EB Simplex

According to the Debra International Website:

Before the late 1980s, the likely targets of genetic mutation in EBS were unknown. A variety of studies suggested conflicting mechanisms of disease. Consistent with the prevailing theory about the role of collagenase in RDEB, for example, in 1983 Takamori and colleagues suggested that tesintraepidermal blisters arose in EBS as the result of the release of one or more epidermal derived proteases that had specificity for targets in basilar keratinocytes. Their in vitro model using EBS blister fluid and normal human skin organ explants tended to confirm that hypothesis, although subsequent work by Fine and co-workers demonstrated the nonspecificity of these findings. In 1983, Sanchez and colleagues demonstrated reduced in vitro activity of a fibroblast-derived enzyme, gelatinolytic protease, which was produced by fibroblast cultures established from patients who had generalized and localized forms of EBS. Unfortunately, these findings could not be later reproduced by other investigators. An alternate hypothesis, proposed in 1985 by Fine and Griffith, was that the mechanical fragility observed in EBS skin reflected the presence of an abnormality in a glycosylated cell membrane component of the keratinocyte, a mechanism suggested in part by the altered staining of EBS epidermis by selective lectins and the lack of apparent concurrent abnormal staining of EBS skin by the only antikeratin monoclonal antibodies available for study at that time.

On the other hand, early electron microscopy studies repeatedly demonstrated disruption of keratin filaments in EBS keratinocytes in lesional skin, and the clumping keratin tonofilaments in Dowling-Meara EBS led Anton- Lamprecht and Schnyder to suggest as early as 1982 that keratins might be the target of mutation or injury in this disease. This hypothesis was further echoed in 1991 by two independent groups of investigators from London and Japan, based on their studies using immunohistochemical and ultrastructural techniques. One of these groups, led by Eady and Leigh, further postulated that the EBS keratinocyte was characterized by the presence of a structurally abnormal intracytoplasmic network of filaments of keratins 5 and 14. In that same year, two different laboratories reported dramatic findings in EBS using molecular biologic approaches. Bonifas, Rothman, and Epstein used linkage analysis to demonstrate the presence of keratin gene mutations in two families with the Koebner variant of generalized EBS. Fuchs and colleagues independently mapped mutations in the keratin 14 gene in several patients with Dowling-Meara EBS and elegantly demonstrated the pathogenicity of these mutations by way of keratinocyte cell culture and transgenic mouse models. These investigators and others have subsequently demonstrated that mutations in the genes for keratin 5 and keratin 14 form the molecular basis for disease in the Koebner, Weber-Cockayne, Dowling-Meara, and mottled pigmentation subtypes of EBS, and that the site of mutation in the keratin gene correlates well with severity of disease and EBS subtype. A much more de- tailed discussion of these keratin gene mutations may be found in chapter 14.

In 1996, McLean and colleagues demonstrated that mutations in the gene for plectin, a constituent of skeletal muscle that is also present just inside the inferiormost aspect of the basilar keratinocyte plasma membrane, forms the molecular basis of the subtype of generalized EBS that is associated with congenital muscular dystrophy. In 1997, Koss-Harnes and colleagues found that skin from patients with the Ogna subtype of EBS exhibited strongly reduced binding of some anti-rat plectin antibodies to the basal keratinocytes, consistent with the co-assignment of the EBS1-GPT loci and the plectin PLEC1 locus to the same 8q24 chromosome band.

What is Epidermolysis Bullosa (EB)?

EB is a group of inherited conditions in which the skin blisters extremely easily. There are three main types of EB. Each is a quite distinct disorder – as different from the other forms of EB as chicken pos is from measles. If you have EB Simplex, then you cannot later develop one of the other forms of EB (dystrophic or junctional)

EB Simplex

People with EB Simplex develop blisters on their feet (and usually also on their hands), in response to friction. Walking even short distances is often enough to cause blisters; the problem is at its worst in hot weather. Many people also experience blisters under tight clothing and sometimes in their mouths. The first sign that a baby may have inherited the condition is often the appearance of blisters under the waistband and elasticated areas of nappies, though blisters may not be seen for the first time until a child starts to walk, or occasionally even later.

EB Simplex is a dominantly inherited condition. One parent of an affected person will usually also have the condition, though it is possible for EB Simplex to appear ‘sporadically’ ie, to appear for the first time in a person who has no other affected family member.

Anyone who has EBSimplex, 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 EBSimplex if one parent is affected – like tossing a coin- there is a 1 in 2 chance that the coin will land ‘head’side up each time that the coin is tossed.

What is the cause?

There has recently been a considerable amount of international research into the cause of EB Simplex and this is now known. The problem lies in the genes which hold the instructions necessary for production of certain proteins (keratins) in the top layer of skin. These instructions have a minor fault, rather like a typing error, with the result that the keratins are incorrectly formed, and unable to fulfil their normal role as scaffolding for the topmost layer of skin. The end result is that the top layer of skin does not ‘stick’ securely to the layer beneath it, and where the two layers separate, there is a blister.

Is there a cure?

No yet – but research continues. There is still a long way to go, but a cure may ultimately be possible.

Is there treatment?

No treatments will stop blisters occurring. It is important to prevent blisters becoming infected. Most people find it helpful to burst blisters, using a sterile needle (or sterile scissors) and to soak their feet in cold water, perhaps containing an antiseptic such as potassium permanganate vailable from your doctor. A non-stick dressing, such as Melolin (?) can then be applied if necessary, held in place with either adhesive tape such as Micropore (?) (Hypo-Fix is the American version), or with a bandage. Many people find dressings unnecessary. DEBRA can advise on the most suitable products if you do need dressings. Choice of footwear is important – choose well-fitting, soft leather shoes. Many people find it helpful to carry a spare pair of shoes and change them partway through the day. Keeping cool is the single most useful measure! Many EB Simplex sufferers find that their blisters are worst in their teens and early twentis, and become easier to cope with as they grow older.

What help is available?

Children with EB Simplex often lose time from school because of transport difficulties. If a family car is not available, local authorities can often be persuaded to provide transport to and from school. Explaining what EB is to staff at school will usually ensure that your child is treated sypathetically, particularly with regard to games lessons.

It might be worthwhile applying for a disabled persons orange car badge if you do have a car. These are available from your Local Authority. Some people with EB Simplex have successfully applied for DLA, which provides financial or practical help towards mobility.

DEBRA can offer advise on all these points as well as many others Their regular newlsetters keep members up to date with research developments, and are used by EB sufferers and their families as a place to exchange experiences and pass on practical tips.

What is the cause of EB Simplex?

Through research it is now known that the genes that carry the instructions necessary to produce the proteins in the top layer (keratins) are faulty. This results in incorrectly formed keratins, deeming them unable to perform their normal role as a ‘scaffolding’ for the top most layer of skin. It appears as though there is a mutation (a change in the genetic material) within Keratin genes K5 or its partner K14. So as a result, the top layer of skin falls apart, resulting in a blister. Although EB Simplex is considered a non-scarring form of EB, secondary infection may cause scarring.

How is EB Simplex Inherited?

Even though some forms of EB Simplex are localized it is important to know that all skin cells are affected. Therefore, all skin surfaces are prone to develop generalized blistering.

Weber-Cockayne Subtype of EB Simplex:

This form is also termed localized EB simplex. This disorder usually presents in childhood or adolescence. It may also occur in an infant or adult life. In many instances it presents itself in infancy from friction induced by shoes and starting to walk.

People with Weber Cockayne EB Simplex develop blisters on their feet and hands, (usually palms and soles) in response to friction. These wounds usually heal without scarring. Walking even short distances is often enough to cause blisters. They may experience thickening of the skin (keratoderma) on the soles of the feet. This type of EBS usually does not involve nails or mucous membranes. Most individuals seem to be more prone to blisters in warmer climates and during periods of strenuous activity such as jogging, marching or walking. With trauma or friction rarely the blistering can be (generalized) or appear on other parts of the body.

Mutations are in the genes encoding K5 or K14.

Koebner Subtype of EB Simplex:

This is a form of generalized EB simplex. This disorder usually presents at birth or infancy. Blisters are noted to be widespread over the body’s surface. Though it is not a common feature of this type of EB to scar on rare occasions it does happen. There may be mild involvement of mucous membranes. Fingernails and toenails are sometimes involved. Localized thickening of the skin (keratoderma) on the soles of the feet and the palms of the hands may occur especially as one gets older.

Mutations are in the genes encoding K5 or K14.

Dowling Meara Subtype of EB Simplex:

EBS-DM is a generalized form of EB simplex. This type of EB is probably the most severe form of EB Simplex.

Infants are often born with widespread grouping of blisters on the face, trunk and limbs. Blisters on hands and feet often eventually cause confluent keratoderma (thickening of the skin). In many cases these calluses form complete thickening of the palms and soles. If the thickening is severe enough it may limit the range of motion of a joint. In such cases, consultation from a surgeon may be necessary to determine the best course of treatment.

Heat may exacerbate blistering. Milia (tiny cysts on skin) may be present after blisters have healed. Nail thickening and discoloration is a common feature.

Blistering in Dowling Meara EBS can involve organs including the oral cavity, gastrointestinal tract and rarely, the upper respiratory tree.

Electron microscopy shows clumps of keratin filaments, which are not seen in other forms of EB simplex.

Mutations are usually in the genes encoding K5 or K14.

Since EBS-DM is the most severe form of EBS, the widespread blistering may lead to death in infancy. However, blistering tends to become smaller and less problematic for most patients as they grow older.

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

Common Manifestations of EBS:

Uncommon Manifestations of EBS:

Rare Manifestations of EBS:

There is no evidence that people with EBS are at a higher risk for developing squamous cell carcinoma or malignant melanoma, however, suspicious wounds/lesions should always be evaluated by your dermatologist.

Other Subtypes of EB Simplex include:

EB Simplex Superficialis, EB Simplex with Mottled Pigmentation and Kallins Syndrome.

There is a recessively inherited simplex that accompanies Muscular Dystrophy which appears to be a mutation in the Plectin gene.

AGGRAVATING FACTORS:

EXTRACUTANEOUS FINDINGS:

PATHOLOGIC FINDINGS:

Picture of a blister on a patient with Simplex-Weber-Cockayne subtype.

B) EB Simplex- Weber-Cockayne variant

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

EXTRACUTANEOUS FINDINGS: none

PATHOLOGIC FINDINGS:

Picture of blisters on a patient with Simplex-Dowling-Meara subtype.

C) EB Simplex- Dowling-Meara variant (Herpetiformis)

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

EXTRACUTANEOUS FINDINGS:

PATHOLOGIC FINDINGS:

D) EB Simplex Mottled hyperpigmentation

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

EXTRACUTANEOUS FINDINGS:

PATHOLOGIC FINDINGS:

E) EB Simplex- Kallin Syndrome

INHERITANCE: Autosomal Recessive

CUTANEOUS FINDINGS:

EXTRACUTANEOUS FINDINGS:

PATHOLOGIC FINDINGS:

F) EB Simplex- Ogna variant

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

EXTRACUTANEOUS FINDINGS: none

PATHOLOGIC FINDINGS:

G) EB Simplex- Bart variant

INHERITANCE: Autosomal dominant

CUTANEOUS FINDINGS:

EXTRACUTANEOUS FINDINGS:

PATHOLOGIC FINDINGS:

H) EB Simplex- Mendes de Costa variant

INHERITANCE: X-linked Recessive

CUTANEOUS FINDINGS:

EXTRACUTANEOUS FINDINGS:

PATHOLOGIC FINDINGS:

I) EB Simplex- Letalis variant

INHERITANCE: Autosomal Recessive

CUTANEOUS FINDINGS:

EXTRACUTANEOUS FINDINGS:

PATHOLOGIC FINDINGS:

J) EB Simplex- Superficialis

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

EXTRACUTANEOUS FINDINGS:

PATHOLOGIC FINDINGS:

Most of the above information was compiled from information from Stanford University, Debra U.S. &  Debra UK (thank you grandma Shirley for typing this up! )