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This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (March 2009) |
| Epidermolytic hyperkeratosis |
| Classification and external resources |
| ICD-10 |
Q80.3 |
| OMIM |
113800 |
| DiseasesDB |
33392 |
| eMedicine |
derm/590 |
| MeSH |
D017488 |
Epidermolytic hyperkeratosis, (also known as Bullous congenital ichthyosiform erythroderma,[1] Bullous ichthyosiform erythroderma,[2]:482 or bullous congenital ichthyosiform erythroderma Brocq[3]) is a rare ichthyosis skin disease affecting around 1 in 250,000 people.
It involves the clumping of keratin filaments.[4][5]:562
Contents
- 1 Presentation
- 2 Genetics
- 3 Key findings
- 4 Treatment
- 4.1 Gene Therapy
- 4.2 Next Steps
- 4.3 Maintenance
- 5 See also
- 6 References
Presentation[edit]
Epidermolytic hyperkeratosis is a skin disorder that is present at birth. Affected babies may have very red skin (erythroderma) and severe blisters. Because newborns with this disorder are missing the protection provided by normal skin, they are at risk of becoming dehydrated and developing infections in the skin or throughout the body (sepsis).
As affected individuals get older, blistering is less frequent, erythroderma becomes less evident, and the skin becomes thick (hyperkeratotic), especially over joints, on areas of skin that come into contact with each other, or on the scalp or neck. This thickened skin is usually darker than normal. Bacteria can grow in the thick skin, often causing a distinct odor.
Epidermolytic hyperkeratosis can be categorized into two types. People with PS-type epidermolytic hyperkeratosis have thick skin on the palms of their hands and soles of their feet (palmoplantar or palm/sole hyperkeratosis) in addition to other areas of the body. People with the other type, NPS-type, do not have extensive palmoplantar hyperkeratosis but do have hyperkeratosis on other areas of the body.
Epidermolytic hyperkeratosis is part of a group of conditions called ichthyoses, which refers to the scaly skin seen in individuals with related disorders. However, in epidermolytic hyperkeratosis, the skin is thick but not scaly as in some of the other conditions in the group. http://ghr.nlm.nih.gov/condition/epidermolytic-hyperkeratosis [6]
Genetics[edit]
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.
- Keratin 1 is associated with the variants affecting the palms and soles.
- Keratin 10 is associated with the variants in which these are unaffected.
Key findings[edit]
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
Treatment[edit]
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, isotretinoin
Gene Therapy[edit]
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 liposom 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[edit]
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 dilema. 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. It seems in 2013 Clinical trials are being planned to test this new approach.
Maintenance[edit]
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[edit]
- Nonbullous ichthyosiform erythroderma
- Ichthyosis bullosa of Siemens
- Ichthyosis
- Isotretinoin (Accutane)
- Hyperkeratosis
- List of cutaneous conditions
- List of cutaneous conditions caused by mutations in keratins
- List of verrucous carcinoma subtypes
References[edit]
- ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.
- ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0.
- ^ synd/1036 at Who Named It?
- ^ Cheng J, Syder AJ, Yu QC, Letai A, Paller AS, Fuchs E (September 1992). "The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiation-specific epidermal keratin genes". Cell 70 (5): 811–9. doi:10.1016/0092-8674(92)90314-3. PMID 1381287.
- ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
- ^ "What is epidermolytic hyperkeratosis?". Retrieved 2011-11-03.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ "Gene Therapy - Gene therapy progress and prospects: the skin - easily accessible, but still far away". Retrieved 2008-01-03.
- ^ http://www.pnas.org/content/early/2012/07/03/1118425109
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Cytoskeletal defects
|
|
| Microfilaments |
| Myofilament |
| Actin |
- Hypertrophic cardiomyopathy 11
- Dilated cardiomyopathy 1AA
- DFNA20
- Nemaline myopathy 3
|
|
| Myosin |
- Elejalde syndrome
- Hypertrophic cardiomyopathy 1, 8, 10
- Usher syndrome 1B
- Freeman–Sheldon syndrome
- DFN A3, 4, 11, 17, 22; B2, 30, 37, 48
- May-Hegglin anomaly
|
|
| Troponin |
- Hypertrophic cardiomyopathy 7, 2
- Nemaline myopathy 4, 5
|
|
| Tropomyosin |
- Hypertrophic cardiomyopathy 3
- Nemaline myopathy 1
|
|
| Titin |
- Hypertrophic cardiomyopathy 9
|
|
|
| Other |
- Fibrillin
- Marfan syndrome
- Weill-Marchesani syndrome
- Filamin
- FG syndrome 2
- Boomerang dysplasia
- Larsen syndrome
- Terminal osseous dysplasia with pigmentary defects
|
|
|
| IF |
| 1/2 |
- Keratinopathy (keratosis, keratoderma, hyperkeratosis): KRT1
- Striate palmoplantar keratoderma 3
- Epidermolytic hyperkeratosis
- IHCM
- KRT2E (Ichthyosis bullosa of Siemens)
- KRT3 (Meesmann juvenile epithelial corneal dystrophy)
- KRT4 (White sponge nevus)
- KRT5 (Epidermolysis bullosa simplex)
- KRT8 (Familial cirrhosis)
- KRT10 (Epidermolytic hyperkeratosis)
- KRT12 (Meesmann juvenile epithelial corneal dystrophy)
- KRT13 (White sponge nevus)
- KRT14 (Epidermolysis bullosa simplex)
- KRT17 (Steatocystoma multiplex)
- KRT18 (Familial cirrhosis)
- KRT81/KRT83/KRT86 (Monilethrix)
- Naegeli–Franceschetti–Jadassohn syndrome
- Reticular pigmented anomaly of the flexures
|
|
| 3 |
- Desmin: Desmin-related myofibrillar myopathy
- Dilated cardiomyopathy 1I
- Peripherin: Amyotrophic lateral sclerosis
|
|
| 4 |
- Neurofilament: Parkinson's disease
- Charcot–Marie–Tooth disease 1F, 2E
- Amyotrophic lateral sclerosis
|
|
| 5 |
- Laminopathy: LMNA
- Mandibuloacral dysplasia
- Dunnigan Familial partial lipodystrophy
- Emery-Dreifuss muscular dystrophy 2
- Limb-girdle muscular dystrophy 1B
- Charcot–Marie–Tooth disease 2B1
- LMNB
- Barraquer–Simons syndrome
- LEMD3
- Buschke–Ollendorff syndrome
- Osteopoikilosis
- LBR
- Pelger-Huet anomaly
- Hydrops-ectopic calcification-moth-eaten skeletal dysplasia
|
|
|
| Microtubules |
| Kinesin |
- Charcot–Marie–Tooth disease 2A
- Hereditary spastic paraplegia 10
|
|
| Dynein |
- Primary ciliary dyskinesia
- Short rib-polydactyly syndrome 3
- Asphyxiating thoracic dysplasia 3
|
|
| Other |
- Tauopathy
- Cavernous venous malformation
|
|
|
| Membrane |
- Spectrin: Spinocerebellar ataxia 5
- Hereditary spherocytosis 2, 3
- Hereditary elliptocytosis 2, 3
Ankyrin: Long QT syndrome 4
- Hereditary spherocytosis 1
|
|
| Catenin |
- APC
- Gardner's syndrome
- Familial adenomatous polyposis
- plakoglobin (Naxos syndrome)
- GAN (Giant axonal neuropathy)
|
|
| Other |
- desmoplakin: Striate palmoplantar keratoderma 2
- Carvajal syndrome
- Arrhythmogenic right ventricular dysplasia 8
- plectin: Epidermolysis bullosa simplex with muscular dystrophy
- Epidermolysis bullosa simplex of Ogna
- plakophilin: Skin fragility syndrome
- Arrhythmogenic right ventricular dysplasia 9
- centrosome: PCNT (Microcephalic osteodysplastic primordial dwarfism type II)
|
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See also: cytoskeletal proteins
- B structural
- perx
- skel
- cili
- mito
- nucl
- sclr
- DNA/RNA/protein synthesis
- membrane
- transduction
- trfk
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