Epidermolysis Bullosa
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Epidermolysis bullosa (EB) is a group of rare medical conditions that result in easy
blistering A blister is a small pocket of fluid in the upper layer of the skin caused by heat, electricity, chemicals, light, radiation, or friction Blister(s) or Blistering may also refer to: * Anti-torpedo bulge, also known as an anti-torpedo blister * ...
of the
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
and
mucous membranes A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
. Blisters occur with minor trauma or friction and are painful. Its severity can range from mild to fatal. Inherited EB is a rare disease with a prevalence in the United States of 8.2 per million live births. Those with mild cases may not develop symptoms until they start to crawl or walk. Complications may include esophageal narrowing,
squamous cell skin cancer Squamous-cell skin cancer, also known as cutaneous squamous-cell carcinoma (cSCC), is one of the main types of skin cancer along with basal cell cancer and melanoma. It usually presents as a hard lump with a scaly top but can also form an ulcer. O ...
, and the need for
amputations Amputation is the removal of a limb by trauma, medical illness, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on ind ...
. EB is due to a
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
in at least one of 16 different genes. Some types are
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
while others are autosomal recessive. The underlying mechanism is a defect in attachment between or within the layers of the skin. Loss or diminished function of C7 leads to weakness in the structural architecture of the dermal–epidermal junction (DEJ) and mucosal membranes. There are four main types:
epidermolysis bullosa simplex Epidermolysis bullosa simplex (EBS) is a disorder resulting from mutations in the genes encoding keratin 5 or keratin 14.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. . Epidermolysis bullosa s ...
(EBS), dystrophic epidermolysis bullosa (DEB), junctional epidermolysis bullosa (JEB), and
Kindler syndrome Kindler syndrome (also known as "bullous acrokeratotic poikiloderma of Kindler and Weary",) is a rare congenital disease of the skin caused by a mutation in the KIND1 gene. Symptoms and signs Infants and young children with Kindler syndrome hav ...
. The diagnosis is suspected based on symptoms and confirmed by
skin biopsy Skin biopsy is a biopsy technique in which a skin lesion is removed to be sent to a pathologist to render a microscopic diagnosis. It is usually done under local anesthetic in a physician's office, and results are often available in 4 to 10 days. ...
or
genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
. There is no cure for the condition. Management involves
wound care The history of wound care spans from prehistory to modern medicine. Wounds naturally heal by themselves, but hunter-gatherers would have noticed several factors and certain herbal remedies would speed up or assist the process, especially if it w ...
, pain control, controlling
infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...
s, nutritional support, and prevention and treatment of complications. About half a million people are affected globally. It occurs equally commonly in males and females.


Classification

Epidermolysis bullosa refers to a group of disorders that involve the formation of blisters following trivial trauma. Over 300 mutations have been identified in this condition. They have been classified into the following types:James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. .Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. .


Epidermolysis bullosa simplex

Epidermolysis bullosa simplex Epidermolysis bullosa simplex (EBS) is a disorder resulting from mutations in the genes encoding keratin 5 or keratin 14.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. . Epidermolysis bullosa s ...
(EBS) is a form of EB that causes blisters at the site of rubbing. It typically affects the hands and feet, and is typically inherited in an
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
manner, affecting the
keratin Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. Alpha-keratin (α-keratin) is a type of keratin found in vertebrates. It is the key structural material making up scales, hair, nails, feathers, ho ...
genes
KRT5 Keratin 5, also known as KRT5, K5, or CK5, is a protein that is encoded in humans by the ''KRT5'' gene. It dimerizes with keratin 14 and forms the intermediate filaments (IF) that make up the cytoskeleton of basal epithelial cells. This protein is ...
and
KRT14 Keratin 14 is a member of the type I keratin family of intermediate filament proteins. Keratin 14 was the first type I keratin sequence determined. Keratin 14 is also known as cytokeratin-14 (CK-14) or keratin-14 (KRT14). In humans it is encoded b ...
. Therefore, there is a failure in keratinization, which affects the integrity and the ability of the skin to resist mechanical stresses.


Junctional epidermolysis bullosa

Junctional epidermolysis bullosa (JEB) is an inherited disease affecting
laminin Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...
and collagen. This disease is characterized by blister formation within the
lamina lucida The lamina lucida is a component of the basement membrane which is found between the epithelium and underlying connective tissue (e.g., epidermis and dermis of the skin). It is a roughly 40 nanometre wide electron-lucent zone between the plasma ...
of the basement membrane zone and is inherited in an autosomal recessive manner. It also presents with blisters at the site of friction, especially on the hands and feet, and has variants that can occur in children and adults. Less than one person per million people is estimated to have this form of EB.


Dystrophic epidermolysis bullosa

Dystrophic epidermolysis bullosa (DEB) is an inherited variant affecting the skin and other organs. DEB is caused by genetic defects (or
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
s) within the human COL7A1 gene encoding the
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
type VII collagen (collagen VII). DEB-causing mutations can be either autosomal dominant or autosomal recessive. Epidermis bullosa pruriginosa and albopapuloid epidermolysis bullosa (Pasini's disease) are rare subtypes of this disease.


Other genetic


Epidermolysis bullosa acquisita


Acral peeling


Pathophysiology

The human
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
consists of two layers: an outermost layer called the epidermis and a layer underneath called the dermis. In individuals with healthy skin, there are protein anchors between these two layers (Dermo epidermal junction) that prevent them from moving independently from one another (shearing). In people born with EB, the two skin layers lack the protein anchors that hold them together, resulting in extremely fragile skin—even minor mechanical friction (like rubbing or pressure) or trauma will separate the layers of the skin and form blisters and painful sores. EB  individuals manifest unremitting skin blistering that evolves into chronic wounds, inflammation, and fibrosis. People with EB have compared the sores with third-degree burns. Furthermore, as a complication of the chronic skin damage, people with EB have an increased risk of malignancies (cancers) of the skin. Virtually any organ lined or covered by epithelium may be injured in inherited EB. External eye, esophagus, upper airway, and genitourinary tract are the epithelial surfaced tissues that are at particular risk.


Diagnosis

EB can be diagnosed either by a skin (punch) biopsy at the edge of a wound with immunofluorescent mapping, or via blood sample and genetic testing.


Treatment

The combination of birch bark extract from ''
Betula pendula ''Betula pendula'', commonly known as silver birch, warty birch, European white birch, or East Asian white birch, is a species of tree in the family Betulaceae, native to Europe and parts of Asia, though in southern Europe, it is only found ...
'' and ''
Betula pubescens ''Betula pubescens'' (syn. ''Betula alba''), commonly known as downy birch and also as moor birch, white birch, European white birch or hairy birch, is a species of deciduous tree, native and abundant throughout northern Europe and northern Asia ...
'' is used to treat epidermolysis bullosa. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Research has focused on changing the mixture of
keratin Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. Alpha-keratin (α-keratin) is a type of keratin found in vertebrates. It is the key structural material making up scales, hair, nails, feathers, ho ...
s produced in the skin. There are 54 known keratin genes—of which 28 belong to the type I intermediate filament genes and 26 to type II—which work as heterodimers. Many of these genes share substantial structural and functional similarity, but they are specialized to cell type and/or conditions under which they are normally produced. If the balance of production could be shifted away from the mutated, dysfunctional keratin gene toward an intact keratin gene, symptoms could be reduced. For example,
sulforaphane Sulforaphane (sometimes sulphoraphane in British English) is a compound within the isothiocyanate group of organosulfur compounds. It is produced when the enzyme myrosinase transforms glucoraphanin, a glucosinolate, into sulforaphane upon damage ...
, a compound found in
broccoli Broccoli (''Brassica oleracea'' var. ''italica'') is an edible green plant in the cabbage family (family Brassicaceae, genus ''Brassica'') whose large flowering head, stalk and small associated leaves are eaten as a vegetable. Broccoli is cla ...
, was found to reduce blistering in a mouse model to the point where affected pups could not be identified visually, when injected into pregnant mice (5 μmol/day = 0.9 mg) and applied topically to newborns (1 μmol/day = 0.2 mg in
jojoba oil Jojoba oil is the liquid produced in the seed of the ''Simmondsia chinensis'' ( jojoba) plant, a shrub, which is native to southern Arizona, southern California, and northwestern Mexico. The oil makes up approximately 50% of the jojoba seed by w ...
). As of 2008 clinical research at the
University of Minnesota The University of Minnesota, formally the University of Minnesota, Twin Cities, (UMN Twin Cities, the U of M, or Minnesota) is a public university, public Land-grant university, land-grant research university in the Minneapolis–Saint Paul, Tw ...
has explored allogeneic bone marrow transplantation for RD and junctional EB, treating a two-year-old child who is one of two brothers with EB. A second transplant has also been performed on the child's older brother, and a third transplant is scheduled for a California baby. A clinical trial is planned for 30 subjects. However, the immune suppression that bone marrow transplantation requires causes a risk of serious infections with large scale blisters and skin erosion. Indeed, at least four people have died in the course of either preparation for or institution of bone marrow transplantation for EB, out of only a small group of patients treated so far. The mechanism of action of this therapy is unclear as hematopoietic stem cells are not thought to contribute to epithelial lineages. Rather, it is speculated that cross-correction from tissue-resident graft-derived immune cells contributes to the observed clinical benefit. A pilot study performed in 2015 suggests that systemic granulocyte-colony stimulating factor (G-CSF) may promote increased wound healing in people with dystrophic EB. Transplanting skin derived from genetically modified stem cells onto the wound surfaces has been studied with a report of improvements in one person. A 2017 clinical trial with male RDEB ( recessive dystrophic EB) patients conducted successful grafting of type VII gene corrected keratinocytes (COL7A1 gene correction using retrovirus transduction), without any serious adverse effects. Type VII collage formation was observed at the dermis-epidermis junction in significant amounts. A 2020 study demonstrated the safe allogenic grafting of acellular dermal matrix/scaffolds in EB patients without any observed infection or necrosis and instead noted fewer required dressing changes, promoted wound healing, pain reduction, and an overall improvement in the quality of life of the patients.


Monitoring

The Epidermolysis Bullosa Disease Activity and Scarring index (EBDASI) is a scoring system that objectively quantifies the severity of EB. The EBDASI is a tool for clinicians and patients to monitor the severity of the disease. It has also been designed to evaluate the response to new therapies for the treatment of EB. The EBDASI was developed and validated by Professor Dedee Murrell and her team of students and fellows at the St George Hospital,
University of New South Wales The University of New South Wales (UNSW), also known as UNSW Sydney, is a public research university based in Sydney, New South Wales, Australia. It is one of the founding members of Group of Eight, a coalition of Australian research-intensiv ...
, in Sydney, Australia. It was presented at the International Investigative Dermatology congress in Edinburgh in 2013 and a paper-based version was published in the ''Journal of the American Academy of Dermatology'' in 2014.


Prognosis

A 2014 study classified cases into three types—EBS, JEB and DEB—and reviewed their times of death. The first two types tended to die in infancy and the last in early adulthood. In a survey of 11 families affected by the disease, lack of awareness of the disease by both the public and health care providers raised concerns about the care provided.


Epidemiology

An estimated 20 per million live births are diagnosed with EB, and 9 per million people in the general population have the condition. Of these cases, approximately 92% are EBS, 5% are DEB, 1% are JEB, and 2% are unclassified. Carrier frequency ranges from 1 in 333 for JEB, to 1 in 450 for DEB; the carrier frequency for EBS is presumed to be much higher than JEB or DEB. The disorder occurs in every racial and ethnic group and affects both sexes.


Society and culture

In 2010, Emma Fogarty, a campaigner for DEBRA Ireland (the EB charity) was awarded a
People of the Year Award The People of the Year Awards was an annual award show in Ireland. Organised by the Rehab Group, it was televised by Raidió Teilifís Éireann (RTÉ). The Awards provided a unique opportunity for the Irish public to honour outstanding contribut ...
. Actor
Colin Farrell Colin James Farrell (; born 31 May 1976) is an Irish actor. A leading man in projects across various genres in both blockbuster and independent films since the 2000s, he has received numerous accolades including a Golden Globe Award. ''The ...
has campaigned with Fogarty on behalf of affected people. In 2014, Pearl Jam lead vocalist Eddie Vedder together with his wife Jill McCormick co-founded the EB Research Partnership, a non-profit organization dedicated to finding a cure for EB. McCormick is childhood friends with Ryan Fullmer, whose son, Michael, was born with EB. Vedder, McCormick, Ryan Fullmer, and his wife, Heather founded Heal EB. In 2014, they merged Heal EB with the Jackson Gabriel Research Foundation to create the EB Research Partnership. The EBRP hosts several annual fundraising events. To date, they have raised $12 million to fund research to find a cure. On March 1, 2019, heavyweight boxer Luis Ortiz was named an honorary ambassador for the EB community by the EB Research Partnership. Ortiz's daughter, Lismercedes, was born with EB.


Movies

The condition was brought to public attention in 2004 in the UK through the
Channel 4 Channel 4 is a British free-to-air public broadcast television network operated by the state-owned enterprise, state-owned Channel Four Television Corporation. It began its transmission on 2 November 1982 and was established to provide a four ...
documentary ''The Boy Whose Skin Fell Off'', chronicling the life and death of Jonny Kennedy, an Englishman with EB. In the United States, the same could be said of the HBO documentary ''
My Flesh and Blood ''My Flesh and Blood'' is a 2003 documentary film by Jonathan Karsh chronicling a year in the life of the Tom family. The Tom family is notable as the mother, Susan Tom, adopted eleven children, most of whom had serious disabilities or diseases. ...
'' from 2003. Additionally, the film ''Butterfly Girl'' follows Abigail Evans with the disease. In Canada,
The Sports Network The Sports Network (TSN) is a Canadian English language sports specialty channel established by the Labatt Brewing Company in 1984 as part of the first group of Canadian specialty cable channels. Since 2001, it has been majority-owned by comm ...
's award-winning documentary on Jonathan Pitre led to extensive coverage on the boy's disease, treatment, and death.


Other names

Other terms used to describe those affected include "butterfly children" as the skin is fragile as a butterfly's wings, "cotton wool babies", or "crystal skin children".


References


External links


GeneReviews/NCBI/UW/NIH entry on Epidermolysis Bullosa Simplex

Questions and Answers about Epidermolysis Bullosa
nbsp;- US National Institute of Arthritis and Musculoskeletal and Skin Diseases {{Congenital malformations and deformations of integument Genodermatoses Rare diseases Wikipedia medicine articles ready to translate