) often remove too much scale, leaving a very fragile epidermis (underlying living cell layers) exposed. Severe palmoplantar keratoderma is very difficult to treat. A combination of therapies may help, including: application of a barrier repair formula containing ceramides or cholesterol; application of a barrier repair formula containing petrolatum or lanolin; topical or systemic anti-bacterial agents; and cautious use of keratolytics (lotions containing alpha-hydroxy acids, propylene glycol, lactic acid or urea). Since bacterial colonization is almost always present due to the scaling, it is recommended that patients wash with antiseptic soap 2-3 times per week.
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For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Contact for additional information about epidermolytic ichthyosis:
Prof. Maurice A.M. van Steensel, MD, PhD
Professor of Genetic Dermatology
Department of Dermatology
Maastricht University Medical Center
PO Box 5800
6202 AZ Maastricht
Epidermolytic Ichthyosis Resources
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Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010;63(4):607-41. http://www.ncbi.nlm.nih.gov/pubmed/20643494
Williams ML, Elias PM. Enlightened therapy of the disorders of cornification. Clin Dermatol. 2003;21(4):269-73.
DiGiovanna JJ, Robinson-Bostom L. Ichthyosis: etiology, diagnosis, and management. Am J Clin Dermatol. 2003;4:81-95.
Schmuth M, Yosipovich G, Williams ML, et al. Pathogenesis of the Permeability Barrier Abnormality in Epidermolytic Hyperkeratosis. J Inves Derm. 2001;17(4):837-847.
Buxman M, Hickman J, Ragsdale W, Stretcher G, Krochmal L, Wehr RF. Therapeutic activity of lactate 12% lotion in the treatment of ichthyosis. Active versus vehicle and active versus a petroleum cream. J Am Acad Dermatol. 1986;15(6):1253-1258.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Epidermolytic Hyperkeratosis; EHK. Entry No: 113800. Last Edited April 27, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed July 31, 2012.
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