About EB Dystrophic

EB Dystrophic

According to the Debra International Website:

Dystrophic EB

Some of the very earliest research on inherited EB was directed toward DEB. In 1969, Eisen postulated that excessive fibroblast collagenase activity was the underlying cause of subepidermal blister formation and dermal collagenolysis in patients with DEB. Subsequent in vitro studies in the 1970s by Lazarus and Bauer and co-workers suggested that this mechanism was correct. The possible pathogenicity of skin collagenase in RDEB was further supported by the intriguing observation by Bauer and colleagues in 1980 that the treatment of a series of RDEB patients with systemic phenytoin led both to a reduction in blister counts and to the reduced synthesis of collagenase by dermal fibroblasts from these patients. Interest in collagenase as a primary cause of RDEB waned by the late 1980s as data increasingly suggested type VII collagen as a more likely primary target. In 1992, Hovnanian and colleagues provided the final evidence against tissue collagenase being the underlying basis for RDEB by demonstrating, using molecular techniques, a lack of linkage between the collagenase gene and the RDEB phenotype.

In 1986, Heagerty, Eady, and co-workers demonstrated that RDEB skin basement membrane stained poorly or not at all when a monoclonal antibody (LH 7:2), subsequently proven by Leigh and others to react against type VII collagen, was used as an immunohistochemical probe. This finding proved to be the basis for the eventual identification of the molecular etiology of RDEB since one year previously Lunstrom and colleagues had shown that the anchoring fibril, a basement membrane-associated structure known for many years to be absent or reduced in number in RDEB skin, was composed of type VII collagen. These collective findings therefore suggested that type VII collagen might indeed he the target for genetic mutation in RDEB. In 1992, Rynnanen, Uitto, and colleagues demonstrated linkage of the type VII collagen gene to DDEB. Similar findings were reported in RDEB by Uitto, Christiano, and co-workers, beginning in 1993, followed by the mapping of specific mutations in the type VH collagen gene in numerous DDEB and RDEB kindreds. Collectively, these findings have convincingly demonstrated that the underlying molecular cause of all forms of DEB is the presence of mutations in the gene encoding for the anchoring fibril-specific protein, type VII collagen.

EB Acquisita

In 1981, Yaoita and colleagues demonstrated that skin from patients with EB acquisita contains in vivo-bound immunoglobulins in the lamina densa of the dermoepidermal junction, distinguishing them from those immunoreactants observed in another autoimmune. subepidermal, blistering disease, bullous pemphigoid. In the early 1980s, Gammon and co-workers showed that EB acquisita sera contained autoantibodies that bound to either or both the lamina densa and adjacent anchoring fibrils of normal human skin, and then devised an elegant in vitro model, termed the leukocyte attachment assay, to demonstrate the temporal relationship between the binding or. attachment of EB acquisita autoantibodies, complement, and functional leukocytes along the dermoepidermal junction and the subsequent development of microvesiculaton. In 1984, Woodley and colleagues identified in skin extracts two protein bands, having molecular weights of 290 and 145 kD, which reacted specifically with EB acquisita autoantibodies. In 1987, Woodley further showed that these autoantibodies recognize type VII collagen. In 1988, Gammon et al. showed that patients with EB acquisita were likely to have the HLA-DR2 histocompatability haplotype, adding further evidence to the role of immunogeneticity to this disease. Finally, Lapiere and co-workers in 1993 demonstrated that autoantibodies in EB acquisita sera recognize only limited epitopes in the type VII collagen molecule.


According to the Debra U.S. Website:

Dystrophic Epidermolysis Bullosa

What Is The Cause Of Dystrophic EB?

Through research it is now known that the genes that carry the instructions necessary to produce the proteins in the basement membrane zone of the skin, are faulty. This results in incorrectly formed anchoring fibrils, deeming them unable to perform their normal role as a ‘stable interweave’ between the dermal and epidermal layers of the skin.

Mutation (a change in the genetic material) occurs within the collagen VII gene, which encodes the protein of the anchoring fibril. Anchoring fibrils hold together the two layers of skin. As a result, there is a lack of adherence and disruption of the skin when any friction or trauma occurs to an area. Where the two layers separate there is a blister. Blistering in the various types of dystrophic EB causes scarring.

There are two major types of DEB:

  • Dominant Dystrophic Epidermolysis Bullosa
  • Recessive Dystrophic Epidermolysis Bullosa ( Major subtypes of RDEB are listed below.)
    1. Recessive Dystrophic Epidermolysis Bullosa- Hallopeau Siemens
    2. Recessive Dystrophic EB-non Hallopeau Siemens
    3. Recessive Dystrophic EB inversa
      • Transient Bullous Dermatosis of the Newborn *(TBDN) appears to be a form of DDEB noted by blistering and skin fragility that appears from changes in the collagen VII gene. For reasons unknown the problem seems to correct itself during infancy.
      • Squamous Cell Carcinoma and Recessive Dystrophic EB: The incidence of squamous cell carcinoma is more common in the severely affected individual, RDEB Hallopeau-Siemens. There have also been reports of Squamous Cell Carcinoma in patients with RDEB non Hallopeau- Siemens.
      • EPIDERMOLYSIS BULLOSA AQUISITA
        • negative family history for EB
        • trauma induced as well as spontaneous blisters in generalized distribution especially prominent on acral and extensor surfaces
        • lesions heal with atrophy, scarring and milia
        • in general lesions appear non inflammatory
        • nail dystrophy and scarring alopecia may be present
        • usual onset is between the ages of 40 and 60 but cases arising in childhood have been described
        • oral, conjuctival and nasopharyngeal mucosal involvement may occur
        • some patients go on to fulfill the diagnostic criteria for SLE thus bullous SLE and EB aquisita appear to be related immunologic diseases
        • sub-basement membrane blister, often with perivascular mixed infiltrate containing eosinophils
        • Brunstig-Perry pemphigoid is probably a localized variant of epidermolysis bullosa aquisita

How is Dominant Dystrophic Epidermolysis Bullosa Inherited?

DDEB is an autosomal dominant condition. One parent of an affected person will usually also have the condition. It is possible for DDEB to appear ‘sporadically’ (to appear for the first time in a person who has no other affected family member). Anyone who has DDEB whether male or female, can pass the condition on to his or her children. Each time a pregnancy occurs, there is a 1 in 2 chance that the child will inherit DDEB.

Electron microscopic evaluation reveals skin separation at the level of the sub lamina densa of the basement membrane zone, with normal or decreased number of anchoring fibrils.

Mutations are noted in the genes encoding collagen VII either the gene from the mother or from the father. The change that results, decreases the functioning of the anchoring fibrils, but does not eliminate the anchoring fibrils

Dominant Dystrophic Epidermolysis Bullosa :

There is usually generalized blistering noted at birth. Blistering may be generalized or appear only on the hands, feet, elbows or knees: this is usually due to mechanical trauma. Rarely does scarring cause immobility and deformity of the hands and feet. Small cysts or milia are seen at sites of scarring. There may be mild involvement of the mucous membranes, nails may be thick, dystrophic or destroyed. Some affected by this form of EB may note the presence of small, firm flesh colored or white skin elevations that appear spontaneously on the trunk and extremeties of their body, that are called albopapuloid lesions.

How is Recessive Dystrophic Epidermolysis Bullosa Inherited?

RDEB is an autosomal recessive inherited condition. This means both parents are carriers, yet they are unaffected. When each parent has a copy of the altered gene, there is a 1 in 4 chance or 25% that the child will be affected. Unfortunately, there is no test to detect carriers for RDEB. We are made aware that the parents are carriers after their child is born.

Electron microscopic evaluation reveals skin separation at the level of the sub lamina densa, with absence of anchoring fibrils in RDEB-HS.

There are reduced or occasionally abnormal appearing anchoring fibrils in RDEB-nHS.

Mutations in RDEB are found in both the mothers and the fathers gene encoding collagen VII.

Recessive Dystrophic Epidermolysis Bullosa:

Although in some cases this form of EB can be mild with generalized blistering, typically the recessive forms of EB tend to be more severe. Onset is usually at birth with areas of missing skin. Generalized blistering then scarring can occur on skin surfaces and mucous membranes. Scarring may limit range of motion of extremities. Fusion of fingers and toes and contractures cause deformity and loss of function.

In some cases there is relatively mild blistering on hands, feet, elbows, and knees; these cases are very similar to dominant dystrophic EB. However, recessive dystrophic epidermolysis bullosa typically is characterized as follows:

Blistering onset is at birth or soon afterwards. In some cases, nearly all skin surfaces and mucous membranes (from mouth to anus) are covered by blisters. Large areas may be devoid of skin. There is widespread scarring and deformity. Fingers and toes may become immobile. With recurrent scarring, fingers and/or toes may fuse together. Hands and arms may become fixed in a flexed position with resulting contractures. There is usually loss of the nails of the fingers and toes. Teeth may be malformed and delayed in appearing through the gums. Because routine dental care can raise blisters, many persons with RDEB have a higher than normal incidence of cavities. Blistering on the mucosal surfaces often cause scarring within the mouth and gastrointestinal tract. The ingestion of food may be limited due to microstomia (inability to fully open mouth due to scarring and contractures of the perioral region), painful swallowing, difficulty chewing, (due to poor dentition) esophageal webbing. In many cases chronic malnutrition, growth retardation and anemia may ensue. Involvement of the eyes can include eyelid inflammation with adhesions to the eyeball, as well as inflammation of the cornea or the conjunctiva (the mucous membrane covering the eyeball and the underside of the lids).

RDEB inversa is a rare subtype of RDEB, blistering is noted on intertriginous (areas where skin rubs on skin i.e. axilla and groin) Lumbosacral areas may be affected as well.

Common Manifestations of DEB:

*Since EB varies in severity these manifestations may or may not be experienced by the individual affected.

  • Generalized blistering.
  • Absent or dystrophic nail – Presence of a rough, thick or changed finger or toenail.
  • Milia – tiny skin cysts.
  • Atrophic scarring – Depressions in skin as a result of thinning in epidermis or or dermis.
  • Anemia – A reduced amount of red blood cells, volume of red blood cells, amount of hemoglobin. Hemoglobin is the oxygen carrying portion of the red blood cell. The heme aspect of hemoglobin, is the iron compound that makes up the pigment part of the hemoglobin molecule. May affect a person with DDEB however, it is more common in the severely affected individual (RDEB Hallopeau Siemens and RDEB non-Hallopeau-Siemens and RDEB inversa).
  • Growth retardation. This is more common in a severely affected individual.
  • Problems with the soft tissue inside the mouth.
  • Ocular (eye) involvement is more common in severely affected individuals. (RDEB-HS/RDEB non-HS and RDEB inversa.)
  • Dental caries – Presence of cavities. This is more common in (RDEB-HS and RDEB inversa).
  • Gastrointestinal tract: Involvement of the GI tract may include blisters in mouth, esophagus and/or anal margins. (Problems may exists in those with DDEB however it is more commonly seen in the more severe types of RDEB.)
  • Pseudosyndactyly – Fusion of fingers and/or toes. This manifestation is more common in the severely affected individual (RDEB HS, RDEB non-HS and RDEB inversa).

Rare Manifestations of DEB:

  • Granulation tissue – Capillary formation during tissue healing. Would be a rare occurrence in a person affected with either form of DEB. (This manifestation may be seen in a person severely affected with Junctional EB.)
  • Enamel hypoplasia – Underdeveloped enamel upon the teeth. This is more prevalent in patients with JEB.
  • Respiratory tract involvement. Rare occurrences have been noted in the more severely affected individual.
  • Genitourinary tract involvement. Rare occurrences involving the GU tract such as urethral stenosis and/or scarring have been reported.

Skin Cancers and Dystrophic Epidermolysis Bullosa

It is important to note that skin cancers usually react differently in a patient with EB. The more severely affected individual (RDEB) appears to be more at risk for developing squamous cell carcinoma. These localized skin cell tumors have the ability to grow faster and spread to other areas of the body more rapidly then they would on a less compromised individual. Patients and caregivers need to examine skin carefully for any changes. It is important to perform self examinations of your skin at home. Many times it is helpful to have family members look at areas that are not often viewed by the affected individual, such as the back or upon the scalp. Mirrors can be helpful in detecting growths on the back of trunk and extremities when you are self examining.

Any suspicious lesions, moles or markings should be evaluated by a dermatologist. Yearly full body exams are usually recommended, however, in some instances your dermatologist may modify the frequency of skin exams.

  • Squamous Cell Carcinoma and Dominant Dystrophic Epidermolysis Bullosa: It is a rare occurrence for the person affected with DDEB to develop squamous cell carcinoma.
  • Melanoma and Dystrophic EB: Rare occurrences of melanoma have been reported in Dominant Dystrophic EB and Recessive Dystrophic EB.
  • Basal Cell Carcinoma and Dystrophic EB: Rare, but has been reported in a small percentage of individuals with Dominant Dystrophic EB.

Changes in skin that warrant visit to physician for prompt evaluation include the following:

Chronic non-healing wound.

  • Deep ulcers.
  • Any unusually thick, raised and/or crusted areas.
  • Make note of any changes in the pattern of healing. Although there are variations in healing rates among each wound, it is important to monitor and note any changes, especially to areas prone to blistering.
  • Any change in sensation on the non-healing area.
  • Any changes in size, shape, diameter and color on existing growths and development of new growths.
  • Pus or foul smelling odor.

Generally biopsies are obtained to confirm the presence of skin cancer. However, if a biopsy is obtained from a suspicious growth and the results are negative, please continue to monitor the area. If the area is still not healing please notify your physician, it may be necessary to re-biopsy the area.

For helpful hints on self examination please note the following web-site for the Skin Cancer Foundation

http://www.skincancer.org/self_exam/spot_skin_cancer.html

How is EB Treated?

Because EB involves many systems of the body, parents and health professionals must take a ‘team approach’ , to the treatment of an EB patient. Intense and total patient care often must be provided, particularly for young and growing children. The severe forms of EB require hours of intensive nursing care that in many ways is similar to that given to burn patients. Much of this care is often provided by the parents; however, the education of all people who have contact with the patient is essential. These people may include the primary care physician (often a pediatrician), the dermatologist, the nurse, the pediatric dentist, the specialist in gastrointestinal (digestive) diseases, the dietitian or nutritionist, the plastic surgeon, the psychologist or social worker, and the genetic counselor, as well as teachers, relatives, baby sitters, and others.

So far, research has not yet found a cure for epidermolysis bullosa or a treatment to completely control any form of EB. However, many complications can be lessened or avoided through early intervention. Many persons with milder forms have minimal symptoms and may require little or no treatment.

In all cases, treatment of EB is directed towards the symptoms and is largely supportive. This care should focus on prevention of infection, protection of the skin against trauma, attention to nutritional deficiencies and dietary complications, minimization of deformities and contractures, and the need for psychological support for the entire family.


According to the Telemedicine Website of Stanford University:

Dystrophic: blistering below the lamina densa level

AF1, AF2, LH7:2, L3d, np185, np32 (all mAb directed against type VII collagen) usually show absent IF staining in Hallopeau-Siemens recessive dystrophic EB, and reduced or absent staining in involved skin areas of most of the dominant subtypes. A large variety of mutations of the COL7A1 gene coding for type VII collagen has been demonstrated in a number of families with both dominant and recessive forms of dystrophic epidermolysis bullosa. No other genes have yet been reported to be affected in this group of diseases.

A) Dystrophic EB- Cockayne-Touraine

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

  • acral and generalized blistering and erosions occur at birth or during early infancy
  • nails are variably involved, toenails>fingernails
  • squamous cell carcinoma infrequently occur

EXTRACUTANEOUS INVOLVEMENT:

  • oral mucosal involvement is generally mild, but occasionally includes esophageal stenosis
  • teeth are normal or mildly dystrophic
  • keratitis may occur

PATHOLOGIC FINDINGS:

  • blistering beneath the basement membrane
  • anchoring fibrils may be decreased in number and poorly developed

B) Dystrophic EB- Minimus

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

  • mild generalized blistering in early childhood
  • minimal acral blistering in later childhood
  • some nails, especially toenails may be dystrophic and may constitute the only residual manifestation in adults

EXTRACUTANEOUS FINDINGS: none

PATHOLOGIC FINDINGS:

  • blistering at a level below the basement membrane
  • normal appearing anchoring fibrils in noninvolved areas

C) Dystrophic EB- Pretibial

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

  • blisters that heal with scarring and atrophy are concentrated in the pretibial area and on the dorsa of the feet with minimal to no involvement elsewhere

EXTRACUTANEOUS FINDINGS:

  • occasionally the oral mucosa is minimally involved
  • teeth are normal or near normal

PATHOLOGIC FINDINGS:

  • blistering below the level of the basement membrane
  • anchoring fibrils are present in nonaffected areas

D) Dystrophic EB- Albopapuloidea (Pasini variant)

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

  • generalized blistering and development of erosions beginning at birth
  • later there is concentration of lesions at acral sites
  • plaque and papular scars, lighter than surrounding skin, are characteristic
  • nail involvement is variable, occurs mainly on toenails

EXTRACUTANEOUS FINDINGS:

  • mucosal involvement is usually mild
  • teeth are near normal

PATHOLOGIC FINDINGS:

  • sub-basement membrane blistering
  • anchoring fibrils may be well developed in noninvolved skin

E) Dystrophic EB- Hallopeau-Siemens (Gravis)

INHERITANCE: Autosomal Recessive

CUTANEOUS FINDINGS:

  • blisters and erosions are frequently present at birth
  • there is marked scarring with gradual mitten deformity of hands, syndactyly of toes, nail dystrophy and loss, and occasional development of squamous cell carcinoma
  • albopapuloid lesions may occur
  • milder variants may be distinct entities including centripetal progressive variant

EXTRACUTANEOUS FINDINGS:

  • oral, esophageal, anal, and vaginal mucosae are frequently involved
  • bladder, urethra, and kidney are less commonly affected
  • teeth are dystrophic
  • ocular involvement is most commonly keratitis
  • anemia is common
  • in severely affected individuals, growth and development is retarded
  • overall life span is shortened, especially in severely involved individuals

PATHOLOGIC FINDINGS:

  • sub-basement membrane blistering
  • anchoring fibrils are absent or reduced in number and poorly developed at a distance from actively involved areas in severely affected individuals

F) Dystrophic EB- Inversa

INHERITANCE: Autosomal Recessive

CUTANEOUS FINDINGS:

  • blisters and erosions are frequently present at birth
  • skin fragility is most prominent in axillae, groin, inframammary and neck regions
  • nail changes are present usually only on toenails
  • scarring alopecia often present
  • milia often form

NONCUTANEOUS FINDINGS:

  • oral mucosa and esophagus may be severely involved relative to skin involvement
  • tongue is usually bound to the floor of the mouth
  • occasional ocular involvement, usually keratitis
  • teeth may be mildly dystrophic
  • normal stature
  • receding chin

PATHOLOGIC FINDINGS:

  • sub-basement membrane blistering
  • anchoring fibrils are reduced in number and poorly developed in susceptible skin

G) Dystrophic EB- Transient bullous dermolysis of the newborn

INHERITANCE: Autosomal Dominant; Some may be Autosomal

Recessive

CUTANEOUS FINDINGS:

  • generalized blisters and erosions present in a generalized distribution at birth, especially prominent on extremities
  • lesions heal with milia and minimal scarring and atrophy
  • nail dystrophy absent
  • disappearance of apparent clinical disease within first year of life

EXTRACUTANEOUS FINDINGS: none

PATHOLOGIC FINDINGS:

  • sub-basement membrane blistering
  • anchoring fibrils are reduced in affected areas
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