Epidermolytic hyperkeratosis
Epidermolytic hyperkeratosis is a rare congenital skin disorder characterized by thick, scaly, and blistered skin, typically presenting at birth. The condition derives its name from "epidermolytic," indicating fragile skin, and "hyperkeratosis," referring to the thickening of the outer skin layer. Genetic mutations, primarily affecting keratin-1 and keratin-10 genes, are often responsible for the disorder, with about 50 percent of cases showing autosomal dominant inheritance or spontaneous mutations. Clinically, the disorder is diverse, with six phenotypes categorized based on palm and sole involvement, leading to varying degrees of symptoms, including blistering, scaling, and redness.
Patients may experience complications such as skin infections and, in rare cases, cardiac disturbances. Diagnosis typically involves visual assessments, skin biopsies, and electron microscopy to differentiate it from similar disorders. Current treatments focus on symptom relief, utilizing moisturizers, topical retinoids, and antibiotics for infection control. Prenatal detection methods exist but are not always reliable, as many cases arise spontaneously. Despite the challenges, symptoms often improve with age, but individuals may face physical and psychological difficulties due to the visible nature of the condition. Genetic counseling is recommended for affected families, providing support and resources for coping with the disorder.
Epidermolytic hyperkeratosis
ALSO KNOWN AS: Bullous congenital ichthyosiform erythroderma; bullous ichthyosiform erythroderma; bullous congenital ichthyosiform erythroderma of Brocq; BCIE; BIE; EHK
DEFINITION Epidermolytic hyperkeratosis is a rare congenital skin disorder which causes thick, scaly, red blistered skin in neonates. As the name suggests, epidermolytic refers to fragile skin, while hyperkeratosis implies thickening of the outermost layer of the skin.
Risk Factors
There are no known risk factors for this disorder, but it may be inherited as an autosomal dominant trait or by a spontaneous mutation.
Etiology and Genetics
Epidermolytic hyperkeratosis was discovered in 1902 by Louis-Anne-Jean Brocq. Since then, genetic studies have determined that up to 50 percent of cases exhibit an autosomal dominant inheritance caused by spontaneous mutation. Mutations on the keratin-1 and/or keratin-10 gene clusters found on chromosomes 12q and 17q have been linked to this disorder. Keratin, which is produced by keratinocytes, provides integrity to skin, hair, and nail cells. Therefore, mutations to the keratin cells cause structural instability and weakness of the keratinocytes, leading to an unsupported epidermis. As a result, blistering, hyperkeratosis, and scaling of the epidermis occur after minimal trauma.
The diversity of epidermolytic hyperkeratosis is remarkable. Six clinical phenotypes have been characterized based on palmoplantar involvement (pertaining to the palms of the hand and soles of the feet). Three of these subtypes, which are classified as NPS-1, NPS-2, and NPS-3, have minimal palm or sole involvement. Patients have varying degrees of redness and scaling of the skin, balance abnormalities, and blistering. Spinelike rigid scales are often seen in this subgroup. Notably, mutations on keratin 1 have been associated with the NPS subtypes.
The remaining three subtypes, which are classified as PS-1, PS-2, and PS-3, have severe palm and sole involvement. Palmoplantar hyperkeratosis occurs in roughly 60 percent of patients. A typical smooth hyperkeratosis with a distinct border is often present. Tense hands and feet have been reported within the PS subtypes as well. Palmoplantar epidermolytic hyperkeratosis has been linked to mutations on the keratin-10 gene.
Lastly, a rare variant of epidermolytic hyperkeratosis is thought to occur by a spontaneous mutation during the early phase of embryogenesis and presents with a mosaic pattern of hyperkeratosis. In this particular subtype, normal skin is interchanged with streaks of hyperkeratosis. The distribution of the streaks can take on a tight and/or widespread pattern. It is interesting to note that the keratin mutations were not found on the portions of normal skin in individuals with a mosaic skin pattern. It is not surprising that carriers of this type of mutation can pass on the gene to subsequent generations.
Symptoms
Mild to severe blistering, peeling, and erosive skin appears at birth. Over time, the redness and blistering of the skin subsides and hyperkeratosis persists. This results in thick, scaly, waxy, rigid skin predominantly at the joint flexures. Depending on the mutation, there can be scalp, palm, and/or sole involvement; the hair and nails are not affected. In rare instances, cardiac disturbances can occur in conjunction with skin disorders.
Screening and Diagnosis
According to a 2023 study published by the US National Library of Medicine, the condition affected 1 in 200,000 to 300,000 infants in the United States. The distinct widespread thick erythroderma with blisters present at birth is typically the first indicator of epidermolytic hyperkeratosis. In addition, the skin usually gives off a pungent odor. Misdiagnosis often occurs with another genetic disorder known as nonbullous congenital ichthyosiform erythroderma, which lacks the presentation of blisters. Electron microscopy along with a skin biopsy is often performed to obtain a definitive diagnosis.
Treatment and Therapy
Treatment is limited to symptomatic relief with lactate lotion, topical/systemic retinoids (tretinoin), vitamin A derivatives, 10 percent glycerin and antibacterial soap. Excessive moisturization and soaking baths are important. During the neonatal period, prevention of sepsis and fluid/electrolyte imbalance is imperative to prevent mortality. Parents of newborns should be advised on proper wound and blister care. As the child grows, oral and topical antibiotics are used to control bacterial colonization due to open skin wounds. Fungal infections are also of concern. Gene therapy is thought to be the best treatment option for this condition, and has been the major focus of hyperkeratosis-related research throughout the late twentieth and early twenty-first centuries. Researchers at Baylor College of Medicine first developed an artificial RNA which could rewrite affected keratin-10 genes in 1998, and in 2012, researchers at Northwestern University developed a method of delivering the RNA topically.
Prevention and Outcomes
The probability of epidermolytic hyperkeratosis is unpredictable since half of the cases are spontaneous mutations. Prenatal detection can be useful via fetal skin biopsy or by examining DNA extracts with a confirmed family history. Similar to other autosomal dominant epidermolytic diseases, symptoms improve over time. In fact, by adolescence, blistering diminishes and mild redness and scaling of the skin follow. Many patients suffer from physical and psychological difficulties associated with the apparent scales, tender skin, as well as odor. In some cases, minor learning difficulties have been attributed to prenatal complications. Genetic counseling and support groups are also advised for parents with children who are affected.
Bibliography
Hall, John C. Sauer’s Manual of Skin Diseases. 10th ed. Philadelphia: Lippincott, 2010. Print.
Jonca, Nathalie, and Juliette Mazereeuw-Hautier. "Superficial Epidermolytic Ichthyosis." Orphanet, Dec. 2012, www.orpha.net/en/disease/detail/455. Accessed 9 Sept. 2024.
Rice, Ashley S., and Jonathan S. Crane. "Epidermolytic Hyperkeratosis." National Library of Medicine, 31 July 2023, www.ncbi.nlm.nih.gov/books/NBK544323/. Accessed 9 Sept. 2024.
Silverberg, Nanette B. Atlas of Pediatric Cutaneous Biodiversity: Comparative Dermatologic Atlas of Pediatric Skin of All Colors . New York: Springer, 2012. Print.
Sybert, Virginia P. Genetic Skin Disorders. New York: Oxford UP, 1997. Print.
Turkington, Carol A., and Jeffrey S. Dover. Skin Deep: An A-Z of Skin Disorders, Treatments, and Health. New York: Facts On File, 1998. Print.
Zheng, Dan, et al. "Topical Delivery of siRNA-Based Sperical Nucleic Acid Nanoparticle Conjugates for Gene Regulation." Proceedings of the National Academy of Sciences 109.30 (2012): 11975–80. Print.