Epidermolytic hyperkeratosis

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Epidermolytic Ichthyosis (EI)
Other namesBullous epidermis ichthyosis
Epidetmolytic ichtyosis.jpg
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Epidermolytic ichthyosis (EI), [lower-alpha 1] is a rare and severe form of ichthyosis that affects around 1 in 300,000 people. It is caused by a genetic mutation, and thus cannot be completely cured without some form of gene therapy.

Contents

While some research has been done into possible gene therapy treatments, the work hasn't yet been successfully developed to the stage where it can be routinely given to patients.

The condition involves the clumping of keratin filaments. [5] [6] : 562 

Genetics

It is possible to classify epidermolytic hyperkeratosis based upon palm and sole hyperkeratosis. [7]

This is a dominant [8] genetic condition caused by mutations in the genes encoding the proteins keratin 1 or keratin 10.

Diagnosis

The condition can be diagnosed via exam that reveals; generalized redness; thick, generally dark, scales that tend to form parallel rows of spines or ridges, especially near large joints; the skin is fragile and blisters easily following trauma; extent of blistering and amount of scale is variable.[ citation needed ]

Treatment

Oral retinoids have proven effective in treating this disorder. Depending on the side effects they may improve the quality of life. [9] Examples are etretinate, acitretin, and isotretinoin.

Gene therapy

Gene therapy is really the only true therapy on the horizon for sufferers of EHK.

Over the past 10 years since the first EHK mouse model was developed, many ideas have been discussed about how best to cure EHK. Back as far as 1994 researchers were discussing new promising ideas such as topical lotions that would deliver ribozymes in a liposome cream. Ribozymes are a small piece of synthetic RNA which can digest RNA molecules. When cells make a protein from a gene on a chromosome sitting in the nucleus, the gene is first transcribed as a piece of RNA. This RNA is then translated into a protein. Ribozymes can be designed to destroy RNA molecules with specific sequences. In theory, this will stop the production of the protein encoded by the mutant alleles of the gene.

Successful gene therapy solutions have been recently achieved on mouse models by Jiang Chen M.D., a post-doctoral fellow in the laboratory of Dennis Roop, Ph.D., in the Center for Cutaneous Molecular Biology at Baylor College of Medicine. In 1998 they developed an inducible mouse model for epidermolysis hyperkeratosis which is viable, because the expression of a mutant K10 allele can be restricted to a focal area of the skin. "Once the mutant K10 allele is activated in epidermal stem cells by topical application of an inducer, these stem cells continuously give rise to defective progeny that form hyperkeratotic lesions which persist for the life of the mouse. It was observed that partial suppression of the mutant K10 gene may be sufficient to eliminate the disorder."

To test this observation, Dr. Chen and his team of researchers developed siRNAs that target the mutant K10 gene products for degradation, without affecting normal K10 gene products. Dr. Chen observed that under these conditions, an efficient knock-down of mutant, but not normal, K10 genes could be achieved. The results allowed the normal K10 genes to function properly building healthy skin tissues. He claims that these results may prove to be a very vital step forward in forging a novel gene therapy and possible permanent corrective therapy for this debilitating skin disorder.

Next steps

The challenge has always been how to deliver the siRNA using a topical method or retroviral vectors and ex vivo gene transfer. [10] In 2011/12 a team at Northwestern University claim to have solved the topical delivery of siRNA dilemma. Personalized siRNA can be delivered in a commercial moisturizer or phosphate-buffered saline, and do not require barrier disruption or transfection agents, such as liposomes, peptides, or viruses. "Topical application of nucleic acids offers many potential therapeutic advantages for suppressing genes in the skin, and potentially for systemic gene delivery. However, the epidermal barrier typically precludes entry of gene-suppressing therapy unless the barrier is disrupted. We now show that spherical nucleic acid nanoparticle conjugates (SNA-NCs), gold cores surrounded by a dense shell of highly oriented, covalently immobilized siRNA, freely penetrate almost 100% of keratinocytes in vitro, mouse skin, and human epidermis within hours after application." [11] This new discovery may soon offer hope to all suffering from mono-genetic diseases such as EHK. This may lead to promising personalized, topically delivered gene therapy of cutaneous tumors, skin inflammation, and dominant negative genetic skin disorders.

[12] UPDATE: OCTOBER 2014 As of late, Paller reports "we are using a new nanotechnology-based technique called 'spherical nucleic acids' (SNAs) to suppress the production of the abnormal keratin 10 gene that is the most common change leading to epidermolytic ichthyosis. We continue to screen candidate SNAs to find a few that clearly suppress the abnormal keratin 10 gene much more than the normal keratin 10 gene. In the meantime, we have developed several tools towards this effort, which can also be used by other researchers. Most recently we've developed a special 'lentivirus reporter construct' in which we can see through changes in fluorescence whether or not our SNA works."

Dr. Paller and her team recently received more good news with regard to progressing their research. "We just received a grant from the National Institutes of Health (NIH) to continue this effort based on our preliminary data collected with FIRST's funding support. FIRST has been instrumental in furthering our research efforts related to ichthyosis," she said.

Maintenance

Until gene therapy solutions finally become reality, EHK sufferers must treat their fragile skin carefully. Most have learned that taking regular extended baths allows patients to care for their fragile skin and keep it manageable. Baths that include sea salt seem to improve the process of softening and removing the thickened skin. Ointments like Petroleum Jelly, Aveeno, and other barrier type ointment help hold the moisture in the skin after a bath.

See also

Related Research Articles

<span class="mw-page-title-main">Harlequin-type ichthyosis</span> Genetic skin disease

Harlequin-type ichthyosis is a genetic disorder that results in thickened skin over nearly the entire body at birth. The skin forms large, diamond/trapezoid/rectangle-shaped plates that are separated by deep cracks. These affect the shape of the eyelids, nose, mouth, and ears and limit movement of the arms and legs. Restricted movement of the chest can lead to breathing difficulties. These plates fall off over several weeks. Other complications can include premature birth, infection, problems with body temperature, and dehydration. The condition is the most severe form of ichthyosis, a group of genetic disorders characterised by scaly skin.

<span class="mw-page-title-main">Lamellar ichthyosis</span> Medical condition

Lamellar ichthyosis, also known as ichthyosis lamellaris and nonbullous congenital ichthyosis, is a rare inherited skin disorder, affecting around 1 in 600,000 people.

<span class="mw-page-title-main">Keratin 1</span>

Keratin 1 is a Type II intermediate filament (IFs) of the intracytoplasmatic cytoskeleton. Is co-expressed with and binds to Keratin 10, a Type I keratin, to form a coiled coil heterotypic keratin chain. Keratin 1 and Keratin 10 are specifically expressed in the spinous and granular layers of the epidermis. In contrast, basal layer keratinocytes express little to no Keratin 1. Mutations in KRT1, the gene encoding Keratin 1, have been associated with variants of the disease bullous congenital ichthyosiform erythroderma in which the palms and soles of the feet are affected. Mutations in KRT10 have also been associated with bullous congenital ichthyosiform erythroderma; however, in patients with KRT10 mutations the palms and soles are spared. This difference is likely due to Keratin 9, rather than Keratin 10, being the major binding partner of Keratin 1 in acral keratinocytes.

<span class="mw-page-title-main">Keratin 2A</span>

Keratin 2A also known as keratin 2E or keratin 2 is a protein that in humans is encoded by the KRT2A gene.

<span class="mw-page-title-main">Keratin 10</span> Protein-coding gene in the species Homo sapiens

Keratin, type I cytoskeletal 10 also known as cytokeratin-10 (CK-10) or keratin-10 (K10) is a protein that in humans is encoded by the KRT10 gene. Keratin 10 is a type I keratin.

<span class="mw-page-title-main">Keratosis pilaris</span> Skin condition characterized by small bumps caused by overproduction of keratin

Keratosis pilaris is a common, autosomal-dominant, genetic condition of the skin's hair follicles characterized by the appearance of possibly itchy, small, gooseflesh-like bumps, with varying degrees of reddening or inflammation. It most often appears on the outer sides of the upper arms, thighs, face, back, and buttocks; KP can also occur on the hands, and tops of legs, sides, or any body part except glabrous (hairless) skin. Often the lesions can appear on the face, which may be mistaken for acne or folliculitis.

<span class="mw-page-title-main">Hyperkeratosis</span> Medical condition

Hyperkeratosis is thickening of the stratum corneum, often associated with the presence of an abnormal quantity of keratin, and also usually accompanied by an increase in the granular layer. As the corneum layer normally varies greatly in thickness in different sites, some experience is needed to assess minor degrees of hyperkeratosis.

<span class="mw-page-title-main">ABCA12</span> Protein-coding gene in the species Homo sapiens

ATP-binding cassette sub-family A member 12 also known as ATP-binding cassette transporter 12 is a protein that in humans is encoded by the ABCA12 gene.

<span class="mw-page-title-main">Genodermatosis</span> Medical condition

Genodermatosis is a hereditary skin disease with three inherited modes including single gene inheritance, multiple gene inheritance and chromosome inheritance. There are many different types of genodermatosis, the prevalence of genodermatosis ranges from 1 per 6000 people to 1 per 500,000 people. Genodermatosis has influence on the texture, color and structure of skin cuticle and connective tissue, specific lesion site and clinical manifestations on the body vary depending on the type. In the spite of the variety and complexity of genodermatosis, there are still some common methods that can help people diagnose. After diagnosis, different types of genodermatosis require different levels of therapy including interventions, nursing interventions and treatments. Among that, research of therapy for some new, complex and rare types are still in the developing stage. The impact of genodermatosis not only can be seen in body but also can be seen in all aspects of patients' life, including but not limited to psychological, family life, economic conditions and social activities. Accordingly, the patients need treatment, support and help in these areas.

<span class="mw-page-title-main">CHILD syndrome</span> Medical condition

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects is a genetic disorder with onset at birth seen almost exclusively in females. The disorder is related to CPDX2, and also has skin and skeletal abnormalities, distinguished by a sharp midline demarcation of the ichthyosis with minimal linear or segmental contralateral involvement.

<span class="mw-page-title-main">Ichthyosis bullosa of Siemens</span> Medical condition

Ichthyosis bullosa of Siemens is a type of familial, autosomal dominant ichthyosis, a rare skin disorder. It is also known as bullous congenital ichthyosiform erythroderma of Siemens or ichthyosis exfoliativa. It is a genetic disorder with no known cure which is estimated to affect about 1 in 500,000 people.

Congenital ichthyosiform erythroderma, also known as nonbullous congenital ichthyosiform erythroderma, is a rare type of the ichthyosis family of skin diseases which occurs in 1 in 200,000 to 300,000 births. The disease comes under the umbrella term autosomal recessive congenital ichthyosis, which include non-syndromic congenital ichthyoses such as harlequin ichthyosis and lamellar ichthyosis.

Ichthyosis hystrix is a group of rare skin disorders in the ichthyosis family of skin disorders characterized by massive hyperkeratosis with an appearance like spiny scales. This term is also used to refer to a type of epidermal nevi with extensive bilateral distribution.

Keratitis–ichthyosis–deafness syndrome, also known as ichthyosiform erythroderma, corneal involvement, and deafness, presents at birth/infancy and is characterized by progressive corneal opacification, either mild generalized hyperkeratosis or discrete erythematous plaques, and neurosensory deafness.

Trichorrhexis invaginata is a distinctive hair shaft abnormality that may occur sporadically, either in normal hair or with other hair shaft abnormalities, or regularly as a marker for Netherton syndrome. The primary defect appears to be abnormal keratinization of the hair shaft in the keratogenous zone, allowing for intussusception of the fully keratinized and hard distal shaft into the incompletely keratinized and soft proximal portion of the shaft.

<span class="mw-page-title-main">Inflammatory linear verrucous epidermal nevus</span> Medical condition

Inflammatory Linear Verrucous Epidermal Nevus is a rare disease of the skin that presents as multiple, discrete, red papules that tend to coalesce into linear plaques that follow the Lines of Blaschko. The plaques can be slightly warty (psoriaform) or scaly (eczema-like). ILVEN is caused by somatic mutations that result in genetic mosaicism. There is no cure, but different medical treatments can alleviate the symptoms.

Howel–Evans syndrome is an extremely rare condition involving thickening of the skin in the palms of the hands and the soles of the feet (hyperkeratosis). This familial disease is associated with a high lifetime risk of esophageal cancer. For this reason, it is sometimes known as tylosis with oesophageal cancer (TOC).

Ichthyosis prematurity syndrome (IPS) is a dermatological disease with known genetic causes. This syndrome is a rare subcategory of autosomal recessive congenital ichthyosis (ARCI). It is associated with complications in the mid-trimester of a pregnancy leading to premature births. Although most prevalent in individuals of Scandinavian origin, there have also been scattered cases in people of Japanese, Italian and Indian ethnicity. This disorder is also referred to as ichthyosis congenital type IV.

<span class="mw-page-title-main">Ichthyosis with confetti</span> Medical condition

Ichthyosis en confetti, is a very rare form of congenital ichthyosis in which healthy patches of normal skin co-exist within the abnormal skin areas. The condition is caused by a frameshift mutation in the keratin 10 gene (KRT10); mutant keratin 10 accumulates in the nucleolus, a sub-nuclear structure, rather than within cellular intermediate filaments like the wild-type protein. Children with the condition exhibit red, flaky skin; however, for reasons not yet totally clear, wild type clonal patches of skin start to appear, in place of the red, flaky skin. Due to the clonal nature of the growth of the normal skin cells, it appears the patient is covered with confetti, hence the name of the condition. It has been hypothesized that this is the result of a combination of mitotic recombination and natural selection within the skin.

References

  1. ↑ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN   978-1-4160-2999-1.
  2. ↑ Bullous ichthyosiform erythroderma (Concept Id: C0079153) - MedGen - NCBI , retrieved 2023-08-10
  3. ↑ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN   0-07-138076-0.
  4. ↑ synd/1036 at Who Named It?
  5. ↑ Cheng J, Syder AJ, Yu QC, Letai A, Paller AS, Fuchs E (September 1992). "The genetic basis of epidermolytic ichthyosis: a disorder of differentiation-specific epidermal keratin genes". Cell. 70 (5): 811–9. doi:10.1016/0092-8674(92)90314-3. PMID   1381287. S2CID   31906051.
  6. ↑ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN   0-7216-2921-0.
  7. ↑ DiGiovanna JJ, Bale SJ (August 1994). "Clinical heterogeneity in epidermolytic hyperkeratosis". Arch Dermatol. 130 (8): 1026–35. doi:10.1001/archderm.130.8.1026. PMID   8053700.
  8. ↑ Ross R, DiGiovanna JJ, Capaldi L, Argenyi Z, Fleckman P, Robinson-Bostom L (July 2008). "Histopathologic characterization of epidermolytic hyperkeratosis: a systematic review of histology from the National Registry for Ichthyosis and Related Skin Disorders". J. Am. Acad. Dermatol. 59 (1): 86–90. doi:10.1016/j.jaad.2008.02.031. PMC   2517215 . PMID   18571597.
  9. ↑ Brecher AR, Orlow SJ (2003). "Oral retinoid therapy for dermatologic conditions in children and adolescents". J. Am. Acad. Dermatol. 49 (2): 171–82, quiz 183–6. doi:10.1067/S0190-9622(03)01564-0. PMID   12894062.
  10. ↑ Hengge, U. R. (2006). "Gene therapy progress and prospects: the skin - easily accessible, but still far away". Gene Therapy. 13 (22): 1555–1563. doi: 10.1038/sj.gt.3302855 . PMID   16957767.
  11. ↑ Zheng, Dan; Giljohann, David A.; Chen, David L.; Massich, Matthew D.; Wang, Xiao-Qi; Iordanov, Hristo; Mirkin, Chad A.; Paller, Amy S. (2012). "Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation". Proceedings of the National Academy of Sciences. 109 (30): 11975–11980. Bibcode:2012PNAS..10911975Z. doi: 10.1073/pnas.1118425109 . PMC   3409786 . PMID   22773805.
  12. ↑ "FIRST Funded Research | Foundation for Ichthyosis & Related Skin Types (FIRST)". Archived from the original on 2020-10-30. Retrieved 2015-08-24.
  1. ↑ also known as bullous epidermis ichthyosis (BEI), epidermolytic hyperkeratosis (EHK), bullous congenital ichthyosiform erythroderma (BCIE), [1] bullous ichtyosiform erythroderma congenita, [2] bullous ichthyosiform erythroderma [3] : 482  or bullous congenital ichthyosiform erythroderma Brocq, [4]
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