About EB Simplex

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 intraepidermal 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?

EB Simplex is usually inherited as an autosomal dominant condition. One parent of an affected person will usually also have the condition, though it is possible for EB simplex to appear ‘sporadically’ (to appear for the first time in a person who has no other affected family member). Anyone who has EB simplex 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 EB simplex.
Some precipitating factors that may cause an outbreak of blistering may include the following:
  • Physical stress
  • Emotional stress
  • Warmer climates
  • Infections
  • Sexual maturation

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:

  • Blisters
  • Keratoderma – Thickened skin on palms of hands and soles of feet. Confluent keratoderma in EBS-DM.
  • Nail dystrophy – The presence of rough, thickened or absent finger or toenails.
  • Problems with the soft tissue inside the mouth.

Uncommon Manifestations of EBS:

  • Milia – Tiny skin cysts.
  • Atrophic scarring – Depressions in skin as a result of thinning in epidermis 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. Anemia is more common in the severely affected individual.
  • Growth retardation. This is more common in a severely affected individual.
  • Gastrointestinal tract – Involvement of the GI tract may include blisters in mouth, esophagus and/or anal margins.

Rare Manifestations of EBS:

  • Granulation tissue – The appearance of red fleshy tissue which is capillary formation during tissue healing This would be a rare occurrence in a person affected with EBS. This is more commonly seen in a person severely affected with Junctional EB.
  • Dental caries (cavities) – This is more common in people affected with RDEB or JEB however, if mouth care is not performed regularly it will increase chances of cavities.
  • Ocular (eye) involvement is more commonly seen in people with RDEB or JEB however, it has been reported in some forms of EBS.
  • Pseudosyndactyly – Fusion of fingers and/or toes. This manifestation is more commonly seen in RDEB. In rare instances it has been reported in EBS-DM.
  • 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 have been reported in some forms 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.

Simplex: blistering at basal cell level or above
Three groups have demonstrated that the primary defects within certain kindreds of individuals with dominant and recessive forms of EB simplex have mutations in keratin genes 5 and 14. A series of transgenic mice was developed into which had been inserted a defective keratin gene. The resulting animals and their offspring developed clinical disease characterized by severe intraepidermal blistering and ultrastructural evidence for tonofilament clumping which closely resembles subtypes of EB simplex patients clinically and pathologically. It appears likely that genes which code for proteins involved with the insertion of keratin filaments to hemidesmosmes such as BP230 and HD1 may also be affected in epidermolysis bullosa simplex, but mutations have yet to be demonstrated.
A) EB Simplex- Koebner variant
INHERITANCE: Autosomal Dominant
CUTANEOUS FINDINGS:
  • onset at birth or within the first few weeks of life
  • congenital lesions may heal with scarring, lesions after birth heal without scarring
  • distribution is generalized but acral areas are most frequently affected, flexor sites may be involved especially in warmer weather
  • mild to moderate hyperkeratosis of soles is common
  • often improvement at puberty especially in women

AGGRAVATING FACTORS:

  • warm weather
  • accompanying hyperhydrosis of feet is common
  • secondary bacterial infections common

EXTRACUTANEOUS FINDINGS:

  • teeth are normal
  • nails may show transient mild involvement
  • oral and nasopharyngeal mucosa involvement is mild to moderate and usually decreases with age
  • occasional eye abnormalities, including myopia magna

PATHOLOGIC FINDINGS:

  • basal cell cytolysis, minimal to mild dyskeratosis
  • tonofilament clumping at EM level
Picture of a blister on a patient with Simplex-Weber-Cockayne subtype.

B) EB Simplex- Weber-Cockayne variant

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

  • trauma induced blistering primarily on hands and feet
  • onset is frequently delayed
  • more substantial trauma sometimes necessary to produce blisters compared to other EBS forms
  • hyperhidrosis of the feet is common
  • mild hyperkeratosis of palms and soles often present

EXTRACUTANEOUS FINDINGS: none

PATHOLOGIC FINDINGS:

  • basal cell cytolysis with mild dyskeratosis
  • tonofilaments disorganized but not clumped at EM level
Picture of blisters on a patient with Simplex-Dowling-Meara subtype.

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

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

  • blisters and erosions present at birth or arising shortly thereafter
  • acral sites most often affected, but generalized pattern may also occur
  • milia may be present at healed sites
  • focal atrophy sometimes present, scarring is rare, except at sites of congenital lesions
  • nail dystrophy common
  • prominent hyperkeratosis of the soles and palms
  • often there is improvement at puberty especially with nail dystrophy

EXTRACUTANEOUS FINDINGS:

  • oral blistering is common
  • esophageal involvement occurs including expectoration of esophageal casts
  • mild flexure contractions may occur
  • occasional dental abnormalities including natal teeth, anodontia

PATHOLOGIC FINDINGS:

  • basal cell cytolysis with dyskeratosis
  • tonofilament clumping prominent at EM level

D) EB Simplex Mottled hyperpigmentation

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

  • widespread blistering, sometimes in herpetiform or annular pattern, extremities especially affected
  • onset at or shortly after birth
  • lesions heal without scarring and with extreme rapidity when there is fever
  • postblistering hyper or hypopigmentation
  • mottled hypopigmentation of the neck, upper inner arms, thighs and abdomen develops in early childhood
  • during later childhood, blistering improves but pigmentary changes worsen and hyperkeratotic acral lesions develop
  • onycholysis and thickened curved nails in some patients,
  • sometimes nails are repeatedly lost, fingernails regrow normally, but toenails may remain dystrophic
  • diffuse hyperkeratosis of soles and punctate hyperkeratosis of palms

EXTRACUTANEOUS FINDINGS:

  • oral blistering only in perinatal period
  • teeth are highly carious in some individuals

PATHOLOGIC FINDINGS:

  • basal cell cytolysis causing blistering

E) EB Simplex- Kallin Syndrome

INHERITANCE: Autosomal Recessive

CUTANEOUS FINDINGS:

  • hand and foot blistering beginning at age three months to 1 year
  • scalp hair is brittle with transient nonscarring alopecia
  • nails may be thickened and curved
  • lesions heal without scarring

EXTRACUTANEOUS FINDINGS:

  • anodontia and a disorder of mineralization of the teeth
  • myopia and hearing loss may occur

PATHOLOGIC FINDINGS:

  • intraepidermal blistering, level uncertain

F) EB Simplex- Ogna variant

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

  • generalized blistering and bruising in response to trauma, mainly on the hands and feet
  • Onychogryphosis of the great toenails frequent and tends to be lifelong but is less severe in adulthood

EXTRACUTANEOUS FINDINGS: none

PATHOLOGIC FINDINGS:

  • blistering due to basal cell cytolysis

G) EB Simplex- Bart variant

INHERITANCE: Autosomal dominant

CUTANEOUS FINDINGS:

  • large partial thickness erosions at birth that heal with fine scarring
  • after birth, blisters occur in a generalized distribution and heal without scarring
  • nails are sometimes dystrophic
  • frequent congenital localized absence of the skin on one or more extremities, this is the key distinguishing feature

EXTRACUTANEOUS FINDINGS:

  • oral mucosa is often involved

PATHOLOGIC FINDINGS:

  • blisters due to basal cell cytolysis, or intraepidermal blistering

H) EB Simplex- Mendes de Costa variant

INHERITANCE: X-linked Recessive

CUTANEOUS FINDINGS:

  • blistering which may or may not be trauma induced occurs during the first two years of life
  • alopecia, nonscarring
  • reticulated hyperpigmentation
  • atrophy involving the face and extremities

EXTRACUTANEOUS FINDINGS:

  • microcephaly

PATHOLOGIC FINDINGS:

  • blistering due to basal cell cytolysis

I) EB Simplex- Letalis variant

INHERITANCE: Autosomal Recessive

CUTANEOUS FINDINGS:

  • erosions may be present at birth
  • trauma induced blistering of hands and feet soon after birth, which soon become generalized
  • later in childhood, blisters may be restricted to acral areas
  • mild nail involvement
  • atrophy and milia at sites of healed lesions

EXTRACUTANEOUS FINDINGS:

  • oral ulceration
  • teeth are normal
  • anemia is common
  • sometimes associated muscular dystrophy or congenital myasthenia gravis
  • growth retardation has been observed
  • in one study, ten of thirteen patients died prior to age 20 months although the precise cause of death in each case was unknown

PATHOLOGIC FINDINGS:

  • blistering due to basal cell cytolysis

J) EB Simplex- Superficialis

INHERITANCE: Autosomal Dominant

CUTANEOUS FINDINGS:

  • blisters and erosions on extremities only or generalized but palms and soles are spared
  • atrophy and sometimes milia are present over healed areas
  • nail dystrophy is common

EXTRACUTANEOUS FINDINGS:

  • oral and conjunctival vesiculation and erosion common

PATHOLOGIC FINDINGS:

  • blistering just below the level of the stratum corneum

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! )

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